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Zhu JX, Pan ZN, Li D. Intracellular calcium channels: Potential targets for type 2 diabetes mellitus? World J Diabetes 2025; 16:98995. [DOI: 10.4239/wjd.v16.i4.98995] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Revised: 12/09/2024] [Accepted: 01/23/2025] [Indexed: 02/28/2025] Open
Abstract
Type 2 diabetes mellitus (T2DM) is a prevalent metabolic disorder. Despite the availability of numerous pharmacotherapies, a range of adverse reactions, including hypoglycemia, gastrointestinal discomfort, and lactic acidosis, limits their patient applicability and long-term application. Therefore, it is necessary to screen novel therapeutic drugs for T2DM treatment that have high efficacy but few adverse effects. AMP-activated protein kinase (AMPK) stands out as one of the most powerful targets for T2DM treatment. It can be activated through energy-sensing or calcium signaling. Medications that activate AMPK through the energy-sensing mechanism exhibit remarkable potency, but they are accompanied by lactic acidosis, carrying an alarmingly high mortality rate. Interestingly, medications that activate AMPK through calcium signaling, such as gliclazide, seldom induce lactic acidosis. However, the efficacy of gliclazide is much lower than metformin. Therefore, it is necessary to explore targets that activate AMPK via calcium signaling to avoid lactic acidosis while maintaining high potency. Ion channels are the main controller of intracellular calcium flow. Specific agonists and inhibitors targeting ion channels have been reported to activate AMPK. In this review, we will summarize the structure and function of calcium-permeable ion channels and discuss the potential of targeting these calcium channels for T2DM treatment.
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Affiliation(s)
- Jia-Xuan Zhu
- Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310014, Zhejiang Province, China
| | - Zhao-Nan Pan
- Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310014, Zhejiang Province, China
| | - Dan Li
- Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310014, Zhejiang Province, China
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Hu Y, Lu S, Xue C, Hu Z, Wang Y, Zhang W, Wang D, Wang J, Ding G, Yu J, Hu Y, Liu Y. Exploring the protective effect of metformin against sarcopenia: insights from cohort studies and genetics. J Transl Med 2025; 23:356. [PMID: 40119457 PMCID: PMC11927167 DOI: 10.1186/s12967-025-06357-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Accepted: 03/08/2025] [Indexed: 03/24/2025] Open
Abstract
BACKGROUND The impact of metformin on sarcopenia remains uncertain. This study aimed to investigate whether metformin influences sarcopenia risk and evaluate the effects of potential drug targets on sarcopenia traits. METHODS We analyzed data from the National Health and Nutrition Examination Survey (NHANES) (n = 3549) to assess the association between metformin use and sarcopenia risk in elderly patients with type 2 diabetes. Mendelian randomization (MR) analysis using genome-wide association studies (GWAS) from UK Biobank (n = 1,366,167) and FinnGen (n = 218,007), with expression quantitative trait loci (eQTL) as instrumental variables, examined the causal effect of metformin-related targets on sarcopenia traits, while molecular docking explored the interaction between metformin and its drug targets. RESULTS Metformin use was associated with increased grip strength (OR = 2.46; 95% CI 1.49-2.38) and skeletal muscle mass (OR = 1.24; 95% CI 0.20-2.28), as well as reduced mortality (HR = 0.62; 95% CI 0.54-0.71). MR analysis suggested a possible link between GDF15 gene expression and sarcopenia traits, with no evidence of genetic confounding. Molecular docking indicated stable binding between metformin and GDF15. CONCLUSION This study suggests that metformin may lower sarcopenia risk, particularly in elderly patients with type 2 diabetes, with GDF15 identified as a promising target for sarcopenia treatment.
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Affiliation(s)
- Yanyan Hu
- Department of Geriatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Shan Lu
- Women and Children Department of the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Cheng Xue
- Department of Geriatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Zhaonian Hu
- Department of Psychology, School of Social and Behavioral Sciences, Nanjing University, Nanjing, Jiangsu, China
| | - Yifei Wang
- Department of Geriatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Wensong Zhang
- Department of the Core Facility, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Dan Wang
- Department of Geriatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jizheng Wang
- Department of Geriatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Guoxian Ding
- Department of Geriatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jing Yu
- Department of Geriatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
| | - Yifang Hu
- Department of Geriatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
- Department of the Clinical Medical Research, The Friendship Hospital of Ili Kazakh Autonomous Prefecture, Yining, Xinjiang, China.
| | - Yun Liu
- Department of Geriatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
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Apperley L, Parkinson J, Senniappan S. Liraglutide Treatment Improves Glycaemic Dysregulation, Body Composition, Cardiometabolic Variables and Uncontrolled Eating Behaviour in Adolescents with Severe Obesity. J Clin Res Pediatr Endocrinol 2025; 17:68-75. [PMID: 39311553 PMCID: PMC11923471 DOI: 10.4274/jcrpe.galenos.2024.2023-10-10] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/20/2025] Open
Abstract
Objective Childhood obesity is associated with long-term health complications. Liraglutide is approved for use in adolescents for weight loss and has shown beneficial outcomes in clinical trials. Continuous glucose monitoring (CGM) is widely used in type 1 diabetes mellitus. To look at the effect of liraglutide treatment on cardiometabolic variables, glycaemic control (as assessed by CGM), body composition, quality-of-life and satiety levels in adolescents with severe obesity. Methods Patients aged 12 to 17.9 years were commenced on liraglutide in addition to lifestyle support. Pediatric Quality of Life 4.0 generic scale and Three-factor Eating Questionnaire R18 were completed at baseline and after 3-months. Results Twenty-four subjects (10 male: 14 female) took part. Significant improvements in weight, body mass index (BMI), BMI standard deviation scores, percentage body fat and fat mass following liraglutide treatment. A significant reduction in glycated haemoglobin, triglyceride and cholesterol levels, as well as a reduction in uncontrolled eating behaviour were observed. The time spent within normal glucose range (3.9-7.8 mmol/L; 70.2-140.4 mg/dL) was lower than in healthy peers (91.76% vs. 97.00%) at baseline but improved after liraglutide treatment. The cohort reported lower health-related quality-of-life scores and exhibited more uncontrolled eating and emotional eating behaviours, compared to the healthy population. Conclusion We report, for the first time, the role of CGM in identifying glycaemic dysregulation in children and young people with obesity before and after liraglutide treatment. The results have shown significant potential for liraglutide treatment in improving outcomes. Earlier identification of glycaemic dysregulation and targeted therapy could potentially reduce the long-term risk of developing type 2 diabetes mellitus.
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Affiliation(s)
- Louise Apperley
- Alder Hey Children’s Hospital, Clinic of Pediatric Endocrinology, Liverpool, United Kingdom
| | - Jennifer Parkinson
- Alder Hey Children’s Hospital, Clinic of Pediatric Endocrinology, Liverpool, United Kingdom
| | - Senthil Senniappan
- Alder Hey Children’s Hospital, Clinic of Pediatric Endocrinology, Liverpool, United Kingdom
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Karakasis P, Patoulias D, Fragakis N, Mantzoros CS. Effect of glucagon-like peptide-1 receptor agonists and co-agonists on body composition: Systematic review and network meta-analysis. Metabolism 2025; 164:156113. [PMID: 39719170 DOI: 10.1016/j.metabol.2024.156113] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Revised: 12/20/2024] [Accepted: 12/20/2024] [Indexed: 12/26/2024]
Abstract
BACKGROUND AND AIMS While glucagon-like peptide-1 receptor agonists (GLP-1RAs) effectively reduce body weight, their impact on lean mass remains uncertain. This meta-analysis evaluated the effects of GLP-1RAs and GLP-1/GIP receptor dual agonists (GLP-1/GIP-RAs) on body composition, focusing on total weight, fat mass, and lean mass in adults with diabetes and/or overweight/obesity. METHODS A systematic search of Medline, Embase, and the Cochrane Library was conducted through November 12, 2024. Data were analyzed using random-effects pairwise and network meta-analyses to compare interventions with placebo or active comparators. RESULTS Twenty-two randomized controlled trials (2258 participants) were included. GLP-1RAs significantly reduced total body weight (MD -3.55 kg, 95 %-CI [-4.81, -2.29]), fat mass (MD -2.95 kg, 95 %-CI [-4.11, -1.79]), and lean mass (MD -0.86 kg, 95 %-CI [-1.30, -0.42]), with lean mass loss comprising approximately 25 % of the total weight loss. However, the relative lean mass, defined as percentage change from baseline, was unaffected. Liraglutide, at 3.0 mg weekly or 1.8 mg daily, was the only GLP-1RA to achieve significant weight reduction without significantly reducing lean mass. Tirzepatide (15 mg weekly) and semaglutide (2.4 mg weekly) were the most effective for weight and fat mass reduction but were among the least effective in preserving lean mass. CONCLUSIONS Potent GLP-1 RAs, such as tirzepatide and semaglutide, demonstrate greater overall weight loss but are associated with a significant reduction in lean mass.
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Affiliation(s)
- Paschalis Karakasis
- Second Department of Cardiology, Hippokration General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece.
| | - Dimitrios Patoulias
- Second Propedeutic Department of Internal Medicine, Faculty of Medicine, School of Health Sciences Aristotle, University of Thessaloniki, Greece
| | - Nikolaos Fragakis
- Second Department of Cardiology, Hippokration General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Christos S Mantzoros
- Beth Israel Deaconess Medical Center and Boston VA Healthcare System, Harvard Medical School, Boston, MA, USA
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Bae JH, Cho YM. Incretin hormones: Revolutionizing the treatment landscape for kidney and liver diseases in type 2 diabetes and obesity. J Diabetes Investig 2025; 16:183-186. [PMID: 39460581 PMCID: PMC11786174 DOI: 10.1111/jdi.14336] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Revised: 10/07/2024] [Accepted: 10/09/2024] [Indexed: 10/28/2024] Open
Abstract
Several ongoing trials are evaluating incretin-based therapies, including GLP-1 receptor agonists, for their effects on CKD and MASLD. These studies will offer insights into their potential for metabolic diseases in people with type 2 diabetes and obesity.
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Affiliation(s)
- Jae Hyun Bae
- Department of Internal MedicineSeoul National University HospitalSeoulKorea
| | - Young Min Cho
- Department of Internal MedicineSeoul National University HospitalSeoulKorea
- Department of Internal MedicineSeoul National University College of MedicineSeoulKorea
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Jiao R, Lin C, Cai X, Wang J, Wang Y, Lv F, Yang W, Ji L. Characterizing body composition modifying effects of a glucagon-like peptide 1 receptor-based agonist: A meta-analysis. Diabetes Obes Metab 2025; 27:259-267. [PMID: 39431379 DOI: 10.1111/dom.16012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 09/18/2024] [Accepted: 09/28/2024] [Indexed: 10/22/2024]
Abstract
AIM Diabetes is an independent risk factor for muscle mass loss, with possible mechanisms including impaired insulin signalling and chronic inflammation. The use of a glucagon-like peptide 1 (GLP-1) receptor-based agonist could lead to weight reduction, which might result from the loss of both fat and skeletal muscle. However, the body composition-modifying effects of GLP-1 receptor-based agonists have not been systematically characterized. METHODS PubMed, EMBASE, the Cochrane Center Register of Controlled Trials for Studies and Clinicaltrial.gov were searched from inception to October 2023. Randomized controlled trials of GLP-1 receptor agonist or glucose-dependent insulinotropic polypeptide/GLP-1 receptor dual agonist, which reported the changes of body composition, were included. The results were computed as weighted mean differences (WMDs) and 95% confidence intervals (CIs) in a random-effects model. RESULTS In all, 19 randomized controlled trials were included. When compared with controls, substantial reductions in fat body mass were observed in patients using GLP-1 receptor-based agonist treatment (WMD = -2.25 kg, 95% CI -3.40 to -1.10 kg), with decrease in areas of both subcutaneous fat (WMD = -38.35 cm2, 95% CI, -54.75 to -21.95 cm2) and visceral fat (WMD = -14.61 cm2, 95% CI, -23.77 to -5.44 cm2). Moreover, greater reductions in lean body mass were also observed in GLP-1 receptor-based agonist users compared with non-users (WMD = -1.02 kg, 95% CI, -1.46 to -0.57 kg), while the changes in lean mass percentage were comparable between GLP-1 receptor-based agonist users and non-users. CONCLUSION Compared with the controls, GLP-1 receptor-based agonist users experienced greater reductions in fat body mass, with body shaping effects in terms of both subcutaneous fat mass and visceral fat mass. Although greater reductions in lean body mass were also observed in GLP-1 receptor-based agonist users, the changes in lean mass percentage were comparable between the users and non-users.
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Affiliation(s)
- Ruoyang Jiao
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
| | - Chu Lin
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
| | - Xiaoling Cai
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
| | - Jingxuan Wang
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
| | - Yuan Wang
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
| | - Fang Lv
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
| | - Wenjia Yang
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
| | - Linong Ji
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
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Xu R, Liu B, Zhou X. Comparison of Glucagon-Like Peptide-1 Receptor Agonists and Sodium-Glucose Cotransporter Protein-2 Inhibitors on Treating Metabolic Dysfunction-Associated Steatotic Liver Disease or Metabolic Dysfunction-Associated Steatohepatitis: Systematic Review and Network Meta-Analysis of Randomised Controlled Trials. Endocr Pract 2024:S1530-891X(24)00867-X. [PMID: 39701283 DOI: 10.1016/j.eprac.2024.11.017] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Revised: 11/11/2024] [Accepted: 11/24/2024] [Indexed: 12/21/2024]
Abstract
OBJECTIVE To assess glucagon-like peptide-1 receptor agonists (GLP-1 receptor agonists) and sodium-glucose cotransporter protein-2 inhibitors (SGLT-2 inhibitors) in patients with metabolic dysfunction-associated steatotic liver disease or metabolic dysfunction-associated steatohepatitis (previously known as nonalcoholic fatty liver disease [NAFLD] and nonalcoholic steatohepatitis [NASH]), we performed a systematic review and network meta-analysis of randomized controlled trials. METHODS The study searched Pubmed, Embase, the Cochrane Library, and Web of Science databases up to November 26, 2023. Two reviewers independently selected the studies, extracted the data, and assessed the risk of bias. RESULTS Thirty-seven studies were included in the analysis. GLP-1 receptor agonists were found to be more effective than placebo in resolving NASH (relative risk: 2.48, 95% CI:1.86 to 3.30). Both drugs were superior to placebo in reducing liver fat content, as well as decreasing levels of liver enzyme. Network meta-analysis indicated that SGLT-2 inhibitors were more effective than GLP-1 receptor agonists in reducing alanine aminotransferase and aspartate aminotransferase levels. According to the surface under the cumulative probability ranking curve values, GLP-1 receptor agonists and SGLT-2 inhibitors consistently ranked among the top 2 in terms of reducing anthropometric data compared to other included drugs. CONCLUSIONS GLP-1 receptor agonists and SGLT-2 inhibitors have significant effects on reducing liver fat content and liver enzymes in NAFLD or NASH patients compared to placebo. GLP-1 receptor agonists were found to be superior to placebo in resolving NASH. SGLT-2 inhibitors were more effective than GLP-1 receptor agonists in reducing alanine aminotransferase and aspartate aminotransferase levels.
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Affiliation(s)
- Ruhan Xu
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
| | - Bo Liu
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
| | - Xianghai Zhou
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China.
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Bussuan RM, Bersch-Ferreira ÂC, Marcadenti A. Association between the number of glucose-lowering drugs in use, diet quality, and nutrient intake among adults with type 2 diabetes mellitus. Nutr Health 2024:2601060241303629. [PMID: 39659244 DOI: 10.1177/02601060241303629] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2024]
Abstract
BACKGROUND The use of several glucose-lowering drugs (GLDs) in individuals with type 2 diabetes mellitus is common, but their effects on dietary intake have been little explored. AIM Our study aimed to examine the association between the number of GLDs used by adults with type 2 diabetes mellitus and their diet quality and nutrient intake. METHODS This is a cross-sectional analysis of baseline data from a Brazilian national multicenter randomized clinical trial involving participants with type 2 diabetes mellitus aged >30 years. We collected sociodemographic, clinical, biochemical, and anthropometric information and food intake data (24-h dietary recall). Diet quality was assessed by the modified Alternative Healthy Eating Index. Multiple linear regression models were used to examine the association of dietary intake with the number of GLDs in use. RESULTS Our analysis included data from a total of 363 participants, mean age of 60.8 ± 9.5 years, and mean glycated hemoglobin of 8.7 ± 1.5%. Of these, 28.1% were taking one GLD; 48.8% were taking two GLDs; and 23.1% were taking ≥3 GLDs. We found no difference in diet quality, but the intake of total polyunsaturated fatty acids and omega-3 and omega-6 fatty acids was different between the three groups (p ≤ 0.03). However, this association was no longer seen after adjusting for age, sex, duration of diabetes, prior diagnosis of dyslipidemia, physical activity and mean monthly family income. CONCLUSIONS We did not find an association between the number of GLDs in use and either diet quality or nutrient intake in individuals with type 2 diabetes mellitus.
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Affiliation(s)
- Renata Maksoud Bussuan
- Graduate Program in Health Sciences (Cardiology), Instituto de Cardiologia do Rio Grande do Sul/Fundação Universitária de Cardiologia, Porto Alegre, Brazil
| | - Ângela Cristine Bersch-Ferreira
- Hcor Research Institute, Hcor, São Paulo, Brazil
- PROADI-SUS Office, Real e Benemérita Associação Portuguesa de Beneficência, São Paulo, Brazil
| | - Aline Marcadenti
- Graduate Program in Health Sciences (Cardiology), Instituto de Cardiologia do Rio Grande do Sul/Fundação Universitária de Cardiologia, Porto Alegre, Brazil
- Hcor Research Institute, Hcor, São Paulo, Brazil
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Dubin RL, Heymsfield SB, Ravussin E, Greenway FL. Glucagon-like peptide-1 receptor agonist-based agents and weight loss composition: Filling the gaps. Diabetes Obes Metab 2024; 26:5503-5518. [PMID: 39344838 DOI: 10.1111/dom.15913] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Revised: 08/15/2024] [Accepted: 08/16/2024] [Indexed: 10/01/2024]
Abstract
Excess adiposity is at the root of type 2 diabetes (T2D). Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as first-line treatments for T2D based on significant weight loss results. The composition of weight loss using most diets consists of <25% fat-free mass (FFM) loss, with the remainder from fat stores. Higher amounts of weight loss (achieved with metabolic bariatric surgery) result in greater reductions in FFM. Our aim was to assess the impact that GLP-1RA-based treatments have on FFM. We analysed studies that reported changes in FFM with the following agents: exenatide, liraglutide, semaglutide, and the dual incretin receptor agonist tirzepatide. We performed an analysis of various weight loss interventions to provide a reference for expected changes in FFM. We evaluated studies using dual-energy X-ray absorptiometry (DXA) for measuring FFM (a crude surrogate for skeletal muscle). In evaluating the composition of weight loss, the percentage lost as fat-free mass (%FFML) was equal to ΔFFM/total weight change. The %FFML using GLP-1RA-based agents was between 20% and 40%. In the 28 clinical trials evaluated, the proportion of FFM loss was highly variable, but the majority reported %FFML exceeding 25%. Our review was limited to small substudies and the use of DXA, which does not measure skeletal muscle mass directly. Since FFM contains a variable amount of muscle (approximately 55%), this indirect measure may explain the heterogeneity in the data. Assessing quantity and quality of skeletal muscle using advanced imaging (magnetic resonance imaging) with functional testing will help fill the gaps in our current understanding.
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Affiliation(s)
- Robert L Dubin
- Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA
| | | | - Eric Ravussin
- Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA
| | - Frank L Greenway
- Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA
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Locatelli JC, Costa JG, Haynes A, Naylor LH, Fegan PG, Yeap BB, Green DJ. Incretin-Based Weight Loss Pharmacotherapy: Can Resistance Exercise Optimize Changes in Body Composition? Diabetes Care 2024; 47:1718-1730. [PMID: 38687506 DOI: 10.2337/dci23-0100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Accepted: 03/22/2024] [Indexed: 05/02/2024]
Abstract
This narrative review highlights the degree to which new antiobesity medications based on gut-derived nutrient-stimulated hormones (incretins) cause loss of lean mass, and the importance of resistance exercise to preserve muscle. Glucagon-like peptide 1 receptor agonists (GLP-1RA) induce substantial weight loss in randomized trials, effects that may be enhanced in combination with glucose-dependent insulinotropic polypeptide (GIP) receptor agonists. Liraglutide and semaglutide (GLP-1RA), tirzepatide (GLP-1 and GIP receptor dual agonist), and retatrutide (GLP-1, GIP, and glucagon receptor triple agonist) are peptides with incretin agonist activity that induce ∼15-24% weight loss in adults with overweight and obesity, alongside beneficial impacts on blood pressure, cholesterol, blood glucose, and insulin. However, these agents also cause rapid and significant loss of lean mass (∼10% or ∼6 kg), comparable to a decade or more of aging. Maintaining muscle mass and function as humans age is crucial to avoiding sarcopenia and frailty, which are strongly linked to morbidity and mortality. Studies indicate that supervised resistance exercise training interventions with a duration >10 weeks can elicit large increases in lean mass (∼3 kg) and strength (∼25%) in men and women. After a low-calorie diet, combining aerobic exercise with liraglutide improved weight loss maintenance compared with either alone. Retaining lean mass during incretin therapy could blunt body weight (and fat) regain on cessation of weight loss pharmacotherapy. We propose that tailored resistance exercise training be recommended as an adjunct to incretin therapy to optimize changes in body composition by preserving lean mass while achieving fat loss.
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Affiliation(s)
- João Carlos Locatelli
- School of Human Sciences (Exercise and Sport Science), University of Western Australia, Perth, Australia
| | - Juliene Gonçalves Costa
- School of Human Sciences (Exercise and Sport Science), University of Western Australia, Perth, Australia
| | - Andrew Haynes
- School of Human Sciences (Exercise and Sport Science), University of Western Australia, Perth, Australia
| | - Louise H Naylor
- School of Human Sciences (Exercise and Sport Science), University of Western Australia, Perth, Australia
| | - P Gerry Fegan
- Department of Endocrinology and Diabetes, Fiona Stanley Hospital, Perth, Australia
- Medical School, Curtin University, Perth, Australia
| | - Bu B Yeap
- Medical School, Curtin University, Perth, Australia
- Medical School, University of Western Australia, Perth, Australia
| | - Daniel J Green
- School of Human Sciences (Exercise and Sport Science), University of Western Australia, Perth, Australia
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Yan X, Ma J, Liu Y, Wang X, Li S, Yan S, Mo Z, Zhu Y, Lin J, Liu J, Jia Y, Liu L, Ding K, Xu M, Zhou Z. Efficacy and safety of visepegenatide, a long-acting weekly GLP-1 receptor agonist as monotherapy in type 2 diabetes mellitus: a randomised, double-blind, parallel, placebo-controlled phase 3 trial. THE LANCET REGIONAL HEALTH. WESTERN PACIFIC 2024; 47:101101. [PMID: 38948164 PMCID: PMC11214404 DOI: 10.1016/j.lanwpc.2024.101101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Revised: 04/17/2024] [Accepted: 05/09/2024] [Indexed: 07/02/2024]
Abstract
Background Type 2 diabetes (T2DM) remains a challenge to treat despite the expansion of various therapeutic classes. Visepegenatide (PB-119) is a once a week, subcutaneous, glucagon-like peptide-1 receptor agonist (GLP-1 RA) injection without the requirement of dose titration that has shown glycaemic control and safety profile in two phase 2 studies conducted in China and the United States, respectively. The aim of this study was to evaluate the efficacy and safety of visepegenatide as a monotherapy in treatment-naïve patients with T2DM. Methods This was a multicentre, double-blind, parallel, placebo-controlled, phase 3 trial conducted in 30 centres in China. Adult participants (aged 18-75 years) with T2DM, glycated haemoglobin (HbA1c) of 7.5%-11.0% [58.47-96.73 mmol/mol], body mass index (BMI) of 18-40 kg/m2, and who had been treated with diet and exercise alone for at least 8 weeks before the screening visit were eligible for enrolment. After a 4-week placebo injection run-in period, participants with HbA1c of 7.0%-10.5% [53.0-91.3 mmol/mol] and fasting plasma glucose (FPG) < 15 mmol/L were randomised in a ratio of 1:1 to receive visepegenatide (150 μg) or placebo subcutaneous injections once a week for 24 weeks. The treatment was extended to another 28 weeks during which all participants received visepegenatide. The primary outcome was a change in HbA1c from baseline to week 24. This study was registered with ClinicalTrials.gov, as NCT04504370. Findings Between November 2, 2020, and November 2, 2022, we randomly assigned 273 adult participants to the visepegenatide (n = 137) and placebo (n = 136) groups. In total, 257 (94.12%) participants, 131 (95.6%) on visepegenatide, and 126 (92.6%) on placebo, completed the double-blinded treatment period. At baseline, the mean (SD) HbA1c was 8.47% (0.81) [69.07 [8.81] mmol/mol], which rapidly decreased to 7.63% (0.80) [59.94 [8.70] mmol/mol] with visepegenatide by week 4 of treatment, and the change from baseline was significantly greater than that in the placebo group (-0.82% [-0.90 to -0.74]; [-8.99 [-9.89 to -8.10] mmol/mol] vs -0.30% [-0.41 to -0.19]; [-3.30 [-4.50 to -2.09] mmol/mol]). At week 24, when evaluating the effects of treatment with treatment policy estimand, the least square mean (LSM change in HbA1c from baseline was -1.36 (95% confidence interval [CI] -1.52 to -1.20) [-14.84 [-16.60 to -13.08] mmol/mol] in the visepegenatide group vs -0.63 (-0.79 to -0.46) [-6.84 [-8.61 to -5.07] mmol/mol] in the placebo group. The reduction in HbA1c was significantly greater with visepegenatide than placebo (LSM difference -0.73, 95% CI -0.96 to -0.50; p < 0.001). When evaluating the treatment estimand with hypothetic policy, the LSM change in HbA1c from baseline in the visepegenatide group (-1.37 [-1.53 to -1.20]) [-14.95 [-16.76 to -13.14] mmol/mol] was significantly greater than the placebo group (-0.63 [-0.81 to -0.45]) [6.90 (-8.89 to -4.90) mmol/mol]. The LSM difference was (-0.74, 95% CI -0.98 to -0.49; [-8.00 [-10.50 to -5.50] mmol/mol]; p < 0.001]. A significantly greater proportion of the visepegenatide group achieved a target HbA1c level of <7% (<53 mmol/mol) than the placebo (50.4% vs 14.2%; p < 0.05) and stringent HbA1c level of ≤6.5% (≤48 mmol/mol) (26.7% vs 7.9%), respectively. There was also a significantly greater improvement in FPG, 2-h postprandial glucose, homeostasis model assessment (HOMA) of beta cell function, post-prandial insulin, fasting, and post-prandial C-peptide level (p < 0.05) with visepegenatide treatment. The number (3 [2.2%]) of participants who received rescue therapy in the visepegenatide group was remarkably lower compared with those (17 [12.5%]) in the placebo group (p < 0.05). During the extended treatment period, visepegenatide consistently maintained the efficacy till week 52 confirmed by all the above endpoints. The reduction in HbA1c at week 52 was -1.39% (-1.58 to -1.19) [-15.14 [-17.28 to -13.01] mmol/mol], which was even greater than that at week 24. There was also a significant improvement in HOMA-insulin resistance (p = 0.004) at week 52 compared with the baseline value. For the placebo→visepegenatide group, which received visepegenatide in the extended treatment period, a notable decrease in HbA1c at week 52 compared to baseline was observed. The change from baseline in HbA1c was -1.49% (-1.68 to -1.30) [-16.27 [-18.37 to -14.16] mmol/mol]. The outcome was in the same direction as the visepegenatide group from the double-blind treatment period. Comprehensive benefits of visepegenatide including weight loss, improvement in lipid profile, and reduction in blood pressure have been demonstrated in this study. Visepegenatide reduced the body weight in a BMI-dependent manner that was prominent in BMI ˃32 kg/m2 with a mean (SD) reduction of -4.77 (13.94) kg at week 52 (p < 0.05). Incidences of gastrointestinal adverse events were less common than other weekly GLP-1 RA in the market, and most of the adverse events were mild and moderate in nature, occurring in the first weeks of the treatment, and were transient. No serious hypoglycaemia or grade 2 hypoglycaemia (blood glucose: ≤3 mmol/L) was reported during the study. Interpretation As a monotherapy, visepegenatide provided rapid without the risk of hypoglycaemia, significant, and sustainable glycaemic control by improving islet β-cell function and insulin resistance. Treatment with visepegenatide induced early treatment response in reducing HbA1c and maintaining glycaemic control for 52 weeks. Meanwhile, visepegenatide provided a comprehensive benefit in body weight loss, lipids, and blood pressure reduction. Visepegenatide had a better safety profile than other weekly GLP-1 RA in participants with T2DM even without the requirement of dose titration. Visepegenatide would provide an optimal treatment approach with its high benefit and low-risk balance. Funding PegBio Co., Ltd.
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Affiliation(s)
- Xiang Yan
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Jianhua Ma
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Yan Liu
- Endocrinology Department, The Third People's Hospital of Datong, Datong City, Shanxi Province, China
| | - Xuhong Wang
- Endocrinology Department, The First Hospital of Qiqihar, Qiqihar, Heilongjiang, China
| | - Sheli Li
- Endocrinology and Metabolism Department, Yan'an University Affiliated Hospital, Baota District, Yan'an, China
| | - Shuang Yan
- Endocrinology Department, The Fourth Affiliated Hospital of Harbin Medical University, Nangang District, Harbin City, China
| | - Zhaohui Mo
- Endocrinology Department, The Third Xiangya Hospital of Central South University, Yuelu District, Changsha, China
| | - Yikun Zhu
- Endocrinology Department, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Jingna Lin
- Endocrinology Department, Tianjin People's Hospital, Hongqiao District, Tianjin, China
| | - Jie Liu
- Endocrinology Department, The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, Henan, China
| | - Ying Jia
- Medical Department, Clinical Development Center, PegBio Co., Ltd, Suzhou, China
| | - Li Liu
- Medical Department, Clinical Development Center, PegBio Co., Ltd, Suzhou, China
| | - Ke Ding
- Medical Department, Clinical Development Center, PegBio Co., Ltd, Suzhou, China
| | - Michael Xu
- Medical Department, Clinical Development Center, PegBio Co., Ltd, Suzhou, China
| | - Zhiguang Zhou
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
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12
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Andraos J, Smith SR, Tran A, Pham DQ. Narrative review of data supporting alternate first-line therapies over metformin in type 2 diabetes. J Diabetes Metab Disord 2024; 23:385-394. [PMID: 38932889 PMCID: PMC11196467 DOI: 10.1007/s40200-024-01406-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Accepted: 02/15/2024] [Indexed: 06/28/2024]
Abstract
Purpose Metformin has been the first-line treatment for type 2 diabetes mellitus as monotherapy or concomitantly with other glucose-lowering therapies due to its efficacy, safety, and affordability. Recent studies on the cardioprotective and renoprotective benefits of glucagon-like peptide-1 receptor agonists (GLP-1 RA) and sodium-glucose cotransporter-2 inhibitors (SGLT-2i) have influenced guidelines on diabetes management to consider these newer agents as alternative first-line therapies. This paper explores the literature supporting the use of these newer medications alone as a first-line agent in place of metformin. Methods A review of citations from the most recent guidelines along with a literature search via PubMed was completed to review (1) what, historically, made metformin first-line (2) if newer agents' benefits remain when used without metformin (3) how newer agents compare against metformin when used without it. Results Evaluation of the historical literature was completed to summarize the key findings that support metformin as a first-line therapy agent. Additionally, an assessment of the literature reveals that the benefits of these two newer classes are independent of concomitant metformin therapy. Finally, studies have demonstrated that these newer agents can be either non-inferior or sometimes superior to metformin when used as monotherapy. Conclusion GLP-1 RA and SGLT-2i can be considered as first line monotherapies for select patients with high cardiovascular risks, renal disease, or weight loss requirements. However, pharmacoeconomic considerations along with lesser long-term safety outcomes should limit these agents' use in certain patients as the management of diabetes continues to transition towards shared-decision making. Supplementary Information The online version contains supplementary material available at 10.1007/s40200-024-01406-6.
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Affiliation(s)
- John Andraos
- Western University of Health Sciences, College of Pharmacy, Pomona, CA USA
| | - Shawn R. Smith
- Western University of Health Sciences, College of Pharmacy, Pomona, CA USA
| | - Amanda Tran
- HOAG, Mary & Dick Allen Diabetes Center, Newport Beach, CA USA
| | - David Q. Pham
- Western University of Health Sciences, College of Pharmacy, Pomona, CA USA
- HOAG, Mary & Dick Allen Diabetes Center, Newport Beach, CA USA
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13
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Argyrakopoulou G, Gitsi E, Konstantinidou SK, Kokkinos A. The effect of obesity pharmacotherapy on body composition, including muscle mass. Int J Obes (Lond) 2024:10.1038/s41366-024-01533-3. [PMID: 38745020 DOI: 10.1038/s41366-024-01533-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2024] [Revised: 04/18/2024] [Accepted: 04/26/2024] [Indexed: 05/16/2024]
Abstract
Obesity pharmacotherapy represents a promising approach to treating obesity and may provide benefits beyond weight loss alone. Maintaining or even increasing muscle mass during weight loss is important to overall health, metabolic function and weight loss maintenance. Drugs such as liraglutide, semaglutide, tirzepatide, and naltrexone/bupropion have shown significant weight loss effects, and emerging evidence suggests they may also have effects on body composition, particularly a positive influence on muscle mass. However, further research is needed to fully understand the mechanism of action of these drugs and their effects on muscle mass. Clinicians should consider these factors when developing an obesity treatment plan for an individual patient.
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Affiliation(s)
| | - Evdoxia Gitsi
- Diabetes and Obesity Unit, Athens Medical Center, 15125, Athens, Greece
| | - Sofia K Konstantinidou
- Diabetes and Obesity Unit, Athens Medical Center, 15125, Athens, Greece
- First Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
| | - Alexander Kokkinos
- First Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
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14
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Xiao Y, Wang J, Zhang Y, Zhang T, Qi X, Hou L, Ma Z, Xu F. Hepatic polypeptide nutrient solution improves high-cholesterol diet-induced rats with nonalcoholic fatty liver disease by activating AMP-activated protein kinase signaling pathway. Food Sci Nutr 2024; 12:3225-3236. [PMID: 38726419 PMCID: PMC11077238 DOI: 10.1002/fsn3.3990] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Revised: 01/08/2024] [Accepted: 01/17/2024] [Indexed: 05/12/2024] Open
Abstract
Hepatic polypeptide nutrient solution (HP) is a mixture of hepatoprotective peptides derived from fresh porcine liver with various effects. However, the role and mechanisms of HP in nonalcoholic fatty liver disease (NAFLD) are still not well understood. We investigated the effects of HP NAFLD rats induced by high-cholesterol diet (HCD) and its underlying mechanisms. Rats were provided with HCD for 4 weeks and then received HP or metformin after 2 weeks of HCD feeding. The study found that HP reduced cholesterol and triglyceride levels in rats with NAFLD (all p < .05). Histopathological examination also showed that HP improved the liver lesions induced by the HCD diet. Furthermore, the oxidative stress and inflammatory responses of NAFLD rats treated with HP were also improved. In addition, it was discovered that HP triggered the activation of AMPK and decreased the expression of SREBP-1c and FAS while enhancing the expression of PPAR α and CPT-1 in liver. These findings indicated that HP might have therapeutic potential for NAFLD, possibly via activating AMPK signaling pathway.
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Affiliation(s)
- Yingying Xiao
- School of Basic MedicineHebei University of Chinese MedicineShijiazhuangHebeiChina
| | - Jianan Wang
- Graduate SchoolHebei University of Chinese MedicineShijiazhuangHebeiChina
| | - Ying Zhang
- School of Basic MedicineHebei University of Chinese MedicineShijiazhuangHebeiChina
| | - Ting Zhang
- Experimental CenterHebei University of Chinese MedicineShijiazhuangHebeiChina
| | - Xingzhong Qi
- Hebei Zhitong Biological Pharmaceutical Co., Ltd.BaodingHebeiChina
| | - Lei Hou
- Hebei Zhitong Biological Pharmaceutical Co., Ltd.BaodingHebeiChina
| | - Zhihong Ma
- School of Basic MedicineHebei University of Chinese MedicineShijiazhuangHebeiChina
- Hebei International Cooperation Center for Ion Channel Function and Innovative Traditional Chinese MedicineShijiazhuangHebeiChina
- Hebei Key Laboratory of Integrative Medicine on Liver‐Kidney PatternsShijiazhuangHebeiChina
| | - Feng Xu
- Hebei Zhitong Biological Pharmaceutical Co., Ltd.BaodingHebeiChina
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15
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Perazza F, Leoni L, Colosimo S, Musio A, Bocedi G, D’Avino M, Agnelli G, Nicastri A, Rossetti C, Sacilotto F, Marchesini G, Petroni ML, Ravaioli F. Metformin and the Liver: Unlocking the Full Therapeutic Potential. Metabolites 2024; 14:186. [PMID: 38668314 PMCID: PMC11052067 DOI: 10.3390/metabo14040186] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Revised: 03/20/2024] [Accepted: 03/22/2024] [Indexed: 04/28/2024] Open
Abstract
Metformin is a highly effective medication for managing type 2 diabetes mellitus. Recent studies have shown that it has significant therapeutic benefits in various organ systems, particularly the liver. Although the effects of metformin on metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated steatohepatitis are still being debated, it has positive effects on cirrhosis and anti-tumoral properties, which can help prevent the development of hepatocellular carcinoma. Furthermore, it has been proven to improve insulin resistance and dyslipidaemia, commonly associated with liver diseases. While more studies are needed to fully determine the safety and effectiveness of metformin use in liver diseases, the results are highly promising. Indeed, metformin has a terrific potential for extending its full therapeutic properties beyond its traditional use in managing diabetes.
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Affiliation(s)
- Federica Perazza
- Department of Medical and Surgical Sciences, IRCCS Azienda Ospedaliero, Universitaria di Bologna, 40138 Bologna, Italy; (F.P.); (L.L.); (G.A.); (A.N.); (C.R.); (F.S.); (G.M.); (M.L.P.)
| | - Laura Leoni
- Department of Medical and Surgical Sciences, IRCCS Azienda Ospedaliero, Universitaria di Bologna, 40138 Bologna, Italy; (F.P.); (L.L.); (G.A.); (A.N.); (C.R.); (F.S.); (G.M.); (M.L.P.)
| | - Santo Colosimo
- Doctorate School of Nutrition Science, University of Milan, 20122 Milan, Italy;
| | | | - Giulia Bocedi
- U.O. Diabetologia, Ospedale C. Magati, Scandiano, 42019 Reggio Emilia, Italy;
| | - Michela D’Avino
- S.C. Endocrinologia Arcispedale Santa Maria Nuova, 42123 Reggio Emilia, Italy;
| | - Giulio Agnelli
- Department of Medical and Surgical Sciences, IRCCS Azienda Ospedaliero, Universitaria di Bologna, 40138 Bologna, Italy; (F.P.); (L.L.); (G.A.); (A.N.); (C.R.); (F.S.); (G.M.); (M.L.P.)
| | - Alba Nicastri
- Department of Medical and Surgical Sciences, IRCCS Azienda Ospedaliero, Universitaria di Bologna, 40138 Bologna, Italy; (F.P.); (L.L.); (G.A.); (A.N.); (C.R.); (F.S.); (G.M.); (M.L.P.)
| | - Chiara Rossetti
- Department of Medical and Surgical Sciences, IRCCS Azienda Ospedaliero, Universitaria di Bologna, 40138 Bologna, Italy; (F.P.); (L.L.); (G.A.); (A.N.); (C.R.); (F.S.); (G.M.); (M.L.P.)
| | - Federica Sacilotto
- Department of Medical and Surgical Sciences, IRCCS Azienda Ospedaliero, Universitaria di Bologna, 40138 Bologna, Italy; (F.P.); (L.L.); (G.A.); (A.N.); (C.R.); (F.S.); (G.M.); (M.L.P.)
| | - Giulio Marchesini
- Department of Medical and Surgical Sciences, IRCCS Azienda Ospedaliero, Universitaria di Bologna, 40138 Bologna, Italy; (F.P.); (L.L.); (G.A.); (A.N.); (C.R.); (F.S.); (G.M.); (M.L.P.)
| | - Maria Letizia Petroni
- Department of Medical and Surgical Sciences, IRCCS Azienda Ospedaliero, Universitaria di Bologna, 40138 Bologna, Italy; (F.P.); (L.L.); (G.A.); (A.N.); (C.R.); (F.S.); (G.M.); (M.L.P.)
| | - Federico Ravaioli
- Department of Medical and Surgical Sciences, IRCCS Azienda Ospedaliero, Universitaria di Bologna, 40138 Bologna, Italy; (F.P.); (L.L.); (G.A.); (A.N.); (C.R.); (F.S.); (G.M.); (M.L.P.)
- Division of Hepatobiliary and Immunoallergic Diseases, Department of Internal Medicine, IRCCS Azienda Ospedaliero, Universitaria di Bologna, 40138 Bologna, Italy
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16
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Jagannath S, Mallanna SH, Nandini CD. Diet-inducing hypercholesterolemia show decreased O-GlcNAcylation of liver proteins through modulation of AMPK. J Physiol Biochem 2024; 80:205-218. [PMID: 37996652 DOI: 10.1007/s13105-023-00997-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Accepted: 11/09/2023] [Indexed: 11/25/2023]
Abstract
O-GlcNAcylation, a nutritionally driven, post-translational modification of proteins, is gaining importance because of its health implications. Changes in O-GlcNAcylation are observed in various disease conditions. Changes in O-GlcNAcylation by diet that causes hypercholesterolemia are not critically looked into in the liver. To address it, both in vitro and in vivo approaches were employed. Hypercholesterolemia was induced individually by feeding cholesterol (H)/high-fat (HF) diet. Global O-GlcNAcylation levels and modulation of AMPK activation in both preventive and curative approaches were looked into. Diet-induced hypercholesterolemia resulted in decreased O-GlcNAcylation of liver proteins which was associated with decreased O-linked N-acetylglucosaminyltransferase (OGT) and Glutamine fructose-6-phosphate amidotransferase-1 (GFAT1). Activation of AMPK by metformin in preventive mode restored the O-GlcNAcylation levels; however, metformin treatment of HepG2 cells in curative mode restored O-GlcNAcylation levels in HF but failed to in H condition (at 24 h). Further, maternal faulty diet resulted in decreased O-GlcNAcylation in pup liver despite feeding normal diet till adulthood. A faulty diet modulates global O-GlcNAcylation of liver proteins which is accompanied by decreased AMPK activation which could exacerbate metabolic syndromes through fat accumulation in the liver.
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Affiliation(s)
- Sanjana Jagannath
- Department of Molecular Nutrition, CSIR-Central Food Technological Research Institute, Mysore, Karnataka, 570020, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Smitha Honnalagere Mallanna
- Department of Molecular Nutrition, CSIR-Central Food Technological Research Institute, Mysore, Karnataka, 570020, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - C D Nandini
- Department of Molecular Nutrition, CSIR-Central Food Technological Research Institute, Mysore, Karnataka, 570020, India.
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.
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17
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Zachou M, Flevari P, Nasiri-Ansari N, Varytimiadis C, Kalaitzakis E, Kassi E, Androutsakos T. The role of anti-diabetic drugs in NAFLD. Have we found the Holy Grail? A narrative review. Eur J Clin Pharmacol 2024; 80:127-150. [PMID: 37938366 PMCID: PMC10781828 DOI: 10.1007/s00228-023-03586-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Accepted: 10/19/2023] [Indexed: 11/09/2023]
Abstract
PURPOSE Non-alcoholic fatty liver disease (NAFLD) has become a leading cause of liver disease, affecting 30% of the global population. NAFLD prevalence is particularly high in obese individuals and patients with type 2 diabetes mellitus (T2DM). NAFLD ranges from simple fat deposition in the liver to necroinflammation and fibrosis (non-alcoholic steatohepatitis (NASH)), NASH-cirrhosis, and/or hepatocellular carcinoma. Insulin resistance plays a key role in NAFLD pathogenesis, alongside dysregulation of adipocytes, mitochondrial dysfunction, genetic factors, and changes in gut microbiota. Since insulin resistance is also a major predisposing factor of T2DM, the administration of anti-diabetic drugs for the management of NAFLD seems reasonable. METHODS In this review we provide the NAFLD-associated mechanisms of action of some of the most widely used anti-diabetic drugs, namely metformin, pioglitazone, sodium-glucose transport protein-2 inhibitors (SGLT2i), glucagon-like peptide 1 receptor analogs (GLP1 RAs), and dipeptyl-peptidase-4 inhibitors (DPP4i) and present available data regarding their use in patients with NAFLD, with and without T2DM. RESULTS Both metformin and DPP4i have shown rather contradictory results, while pioglitazone seems to benefit patients with NASH and is thus the only drug approved for NASH with concomitant significant liver fibrosis by all major liver societies. On the other hand, SGLT2i and GLP1 RAs seem to be beneficiary in patients with NAFLD, showing both remarkable results, with SGLT2i proving to be more efficient in the only head-to-head study so far. CONCLUSION In patients with NAFLD and diabetes, pioglitazone, GLP1 RAs, and SGLT2i seem to be logical treatment options. Larger studies are needed before these drugs can be recommended for non-diabetic individuals.
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Affiliation(s)
- Maria Zachou
- Gastroenterology Department, "Sismanoglio" General Hospital, 151 26, Athens, Greece
| | - Pagona Flevari
- Expertise Center in Rare Haematological Diseases-Haemoglobinopathies, "Laiko" General Hospital, 115 27, Athens, Greece
| | - Narjes Nasiri-Ansari
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 115 27, Athens, Greece
| | | | - Evangelos Kalaitzakis
- Department of Gastroenterology, University Hospital of Heraklion, University of Crete, 715 00, Heraklion, Greece
| | - Eva Kassi
- Unit of Molecular Endocrinology, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 115 27, Athens, Greece
- Endocrine Unit, 1st Department of Propaedeutic Internal Medicine, "Laiko" Hospital, National and Kapodistrian University of Athens, 115 27, Athens, Greece
| | - Theodoros Androutsakos
- Department of Pathophysiology, Medical School, National and Kapodistrian University of Athens, Mikras Asias 75, 115 27, Athens, Greece.
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18
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Lisco G, Disoteo OE, De Tullio A, De Geronimo V, Giagulli VA, Monzani F, Jirillo E, Cozzi R, Guastamacchia E, De Pergola G, Triggiani V. Sarcopenia and Diabetes: A Detrimental Liaison of Advancing Age. Nutrients 2023; 16:63. [PMID: 38201893 PMCID: PMC10780932 DOI: 10.3390/nu16010063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Revised: 12/19/2023] [Accepted: 12/22/2023] [Indexed: 01/12/2024] Open
Abstract
Sarcopenia is an age-related clinical complaint characterized by the progressive deterioration of skeletal muscle mass and strength over time. Type 2 diabetes (T2D) is associated with faster and more relevant skeletal muscle impairment. Both conditions influence each other, leading to negative consequences on glycemic control, cardiovascular risk, general health status, risk of falls, frailty, overall quality of life, and mortality. PubMed/Medline, Scopus, Web of Science, and Google Scholar were searched for research articles, scientific reports, observational studies, clinical trials, narrative and systematic reviews, and meta-analyses to review the evidence on the pathophysiology of di-abetes-induced sarcopenia, its relevance in terms of glucose control and diabetes-related outcomes, and diagnostic and therapeutic challenges. The review comprehensively addresses key elements for the clinical definition and diagnostic criteria of sarcopenia, the pathophysiological correlation be-tween T2D, sarcopenia, and related outcomes, a critical review of the role of antihyperglycemic treatment on skeletal muscle health, and perspectives on the role of specific treatment targeting myokine signaling pathways involved in glucose control and the regulation of skeletal muscle metabolism and trophism. Prompt diagnosis and adequate management, including lifestyle inter-vention, health diet programs, micronutrient supplementation, physical exercise, and pharmaco-logical treatment, are needed to prevent or delay skeletal muscle deterioration in T2D.
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Affiliation(s)
- Giuseppe Lisco
- Section of Internal Medicine, Geriatrics, Endocrinology and Rare Diseases, Interdisciplinary Department of Medicine, University of Bari “Aldo Moro”, 70124 Bari, Italy; (A.D.T.); (V.A.G.); (E.J.); (E.G.)
| | - Olga Eugenia Disoteo
- Unit of Endocrinology, Diabetology, Dietetics and Clinical Nutrition, Sant Anna Hospital, 22020 San Fermo della Battaglia, Italy;
| | - Anna De Tullio
- Section of Internal Medicine, Geriatrics, Endocrinology and Rare Diseases, Interdisciplinary Department of Medicine, University of Bari “Aldo Moro”, 70124 Bari, Italy; (A.D.T.); (V.A.G.); (E.J.); (E.G.)
| | - Vincenzo De Geronimo
- Unit of Endocrinology, Clinical Diagnostic Center Morgagni, 95100 Catania, Italy;
| | - Vito Angelo Giagulli
- Section of Internal Medicine, Geriatrics, Endocrinology and Rare Diseases, Interdisciplinary Department of Medicine, University of Bari “Aldo Moro”, 70124 Bari, Italy; (A.D.T.); (V.A.G.); (E.J.); (E.G.)
| | - Fabio Monzani
- Geriatrics Unit, Department of Clinical & Experimental Medicine, University of Pisa, 56126 Pisa, Italy;
| | - Emilio Jirillo
- Section of Internal Medicine, Geriatrics, Endocrinology and Rare Diseases, Interdisciplinary Department of Medicine, University of Bari “Aldo Moro”, 70124 Bari, Italy; (A.D.T.); (V.A.G.); (E.J.); (E.G.)
| | - Renato Cozzi
- Division of Endocrinology, Niguarda Hospital, 20162 Milan, Italy;
| | - Edoardo Guastamacchia
- Section of Internal Medicine, Geriatrics, Endocrinology and Rare Diseases, Interdisciplinary Department of Medicine, University of Bari “Aldo Moro”, 70124 Bari, Italy; (A.D.T.); (V.A.G.); (E.J.); (E.G.)
| | - Giovanni De Pergola
- Center of Nutrition for the Research and the Care of Obesity and Metabolic Diseases, National Institute of Gastroenterology IRCCS “Saverio de Bellis”, 70013 Castellana Grotte, Italy;
| | - Vincenzo Triggiani
- Section of Internal Medicine, Geriatrics, Endocrinology and Rare Diseases, Interdisciplinary Department of Medicine, University of Bari “Aldo Moro”, 70124 Bari, Italy; (A.D.T.); (V.A.G.); (E.J.); (E.G.)
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Deng M, Wen Y, Yan J, Fan Y, Wang Z, Zhang R, Ren L, Ba Y, Wang H, Lu Q, Fan H. Comparative effectiveness of multiple different treatment regimens for nonalcoholic fatty liver disease with type 2 diabetes mellitus: a systematic review and Bayesian network meta-analysis of randomised controlled trials. BMC Med 2023; 21:447. [PMID: 37974258 PMCID: PMC10655371 DOI: 10.1186/s12916-023-03129-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Accepted: 10/25/2023] [Indexed: 11/19/2023] Open
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) are closely related and mutually contribute to the disease's development. There are many treatment options available to patients. We provide a comprehensive overview of the evidence on the treatment effects of several potential interventions for NAFLD with T2DM. METHODS This systematic review and network meta-analysis included searches of PubMed, Embase, Cochrane Library, and Web of Science from inception to June 30, 2023, for randomised controlled trials of treatment of NAFLD with T2DM. We performed Bayesian network meta-analyses to summarise effect estimates of comparisons between interventions. We applied the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) frameworks to rate all comparative outcomes' certainty in effect estimates, categorise interventions, and present the findings. This study was registered with PROSPERO, CRD42022342373. RESULTS Four thousand three hundred and sixty-nine records were retrieved from the database and other methods, of which 24 records were eligible for studies enrolling 1589 participants. Eight clinical indicators and 14 interventions were finally in focus. Referring to the lower surface under the cumulative ranking curves (SUCRA) and the league matrix table, exenatide and liraglutide, which are also glucagon-like peptide-1 receptor agonists (GLP-1RAs), showed excellent potential to reduce liver fat content, control glycemia, reduce body weight, and improve liver function and insulin resistance. Exenatide was more effective in reducing glycated haemoglobin (HbA1c) (mean difference (MD) 0.32, 95%CI 0.12 to 0.52), lowering BMI (MD 0.81, 95%CI 0.18 to 1.45), and lowering alanine transaminase (ALT) (MD 10.96, 95%CI 5.27 to 16.66) compared to liraglutide. However, this evidence was assessed as low certainty. Omega-3 was the only intervention that did not have a tendency to lower HbA1c, with standard-treatment (STA-TRE) as reference (MD - 0.17, 95%CI - 0.42 to 0.07). Glimepiride is the only intervention that causes an increase in ALT levels, with standard-treatment (STA-TRE) as reference (MD - 11.72, 95%CI - 17.82 to - 5.57). Based on the available evidence, the treatment effects of pioglitazone, dapagliflozin, and liraglutide have a high degree of confidence. CONCLUSIONS The high confidence mandates the confident application of these findings as guides for clinical practice. Dapagliflozin and pioglitazone are used for glycaemic control in patients with NAFLD combined with T2DM, and liraglutide is used for weight loss therapy in patients with abdominal obesity. The available evidence does not demonstrate the credibility of the effectiveness of other interventions in reducing liver fat content, visceral fat area, ALT, and insulin resistance. Future studies should focus on the clinical application of GLP-1Ras and the long-term prognosis of patients.
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Affiliation(s)
- Manjun Deng
- Department of Hepatopancreatobiliary Surgery, Affiliated Hospital of Qinghai University, Xining, 810001, Qinghai, China
- Qinghai Research Key Laboratory for Echinococcosis, Xining, 810000, Qinghai, China
| | - Yonghao Wen
- Department of Hepatopancreatobiliary Surgery, Affiliated Hospital of Qinghai University, Xining, 810001, Qinghai, China
| | - JingXin Yan
- Department of Hepatopancreatobiliary Surgery, Affiliated Hospital of Qinghai University, Xining, 810001, Qinghai, China
- Department of Interventional Therapy, Affiliated Hospital of Qinghai University, Xining, 810001, Qinghai, China
| | - Yichen Fan
- Department of Hepatopancreatobiliary Surgery, Affiliated Hospital of Qinghai University, Xining, 810001, Qinghai, China
| | - Zhixin Wang
- Department of Hepatopancreatobiliary Surgery, Affiliated Hospital of Qinghai University, Xining, 810001, Qinghai, China
- Qinghai Research Key Laboratory for Echinococcosis, Xining, 810000, Qinghai, China
| | - Ruixia Zhang
- Department of Endocrinology, Affiliated Hospital of Qinghai University, Xining, 810001, Qinghai, China
| | - Li Ren
- Department of Hepatopancreatobiliary Surgery, Affiliated Hospital of Qinghai University, Xining, 810001, Qinghai, China
- Qinghai Research Key Laboratory for Echinococcosis, Xining, 810000, Qinghai, China
| | - Yinggui Ba
- Department of Nephrology, Affiliated Hospital of Qinghai University, Xining, 810001, Qinghai, China
| | - Haijiu Wang
- Department of Hepatopancreatobiliary Surgery, Affiliated Hospital of Qinghai University, Xining, 810001, Qinghai, China
- Qinghai Research Key Laboratory for Echinococcosis, Xining, 810000, Qinghai, China
| | - Qian Lu
- Department of Hepatopancreatobiliary Surgery, Tsinghua Changgung Hospital, Tsinghua University, Beijing, 102218, China.
| | - Haining Fan
- Department of Hepatopancreatobiliary Surgery, Affiliated Hospital of Qinghai University, Xining, 810001, Qinghai, China.
- Qinghai Research Key Laboratory for Echinococcosis, Xining, 810000, Qinghai, China.
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20
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Yilmaz A, Hanlioğlu S, Demiral G, Karatepe O. The efficacy of liraglutide combined with intragastric balloon on weight loss. REVISTA DA ASSOCIACAO MEDICA BRASILEIRA (1992) 2023; 69:e20230571. [PMID: 37971120 PMCID: PMC10645169 DOI: 10.1590/1806-9282.20230571] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/19/2023] [Accepted: 08/22/2023] [Indexed: 11/19/2023]
Abstract
OBJECTIVE Intragastric balloon placement is an effective method for weight reduction. The aim of this study was to evaluate the efficacy of combining liraglutide with intragastric balloon. METHODS Initially, demographic data of patients such as age, gender, comorbid diseases, adverse events, initial weight, height, body mass index, percent body fat, and waist-hip ratio were collected. Weight, body mass index, percent body fat, and waist-hip ratio were measured in the second, third, fourth, fifth, and sixth months. Then, intragastric balloon was removed and liraglutide was stopped. RESULTS A total of 50 patients were included in the study, of whom 28 (56%) were in Group A (intragastric balloon) and 22 (44%) were in Group B (plus liraglutide). Weight change at the time of balloon removal was higher in Group B [median weight change 13.8 (7.8 min to 16.8 max) versus 7.9 (4.8 min to 11.8 max); p<0.01]. When the weight, percent body fat, body mass index, and waist-hip ratio changes were compared according to gender, no significant difference was observed in the groups. Comorbid diseases were hypertension in 7 patients (4 in Group A and 3 in Group B) and diabetes in 9 patients (5 in Group A and 4 in Group B). No statistical significance was found. CONCLUSION Liraglutide has benefits in terms of weight, percent body fat, and body mass index reduction when administered with intragastric balloon.
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Affiliation(s)
- Ahmet Yilmaz
- Medipol University, Faculty of Medicine, Department of General Surgery – İstanbul, Turkey
| | | | - Gökhan Demiral
- Recep Tayyip Erdoğan University, Faculty of Medicine, Department of General Surgery – Rize, Turkey
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21
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Arriola-Montenegro J, Beas R, Cerna-Viacava R, Chaponan-Lavalle A, Hernandez Randich K, Chambergo-Michilot D, Flores Sanga H, Mutirangura P. Therapies for patients with coexisting heart failure with reduced ejection fraction and non-alcoholic fatty liver disease. World J Cardiol 2023; 15:328-341. [PMID: 37576545 PMCID: PMC10415861 DOI: 10.4330/wjc.v15.i7.328] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 06/09/2023] [Accepted: 06/21/2023] [Indexed: 07/25/2023] Open
Abstract
Heart failure with reduced ejection fraction (HFrEF) and nonalcoholic fatty liver disease (NAFLD) are two common comorbidities that share similar pathophysiological mechanisms. There is a growing interest in the potential of targeted therapies to improve outcomes in patients with coexisting HFrEF and NAFLD. This manuscript reviews current and potential therapies for patients with coexisting HFrEF and NAFLD. Pharmacological therapies, including angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, mineralocorticoids receptor antagonist, and sodium-glucose cotransporter-2 inhibitors, have been shown to reduce fibrosis and fat deposits in the liver. However, there are currently no data showing the beneficial effects of sacubitril/valsartan, ivabradine, hydralazine, isosorbide nitrates, digoxin, or beta blockers on NAFLD in patients with HFrEF. This study highlights the importance of considering HFrEF and NAFLD when developing treatment plans for patients with these comorbidities. Further research is needed in patients with coexisting HFrEF and NAFLD, with an emphasis on novel therapies and the importance of a multidisciplinary approach for managing these complex comorbidities.
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Affiliation(s)
- Jose Arriola-Montenegro
- Department of Internal Medicine, University of Minnesota, Minneapolis, MN 55455, United States.
| | - Renato Beas
- Department of Medicine, Indiana University School of Medicine, Indiana, IN 46202, United States
| | | | | | | | | | - Herson Flores Sanga
- Department of Telemedicine, Cardiology, Hospital Nacional Carlos Alberto Seguin Escobedo, Arequipa 8610, Peru
| | - Pornthira Mutirangura
- Department of Medicine, University of Minnesota, Minneapolis, MN 55415, United States
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22
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Haddad F, Dokmak G, Bader M, Karaman R. A Comprehensive Review on Weight Loss Associated with Anti-Diabetic Medications. Life (Basel) 2023; 13:1012. [PMID: 37109541 PMCID: PMC10144237 DOI: 10.3390/life13041012] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Revised: 04/11/2023] [Accepted: 04/12/2023] [Indexed: 04/29/2023] Open
Abstract
Obesity is a complex metabolic condition that can have a negative impact on one's health and even result in mortality. The management of obesity has been addressed in a number of ways, including lifestyle changes, medication using appetite suppressants and thermogenics, and bariatric surgery for individuals who are severely obese. Liraglutide and semaglutide are two of the five Food and Drug Administration (FDA)-approved anti-obesity drugs that are FDA-approved agents for the treatment of type 2 diabetes mellitus (T2DM) patients. In order to highlight the positive effects of these drugs as anti-obesity treatments, we analyzed the weight loss effects of T2DM agents that have demonstrated weight loss effects in this study by evaluating clinical studies that were published for each agent. Many clinical studies have revealed that some antihyperglycemic medications can help people lose weight, while others either cause weight gain or neutral results. Acarbose has mild weight loss effects and metformin and sodium-dependent glucose cotransporter proteins-2 (SGLT-2) inhibitors have modest weight loss effects; however, some glucagon-like peptide-1 (GLP-1) receptor agonists had the greatest impact on weight loss. Dipeptidyl peptidase 4 (DPP-4) inhibitors showed a neutral or mild weight loss effect. To sum up, some of the GLP-1 agonist drugs show promise as weight-loss treatments.
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Affiliation(s)
- Fatma Haddad
- Pharmaceutical Sciences Department, Faculty of Pharmacy, Al-Quds University, Jerusalem 9103401, Palestine; (F.H.); (G.D.); (M.B.)
- Faculty of Life Sciences, University of Bradford, Bradford BD7 1DP, UK
| | - Ghadeer Dokmak
- Pharmaceutical Sciences Department, Faculty of Pharmacy, Al-Quds University, Jerusalem 9103401, Palestine; (F.H.); (G.D.); (M.B.)
| | - Maryam Bader
- Pharmaceutical Sciences Department, Faculty of Pharmacy, Al-Quds University, Jerusalem 9103401, Palestine; (F.H.); (G.D.); (M.B.)
| | - Rafik Karaman
- Pharmaceutical Sciences Department, Faculty of Pharmacy, Al-Quds University, Jerusalem 9103401, Palestine; (F.H.); (G.D.); (M.B.)
- Department of Sciences, University of Basilicata, 85100 Potenza, Italy
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Zhou T, Cao L, Du Y, Qin L, Lu Y, Zhang Q, He Y, Tan D. Gypenosides ameliorate high-fat diet-induced nonalcoholic fatty liver disease in mice by regulating lipid metabolism. PeerJ 2023; 11:e15225. [PMID: 37065701 PMCID: PMC10103699 DOI: 10.7717/peerj.15225] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Accepted: 03/23/2023] [Indexed: 04/18/2023] Open
Abstract
Gypenosides (GP), extracted from the traditional Chinese herb Gynostemma pentaphyllum (Thunb.) Makino, have been used to treat metabolic disorders, including lipid metabolism disorders and diabetes. Although recent studies have confirmed their beneficial effects in nonalcoholic fatty liver disease (NAFLD), the underlying therapeutic mechanism remains unclear. In this study, we explored the protective mechanism of GP against NAFLD in mice and provided new insights into the prevention and treatment of NAFLD. Male C57BL6/J mice were divided into three experimental groups: normal diet, high-fat diet (HFD), and GP groups. The mice were fed an HFD for 16 weeks to establish an NAFLD model and then treated with GP for 22 weeks. The transcriptome and proteome of the mice livers were profiled using RNA sequencing and high-resolution mass spectrometry, respectively. The results showed that GP decreased serum lipid levels, liver index, and liver fat accumulation in mice. Principal component and heatmap analyses indicated that GP significantly modulated the changes in the expression of genes associated with HFD-induced NAFLD. The 164 differentially expressed genes recovered using GP were enriched in fatty acid and steroid metabolism pathways. Further results showed that GP reduced fatty acid synthesis by downregulating the expression of Srebf1, Fasn, Acss2, Acly, Acaca, Fads1, and Elovl6; modulated glycerolipid metabolism by inducing the expression of Mgll; promoted fatty acid transportation and degradation by inducing the expression of Slc27a1, Cpt1a, and Ehhadh; and reduced hepatic cholesterol synthesis by downregulating the expression of Tm7sf2, Ebp, Sc5d, Lss, Fdft1, Cyp51, Nsdhl, Pmvk, Mvd, Fdps, and Dhcr7. The proteomic data further indicated that GP decreased the protein expression levels of ACACA, ACLY, ACSS2, TM7SF2, EBP, FDFT1, NSDHL, PMVK, MVD, FDPS, and DHCR7 and increased those of MGLL, SLC27A1, and EHHADH. In conclusion, GP can regulate the key genes involved in hepatic lipid metabolism in NAFLD mice, providing initial evidence for the mechanisms underlying the therapeutic effect of GP in NAFLD.
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Affiliation(s)
- Tingting Zhou
- Guizhou Engineering Research Center of Industrial Key-technology for Dendrobium Nobile, Zunyi Medical University, Zunyi Medical University, Zunyi, Guizhou, China
| | - Ligang Cao
- Guizhou Engineering Research Center of Industrial Key-technology for Dendrobium Nobile, Zunyi Medical University, Zunyi Medical University, Zunyi, Guizhou, China
| | - Yimei Du
- Guizhou Engineering Research Center of Industrial Key-technology for Dendrobium Nobile, Zunyi Medical University, Zunyi Medical University, Zunyi, Guizhou, China
| | - Lin Qin
- Guizhou Engineering Research Center of Industrial Key-technology for Dendrobium Nobile, Zunyi Medical University, Zunyi Medical University, Zunyi, Guizhou, China
- Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi Medical University, Zunyi, Guizhou, China
| | - Yanliu Lu
- Guizhou Engineering Research Center of Industrial Key-technology for Dendrobium Nobile, Zunyi Medical University, Zunyi Medical University, Zunyi, Guizhou, China
- Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi Medical University, Zunyi, Guizhou, China
| | - Qianru Zhang
- Guizhou Engineering Research Center of Industrial Key-technology for Dendrobium Nobile, Zunyi Medical University, Zunyi Medical University, Zunyi, Guizhou, China
- Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi Medical University, Zunyi, Guizhou, China
| | - Yuqi He
- Guizhou Engineering Research Center of Industrial Key-technology for Dendrobium Nobile, Zunyi Medical University, Zunyi Medical University, Zunyi, Guizhou, China
- Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi Medical University, Zunyi, Guizhou, China
| | - Daopeng Tan
- Guizhou Engineering Research Center of Industrial Key-technology for Dendrobium Nobile, Zunyi Medical University, Zunyi Medical University, Zunyi, Guizhou, China
- Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi Medical University, Zunyi, Guizhou, China
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Dong Z, Yang J, Tian M, Wang X, Qin X, Huang Q, Wang J. Mechanism of Bile‐Processed Coptidis Rhizoma to Treat Nonalcoholic Fatty Liver Disease in Type 2 Diabetes Mellitus Based on UPLC‐Q‐TOF/MS and Network Pharmacology. ChemistrySelect 2023. [DOI: 10.1002/slct.202204236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/05/2023]
Affiliation(s)
- Zhaowei Dong
- State Key Laboratory of Southwestern Chinese Medicine Resources Chengdu University of Traditional Chinese Medicine Chengdu China
- College of Pharmacy Chengdu University of Traditional Chinese Medicine Chengdu China
| | - Jingjing Yang
- State Key Laboratory of Southwestern Chinese Medicine Resources Chengdu University of Traditional Chinese Medicine Chengdu China
- College of Pharmacy Chengdu University of Traditional Chinese Medicine Chengdu China
| | - Maoying Tian
- State Key Laboratory of Southwestern Chinese Medicine Resources Chengdu University of Traditional Chinese Medicine Chengdu China
- College of Pharmacy Chengdu University of Traditional Chinese Medicine Chengdu China
| | - Xi Wang
- State Key Laboratory of Southwestern Chinese Medicine Resources Chengdu University of Traditional Chinese Medicine Chengdu China
- College of Pharmacy Chengdu University of Traditional Chinese Medicine Chengdu China
| | - Xiaoyan Qin
- State Key Laboratory of Southwestern Chinese Medicine Resources Chengdu University of Traditional Chinese Medicine Chengdu China
- College of Pharmacy Chengdu University of Traditional Chinese Medicine Chengdu China
| | - Qinwan Huang
- State Key Laboratory of Southwestern Chinese Medicine Resources Chengdu University of Traditional Chinese Medicine Chengdu China
- College of Pharmacy Chengdu University of Traditional Chinese Medicine Chengdu China
| | - Jin Wang
- State Key Laboratory of Southwestern Chinese Medicine Resources Chengdu University of Traditional Chinese Medicine Chengdu China
- College of Ethnic Medicine Chengdu University of Traditional Chinese Medicine Chengdu China
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Salmen T, Bobirca FT, Bica IC, Mihai DA, Pop C, Stoian AP. The Safety Profile of Sodium-Glucose Cotransporter-2 Inhibitors and Glucagon-like Peptide 1 Receptor Agonists in the Standard of Care Treatment of Type 2 Diabetes Mellitus. Life (Basel) 2023; 13:life13030839. [PMID: 36983994 PMCID: PMC10051290 DOI: 10.3390/life13030839] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2023] [Revised: 03/07/2023] [Accepted: 03/10/2023] [Indexed: 03/30/2023] Open
Abstract
AIM We evaluated the safety of sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP-1 RAs) for their use with other glucose-lowering drugs and drugs for the treatment of type 2 diabetes mellitus (T2DM), in a standard-of-care regimen with maximum tolerated doses, and, respectively, when compared with metformin. METHODS We conducted a retrospective, observational study on 405 patients that were seen in the outpatient clinic of the N Paulescu National Institute for Diabetes Mellitus, Bucharest, Romania, in 2019. Their demographics, metabolic parameters, and medication safety were evaluated at three follow-up visits, from baseline, six months, and twelve months. RESULTS Both SGLT-2is and GLP-1 RAs are safe regarding creatinine, eGFR, urea, GOT, and GPT upon the comparison of the data from the six- and twelve-month visits with the initial visit, and also the twelve-month visit with the six-month visit. Moreover, when comparing SGLT-2is and GLP-1 RAs with metformin, there are safety data only for urea. CONCLUSIONS In this retrospective analysis, both SGLT-2is and GLP-1 RAs, when used in conjunction with other glucose-lowering, blood-pressure-lowering, and lipid-lowering medications, appeared to be safe for the management of T2DM.
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Affiliation(s)
- Teodor Salmen
- Doctoral School of Carol Davila, University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Florin-Teodor Bobirca
- Department of General Surgery, Carol Davila, University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Ioana-Cristina Bica
- Doctoral School of Carol Davila, University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Doina-Andrada Mihai
- Department of Diabetes, Nutrition and Metabolic Diseases, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Corina Pop
- Department of Gastroenterology and Internal Medicine, Carol Davila, University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Anca Pantea Stoian
- Department of Diabetes, Nutrition and Metabolic Diseases, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania
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Integrative analyses of biomarkers and pathways for metformin reversing cisplatin resistance in head and neck squamous cell carcinoma cells. Arch Oral Biol 2023; 147:105637. [PMID: 36738487 DOI: 10.1016/j.archoralbio.2023.105637] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 01/23/2023] [Accepted: 01/29/2023] [Indexed: 02/04/2023]
Abstract
OBJECTIVES In this study, transcriptome sequencing were performed to elucidate the molecular mechanism by which metformin inhibits head and neck squamous cell carcinoma (HNSCC) cells progression and sensitizes HNSCC cells to chemotherapy. We aimed to propose a novel chemotherapeutic approach with high efficacy and few side effects and provide a new strategy for HNSCC treatment. DESIGN The effects of metformin on the biological behaviors of HNSCC cells were validated by CCK8 cell proliferation assays, would healing assays and flow cytometric apoptosis assays. The appropriate metformin concentrations for the experimental pretreatment of HNSCC cells were selected based on experimental results, and the treated cells were subjected to transcriptome sequencing. After bioinformatics analysis and intersection with a post-chemotherapy resistance dataset from the GEO database numbered GSE102787, the genes were identified and used to predict potential metformin targets after functional enrichment analysis. RESULTS Metformin significantly inhibited the proliferation and migration and induced the apoptosis of Cal27 and FaDu cells. A total of 284 genes that are potentially targeted by metformin during HNSCC cell sensitization were identified by bioinformatics, and ten hub genes with high connectivity were selected. In particular, Fen1 overexpression was associated with poor prognosis in HNSCC patients. CONCLUSIONS Our study demonstrates that Fen1 is overexpressed in HNSCC tissues compared with normal tissues and that Fen1 overexpression is a poor prognostic factor in HNSCC patients. Metformin enhances the ability of cisplatin to inhibit HNSCC progression. Further studies are needed to explore the therapeutic value of Fen1 in HNSCC.
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27
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Zhao Y, Zhao W, Bu H, Toshiyoshi M, Zhao Y. Liraglutide on type 2 diabetes mellitus with nonalcoholic fatty liver disease: A systematic review and meta-analysis of 16 RCTs. Medicine (Baltimore) 2023; 102:e32892. [PMID: 36820578 PMCID: PMC9907937 DOI: 10.1097/md.0000000000032892] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/12/2023] Open
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is a common comorbidity of type 2 diabetes mellitus (T2DM). Our aim is to investigate the effects of liraglutide on T2DM with NAFLD. METHODS Relevant articles published from the earliest publication to March 2022 were selected from several databases. The Cochrane Collaboration's RevMan software was used for the analysis. RESULTS Sixteen studies are selected for this meta-analysis, which includes totally 634 patients in the treatment group and 630 patients in the control group. As a result, 14 studies show that fasting plasma glucose levels of the experimental group are lower than that of the control group; 15 studies show that glycosylated hemoglobin A1c levels of the experimental group are lower than that of the control group; 13 studies show that triglyceride levels of the experimental group are lower than that of the control group; twelve studies show that total cholesterol levels of the experimental group are lower than that of the control group; 10 studies show that alanine aminotransferase levels of the experimental group is lower than that of the control group; 10 studies show that no significant difference in changes in aspartate transaminase between 2 groups; 13 studies show that low density lipoprotein cholesterol levels of the experimental group is lower than that of the control group; 9 studies show that no significant difference in changes in high density lipoprotein cholesterol between 2 groups; 7 studies mentioned adverse effects and the difference is significant. CONCLUSION Liraglutide is potentially curative for T2DM with NAFLD.
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Affiliation(s)
- Yan Zhao
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Wenli Zhao
- Department of Public Health, International College, Krirk University, Bangkok, Thailand
- Liver Center, Saga University Hospital, Saga University, Saga, Japan
| | - Huaien Bu
- School of Health Science and Engineering, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Maeda Toshiyoshi
- International Education College, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Ye Zhao
- Department of Public Health, International College, Krirk University, Bangkok, Thailand
- * Correspondence: Ye Zhao, Department of Public Health, International College, Krirk University, Bangkok 10220, Thailand (e-mail: )
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Suplotova LA, Fedorova AI, Kulmametova DS, Dushina TS, Makarova OB. Prospects for the use of drugs from the group of agonists of glucagon-like peptide-1 receptors in the treatment of non-alcoholic fatty liver disease. MEDITSINSKIY SOVET = MEDICAL COUNCIL 2023:148-155. [DOI: 10.21518/2079-701x-2022-16-23-148-155] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases. To a large extent, the development of this disease is associated with metabolic syndrome. There is a pathogenetic association of NAFLD with obesity, type 2 diabetes mellitus (DM2), cardiovascular diseases and chronic kidney disease. Numerous studies demonstrate that an increase in the incidence of NAFLD occurs in parallel with an increase in the prevalence of obesity and DM 2. A number of scientific studies in the field of medicine have made it possible to identify the main pathogenetic mechanisms of the development of the disease, as well as the possibility of using various pharmacological drugs to correct these conditions. Currently, the possibility of using in the future a group of drugs that have a single mechanism for controlling the development of hepatic steatosis, and further progression with the formation of inflammation, cirrhosis and, in some cases, hepatocellular carcinoma, is being considered. Of particular interest is a class of drugs intended for the treatment of type 2 diabetes and obesity – glucagon-like peptide-1 receptor agonists (arGLP-1). A search was made of clinical studies, meta-analyses, literature reviews in databases and registries of medical publications over a period of 10 years. Changes in anthropometric indications, changes in non-invasive markers of liver steatosis, inflammation and fibrosis, as well as histological data on the background of the use of drugs of the arGLP-1 class were studied. It has been demonstrated that the study drug class may have a significant potential for impact on NAFLD. However, further studies with sufficient duration and histological evaluation are needed to fully evaluate the effectiveness of arGLP-1 in the treatment of NAFLD.
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GLP-1 Receptor Agonists in Non-Alcoholic Fatty Liver Disease: Current Evidence and Future Perspectives. Int J Mol Sci 2023; 24:ijms24021703. [PMID: 36675217 PMCID: PMC9865319 DOI: 10.3390/ijms24021703] [Citation(s) in RCA: 97] [Impact Index Per Article: 48.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 01/10/2023] [Accepted: 01/12/2023] [Indexed: 01/18/2023] Open
Abstract
To date, non-alcoholic fatty liver disease (NAFLD) is the most frequent liver disease, affecting up to 70% of patients with diabetes. Currently, there are no specific drugs available for its treatment. Beyond their anti-hyperglycemic effect and the surprising role of cardio- and nephroprotection, GLP-1 receptor agonists (GLP-1 RAs) have shown a significant impact on body weight and clinical, biochemical and histological markers of fatty liver and fibrosis in patients with NAFLD. Therefore, GLP-1 RAs could be a weapon for the treatment of both diabetes mellitus and NAFLD. The aim of this review is to summarize the evidence currently available on the role of GLP-1 RAs in the treatment of NAFLD and to hypothesize potential future scenarios.
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Santini S, Vionnet N, Pasquier J, Gonzalez-Rodriguez E, Fraga M, Pitteloud N, Favre L. Marked weight loss on liraglutide 3.0 mg: Real-life experience of a Swiss cohort with obesity. Obesity (Silver Spring) 2023; 31:74-82. [PMID: 36478514 PMCID: PMC10107497 DOI: 10.1002/oby.23596] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2022] [Revised: 08/25/2022] [Accepted: 08/26/2022] [Indexed: 12/12/2022]
Abstract
OBJECTIVE This study investigated the effectiveness of liraglutide 3.0 mg daily in combination with a standardized multidisciplinary intervention on body weight and body composition changes in a real-life setting. METHODS A prospective, observational cohort study design was used. Adult patients with BMI > 35 kg/m2 , or BMI > 28 kg/m2 with greater than or equal to one metabolic comorbidity, were included (n = 54, 65% women). Liraglutide treatment was covered by Swiss health insurance. Clinical and biological data were collected at baseline, 4 months, and 10 months. Body composition was assessed by dual-energy x-ray absorptiometry at baseline and 10 months. RESULTS At 10 months, mean (SD) percentage weight loss (WL%) was -12.4% (5.5%) or -14.1 (6.6) kg. WL% was ≥5% in 87% of patients at 4 months and in 96% at 10 months. WL% was higher in women (-9.5% [3.1%] vs. men -7.2% [2.5%], p = 0.02) at 4 months and persisted at 10 months (-13.7% [5.2%] vs. -9.6% [5.1%], p = 0.006). WL% was associated with baseline percentage fat mass but not with age or BMI. Body composition showed a decrease in fat mass, visceral adipose tissue, and absolute lean mass. CONCLUSIONS In a real-world setting, liraglutide 3.0 mg led to beneficial changes in WL and body composition, with a greater impact in women.
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Affiliation(s)
- Sara Santini
- Division of Endocrinology, Diabetology, and Metabolism, Lausanne University Hospital, Lausanne, Switzerland
| | - Nathalie Vionnet
- Division of Endocrinology, Diabetology, and Metabolism, Lausanne University Hospital, Lausanne, Switzerland
| | - Jérôme Pasquier
- Center for Primary Care and Public Health (Unisanté), University of Lausanne, Lausanne, Switzerland
| | - Elena Gonzalez-Rodriguez
- Interdisciplinary Center for Bone Diseases, Lausanne University Hospital, Lausanne, Switzerland
- Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland
| | - Montserrat Fraga
- Division of Gastroenterology and Hepatology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
| | - Nelly Pitteloud
- Division of Endocrinology, Diabetology, and Metabolism, Lausanne University Hospital, Lausanne, Switzerland
- Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland
| | - Lucie Favre
- Division of Endocrinology, Diabetology, and Metabolism, Lausanne University Hospital, Lausanne, Switzerland
- Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland
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Anggreini P, Kuncoro H, Sumiwi SA, Levita J. Role of the AMPK/SIRT1 pathway in non‑alcoholic fatty liver disease (Review). Mol Med Rep 2022; 27:35. [PMID: 36562343 PMCID: PMC9827347 DOI: 10.3892/mmr.2022.12922] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Accepted: 10/26/2022] [Indexed: 12/24/2022] Open
Abstract
Non‑alcoholic fatty liver disease (NAFLD) is an increasingly prevalent ailment worldwide. Moreover, de novo lipogenesis (DNL) is considered a critical factor in the development of NAFLD; hence, its inhibition is a promising target for the prevention of fatty liver disease. There is evidence to indicate that AMP‑activated protein kinase (AMPK) and sirtuin 1 (SIRT1) may play a crucial role in DNL and are the regulatory proteins in type 2 diabetes mellitus, obesity and cardiovascular disease. Therefore, AMPK and SIRT1 may be promising targets for the treatment of NAFLD. The present review article thus aimed to summarize the findings of clinical studies published during the past decade that suggested the beneficial effects of AMPK and SIRT1, using their specific activators and their combined effects on fatty liver disease.
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Affiliation(s)
- Putri Anggreini
- Doctoral Program in Pharmacy, Faculty of Pharmacy, Padjadjaran University, Sumedang, West Java 46363, Indonesia,Laboratory of Pharmaceutical Research and Development, Faculty of Pharmacy, Mulawarman University, Samarinda, East Borneo 75119, Indonesia
| | - Hadi Kuncoro
- Laboratory of Pharmaceutical Research and Development, Faculty of Pharmacy, Mulawarman University, Samarinda, East Borneo 75119, Indonesia,Correspondence to: Dr Hadi Kuncoro, Laboratory of Pharmaceutical Research and Development, Faculty of Pharmacy, Mulawarman University, Muara Muntai Street, Gunung Kelua, Samarinda, East Borneo 75119, Indonesia, E-mail:
| | - Sri Adi Sumiwi
- Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Padjadjaran University, Sumedang, West Java 46363, Indonesia
| | - Jutti Levita
- Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Padjadjaran University, Sumedang, West Java 46363, Indonesia
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Che W, Zhao M, Li X, Li C, Cho WC, Yu S. Current insights in molecular characterization of non-alcoholic fatty liver disease and treatment. Front Endocrinol (Lausanne) 2022; 13:1002916. [PMID: 36523601 PMCID: PMC9744925 DOI: 10.3389/fendo.2022.1002916] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Accepted: 10/14/2022] [Indexed: 11/30/2022] Open
Abstract
There is a continuously rising incidence of non-alcoholic fatty liver disease (NAFLD) around the world, which parallels the increasing incidence of metabolic diseases. NAFLD is a range of liver conditions that contains simple non-alcoholic fatty liver and advanced non-alcoholic steatohepatitis. In serious cases, NAFLD may develop into cirrhosis or even liver cancer. NAFLD has an intense relationship with metabolic syndrome, type 2 diabetes mellitus. It is known that gut microbiota, and functional molecules such as adenosine monophosphate-activated protein kinase JNK, and peroxisome proliferator-activated receptors (PPARs) in progressing and treating NAFLD. Traditionally, the conventional and effective therapeutic strategy is lifestyle intervention. Nowadays, new medicines targeting specific molecules, such as farnesoid X receptor, PPARs, and GLP-1 receptor, have been discovered and shown beneficial effects on patients with NAFLD. In this article, we focus on the molecular mechanisms and therapeutic approaches to NAFLD.
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Affiliation(s)
- Wensheng Che
- Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Ming Zhao
- Chengdu Medical College, Chengdu, China
- Department of Gastroenterology, The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
| | - Xiaoqing Li
- Department of Pathology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Chunlong Li
- Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - William C. Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital, Kowloon, Hong Kong SAR, China
| | - Shan Yu
- Department of Pathology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
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Zhang GH, Yuan TH, Yue ZS, Wang L, Dou GR. The presence of diabetic retinopathy closely associated with the progression of non-alcoholic fatty liver disease: A meta-analysis of observational studies. Front Mol Biosci 2022; 9:1019899. [PMID: 36458094 PMCID: PMC9706004 DOI: 10.3389/fmolb.2022.1019899] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Accepted: 11/01/2022] [Indexed: 07/30/2023] Open
Abstract
Background and Objective: Although growing evidence indicates that non-alcoholic fatty liver disease is related to diabetic retinopathy (DR), research results significantly vary. Therefore, we conducted a meta-analysis to assess the association between the progression of non-alcoholic fatty liver disease and the onset of DR. Methods: PubMed, Embase, and Cochrane databases were searched until 7 November 2021. Combined odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the association. Results: We identified 18 studies involving 12,757 patients. The pooled effect assessment showed that liver fibrosis was positively correlated with DR (OR = 1.69, 95%CI 1.30-2.20; p < 0.0001); non-alcoholic fatty liver disease was not associated with the risk of DR (OR = 1.15, 95%CI 0.75-1.76; p = 0.51); non-alcoholic fatty liver disease was positively correlated with DR in patients with type 1 diabetes (OR = 2.96, 95%CI 1.48-5.94; p = 0.002). In patients with type 2 diabetes, there was no association between non-alcoholic fatty liver disease and DR (OR = 0.92, 95%CI 0.59-1.43; p = 0.70). Subgroup analysis showed no correlation in both Asian and Caucasian races. Conclusion: There is a significant correlation between liver fibrosis and DR. This suggests that the ocular examination of DR could be helpful in predicting whether patients with non-alcoholic fatty liver disease would progress to liver fibrosis.
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Affiliation(s)
- Guo-heng Zhang
- Department of Ophthalmology, Eye Institute of Chinese PLA, Xijing Hospital, Fourth Military Medical University, Xi’an, China
- Department of Ophthalmology, 942 Hospital of the Joint Logistics Support Force of the Chinese People’s Liberation Army, Yin’chuan, China
| | - Tian-hao Yuan
- Department of Ophthalmology, Eye Institute of Chinese PLA, Xijing Hospital, Fourth Military Medical University, Xi’an, China
- Department of The Cadet Team 6 of School of Basic Medicine, Fourth Military Medical University, Xi’an, China
| | - Zhen-sheng Yue
- Department of Ophthalmology, Eye Institute of Chinese PLA, Xijing Hospital, Fourth Military Medical University, Xi’an, China
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, China
| | - Lin Wang
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, China
| | - Guo-Rui Dou
- Department of Ophthalmology, Eye Institute of Chinese PLA, Xijing Hospital, Fourth Military Medical University, Xi’an, China
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Huang Y, Wang X, Yan C, Li C, Zhang L, Zhang L, Liang E, Liu T, Mao J. Effect of metformin on nonalcoholic fatty liver based on meta-analysis and network pharmacology. Medicine (Baltimore) 2022; 101:e31437. [PMID: 36316840 PMCID: PMC9622616 DOI: 10.1097/md.0000000000031437] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Whether metformin is related to nonalcoholic fatty liver disease (NAFLD) is controversial. Our aim was to investigate the relationship between metformin and NAFLD that may predict the metformin potential of these lesions and new prevention strategies in NAFLD patients. METHODS The meta-analysis was analyzed by Revman 5.3 softwares systematically searched for works published through July 29, 2022. Network pharmacology research based on databases, Cytoscape 3.7.1 software and R software respectively. RESULTS The following variables were associated with metformin in NAFLD patients: decreased of alanine aminotransferase (ALT) level (mean difference [MD] = -10.84, 95% confidence interval [CI] = -21.85 to 0.16, P = .05); decreased of aspartate amino transferase (AST) level (MD = -4.82, 95% CI = -9.33 to -0.30, P = .04); decreased of triglyceride (TG) level (MD = -0.17, 95% CI = -0.26 to -0.08, P = .0002); decreased of total cholesterol (TC) level (MD = -0.29, 95% CI = -0.47 to -0.10, P = .003); decreased of insulin resistance (IR) level (MD = -0.42, 95% CI = -0.82 to -0.02, P = .04). In addition, body mass index (BMI) (MD = -0.65, 95% CI = -1.46 to 0.16, P = .12) had no association with metformin in NAFLD patients. 181 metformin targets and 868 NAFLD disease targets were interaction analyzed, 15 core targets of metformin for the treatment of NAFLD were obtained. The effect of metformin on NAFLD mainly related to cytoplasm and protein binding, NAFLD, hepatitis B, pathway in cancer, toll like receptor signaling pathway and type 2 diabetes mellitus (T2DM). The proteins of hypoxia inducible factor-1 (HIF1A), nuclear factor erythroid 2-related factor (NFE2L2), nitric oxide synthase 3 (NOS3), nuclear receptor subfamily 3 group C member 1 (NR3C1), PI3K catalytic subunit alpha (PIK3CA), and silencing information regulator 2 related enzyme 1 (SIRT1) may the core targets of metformin for the treatment of NAFLD. CONCLUSION Metformin might be a candidate drug for the treatment of NAFLD which exhibits therapeutic effect on NAFLD patients associated with ALT, AST, TG, TC and IR while was not correlated with BMI. HIF1A, NFE2L2, NOS3, NR3C1, PIK3CA, and SIRT1 might be core targets of metformin for the treatment of NAFLD.
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Affiliation(s)
- Yuanshe Huang
- AnShun University, Guizhou Anshun, China
- College of Pharmaceutical Sciences, Southwest University, Chongqing, China
| | - Xiaodong Wang
- Chongqing Medical and Pharmaceutical College, Chongqing, China
| | - Chen Yan
- An Shun City People’s Hospital, Anshun, China
| | - Chen Li
- Department of Biology, Chemistry, Pharmacy, Free University of Berlin, Berlin, Germany
| | - Lidan Zhang
- College of Pharmaceutical Sciences, Southwest University, Chongqing, China
| | - Lai Zhang
- AnShun University, Guizhou Anshun, China
| | - E Liang
- AnShun University, Guizhou Anshun, China
| | | | - Jingxin Mao
- College of Pharmaceutical Sciences, Southwest University, Chongqing, China
- Chongqing Medical and Pharmaceutical College, Chongqing, China
- *Correspondence: Jingxin Mao, Chongqing Medical and Pharmaceutical College, Chongqing 400030, China (e-mail: )
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Khalifa O, H. Mroue K, Mall R, Ullah E, S. Al-Akl N, Arredouani A. Investigation of the Effect of Exendin-4 on Oleic Acid-Induced Steatosis in HepG2 Cells Using Fourier Transform Infrared Spectroscopy. Biomedicines 2022; 10:biomedicines10102652. [PMID: 36289914 PMCID: PMC9599706 DOI: 10.3390/biomedicines10102652] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 07/10/2022] [Accepted: 07/13/2022] [Indexed: 12/04/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a common liver lesion that is untreatable with medications. Glucagon-like peptide-1 receptor (GLP-1R) agonists have recently emerged as a potential NAFLD pharmacotherapy. However, the molecular mechanisms underlying these drugs’ beneficial effects are not fully understood. Using Fourier transform infrared (FTIR) spectroscopy, we sought to investigate the biochemical changes in a steatosis cell model treated or not with the GLP-1R agonist Exendin-4 (Ex-4). HepG2 cells were made steatotic with 400 µM of oleic acid and then treated with 200 nM Ex-4 in order to reduce lipid accumulation. We quantified steatosis using the Oil Red O staining method. We investigated the biochemical alterations induced by steatosis and Ex-4 treatment using Fourier transform infrared (FTIR) spectroscopy and chemometric analyses. Analysis of the Oil Red O staining showed that Ex-4 significantly reduces steatosis. This reduction was confirmed by FTIR analysis, as the phospholipid band (C=O) at 1740 cm−1 in Ex-4 treated cells is significantly decreased compared to steatotic cells. The principal component analysis score plots for both the lipid and protein regions showed that the untreated and Ex-4-treated samples, while still separated, are clustered close to each other, far from the steatotic cells. The biochemical and structural changes induced by OA-induced lipotoxicity are at least partially reversed upon Ex-4 treatment. FTIR and chemometric analyses revealed that Ex-4 significantly reduces OA-induced lipid accumulation, and Ex-4 also restored the lipid and protein biochemical alterations caused by lipotoxicity-induced oxidative stress. In combination with chemometric analyses, FTIR spectroscopy may offer new approaches for investigating the mechanisms underpinning NAFLD.
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Affiliation(s)
- Olfa Khalifa
- Diabetes Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, Doha 34110, Qatar
| | - Kamal H. Mroue
- Qatar Environment and Energy Research Institute, Hamad Bin Khalifa University (HBKU), Qatar Foundation, Doha 34110, Qatar
| | - Raghvendra Mall
- Qatar Computing Research Institute, Hamad Bin Khalifa University, Qatar Foundation, Doha 34110, Qatar
- Department of Immunology, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105-3678, USA
| | - Ehsan Ullah
- Qatar Computing Research Institute, Hamad Bin Khalifa University, Qatar Foundation, Doha 34110, Qatar
| | - Nayla S. Al-Akl
- Diabetes Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, Doha 34110, Qatar
| | - Abdelilah Arredouani
- Diabetes Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, Doha 34110, Qatar
- College of Health and Life Sciences, Hamad Bin Khalifa University, Qatar Foundation, Doha 34110, Qatar
- Correspondence:
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He M, Lu B, Opoku M, Zhang L, Xie W, Jin H, Chen S, Li Y, Deng Z. Metformin Prevents or Delays the Development and Progression of Osteoarthritis: New Insight and Mechanism of Action. Cells 2022; 11:3012. [PMID: 36230974 PMCID: PMC9563728 DOI: 10.3390/cells11193012] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2022] [Revised: 09/23/2022] [Accepted: 09/24/2022] [Indexed: 11/17/2022] Open
Abstract
For over 60 years, metformin has been widely prescribed by physicians to treat type 2 diabetes. Along with more in-depth research on metformin and its molecular mechanism in recent decades, metformin has also been proposed as an effective drug to prevent or delay musculoskeletal disorders, including osteoarthritis (OA). The occurrence and development of OA are deemed to be associated with the impaired mitochondrial functions of articular chondrocytes. Metformin can activate the pathways and expressions of both AMPK and SIRT1 so as to protect the mitochondrial function of chondrocytes, thereby promoting osteoblast production. Moreover, the clinical significance of the metformin combination therapy in preventing OA has also been demonstrated. This review aimed to comprehensively summarize the current research progress on metformin as a proposed drug for OA prevention or treatment.
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Affiliation(s)
- Miao He
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Bangbao Lu
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Michael Opoku
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Liang Zhang
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Wenqing Xie
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Hongfu Jin
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Siyu Chen
- Department of Sports Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen 518035, China
| | - Yusheng Li
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Zhenhan Deng
- Department of Sports Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen 518035, China
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Ozeki Y, Masaki T, Kamata A, Miyamoto S, Yoshida Y, Okamoto M, Gotoh K, Shibata H. The Effectiveness of GLP-1 Receptor Agonist Semaglutide on Body Composition in Elderly Obese Diabetic Patients: A Pilot Study. MEDICINES (BASEL, SWITZERLAND) 2022; 9:47. [PMID: 36135828 PMCID: PMC9502467 DOI: 10.3390/medicines9090047] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 08/25/2022] [Accepted: 09/13/2022] [Indexed: 06/16/2023]
Abstract
BACKGROUND AND OBJECTIVES This study aimed to investigate the changes in obesity severity, glucose metabolism, and body composition in patients with obesity and type 2 diabetes mellitus treated with glucagon-like peptide 1 receptor agonist (GLP1-RA) semaglutide. MATERIALS AND METHODS Body weight (BW), metabolic parameters, and body composition were examined before and 3 months after semaglutide administration. The mass of body fat (FM), fat weight percentage (%FM), mass of skeletal muscle (MM), skeletal MM percentage (%MM), and limb muscles were measured using the bioelectrical impedance method. RESULTS Semaglutide dramatically reduced the weight, the body mass index (BMI), and the levels of the glucose metabolic markers, including fasting blood glucose and hemoglobin A1c, and accelerated the loss of excess BW. FM, MM, and %FM after semaglutide treatment also decreased. Conversely, semaglutide had no effect on the %MM after 3 months. In limb muscle analyses, right upper and lower leg muscle percentages, left upper and lower leg muscles, and the ratios of the lower/upper muscles were maintained by semaglutide treatment. CONCLUSIONS These results suggest that the GLP1-RA semaglutide effectively reduces body adiposity while maintaining the MM in obese type 2 diabetic patients.
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Affiliation(s)
- Yoshinori Ozeki
- Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Oita University, Yufu City 879-5593, Oita, Japan
| | - Takayuki Masaki
- Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Oita University, Yufu City 879-5593, Oita, Japan
| | - Akari Kamata
- Faculty of Medicine, Oita University, Yufu City 879-5593, Oita, Japan
| | - Shotaro Miyamoto
- Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Oita University, Yufu City 879-5593, Oita, Japan
| | - Yuichi Yoshida
- Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Oita University, Yufu City 879-5593, Oita, Japan
| | - Mitsuhiro Okamoto
- Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Oita University, Yufu City 879-5593, Oita, Japan
| | - Koro Gotoh
- Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Oita University, Yufu City 879-5593, Oita, Japan
| | - Hirotaka Shibata
- Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Oita University, Yufu City 879-5593, Oita, Japan
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Tsankof A, Neokosmidis G, Koureta E, Veneti S, Cholongitas E, Tziomalos K. Which is the optimal antiobesity agent for patients with nonalcoholic fatty liver disease? Front Endocrinol (Lausanne) 2022; 13:984041. [PMID: 36120448 PMCID: PMC9478023 DOI: 10.3389/fendo.2022.984041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Accepted: 08/12/2022] [Indexed: 11/16/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the commonest chronic liver disease and affects a considerable proportion of the general population worldwide. Obesity is a major risk factor for development and progression of NAFLD and weight loss is an effective intervention for the management of NAFLD. However, few patients achieve substantial and sustained weight loss with lifestyle measures. Therefore, antiobesity agents are frequently considered in patients with NAFLD but there are limited data on their safety and efficacy. In the present review, we discuss the role of antiobesity agents in the management of NAFLD. All approved antiobesity agents appear to reduce transaminase levels and to improve steatosis in patients with NAFLD. However, their effects on fibrosis are less well studied and whether they affect liver-related outcomes, including progression to cirrhosis and hepatocellular cancer, is unknown. The glucagon-like peptide-1 receptor agonists, liraglutide and semaglutide, appear to represent a first-line option in obese patients with NAFLD and type 2 diabetes mellitus (T2DM) since they induce considerable weight loss and have been extensively studied in patients with T2DM. However, more studies are needed to evaluated their effects on liver-related and cardiovascular outcomes in patients with NAFLD, particularly in those without T2DM.
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Affiliation(s)
- Alexandra Tsankof
- First Propedeutic Department of Internal Medicine, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA Hospital, Thessaloniki, Greece
| | - Georgios Neokosmidis
- First Propedeutic Department of Internal Medicine, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA Hospital, Thessaloniki, Greece
| | - Evgenia Koureta
- Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Stavroula Veneti
- First Propedeutic Department of Internal Medicine, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA Hospital, Thessaloniki, Greece
| | - Evangelos Cholongitas
- Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Konstantinos Tziomalos
- First Propedeutic Department of Internal Medicine, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA Hospital, Thessaloniki, Greece
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Moon JS, Hong JH, Jung YJ, Ferrannini E, Nauck MA, Lim S. SGLT-2 inhibitors and GLP-1 receptor agonists in metabolic dysfunction-associated fatty liver disease. Trends Endocrinol Metab 2022; 33:424-442. [PMID: 35491295 DOI: 10.1016/j.tem.2022.03.005] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 02/22/2022] [Accepted: 03/11/2022] [Indexed: 02/07/2023]
Abstract
Metabolic dysfunction-associated fatty liver disease (MAFLD) is a chronic condition that affects nearly one billion people globally, characterized by triacylglycerol accumulation in the liver as a consequence of metabolic abnormalities (obesity and impaired glucose regulation). Low-grade inflammation, oxidative stress, mitochondrial dysfunction, and dysbiosis in gut microbiota are involved in the etiology of MAFLD, and both cardiovascular events and hepatic complications are the long-term consequences. In the absence of approved therapies for this condition, sodium-glucose cotransporter 2 inhibitors (SGLT-2 Is) and glucagon-like peptide 1 receptor agonists (GLP-1 RAs) have the specific advantage of lowering body weight and providing cardiovascular benefits. Here, we discuss potential roles for SGLT-2 Is and GLP-1 RAs in the prevention and treatment of intrahepatic triacylglycerol accumulation and associated inflammation and/or fibrosis.
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Affiliation(s)
- Jun Sung Moon
- Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Republic of Korea
| | - Jun Hwa Hong
- Department of Internal Medicine, Eulji University Hospital, School of Medicine, Daejeon, Republic of Korea
| | - Yong Jin Jung
- Department of Internal Medicine, Boramae Medical Center, Seoul National University College of Medicine, Seoul, Republic of Korea
| | | | - Michael A Nauck
- Diabetes Division, Katholisches Klinikum Bochum, St Josef Hospital (Ruhr-University, Bochum), Bochum, Germany.
| | - Soo Lim
- Department of Internal Medicine, Seoul National University College of Medicine and Seoul National University Bundang Hospital, Seongnam, Republic of Korea.
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40
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Liao X, Liu J, Chen Y, Liu Y, Chen W, Zeng B, Liu Y, Luo Y, Huang C, Guo G, Wang Y, Wang X. Metformin combats obesity by targeting FTO in an m 6A-YTHDF2-dependent manner. J Drug Target 2022; 30:983-991. [PMID: 35481401 DOI: 10.1080/1061186x.2022.2071906] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
Obesity has become a health threat and hard enough to deal with. Evidences show that metformin could inhibit adipogenesis and combat obesity, while its mechanisms remain to be elucidated more comprehensively. In this study, we found that administration of metformin could combat obesity induced by high-fat diet (HFD), indicated by strikingly decreased body weight and weight of inguinal white adipose tissue (iWAT) and epidydimal white adipose tissue (eWAT) compared to the control group. Mechanically, we revealed that metformin could inhibit protein expression of FTO, leading to increased m6A methylation levels of cyclin D1 (Ccnd1) and cyclin dependent kinase 2 (Cdk2), two crucial regulators in cell cycle. Ccnd1 and Cdk2 with increased m6A levels were recognized by YTH m6A RNA binding protein 2 (YTHDF2), causing a YTHDF2-dependent decay and decreased protein expressions. In consequence, mitotic clonal expansion (MCE) process was blocked and adipogenesis was inhibited.
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Affiliation(s)
- Xing Liao
- College of Animal Sciences, Zhejiang University, Hangzhou 310058, China.,Key Laboratory of Molecular Animal Nutrition (Zhejiang University), Ministry of Education, Hangzhou 310058, China.,Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture and Rural Affairs, Hangzhou 310058, China.,Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, Hangzhou 310058, China
| | - Jiaqi Liu
- College of Animal Sciences, Zhejiang University, Hangzhou 310058, China.,Key Laboratory of Molecular Animal Nutrition (Zhejiang University), Ministry of Education, Hangzhou 310058, China.,Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture and Rural Affairs, Hangzhou 310058, China.,Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, Hangzhou 310058, China
| | - Yushi Chen
- College of Animal Sciences, Zhejiang University, Hangzhou 310058, China.,Key Laboratory of Molecular Animal Nutrition (Zhejiang University), Ministry of Education, Hangzhou 310058, China.,Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture and Rural Affairs, Hangzhou 310058, China.,Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, Hangzhou 310058, China
| | - Youhua Liu
- College of Animal Sciences, Zhejiang University, Hangzhou 310058, China.,Key Laboratory of Molecular Animal Nutrition (Zhejiang University), Ministry of Education, Hangzhou 310058, China.,Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture and Rural Affairs, Hangzhou 310058, China.,Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, Hangzhou 310058, China
| | - Wei Chen
- College of Animal Sciences, Zhejiang University, Hangzhou 310058, China.,Key Laboratory of Molecular Animal Nutrition (Zhejiang University), Ministry of Education, Hangzhou 310058, China.,Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture and Rural Affairs, Hangzhou 310058, China.,Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, Hangzhou 310058, China
| | - Botao Zeng
- College of Animal Sciences, Zhejiang University, Hangzhou 310058, China.,Key Laboratory of Molecular Animal Nutrition (Zhejiang University), Ministry of Education, Hangzhou 310058, China.,Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture and Rural Affairs, Hangzhou 310058, China.,Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, Hangzhou 310058, China
| | - Yuxi Liu
- College of Animal Sciences, Zhejiang University, Hangzhou 310058, China.,Key Laboratory of Molecular Animal Nutrition (Zhejiang University), Ministry of Education, Hangzhou 310058, China.,Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture and Rural Affairs, Hangzhou 310058, China.,Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, Hangzhou 310058, China
| | - Yaojun Luo
- College of Animal Sciences, Zhejiang University, Hangzhou 310058, China.,Key Laboratory of Molecular Animal Nutrition (Zhejiang University), Ministry of Education, Hangzhou 310058, China.,Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture and Rural Affairs, Hangzhou 310058, China.,Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, Hangzhou 310058, China
| | - Chaoqun Huang
- College of Animal Sciences, Zhejiang University, Hangzhou 310058, China.,Key Laboratory of Molecular Animal Nutrition (Zhejiang University), Ministry of Education, Hangzhou 310058, China.,Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture and Rural Affairs, Hangzhou 310058, China.,Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, Hangzhou 310058, China
| | - Guanqun Guo
- College of Animal Sciences, Zhejiang University, Hangzhou 310058, China.,Key Laboratory of Molecular Animal Nutrition (Zhejiang University), Ministry of Education, Hangzhou 310058, China.,Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture and Rural Affairs, Hangzhou 310058, China.,Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, Hangzhou 310058, China
| | - Yizhen Wang
- College of Animal Sciences, Zhejiang University, Hangzhou 310058, China.,Key Laboratory of Molecular Animal Nutrition (Zhejiang University), Ministry of Education, Hangzhou 310058, China.,Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture and Rural Affairs, Hangzhou 310058, China.,Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, Hangzhou 310058, China
| | - Xinxia Wang
- College of Animal Sciences, Zhejiang University, Hangzhou 310058, China.,Key Laboratory of Molecular Animal Nutrition (Zhejiang University), Ministry of Education, Hangzhou 310058, China.,Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture and Rural Affairs, Hangzhou 310058, China.,Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, Hangzhou 310058, China
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Ding C, Tang Y, Zhu W, Huang P, Lian P, Ran J, Huang X. Sodium-glucose cotransporter protein-2 inhibitors and glucagon-like peptide-1 receptor agonists versus thiazolidinediones for non-alcoholic fatty liver disease: A network meta-analysis. Acta Diabetol 2022; 59:519-533. [PMID: 34988690 DOI: 10.1007/s00592-021-01830-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2021] [Accepted: 11/22/2021] [Indexed: 02/07/2023]
Abstract
AIMS Non-alcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disorders worldwide. Some hypoglycemic drugs can improve NAFLD. However, it is unclear which of these types of hypoglycemic drugs are more effective for NAFLD. Therefore, we conducted a network meta-analysis to determine the effect of thiazolidinediones (TZDs), sodium-glucose cotransporter 2 (SGLT2) inhibitors, and glucagon-like peptide-1 (GLP-1) receptor agonists on NAFLD patients. METHODS A literature search of PubMed, EMBASE, the Cochrane Library, and Medline was conducted, and the literature from database inception up to April 30, 2021 was obtained. Liver function tests, lipid profiles, body mass index (BMI) and glycemic parameters were obtained from randomized controlled trials. Weighted mean differences (WMDs), relative risks and 95% confidence intervals (CIs) were calculated for continuous outcomes, and the I2 statistic was used to evaluate the heterogeneity of the studies. RESULTS In total, 22 trials, including 1361 patients, were selected. In direct meta-analysis, GLP-1 receptor agonists were superior to TZDs in decreasing alanine aminotransferase (WMD, -0.40, 95% CI: -0.60 to -0.20), γ-glutamyl transferase (WMD, -5.00, 95% CI: -6.47 to -3.53), BMI (WMD, -4.10, 95%CI: -6.55 to -1.65) and triglycerides (WMD, - 0.50, 95% CI: -0.68 to -0.32). Based on Bayesian network meta-analysis, the effect of SGLT-2 inhibitors on weight loss was superior to that of TZDs (WMD, -1.80, 95%CI: -3.30 to -0.41). CONCLUSIONS GLP-1 receptor agonists and SGLT-2 inhibitors improved liver enzymes, BMI, blood lipid, blood glucose and insulin resistance in NAFLD patients.
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Affiliation(s)
- Chen Ding
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Yaxin Tang
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Wenqiang Zhu
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Piaopiao Huang
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Pingan Lian
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Juanli Ran
- Department of Stomatology, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Xiansheng Huang
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, 410011, China.
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42
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Yu L, Hong W, Lu S, Li Y, Guan Y, Weng X, Feng Z. The NLRP3 Inflammasome in Non-Alcoholic Fatty Liver Disease and Steatohepatitis: Therapeutic Targets and Treatment. Front Pharmacol 2022; 13:780496. [PMID: 35350750 PMCID: PMC8957978 DOI: 10.3389/fphar.2022.780496] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Accepted: 02/17/2022] [Indexed: 12/12/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is among the most prevalent primary liver diseases worldwide and can develop into various conditions, ranging from simple steatosis, through non-alcoholic steatohepatitis (NASH), to fibrosis, and eventually cirrhosis and hepatocellular carcinoma. Nevertheless, there is no effective treatment for NAFLD due to the complicated etiology. Recently, activation of the NLPR3 inflammasome has been demonstrated to be a contributing factor in the development of NAFLD, particularly as a modulator of progression from initial hepatic steatosis to NASH. NLRP3 inflammasome, as a caspase-1 activation platform, is critical for processing key pro-inflammatory cytokines and pyroptosis. Various stimuli involved in NAFLD can activate the NLRP3 inflammasome, depending on the diverse cellular stresses that they cause. NLRP3 inflammasome-related inhibitors and agents for NAFLD treatment have been tested and demonstrated positive effects in experimental models. Meanwhile, some drugs have been applied in clinical studies, supporting this therapeutic approach. In this review, we discuss the activation, biological functions, and treatment targeting the NLRP3 inflammasome in the context of NAFLD progression. Specifically, we focus on the different types of therapeutic agents that can inhibit the NLRP3 inflammasome and summarize their pharmacological effectiveness for NAFLD treatment.
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Affiliation(s)
- Lili Yu
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China.,Institute of Precision Medicine, Xinxiang Medical University, Xinxiang, China.,The Third Clinical College of Xinxiang Medical University, Xinxiang, China.,Xinxiang Key Laboratory of Tumor Vaccine and Immunotherapy, Xinxiang Medical University, Xinxiang, China
| | - Wei Hong
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China.,Institute of Precision Medicine, Xinxiang Medical University, Xinxiang, China
| | - Shen Lu
- The Third Clinical College of Xinxiang Medical University, Xinxiang, China
| | - Yanrong Li
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China.,Institute of Precision Medicine, Xinxiang Medical University, Xinxiang, China
| | - Yaya Guan
- The Third Clinical College of Xinxiang Medical University, Xinxiang, China
| | - Xiaogang Weng
- The Third Clinical College of Xinxiang Medical University, Xinxiang, China
| | - Zhiwei Feng
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China.,Institute of Precision Medicine, Xinxiang Medical University, Xinxiang, China.,Xinxiang Key Laboratory of Tumor Vaccine and Immunotherapy, Xinxiang Medical University, Xinxiang, China
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43
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Song JX, An JR, Chen Q, Yang XY, Jia CL, Xu S, Zhao YS, Ji ES. Liraglutide attenuates hepatic iron levels and ferroptosis in db/db mice. Bioengineered 2022; 13:8334-8348. [PMID: 35311455 PMCID: PMC9161873 DOI: 10.1080/21655979.2022.2051858] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Liver pathological changes are as high as 21%-78% in diabetic patients, and treatment options are lacking. Liraglutide is a glucagon-like peptide-1 (GLP-1) receptor that is widely used in the clinic and is approved to treat obesity and diabetes. However, the specific protection mechanism needs to be clarified. In the present study, db/db mice were used to simulate Type 2 diabetes mellitus (T2DM), and they were intraperitoneally injected daily with liraglutide (200 μg/kg/d) for 5 weeks. Hepatic function, pathologic changes, oxidative stress, iron levels, and ferroptosis were evaluated. First, liraglutide decreased serum AST and ALT levels, and suppressed liver fibrosis in db/db mice. Second, liraglutide inhibited the ROS production by upregulating SOD, GSH-PX, and GSH activity as well as by downregulating MDA, 4-HNE, and NOX4 expression in db/db mice. Furthermore, liraglutide attenuated iron deposition by decreasing TfR1 expression and increasing FPN1 expression. At the same time, liraglutide decreased ferroptosis by elevating the expression of SLC7A11 and the Nrf2/HO-1/GPX4 signaling pathway in the livers of db/db mice. In addition, liraglutide decreased the high level of labile iron pools (LIPs) and intracellular lipid ROS induced by high glucose in vitro. Therefore, we speculated that liraglutide played a crucial role in reducing iron accumulation, oxidative damage and ferroptosis in db/db mice.
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Affiliation(s)
- Ji-Xian Song
- Department of Physiology, Institute of Basic Medicine, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, China.,Hebei Technology Innovation Center of TCM Combined Hydrogen Medicine, Shijiazhuang, Hebei, China
| | - Ji-Ren An
- Hebei Technology Innovation Center of TCM Combined Hydrogen Medicine, Shijiazhuang, Hebei, China.,First Clinical College, Liaoning University of Traditional Chinese Medicine, Shenyang, Lioaning, China
| | - Qi Chen
- Department of Physiology, Institute of Basic Medicine, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, China
| | - Xin-Yue Yang
- Department of Physiology, Institute of Basic Medicine, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, China
| | - Cui-Ling Jia
- Department of Physiology, Institute of Basic Medicine, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, China
| | - Shan Xu
- Department of Physiology, Institute of Basic Medicine, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, China
| | - Ya-Shuo Zhao
- Department of Physiology, Institute of Basic Medicine, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, China.,Hebei Technology Innovation Center of TCM Combined Hydrogen Medicine, Shijiazhuang, Hebei, China
| | - En-Sheng Ji
- Department of Physiology, Institute of Basic Medicine, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, China.,Hebei Technology Innovation Center of TCM Combined Hydrogen Medicine, Shijiazhuang, Hebei, China
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Iacobellis G, Baroni MG. Cardiovascular risk reduction throughout GLP-1 receptor agonist and SGLT2 inhibitor modulation of epicardial fat. J Endocrinol Invest 2022; 45:489-495. [PMID: 34643917 DOI: 10.1007/s40618-021-01687-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Accepted: 10/01/2021] [Indexed: 12/17/2022]
Abstract
Epicardial adipose tissue is a novel cardiovascular risk factor. It plays a role in the progression of coronary artery disease, heart failure and atrial fibrillation. Given its rapid metabolism, clinical measurability, and modifiability, epicardial fat works well as therapeutic target of drugs modulating the adipose tissue. Epicardial fat responds to glucagon-like peptide 1 receptor agonists (GLP1A) and sodium glucose co-transporter 2 inhibitors (SGLT2i). GLP-1A and SGLT2i provide weight loss and cardiovascular protective effects beyond diabetes control, as recently demonstrated. The potential of modulating the epicardial fat morphology and genetic profile with targeted pharmacological agents can open new avenues in the pharmacotherapy of diabetes and obesity, with particular focus on cardiovascular risk reduction.
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Affiliation(s)
- G Iacobellis
- Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Miller School of Medicine, University of Miami, 1400 NW 10th Ave, Dominion Tower suite 805-807, Miami, FL, 33136, USA.
| | - M G Baroni
- Endocrinology and Diabetes, Department of Clinical Medicine, Public Health, Life and Environmental Sciences (MeSVA), University of L'Aquila, L'Aquila, Italy
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Khalifa O, Al-Akl NS, Errafii K, Arredouani A. Exendin-4 alleviates steatosis in an in vitro cell model by lowering FABP1 and FOXA1 expression via the Wnt/-catenin signaling pathway. Sci Rep 2022; 12:2226. [PMID: 35140289 PMCID: PMC8828858 DOI: 10.1038/s41598-022-06143-5] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2021] [Accepted: 01/24/2022] [Indexed: 12/19/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the leading chronic liver disease worldwide. Agonists of the glucagon-like peptide-1 receptor (GLP-1R), currently approved to treat type 2 diabetes, hold promise to improve steatosis and even steatohepatitis. However, due to their pleiotropic effects, the mechanisms underlying their protective effect on NAFLD remain elusive. We aimed to investigate these mechanisms using an in vitro model of steatosis treated with the GLP-1R agonist Exendin-4 (Ex-4). We established steatotic HepG2 cells by incubating the cells with 400 µM oleic acid (OA) overnight. Further treatment with 200 nM Ex-4 for 3 h significantly reduced the OA-induced lipid accumulation (p < 0.05). Concomitantly, Ex-4 substantially reduced the expression levels of Fatty Acid-Binding Protein 1 (FABP1) and its primary activator, Forkhead box protein A1 (FOXA1). Interestingly, the silencing of β-catenin with siRNA abolished the effect of Ex-4 on these genes, suggesting dependency on the Wnt/β-catenin pathway. Additionally, after β-catenin silencing, OA treatment significantly increased the expression of nuclear transcription factors SREBP-1 and TCF4, whereas Ex-4 significantly decreased this upregulation. Our findings suggest that direct activation of GLP-1R by Ex-4 reduces OA-induced steatosis in HepG2 cells by reducing fatty acid uptake and transport via FABP1 downregulation.
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Affiliation(s)
- Olfa Khalifa
- Diabetes Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, PO Box: 34110, Doha, Qatar
| | - Neyla S Al-Akl
- Diabetes Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, PO Box: 34110, Doha, Qatar
| | - Khaoula Errafii
- Diabetes Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, PO Box: 34110, Doha, Qatar.,College of Health and Life Sciences, Hamad Bin Khalifa University, Qatar Foundation, Doha, Qatar
| | - Abdelilah Arredouani
- Diabetes Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, PO Box: 34110, Doha, Qatar. .,College of Health and Life Sciences, Hamad Bin Khalifa University, Qatar Foundation, Doha, Qatar.
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Gao L, Huang H, Zhang L, Zhang N, Fu Y, Zhu D, Bi Y, Feng W. Comparison of Beinaglutide Versus Metformin for Weight Loss in Overweight and Obese Non-diabetic Patients. Exp Clin Endocrinol Diabetes 2021; 130:358-367. [PMID: 34856624 PMCID: PMC9286864 DOI: 10.1055/a-1608-0345] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
PURPOSE We compared the efficacy and safety of beinaglutide, a glucagon-like peptide-1 (GLP-1) analogue with metformin in lowering the bodyweight of patients who were overweight/obese and non-diabetic. PATIENTS AND METHODS Seventy-eight non-diabetic patients were randomly selected and beinaglutide or metformin was administered for 12 weeks. The primary endpoints were changes in body weight and the proportions of patients who lost≥5 and≥10% of their baseline body weights. RESULTS A total of 64 patients completed the study; patients in the beinaglutide group exhibited more bodyweight loss than those in the metformin group [(9.5±0.8%; 9.1±0.9 kg) and (5.1±0.9%; 4.5±0.8 kg), respectively, corresponding to a difference of approximately 4.5 kg (95% confidence interval, 2.2-6.9 kg; P<0.01)]. In the beinaglutide group, 90.6 and 40.6% of the patients lost≥5 and≥10% of their body weight, respectively, whereas, in the metformin group, these rates were 46.9 and 12.5%, respectively (P<0.01 and P<0.05). Weight loss following beinaglutide treatment mainly resulted from the loss of fat mass. Compared to metformin, beinaglutide induced a greater decrease in the body mass index, weight circumference, percent body fat, and body fat mass (total, trunk, limb, android, and gynoid). Additionally, beinaglutide decreased serum insulin levels and ameliorated insulin resistance. CONCLUSIONS Beinaglutide is more efficient than metformin at reducing weight and fat mass in patients who are overweight/obese and non-diabetic. Beinaglutide may be a useful therapeutic option for overweight/obesity control in the Chinese population.
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Affiliation(s)
- Lijun Gao
- Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, China
| | - Hong Huang
- Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, China
| | - Lu Zhang
- Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, China
| | - Ningjing Zhang
- Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, China
| | - Yuzhe Fu
- Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, China
| | - Dalong Zhu
- Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, China
| | - Yan Bi
- Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, China
| | - Wenhuan Feng
- Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, China
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Tomlinson B, Patil NG, Fok M, Chan P, Lam CWK. The role of sulfonylureas in the treatment of type 2 diabetes. Expert Opin Pharmacother 2021; 23:387-403. [PMID: 34758676 DOI: 10.1080/14656566.2021.1999413] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
INTRODUCTION Type 2 diabetes (T2D) is increasingly prevalent and associated with increased risk for cardiovascular and renal disease. After lifestyle modification, metformin is usually the first-line pharmacotherapy and sulfonylureas are traditionally added after metformin failure. However, with newer glucose lowering drugs that may have less risk of hypoglycemia or that may reduce cardiovascular and renal events, the position of sulfonylureas is being reevaluated. AREAS COVERED In this article, the authors review relevant publications related to the use of sulfonylureas. EXPERT OPINION Sulfonylureas are potent glucose lowering drugs. The risk of hypoglycemia varies with different drugs within the class and can be minimized by using the safer drugs, possibly in lower doses. Cardiovascular events do not appear to be increased with some of the newer generation drugs. The durability of glycemic control also appears comparable to other newer agents. Sulfonylureas are the preferred treatment for some types of monogenic diabetes and selection of T2D patients who may have greater benefit from sulfonylureas based on certain phenotypes and genotypes is likely to be refined further by precision medicine. Sulfonylureas are inexpensive and readily available everywhere and they are still the most frequently used second-line treatment for T2D in many parts of the world.
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Affiliation(s)
- Brian Tomlinson
- Faculty of Medicine, Macau University of Science and Technology, Macau, China
| | | | - Manson Fok
- Faculty of Medicine, Macau University of Science and Technology, Macau, China
| | - Paul Chan
- Division of Cardiovascular Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei City, Taiwan
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Goon DE, Ab-Rahim S, Mohd Sakri AH, Mazlan M, Tan JK, Abdul Aziz M, Mohd Noor N, Ibrahim E, Sheikh Abdul Kadir SH. Untargeted serum metabolites profiling in high-fat diet mice supplemented with enhanced palm tocotrienol-rich fraction using UHPLC-MS. Sci Rep 2021; 11:21001. [PMID: 34697380 PMCID: PMC8546078 DOI: 10.1038/s41598-021-00454-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Accepted: 10/01/2021] [Indexed: 01/14/2023] Open
Abstract
Excessive high fat dietary intake promotes risk of developing non-alcoholic fatty liver disease (NAFLD) and predisposed with oxidative stress. Palm based tocotrienol-rich fraction (TRF) has been reported able to ameliorate oxidative stress but exhibited poor bioavailability. Thus, we investigated whether an enhanced formulation of TRF in combination with palm kernel oil (medium-chain triglycerides) (ETRF) could ameliorate the effect of high-fat diet (HFD) on leptin-deficient male mice. All the animals were divided into HFD only (HFD group), HFD supplemented with ETRF (ETRF group) and HFD supplemented with TRF (TRF group) and HFD supplemented with PKO (PKO group). After 6 weeks, sera were collected for untargeted metabolite profiling using UHPLC-Orbitrap MS. Univariate analysis unveiled alternation in metabolites for bile acids, amino acids, fatty acids, sphingolipids, and alkaloids. Bile acids, lysine, arachidonic acid, and sphingolipids were downregulated while xanthine and hypoxanthine were upregulated in TRF and ETRF group. The regulation of these metabolites suggests that ETRF may promote better fatty acid oxidation, reduce oxidative stress and pro-inflammatory metabolites and acts as anti-inflammatory in fatty liver compared to TRF. Metabolites regulated by ETRF also provide insight of its role in fatty liver. However, further investigation is warranted to identify the mechanisms involved.
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Affiliation(s)
- Danial Efendy Goon
- Institute of Medical Molecular Biotechnology (IMMB), Faculty of Medicine, Universiti Teknologi MARA (UiTM), Cawangan Selangor, Sungai Buloh, Selangor, Malaysia
- Institute of Pathology, Laboratory and Forensic Medicine (I-PPerForM), Faculty of Medicine, Universiti Teknologi MARA (UiTM), Cawangan Selangor, Sungai Buloh, Selangor, Malaysia
- Department of Biochemistry, Faculty of Medicine, Universiti Teknologi MARA (UiTM), Cawangan Selangor, Sungai Buloh, Selangor, Malaysia
| | - Sharaniza Ab-Rahim
- Department of Biochemistry, Faculty of Medicine, Universiti Teknologi MARA (UiTM), Cawangan Selangor, Sungai Buloh, Selangor, Malaysia.
| | - Amir Hakimi Mohd Sakri
- Institute of Medical Molecular Biotechnology (IMMB), Faculty of Medicine, Universiti Teknologi MARA (UiTM), Cawangan Selangor, Sungai Buloh, Selangor, Malaysia
- Department of Physiology, Faculty of Medicine, Universiti Teknologi MARA (UiTM), Cawangan Selangor, Sungai Buloh, Selangor, Malaysia
| | - Musalmah Mazlan
- Department of Biochemistry, Faculty of Medicine, Universiti Teknologi MARA (UiTM), Cawangan Selangor, Sungai Buloh, Selangor, Malaysia
| | - Jen Kit Tan
- Department of Biochemistry, Faculty of Medicine, Universiti Kebangsaan Malaysia, 56000, Kuala Lumpur, Malaysia
| | - Mardiana Abdul Aziz
- Department of Pathology, Faculty of Medicine, Universiti Teknologi MARA (UiTM), Cawangan Selangor, 47000, Sungai Buloh, Selangor, Malaysia
| | - Norizal Mohd Noor
- Department of Pathology, Faculty of Medicine, Universiti Teknologi MARA (UiTM), Cawangan Selangor, 47000, Sungai Buloh, Selangor, Malaysia
| | - Effendi Ibrahim
- Department of Physiology, Faculty of Medicine, Universiti Teknologi MARA (UiTM), Cawangan Selangor, Sungai Buloh, Selangor, Malaysia
| | - Siti Hamimah Sheikh Abdul Kadir
- Institute of Pathology, Laboratory and Forensic Medicine (I-PPerForM), Faculty of Medicine, Universiti Teknologi MARA (UiTM), Cawangan Selangor, Sungai Buloh, Selangor, Malaysia.
- Department of Biochemistry, Faculty of Medicine, Universiti Teknologi MARA (UiTM), Cawangan Selangor, Sungai Buloh, Selangor, Malaysia.
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Ng CH, Lin SY, Chin YH, Lee MH, Syn N, Goh XL, Koh JH, Quek J, Hao Tan DJ, Mok SF, Tan E, Dan YY, Chew N, Khoo CM, Siddiqui MS, Muthiah M. Antidiabetic Medications for Type 2 Diabetics with Nonalcoholic Fatty Liver Disease: Evidence From a Network Meta-Analysis of Randomized Controlled Trials. Endocr Pract 2021; 28:223-230. [PMID: 34606980 DOI: 10.1016/j.eprac.2021.09.013] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 09/17/2021] [Accepted: 09/25/2021] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Type 2 diabetes mellitus and nonalcoholic fatty liver disease (NAFLD) are closely related, and antidiabetic medications have been shown to be potential therapeutics in NAFLD. Using a network meta-analysis, we sought to examine the effectiveness of antidiabetic agents for the treatment of NAFLD in patients with type 2 diabetes mellitus. METHODS Medline and Embase were searched for randomized controlled trials relating to the use of antidiabetic agents, including sodium-glucose transport protein 2 (SGLT2) inhibitors, glucagon-like peptide-1 receptor agonists, and peroxisome proliferator-activated receptor gamma (PPARγ) agonists, biguanides, sulfonylureas and insulin, on NAFLD in patients with diabetes. The p-score was used as a surrogate marker of effectiveness. RESULTS A total of 14 articles were included in the analysis. PPARγ agonists were ranked as the best treatment in steatosis reduction, resulting in the greatest reduction of steatosis. There was statistical significance between PPARγ agonists [mean difference (MD): -6.02%, confidence interval (CI): -10.37% to -1.67%] and SGLT2 inhibitors (MD: -2.60%, CI: -4.87% to -0.33%) compared with standard of care for steatosis reduction. Compared with PPARγ agonists, SGLT2 inhibitors resulted in a statistical significant reduction in fibrosis (MD: -0.06, CI: -0.10 to -0.02). Body mass index reduction was highest in SGLT2 inhibitors and glucagon-like peptide-1 receptor agonists. Additionally, SGLT2 inhibitors were ranked as the best treatment for increasing high-density lipoprotein and reducing low-density lipoprotein. CONCLUSION Glucagon-like peptide-1 receptor agonists and SGLT2 inhibitors were suitable alternatives for the treatment of NAFLD in those with type 2 diabetes mellitus with a reduction in body mass index, fibrosis, and steatosis. SGLT2 inhibitors also have the added benefit of lipid modulation.
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Affiliation(s)
- Cheng Han Ng
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
| | - Snow Yunni Lin
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Yip Han Chin
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Ming Hui Lee
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Nicholas Syn
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; Biostatistics & Modelling Domain, Saw Swee Hock School of Public Health, Singapore
| | - Xin Lei Goh
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Jin Hean Koh
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Jingxuan Quek
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Darren Jun Hao Tan
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Shao Feng Mok
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; Division of Endocrinology, Department of Medicine, National University Hospital, Singapore, Singapore
| | - Eunice Tan
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; National University Centre for Organ Transplantation, National University Health System, Singapore; Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore, Singapore
| | - Yock Young Dan
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; National University Centre for Organ Transplantation, National University Health System, Singapore; Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore, Singapore
| | - Nicholas Chew
- Division of Cardiology, Department of Medicine, National University Hospital, Singapore, Singapore
| | - Chin Meng Khoo
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; Division of Endocrinology, Department of Medicine, National University Hospital, Singapore, Singapore
| | - Mohammad Shadab Siddiqui
- Department of Internal Medicine, Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University, Virginia
| | - Mark Muthiah
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; National University Centre for Organ Transplantation, National University Health System, Singapore; Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore, Singapore.
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Orsini Federici M, Gentilella R, Corcos A, Torre E, Genovese S. Changing the approach to type 2 diabetes treatment: A comparison of glucagon-like peptide-1 receptor agonists and sulphonylureas across the continuum of care. Diabetes Metab Res Rev 2021; 37:e3434. [PMID: 33900667 PMCID: PMC8519155 DOI: 10.1002/dmrr.3434] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Revised: 09/11/2020] [Accepted: 11/13/2020] [Indexed: 12/19/2022]
Abstract
Despite the importance of individualised strategies for patients with type 2 diabetes mellitus (T2DM) and the availability of alternative treatments, including glucagon-like peptide-1 receptor agonists (GLP-1 RAs), sulphonylureas are still widely used in practice. Clinical evidence shows that GLP-1 RAs may provide better and more durable glycaemic control than sulphonylureas, with lower risk of hypoglycaemia. Other reported benefits of GLP-1 RAs include weight loss rather than weight gain (as observed with sulphonylureas), blood pressure reduction and improvement in lipid profiles. In general, the main adverse events with GLP-1 RAs are gastrointestinal in nature. The respective modes of action of GLP-1 RAs and sulphonylureas contribute to differences in the durability of glycaemic control (related to effects on beta-cells) and effects on body weight. Moreover, the glucose-dependent mode of action of GLP-1 RAs, which favours a low incidence of hypoglycaemia, contrasts with the glucose-independent mode of action of sulphonylureas. Evidence from cardiovascular outcomes trials indicates a consistent finding of cardiovascular safety across the GLP-1 RAs and suggests a class benefit for the long-acting GLP-1 RAs in reducing three-point major adverse cardiovascular events, cardiovascular mortality and all-cause mortality. In contrast, potential concerns relating to an increased incidence of adverse cardiovascular events with sulphonylureas have yet to be fully resolved. Recent updates to management guidelines recommend that treatment selection for patients with T2DM should consider clinical trial evidence of cardiovascular safety. Available evidence suggests that this selection should give preference to GLP-1 RAs over sulphonylureas, especially for patients at high cardiovascular risk.
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Affiliation(s)
| | | | | | - Enrico Torre
- Asl3 GenoveseHead of EndocrinologyDiabetology and Metabolic Diseases SSDGenovaItaly
| | - Stefano Genovese
- Centro Cardiologico Monzino IRCCSHead of DiabetologyEndocrinology and Metabolic Diseases UnitMilanoItaly
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