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Mes JJ, van den Belt M, van der Haar S, Oosterink E, Luijendijk T, Manusama K, van Dam L, de Bie T, Witkamp R, Esser D. Bitter gourd (Momordica charantia L.) supplementation for twelve weeks improves biomarkers of glucose homeostasis in a prediabetic population. JOURNAL OF ETHNOPHARMACOLOGY 2025; 347:119756. [PMID: 40199408 DOI: 10.1016/j.jep.2025.119756] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Revised: 10/09/2024] [Accepted: 04/05/2025] [Indexed: 04/10/2025]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Bitter gourd (Momordica charantia L.) is known for its ability to reduce parameters of diabetes, but its effects on prediabetic subjects have been scarcely studied. AIM OF THE STUDY To assess the efficacy of Momordica charantia supplementation in a prediabetic population on markers of glucose homeostasis. METHODS Two randomized controlled studies were conducted to assess the effect of bitter gourd supplementation in a prediabetic population. Study 1 was a 4-week cross-over intervention trial (n = 30), with freeze-dried bitter gourd (BG) fruit juice (2.4 g/day) or a cucumber-based control product (CC). Study 2 was a parallel trial (n = 38) lasting 12 weeks, with freeze-dried whole fruits (3.6 g/day) or a cucumber-based matched control supplement. Effects on fasting plasma glucose (FPG), insulin, HbA1c, fructosamine, postprandial glucose after an oral glucose tolerance test, and several safety biomarkers were also analyzed in both trials before and after the interventions. RESULTS In Study 1, no significant differences were found between the bitter gourd and placebo interventions. However, a reduction in FPG in subjects with higher baseline values were found following bitter gourd supplementation, which was not observed in the control group. However, in Study 2, we observed significant reductions of FPG (p = 0.014), fasting insulin (p = 0.007), and HOMA-IR (p = 0.003) after a 12-week intervention with the bitter gourd supplement. In addition, between treatment analysis resulted in significant effects on FPG levels (p = 0.026) and HOMA-IR (p = 0.045) with no significant effects on other biomarkers related to glucose metabolism. On average, bitter gourd intervention reduced FPG by ∼0.05 mmol/L per week, whereas FPG remained unchanged following placebo. In both studies, there were no indications of health risks or side effects from consumption of the supplements. CONCLUSION Results suggest that supplementation with bitter gourd fruit can have positive effects on fasting plasma glucose and insulin among prediabetic subjects when provided over an extended period of at least 12 weeks.
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Affiliation(s)
- Jurriaan J Mes
- Wageningen Food & Biobased Research, Food, Health & Consumer Research, Bornse Weilanden 9, 6708 WG, Wageningen, the Netherlands.
| | - Maartje van den Belt
- Wageningen Food & Biobased Research, Food, Health & Consumer Research, Bornse Weilanden 9, 6708 WG, Wageningen, the Netherlands.
| | - Sandra van der Haar
- Wageningen Food & Biobased Research, Food, Health & Consumer Research, Bornse Weilanden 9, 6708 WG, Wageningen, the Netherlands.
| | - Els Oosterink
- Wageningen Food & Biobased Research, Food, Health & Consumer Research, Bornse Weilanden 9, 6708 WG, Wageningen, the Netherlands.
| | - Teus Luijendijk
- Stichting Control in Food & Flowers, Distributieweg 1, 2645 EG, Delfgauw, the Netherlands.
| | - Koen Manusama
- Wageningen University & Research, Division of Human Nutrition & Health, Stippeneng 4, 6708 WE, Wageningen, the Netherlands.
| | - Lotte van Dam
- Wageningen University & Research, Division of Human Nutrition & Health, Stippeneng 4, 6708 WE, Wageningen, the Netherlands.
| | - Tessa de Bie
- Wageningen University & Research, Division of Human Nutrition & Health, Stippeneng 4, 6708 WE, Wageningen, the Netherlands.
| | - Renger Witkamp
- Wageningen University & Research, Division of Human Nutrition & Health, Stippeneng 4, 6708 WE, Wageningen, the Netherlands.
| | - Diederik Esser
- Wageningen Food & Biobased Research, Food, Health & Consumer Research, Bornse Weilanden 9, 6708 WG, Wageningen, the Netherlands.
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Sood A, Sawhney A, Borokhovsky B, Vyas AV, Gupta R. A drug safety evaluation of dapagliflozin for diabetic nephropathies in patients with cardiovascular risk. Expert Opin Drug Saf 2025; 24:241-250. [PMID: 39895014 DOI: 10.1080/14740338.2025.2462671] [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: 06/03/2023] [Revised: 10/23/2023] [Accepted: 12/19/2024] [Indexed: 02/04/2025]
Abstract
INTRODUCTION Diabetic nephropathy is a significant concern for patients with cardiovascular disease. Dapagliflozin, an SGLT2 inhibitor, has emerged as a promising therapeutic approach to managing diabetic nephropathy and reducing cardiovascular risk. AREAS COVERED This review encompasses the research and literature search methodology, including clinical trials and real-world evidence, assessing the safety profile of Dapagliflozin in patients with diabetic nephropathy and cardiovascular risk. EXPERT OPINION Dapagliflozin, an SGLT2 inhibitor, has redefined patient-centric care by simultaneously improving glycemic control, cardiovascular health, and renal outcomes in individuals with type 2 diabetes, cardiovascular disease, and nephropathy.
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Affiliation(s)
- Aayushi Sood
- Department of Internal Medicine, The Wright Center for Graduate Medical Education, Scranton, PA, USA
| | - Aanchal Sawhney
- Department of Internal Medicine, Crozer Chester Medical Center, Upland, PA, USA
| | - Benjamin Borokhovsky
- Department of Internal Medicine, Lehigh Valley Health Network, Allentown, PA, USA
| | - Apurva V Vyas
- Lehigh Valley Heart Institute, Lehigh Valley Health Network, Allentown, PA, USA
| | - Rahul Gupta
- Lehigh Valley Heart Institute, Lehigh Valley Health Network, Allentown, PA, USA
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Matsumoto K, Goto F, Maezawa M, Nakao S, Miyasaka K, Hirofuji S, Shiota K, Ichihara N, Yamashita M, Nokura Y, Yamazaki T, Sugishita K, Tanaka H, Tamaki H, Ishiguro M, Iguchi K, Nakamura M. A retrospective study of seasonal variation in sodium-glucose co-transporter 2 inhibitor-related adverse events using the Japanese adverse drug event report database. Sci Rep 2024; 14:30072. [PMID: 39627353 PMCID: PMC11615253 DOI: 10.1038/s41598-024-81698-z] [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: 07/02/2024] [Accepted: 11/28/2024] [Indexed: 12/06/2024] Open
Abstract
Sodium-glucose co-transporter 2 (SGLT2) inhibitors are a class of drugs used in the clinical management of patients with type 2 diabetes, and their prescriptions have been increasing in recent years. Herein, we performed a retrospective analysis of seasonal variation in SGLT2 inhibitor-associated adverse events recorded in the Japanese Adverse Drug Event Report (JADER) database, an adverse event reporting database which reflects real-world clinical practice. To this end, seasonal variations in SGLT2 inhibitor-related dehydration, cerebral infarction, urinary tract infection, and ketoacidosis were analyzed. Six SGLT2 inhibitors prescribed in Japan (ipragliflozin, empagliflozin, luseogliflozin, canagliflozin, dapagliflozin, and tofogliflozin) were included. The reporting ratio (RR) for SGLT2 inhibitor adverse events per month in the JADER database from April 2014 to December 2023 was determined. The RR for dehydration-related adverse events was highest in the summer months of July and August, as well as in the winter months of December, January, and February. The highest RR for cerebral infarction was in February. No association with seasonal variations in the occurrence of ketoacidosis related to dehydration was observed. Healthcare providers should take adequate precautions against dehydration caused by SGLT2 inhibitors, not only in summer but also in winter. These findings are instructive and informational for health care professionals involved in diabetes care.
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Affiliation(s)
- Kiyoka Matsumoto
- Laboratory of Drug Informatics, Gifu Pharmaceutical University, 1-25-4, Daigaku-nishi, Gifu, 501-1196, Japan
| | - Fumiya Goto
- Laboratory of Drug Informatics, Gifu Pharmaceutical University, 1-25-4, Daigaku-nishi, Gifu, 501-1196, Japan
| | - Mika Maezawa
- Laboratory of Drug Informatics, Gifu Pharmaceutical University, 1-25-4, Daigaku-nishi, Gifu, 501-1196, Japan
| | - Satoshi Nakao
- Laboratory of Drug Informatics, Gifu Pharmaceutical University, 1-25-4, Daigaku-nishi, Gifu, 501-1196, Japan
- Department of Pharmacy, Kyushu University Hospital, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Koumi Miyasaka
- Laboratory of Drug Informatics, Gifu Pharmaceutical University, 1-25-4, Daigaku-nishi, Gifu, 501-1196, Japan
| | - Sakiko Hirofuji
- Laboratory of Drug Informatics, Gifu Pharmaceutical University, 1-25-4, Daigaku-nishi, Gifu, 501-1196, Japan
| | - Kohei Shiota
- Laboratory of Drug Informatics, Gifu Pharmaceutical University, 1-25-4, Daigaku-nishi, Gifu, 501-1196, Japan
| | - Nanaka Ichihara
- Laboratory of Drug Informatics, Gifu Pharmaceutical University, 1-25-4, Daigaku-nishi, Gifu, 501-1196, Japan
| | - Moe Yamashita
- Laboratory of Drug Informatics, Gifu Pharmaceutical University, 1-25-4, Daigaku-nishi, Gifu, 501-1196, Japan
| | - Yuka Nokura
- Laboratory of Drug Informatics, Gifu Pharmaceutical University, 1-25-4, Daigaku-nishi, Gifu, 501-1196, Japan
| | - Tomofumi Yamazaki
- Laboratory of Drug Informatics, Gifu Pharmaceutical University, 1-25-4, Daigaku-nishi, Gifu, 501-1196, Japan
| | - Kana Sugishita
- Laboratory of Drug Informatics, Gifu Pharmaceutical University, 1-25-4, Daigaku-nishi, Gifu, 501-1196, Japan
| | - Hideyuki Tanaka
- Laboratory of Drug Informatics, Gifu Pharmaceutical University, 1-25-4, Daigaku-nishi, Gifu, 501-1196, Japan
| | - Hirofumi Tamaki
- Laboratory of Community Pharmacy, Gifu Pharmaceutical University, 1-25-4, Daigaku-nishi, Gifu, 501- 1196, Japan
| | | | - Kazuhiro Iguchi
- Laboratory of Community Pharmacy, Gifu Pharmaceutical University, 1-25-4, Daigaku-nishi, Gifu, 501- 1196, Japan
| | - Mitsuhiro Nakamura
- Laboratory of Drug Informatics, Gifu Pharmaceutical University, 1-25-4, Daigaku-nishi, Gifu, 501-1196, Japan.
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Zhang YX, Hu HS, Sun BQ. Effectiveness and mechanisms of sodium-dependent glucose transporter 2 inhibitors in type 2 diabetes and heart failure patients. World J Cardiol 2024; 16:611-615. [PMID: 39492970 PMCID: PMC11525801 DOI: 10.4330/wjc.v16.i10.611] [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: 08/16/2024] [Revised: 09/29/2024] [Accepted: 10/11/2024] [Indexed: 10/17/2024] Open
Abstract
We comment on an article by Grubić Rotkvić et al published in the recent issue of the World Journal of Cardiology. We specifically focused on possible factors affecting the therapeutic effectiveness of sodium-dependent glucose transporter inhibitors (SGLT2i) in patients with type 2 diabetes mellitus (T2DM) and their impact on comorbidities. SGLT2i inhibits SGLT2 in the proximal tubules of the kidneys, lowering blood glucose levels by inhibiting glucose reabsorption by the kidneys and causing excess glucose to be excreted in the urine. Previous studies have demonstrated a role of SGLT2i in cardiovascular function in patients with diabetes who take metformin but still have poor glycemic control. In addition, SGLT2i has been shown to be effective in anti-apoptosis, weight loss, and cardiovascular protection. Accordingly, it is feasible to treat patients with T2DM with cardiovascular or renal diseases using SGLT2i.
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Affiliation(s)
- Yan-Xi Zhang
- Department of Clinical Laboratory, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Center for Respiratory Medicine, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, Guangzhou 510120, Guangdong Province, China
| | - Hai-Sheng Hu
- Department of Clinical Laboratory, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Center for Respiratory Medicine, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, Guangzhou 510120, Guangdong Province, China
| | - Bao-Qing Sun
- Department of Clinical Laboratory, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Center for Respiratory Medicine, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, Guangzhou 510120, Guangdong Province, China.
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Tegegne BA, Adugna A, Yenet A, Yihunie Belay W, Yibeltal Y, Dagne A, Hibstu Teffera Z, Amare GA, Abebaw D, Tewabe H, Abebe RB, Zeleke TK. A critical review on diabetes mellitus type 1 and type 2 management approaches: from lifestyle modification to current and novel targets and therapeutic agents. Front Endocrinol (Lausanne) 2024; 15:1440456. [PMID: 39493778 PMCID: PMC11527681 DOI: 10.3389/fendo.2024.1440456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Accepted: 10/02/2024] [Indexed: 11/05/2024] Open
Abstract
Diabetes mellitus (DM) has emerged as an international health epidemic due to its rapid rise in prevalence. Consequently, scientists and or researchers will continue to find novel, safe, effective, and affordable anti-diabetic medications. The goal of this review is to provide a thorough overview of the role that lifestyle changes play in managing diabetes, as well as the standard medications that are currently being used to treat the condition and the most recent advancements in the development of novel medical treatments that may be used as future interventions for the disease. A literature search was conducted using research databases such as PubMed, Web of Science, Scopus, ScienceDirect, Wiley Online Library, Google Scholar, etc. Data were then abstracted from these publications using words or Phrases like "pathophysiology of diabetes", "Signe and symptoms of diabetes", "types of diabetes", "major risk factors and complication of diabetes", "diagnosis of diabetes", "lifestyle modification for diabetes", "current antidiabetic agents", and "novel drugs and targets for diabetes management" that were published in English and had a strong scientific foundation. Special emphasis was given to the importance of lifestyle modification, as well as current, novel, and emerging/promising drugs and targets helpful for the management of both T1DM and T2DM.
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Affiliation(s)
- Bantayehu Addis Tegegne
- Department of Pharmacy, College of Medicine and Health Science, Debre Markos University, Debre Markos, Ethiopia
| | - Adane Adugna
- Department of Medical Laboratory Science, College of Medicine and Health Science, Debre Markos University, Debre Markos, Ethiopia
| | - Aderaw Yenet
- Department of Pharmacy, College of Medicine and Health Science, Debre Markos University, Debre Markos, Ethiopia
| | - Wubetu Yihunie Belay
- Department of Pharmacy, College of Medicine and Health Science, Debre Markos University, Debre Markos, Ethiopia
| | - Yared Yibeltal
- Department of Pharmacy, College of Medicine and Health Science, Debre Markos University, Debre Markos, Ethiopia
| | - Abebe Dagne
- Department of Pharmacy, College of Medicine and Health Science, Debre Markos University, Debre Markos, Ethiopia
| | - Zigale Hibstu Teffera
- Department of Medical Laboratory Science, College of Medicine and Health Science, Debre Markos University, Debre Markos, Ethiopia
| | - Gashaw Azanaw Amare
- Department of Medical Laboratory Science, College of Medicine and Health Science, Debre Markos University, Debre Markos, Ethiopia
| | - Desalegn Abebaw
- Department of Medical Laboratory Science, College of Medicine and Health Science, Debre Markos University, Debre Markos, Ethiopia
| | - Haymanot Tewabe
- Department of Medical Laboratory Science, College of Medicine and Health Science, Debre Markos University, Debre Markos, Ethiopia
| | - Rahel Belete Abebe
- Department of Clinical Pharmacy, School of Pharmacy, College of Medicine and Health Science, University of Gondar, Gondar, Ethiopia
| | - Tirsit Ketsela Zeleke
- Department of Pharmacy, College of Medicine and Health Science, Debre Markos University, Debre Markos, Ethiopia
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Pang S, Li X. Early use of SGLT2 inhibitors reduces the progression of diabetic kidney disease: a retrospective cohort study. Am J Transl Res 2024; 16:4967-4978. [PMID: 39398587 PMCID: PMC11470299 DOI: 10.62347/arya8831] [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: 05/29/2024] [Accepted: 07/29/2024] [Indexed: 10/15/2024]
Abstract
OBJECTIVE To evaluate the potential of sodium-glucose cotransporter 2 (SGLT2) inhibitors in preventing the progression of diabetic kidney disease and to provide guidance for clinical practice to improve renal health management strategies for diabetic patients. METHODS A retrospective analysis was conducted on 178 patients with diabetic kidney disease admitted to Baoji High Tech Hospital from March 2023 to March 2024. Of these, 88 patients who received early treatment with the SGLT2 inhibitor dapagliflozin were included in the early SGLT2-i group, while 90 patients receiving later treatment with SGLT2 inhibitor dapagliflozin were included in the late SGLT2-i group. Clinical data, overall effectiveness, adverse reactions, blood glucose, renal function, lipid levels, and inflammatory markers were compared between the two groups. RESULTS Prior to treatment, there were no differences in blood glucose indicators between the two groups (all P > 0.05). Following treatment, both groups showed reductions in 2-hour postprandial blood glucose (2hPG), fasting plasma glucose (FPG), and glycosylated hemoglobin (HbA1c), with the early SGLT2-i group demonstrating significantly lower values compared to the late SGLT2-i group (all P < 0.05). Similarly, there were no differences in renal function indicators between the two groups before treatment (all P > 0.05). However, following treatment, the early SGLT2-i group showed more noticeable improvements compared to the late SGLT2-i group (P < 0.05). Inflammatory markers and lipid levels followed similar patterns. The overall effectiveness of the early SGLT2-i group was higher than that of the late SGLT2-i group (92.05% vs. 78.89%, P < 0.05), while the incidence of adverse reactions did not differ statistically between the two groups (6.82% vs. 10.00%, P > 0.05). CONCLUSION Early use of SGLT2 inhibitors in diabetic kidney disease patients effectively controls blood glucose and lipid levels, improves renal function, reduces inflammatory responses, and exhibits a low incidence of adverse reactions. This demonstrates high safety and an important role in delaying disease progression. Therefore, it is worth considering clinical promotion and use for this patient population.
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Affiliation(s)
- Shaowei Pang
- Nephrology Department, Baoji High Tech Hospital Baoji 721000, Shaanxi, China
| | - Xiaoli Li
- Nephrology Department, Baoji High Tech Hospital Baoji 721000, Shaanxi, China
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Baghel R, Chhikara N, Kumar P, Tamrakar AK. SGLT2 inhibitors for the treatment of diabetes: a patent review (2019-23). Expert Opin Ther Pat 2024; 34:807-823. [PMID: 39078140 DOI: 10.1080/13543776.2024.2379929] [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: 02/26/2024] [Revised: 05/27/2024] [Accepted: 07/04/2024] [Indexed: 07/31/2024]
Abstract
INTRODUCTION The sodium-glucose co-transporter 2 (SGLT2) inhibitors are FDA-approved class of drugs for diabetes management. They improve glycemic control by inducing glucosuria. Notwithstanding with potent anti-hyperglycemic activity, SGLT2 inhibitors are emerging as drugs with multifaceted therapeutic potential, evidenced for cardioprotective, renoprotective, antihypertensive, and neuroprotective activities. Continuous attempts are being accomplished through structural modification, development of new formulation, or combination with other drugs, to enhance the bioactivity spectrum of SGLT2 inhibitors for better management of diabetes and related complications. AREAS COVERED This review comprises a summary of patent applications, acquired using the Espacenet Patent Search database, concerning SGLT2 inhibitors from 2019 to 2023, with focus on improving therapeutic potentials in management of diabetes and metabolic complications. EXPERT OPINION SGLT2 inhibitors have provided an exciting treatment option for diabetes. Originally developed as anti-hyperglycemic agents, SGLT2 inhibitors exert pleiotropic metabolic responses and have emerged as promising antidiabetic agents with cardio-protective and reno-protective activities. Given their distinct therapeutic profile, SGLT2 inhibitors have revolutionized the management of diabetes and associated complications. Emerging evidences on their therapeutic potential against cancer, male reproductive dysfunctions, and neurodegenerative diseases indicate that further research in this field may unfold novel prospective on their plausible use in the management of other chronic conditions.
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Affiliation(s)
- Rahul Baghel
- Division of Biochemistry and Structural Biology, CSIR-Central Drug Research Institute, Lucknow, India
- Academy of Scientific and Innovative Research (AcSIR) Ghaziabad, Ghaziabad, India
| | - Nikita Chhikara
- Division of Biochemistry and Structural Biology, CSIR-Central Drug Research Institute, Lucknow, India
- Academy of Scientific and Innovative Research (AcSIR) Ghaziabad, Ghaziabad, India
| | - Pawan Kumar
- Division of Biochemistry and Structural Biology, CSIR-Central Drug Research Institute, Lucknow, India
- Academy of Scientific and Innovative Research (AcSIR) Ghaziabad, Ghaziabad, India
| | - Akhilesh Kumar Tamrakar
- Division of Biochemistry and Structural Biology, CSIR-Central Drug Research Institute, Lucknow, India
- Academy of Scientific and Innovative Research (AcSIR) Ghaziabad, Ghaziabad, India
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Chauhan S, Diaz V, Ogbu IR, Sanchez JRP, Manov AE, Shah P. Empagliflozin-Associated Euglycemic Diabetic Ketoacidosis Masked by Urinary Tract Infection. Cureus 2024; 16:e66408. [PMID: 39246944 PMCID: PMC11379832 DOI: 10.7759/cureus.66408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/04/2024] [Indexed: 09/10/2024] Open
Abstract
Sodium-glucose co-transporter 2 (SGLT2) inhibitors have demonstrated efficacy in slowing the progression of chronic kidney disease (CKD), managing conditions such as congestive heart failure (CHF), and reducing cardiovascular and overall mortality in patients with type 2 diabetes mellitus (T2DM). However, their use is associated with complications, including euglycemic diabetic ketoacidosis (euDKA), genital fungal infections, and urinary tract infections (UTIs). Although rare, complications like euDKA can lead to serious consequences if not promptly addressed, as illustrated by this case report of a 90-year-old man with ischemic cardiomyopathy and type 2 diabetes who developed both euDKA and a UTI while on SGLT2 inhibitor therapy. Early identification of euDKA from SGLT2 inhibitor usage prompted cessation of the SGLT2 inhibitor and administration of insulin infusion, ultimately resolving the life-threatening condition.
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Affiliation(s)
| | - Victoria Diaz
- Internal Medicine, Mountainview Hospital, Las Vegas, USA
| | | | | | - Andre E Manov
- Internal Medicine, Sunrise Health GME Consortium, Las Vegas, USA
| | - Pinak Shah
- Internal Medicine, Mountainview Hospital, Las Vegas, USA
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Koopmans SJ, Binnendijk G, Ledoux A, Choi YH, Mes JJ, Guan X, Molist F, Thị Minh TP, van der Wielen N. Momordica charantia fruit reduces plasma fructosamine whereas stems and leaves increase plasma insulin in adult mildly diabetic obese Göttingen Minipigs. PLoS One 2024; 19:e0298163. [PMID: 38498469 PMCID: PMC10947704 DOI: 10.1371/journal.pone.0298163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Accepted: 01/16/2024] [Indexed: 03/20/2024] Open
Abstract
BACKGROUND Traditionally Momordica charantia (Bitter gourd) is known for its blood glucose lowering potential. This has been validated by many previous studies based on rodent models but human trials are less convincing and the physiological mechanisms underlying the bioactivity of Bitter gourd are still unclear. The present study compared the effects of whole fruit or stems-leaves from five different Bitter gourd cultivars on metabolic control in adult diabetic obese Göttingen Minipigs. METHODS Twenty streptozotocin-induced diabetic (D) obese Minipigs (body weight ~85 kg) were subdivided in mildly and overtly D pigs and fed 500 g of obesogenic diet per day for a period of three weeks, supplemented with 20 g dried powdered Bitter gourd or 20 g dried powdered grass as isoenergetic control in a cross-over, within-subject design. RESULTS Bitter gourd fruit from the cultivars "Palee" and "Good healthy" reduced plasma fructosamine concentrations in all pigs combined (from 450±48 to 423±53 and 490±50 to 404±48 μmol/L, both p<0.03, respectively) indicating improved glycemic control by 6% and 17%. These effects were statistically confirmed in mildly D pigs but not in overtly D pigs. In mildly D pigs, the other three cultivars of fruit showed consistent numerical but no significant improvements in glycemic control. The composition of Bitter gourd fruit was studied by metabolomics profiling and analysis identified three metabolites from the class of triterpenoids (Xuedanoside H, Acutoside A, Karaviloside IX) that were increased in the cultivars "Palee" (>3.9-fold) and "Good healthy" (>8.9-fold) compared to the mean of the other three cultivars. Bitter gourd stems and leaves from the cultivar "Bilai" increased plasma insulin concentrations in all pigs combined by 28% (from 53±6 to 67±9 pmol/L, p<0.03). The other two cultivars of stems and leaves showed consistent numerical but no significant increases in plasma insulin concentrations. The effects on plasma insulin concentrations were confirmed in mildly D pigs but not in overtly D pigs. CONCLUSIONS Fruits of Bitter gourd improve glycemic control and stems-leaves of Bitter gourd increase plasma insulin concentrations in an obese pig model for mild diabetes. The effects of Bitter gourd fruit on glycemic control seem consistent but relatively small and cultivar specific which may explain the varying results of human trials reported in the literature.
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Affiliation(s)
- Sietse Jan Koopmans
- Wageningen Livestock Research, Wageningen University & Research, Wageningen, The Netherlands
| | - Gisabeth Binnendijk
- Wageningen Livestock Research, Wageningen University & Research, Wageningen, The Netherlands
| | - Allison Ledoux
- Natural Products Laboratory, Institute of Biology, Leiden University, Leiden, The Netherlands
| | - Young Hae Choi
- Natural Products Laboratory, Institute of Biology, Leiden University, Leiden, The Netherlands
- College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea
| | - Jurriaan J. Mes
- Wageningen Food & Biobased Research, Wageningen University & Research, Wageningen, The Netherlands
| | - Xiaonan Guan
- Schothorst Feed Research, Lelystad, The Netherlands
| | | | - Tâm Phạm Thị Minh
- Department of Food crops and Horticulture, Nong Lam University, Ho Chi Minh City, Vietnam
| | - Nikkie van der Wielen
- Department of Animal Nutrition and Division of Human Nutrition, Wageningen University & Research, Wageningen, The Netherlands
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Nan J, Wang D, Zhong R, Liu F, Luo J, Tang P, Song X, Zhang L. Sodium glucose cotransporter2 inhibitors for type 1 diabetes mellitus: A meta-analysis of randomized controlled trials. Prim Care Diabetes 2024; 18:17-24. [PMID: 37980217 DOI: 10.1016/j.pcd.2023.10.010] [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] [Received: 07/06/2023] [Revised: 10/08/2023] [Accepted: 10/22/2023] [Indexed: 11/20/2023]
Abstract
AIMS Sodium glucose cotransporter2 (SGLT2) inhibitors are controversial in the treatment of type 1 diabetes mellitus (T1DM). This study is a systematic evaluation of the safety of SGLT2 inhibitors usage in T1DM. METHODS Comprehensive literature search in six databases from inception to September 2022. Randomized controlled trials (RCTs) of T1DM treated with SGLT2 inhibitor vs. placebo were included. Data were extracted from the literature that met the inclusion criteria. After quality evaluation by the Cochrane risk bias assessment tool, meta-analysis was performed using Revman 5.4 and Stata 17.1. RESULTS The study consisted of 16 RCTs with 7192 patients. The results indicated that SGLT2inhibitors reduce glycated hemoglobin (HbA1c, Mean difference (MD)- 0.29%, P < 0.05), fasting plasma glucose (FPG, MD-0.85 mmol/L, P < 0.05), mean amplitude of glucose excursions (MAGE, 15.75 mg/dL, P < 0.05), body weight (MD-3.49 kg, P < 0.05), and total insulin dosage (MD-7.14 IU/day, P < 0.05). Furthermore, cautious SGLT2 inhibitors did not induce the risk of hypoglycemia (RR1.00, P = 0.86), urinary tract infections (RR1.02, P = 0.085), and diarrhea (RR1.34, P = 0.523). CONCLUSION Based on this meta-analysis, SGLT22 inhibitors reduce insulin dosage without increasing the risk of hypoglycemia and diabetic ketoacidosis for type 1 diabetes mellitus in 1month.
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Affiliation(s)
- Juanli Nan
- Department of General Practice, The First Affiliated Hospital of Kunming Medical University, Kunming 650031, China
| | - Dekai Wang
- Department of General Practice, The First Affiliated Hospital of Kunming Medical University, Kunming 650031, China
| | - Ruxian Zhong
- Department of General Practice, The First Affiliated Hospital of Kunming Medical University, Kunming 650031, China
| | - Fen Liu
- Department of General Practice, The First Affiliated Hospital of Kunming Medical University, Kunming 650031, China
| | - Jingmei Luo
- Department of General Practice, The First Affiliated Hospital of Kunming Medical University, Kunming 650031, China
| | - Ping Tang
- Department of General Practice, The First Affiliated Hospital of Kunming Medical University, Kunming 650031, China
| | - Xiaoxiao Song
- School of Public Health, Kunming Medical University, Kunming 650500, China
| | - Lihua Zhang
- Department of General Practice, The First Affiliated Hospital of Kunming Medical University, Kunming 650031, China.
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11
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Harris DD, Sabe SA, Xu CM, Sabra M, Broadwin M, Malhotra A, Li JW, Abid MR, Sellke FW. Sodium-glucose co-transporter 2 inhibitor canagliflozin modulates myocardial metabolism and inflammation in a swine model for chronic myocardial ischemia. Surgery 2024; 175:265-270. [PMID: 37940431 PMCID: PMC10841503 DOI: 10.1016/j.surg.2023.09.043] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2023] [Revised: 09/15/2023] [Accepted: 09/26/2023] [Indexed: 11/10/2023]
Abstract
BACKGROUND Inflammation and disruption of cardiac metabolism are prevalent in the setting of myocardial ischemia. Canagliflozin, a sodium-glucose costransporter-2 inhibitor, has beneficial effects on the heart, though the precise mechanisms are unknown. This study investigated the effects of canagliflozin therapy on metabolic pathways and inflammation in ischemic myocardial tissue using a swine model of chronic myocardial ischemia. METHODS Sixteen Yorkshire swine underwent placement of an ameroid constrictor to the left circumflex artery to induce chronic ischemia. Two weeks later, pigs received either no drug (n = 8) or 300 mg canagliflozin (n = 8) daily. Five weeks later, pigs underwent terminal harvest and tissue collection. RESULTS Canagliflozin treatment was associated with a trend toward decreased expression of fatty acid oxidation inhibitor acetyl-CoA carboxylase and decreased phosphorylated/inactivated acetyl-CoA carboxylase, a promotor of fatty acid oxidation, compared with control ischemic myocardium (P = .08, P = .03). There was also a significant modulation in insulin resistance markers p-IRS1, p-PKCα, and phosphoinositide 3-kinase in ischemic myocardium of the canagliflozin group compared with the control group (all P < .05). Canagliflozin treatment was associated with a significant increase in inflammatory markers interleukin 6, interleukin 17, interferon-gamma, and inducible nitric oxide synthase (all P < .05). There was a trend toward decreased expression of the anti-inflammatory cytokines interleukin 10 (P = .16) and interleukin 4 (P = .31) with canagliflozin treatment. CONCLUSION The beneficial effects of canagliflozin therapy appear to be associated with inhibition of fatty acid oxidation and enhancement of insulin signaling in ischemic myocardium. Interestingly, canagliflozin appears to increase the levels of several inflammatory markers, but further studies are required to better understand how canagliflozin modulates inflammatory signaling pathways.
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Affiliation(s)
- Dwight D Harris
- Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Rhode Island Hospital, Providence, RI
| | - Sharif A Sabe
- Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Rhode Island Hospital, Providence, RI
| | - Cynthia M Xu
- Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Rhode Island Hospital, Providence, RI
| | - Mohamed Sabra
- Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Rhode Island Hospital, Providence, RI
| | - Mark Broadwin
- Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Rhode Island Hospital, Providence, RI
| | - Akshay Malhotra
- Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Rhode Island Hospital, Providence, RI
| | - Janelle W Li
- Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Rhode Island Hospital, Providence, RI
| | - M Ruhul Abid
- Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Rhode Island Hospital, Providence, RI
| | - Frank W Sellke
- Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Rhode Island Hospital, Providence, RI.
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12
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Albaik M, Sheikh Saleh D, Kauther D, Mohammed H, Alfarra S, Alghamdi A, Ghaboura N, Sindi IA. Bridging the gap: glucose transporters, Alzheimer's, and future therapeutic prospects. Front Cell Dev Biol 2024; 12:1344039. [PMID: 38298219 PMCID: PMC10824951 DOI: 10.3389/fcell.2024.1344039] [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: 11/24/2023] [Accepted: 01/04/2024] [Indexed: 02/02/2024] Open
Abstract
Glucose is the major source of chemical energy for cell functions in living organisms. The aim of this mini-review is to provide a clearer and simpler picture of the fundamentals of glucose transporters as well as the relationship of these transporters to Alzheimer's disease. This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Electronic databases (PubMed and ScienceDirect) were used to search for relevant studies mainly published during the period 2018-2023. This mini-review covers the two main types of glucose transporters, facilitated glucose transporters (GLUTs) and sodium-glucose linked transporters (SGLTs). The main difference between these two types is that the first type works through passive transport across the glucose concentration gradient. The second type works through active co-transportation to transport glucose against its chemical gradient. Fluctuation in glucose transporters translates into a disturbance of normal functioning, such as Alzheimer's disease, which may be caused by a significant downregulation of GLUTs most closely associated with insulin resistance in the brain. The first sign of Alzheimer's is a lack of GLUT4 translocation. The second sign is tau hyperphosphorylation, which is caused by GLUT1 and 3 being strongly upregulated. The current study focuses on the use of glucose transporters in treating diseases because of their proven therapeutic potential. Despite this, studies remain insufficient and inconclusive due to the complex and intertwined nature of glucose transport processes. This study recommends further understanding of the mechanisms related to these vectors for promising future therapies.
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Affiliation(s)
- Mai Albaik
- Department of Chemistry Preparatory Year Program, Batterjee Medical College, Jeddah, Saudi Arabia
| | | | - Dana Kauther
- Medicine Program, Batterjee Medical College, Jeddah, Saudi Arabia
| | - Hajira Mohammed
- Medicine Program, Batterjee Medical College, Jeddah, Saudi Arabia
| | - Shurouq Alfarra
- Medicine Program, Batterjee Medical College, Jeddah, Saudi Arabia
| | - Adel Alghamdi
- Department of Biology Preparatory Year Program, Batterjee Medical College, Jeddah, Saudi Arabia
| | - Nehmat Ghaboura
- Department of Pharmacy Practice Pharmacy Program, Batterjee Medical College, Jeddah, Saudi Arabia
| | - Ikhlas A. Sindi
- Department of Biology, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
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13
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Kowalski S, Gifford S. In-Home Management of Diabetes and Obesity. Home Healthc Now 2024; 42:6-12. [PMID: 38190158 DOI: 10.1097/nhh.0000000000001223] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2024]
Abstract
The prevalence of type 2 diabetes and obesity is increasing. Research has demonstrated the use of GLP-1 RA and SGLT-2i medications to be safe and effective for the long-term management of T2DM and obesity. As continued research supports the use of GLP-1 RA and SGLT-2i medications for additional indications, home care clinicians will increasingly care for patients on these medications. It is imperative that home care clinicians are aware of patient indications, adverse effects, and potential safety considerations related to these drugs to ensure patient goals are met.
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14
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Lin YW, Lin CH, Lin CL, Lin CH, Lin MH. Association Between Use of Sodium-Glucose Cotransporter-2 Inhibitors or Angiotensin Receptor-Neprilysin Inhibitor and the Risk of Atherosclerotic Cardiovascular Disease With Coexisting Diabetes and Heart Failure. J Cardiovasc Pharmacol Ther 2024; 29:10742484241233872. [PMID: 38438119 DOI: 10.1177/10742484241233872] [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] [Indexed: 03/06/2024]
Abstract
PURPOSE This study was to investigate the association between the use of Sodium-glucose Cotransporter-2 inhibitors (SGLT2i) or angiotensin receptor-neprilysin inhibitor (ARNI; ie, Sacubitril + valsartan, Product name ENTRESTO) and the risk of atherosclerotic cardiovascular disease (ASCVD) in patients with coexisting diabetes and heart failure. Specifically, the study compared outcomes between patients using SGLT2i or valsartan + sacubitril and those not using these medications. METHODS This study utilized data from the National Health Insurance Research Database (NHIRD) from 2017 to 2018. The case group consisted of 8691 patients with coexisting diabetes and heart failure who did not use SGLT2i or Entresto, while the control group consisted of 8691 patients with coexisting diabetes and heart failure who used SGLT2i or Entresto. The primary outcome was ASCVD, including a composite of cardiovascular death and hospitalization for worsening heart failure. Secondary outcomes included all-cause death, cause of cardiovascular death, and recurrence of heart failure, non-fatal myocardial infarction, non-fatal stroke (including ischemic stroke and hemorrhagic stroke) and new renal replacement therapy. RESULTS The study found that the use of SGLT2 inhibitors or ARNI was associated with a lower risk of ASCVD in patients with coexisting diabetes and heart failure. CONCLUSION The study suggests that the use of SGLT2 inhibitors, alone or in combination with Entresto, may be effective in reducing the risk of ASCVD and its associated adverse outcomes in patients with diabetes and heart failure. This finding has important implications for the management of these conditions.
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Affiliation(s)
- Ya-Wen Lin
- School of Nursing, China Medical University, Taichung, Taiwan
- Department of Nursing, HungKuang University, Taichung, Taiwan
| | - Chun-Hsiang Lin
- Department of Neurology, Yuanlin Christian Hospital, Yuanlin, Changhua County, Taiwan
| | - Cheng-Li Lin
- Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan
| | - Che-Huei Lin
- Department of Pharmacy and Master Program, Tajen University, Pingtung, Taiwan
| | - Ming-Hung Lin
- Department of Pharmacy and Master Program, Tajen University, Pingtung, Taiwan
- Department of Nursing, National Taichung University of Science and Technology, Taichung, Taiwan
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15
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Uner BY, Yesildag O. SGLT-2i: Nanoparticular-Based Strategies, Solutions, and Clinical Applications in Opposition to Low Bioavailability. J Pharm Innov 2023; 18:2464-2470. [DOI: 11.https:/doi.org/10.1007/s12247-023-09789-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/26/2023] [Indexed: 03/30/2025]
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16
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Uner BY, Yesildag O. SGLT-2i: Nanoparticular-Based Strategies, Solutions, and Clinical Applications in Opposition to Low Bioavailability. J Pharm Innov 2023; 18:2464-2470. [DOI: 10.1007/s12247-023-09789-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/26/2023] [Indexed: 03/30/2025]
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Xue H, Hao Z, Gao Y, Cai X, Tang J, Liao X, Tan J. Research progress on the hypoglycemic activity and mechanisms of natural polysaccharides. Int J Biol Macromol 2023; 252:126199. [PMID: 37562477 DOI: 10.1016/j.ijbiomac.2023.126199] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 06/19/2023] [Accepted: 08/05/2023] [Indexed: 08/12/2023]
Abstract
The incidence of diabetes, as a metabolic disease characterized by high blood sugar levels, is increasing every year. The predominantly western medicine treatment is associated with certain side effects, which has prompted people to turn their attention to natural active substances. Natural polysaccharide is a safe and low-toxic natural substance with various biological activities. Hypoglycemic activity is one of the important biological activities of natural polysaccharides, which has great potential for development. A systematic review of the latest research progress and possible molecular mechanisms of hypoglycemic activity of natural polysaccharides is of great significance for better understanding them. In this review, we systematically reviewed the relationship between the hypoglycemic activity of polysaccharides and their structure in terms of molecular weight, monosaccharide composition, and glycosidic bonds, and summarized underlying molecular mechanisms the hypoglycemic activity of natural polysaccharides. In addition, the potential mechanisms of natural polysaccharides improving the complications of diabetes were analyzed and discussed. This paper provides some valuable insights and important guidance for further research on the hypoglycemic mechanisms of natural polysaccharides.
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Affiliation(s)
- Hongkun Xue
- College of Traditional Chinese Medicine, Hebei University, No. 342 Yuhua East Road, Lianchi District, Baoding 071002, China
| | - Zitong Hao
- College of Traditional Chinese Medicine, Hebei University, No. 342 Yuhua East Road, Lianchi District, Baoding 071002, China
| | - Yuchao Gao
- College of Traditional Chinese Medicine, Hebei University, No. 342 Yuhua East Road, Lianchi District, Baoding 071002, China
| | - Xu Cai
- Key Laboratory of Particle & Radiation Imaging, Ministry of Education, Department of Engineering Physics, Tsinghua University, No. 30 Shuangqing Road, Haidian District, Beijing 100084, China
| | - Jintian Tang
- Key Laboratory of Particle & Radiation Imaging, Ministry of Education, Department of Engineering Physics, Tsinghua University, No. 30 Shuangqing Road, Haidian District, Beijing 100084, China
| | - Xiaojun Liao
- College of Food Science and Nutritional Engineering, China Agricultural University, No. 17 Qinghua East Road, Haidian District, Beijing 100083, China.
| | - Jiaqi Tan
- College of Traditional Chinese Medicine, Hebei University, No. 342 Yuhua East Road, Lianchi District, Baoding 071002, China; Medical Comprehensive Experimental Center, Hebei University, No. 342 Yuhua East Road, Lianchi District, Baoding 071002, China.
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18
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van Hulten V, Driessen JHM, Starup-Linde JK, Al-Mashhadi ZK, Viggers R, Klungel OH, Souverein PC, Vestergaard P, Stehouwer CDA, van den Bergh JP. The associations of sodium-glucose cotransporter-2 inhibitors versus dipeptidyl peptidase-4 inhibitors as add-on to metformin with fracture risk in patients with type 2 diabetes mellitus. Diabetes Obes Metab 2023; 25:3235-3247. [PMID: 37503747 DOI: 10.1111/dom.15220] [Citation(s) in RCA: 2] [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] [Received: 05/23/2023] [Revised: 06/28/2023] [Accepted: 07/02/2023] [Indexed: 07/29/2023]
Abstract
AIM To investigate whether sodium-glucose cotransporter-2 (SGLT2) inhibitor use as compared to dipeptidyl peptidase-4 (DPP-4) inhibitor use as add-on to metformin is associated with the risk of any fracture or major osteoporotic fractures (MOFs). METHODS A cohort study using the Clinical Practice Research Datalink (CPRD) Aurum database was conducted. All patients aged 18 years and older with a first-ever prescription for a DPP-4 inhibitor or an SGLT2 inhibitor as add-on to metformin between January 1, 2013 and June 30, 2020 were selected. Patients starting with SGLT2 inhibitors were matched (up to 1:3) on propensity scores to patients starting with DPP-4 inhibitors. Propensity scores were calculated based on sex, age, body mass index, comorbidities, comedication and lifestyle factors. Cox proportional hazard models were used to estimate the risk of fracture with SGLT2 inhibitor use as compared to DPP-4 inhibitor use. RESULTS A total of 13 807 SGLT2 inhibitor users (age 55.4 ± 10.6 years, 36.7% female) were included in this study, matched with 28 524 DPP-4 inhibitor users (age 55.4 ± 8.0 years, 36.4% female). The risk of any fracture with current SGLT2 inhibitor use was similar compared with current DPP-4 inhibitor use (adjusted hazard ratio [aHR] 1.09, 95% confidence interval [CI] 0.91-1.31), as was the risk of MOFs (aHR 0.89, 95% CI 0.64-1.22) and the risk of fractures at any of the individual MOF sites. Additionally, no association was found with duration of SGLT2 inhibitor use (longest duration >811 days) for any of the individual SGLT2 inhibitor agents, or after stratification by sex and age. CONCLUSION Use of SGLT2 inhibitors was not associated with the risk of any fracture, MOFs or fracture at the individual MOF sites when compared to DPP-4 inhibitor use.
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Affiliation(s)
- Veerle van Hulten
- Department of Clinical Pharmacy and Toxicology, Maastricht University Medical Centre+ (MUMC+), Maastricht, The Netherlands
- School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, The Netherlands
- Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands
- Division of Pharmacoepidemiology & Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
| | - Johanna H M Driessen
- Department of Clinical Pharmacy and Toxicology, Maastricht University Medical Centre+ (MUMC+), Maastricht, The Netherlands
- School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, The Netherlands
- Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands
- Division of Pharmacoepidemiology & Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
| | - Jakob K Starup-Linde
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Zheer K Al-Mashhadi
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
- Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Rikke Viggers
- Steno Diabetes Center North Denmark, Aalborg, Denmark
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
| | - Olaf H Klungel
- Division of Pharmacoepidemiology & Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
| | - Patrick C Souverein
- Division of Pharmacoepidemiology & Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
| | - Peter Vestergaard
- Steno Diabetes Center North Denmark, Aalborg, Denmark
- Department of Endocrinology, Aalborg University Hospital, Aalborg, Denmark
| | - Coen D A Stehouwer
- Department of Internal Medicine, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre+ (MUMC+), Maastricht, Netherlands
| | - Joop P van den Bergh
- School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, The Netherlands
- Department of Internal Medicine, Division of Rheumatology, Maastricht University Medical Centre+ (MUMC+), Maastricht, The Netherlands
- Department of Internal Medicine, Subdivision of Endocrinology, VieCuri Medical Center, Venlo, The Netherlands
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Gupta R, Maitz T, Egeler D, Mehta A, Nyaeme M, Hajra A, Goel A, Sreenivasan J, Patel N, Aronow WS. SGLT2 inhibitors in hypertension: Role beyond diabetes and heart failure. Trends Cardiovasc Med 2023; 33:479-486. [PMID: 35597430 DOI: 10.1016/j.tcm.2022.05.005] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 05/05/2022] [Accepted: 05/14/2022] [Indexed: 12/15/2022]
Abstract
Type 2 Diabetes Mellitus (T2DM) is a pandemic that affects millions of patients worldwide. Diabetes affects multiple organ systems leading to comorbidities including hypertension. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) recently have been approved for the treatment of T2DM and heart failure with reduced and preserved ejection fraction. Retrospective analyses of clinical trials have noted SGLT2 inhibitors to have a promising effect on blood pressure. Moreover, the observed blood pressure reduction is not just an acute effect of treatment initiation but has been shown to have a long-term impact on both systolic and diastolic blood pressure. The mechanism of action leading to the blood pressure reduction is still unclear; however, proposed mechanisms are related to the natriuretic effect, modification of the renin-angiotensin-aldosterone system, and/or the reduction in the sympathetic nervous system, SGLT2i should be considered as second-line medication in those patients with diabetes or heart disease and concomitant hypertension. This article reviews the pharmacology, side effect profile, and clinical trials surrounding the use of SGLT2i for the treatment of hypertension.
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Affiliation(s)
- Rahul Gupta
- Lehigh Valley Heart Institute, Lehigh Valley Health Network, Allentown, PA, USA.
| | - Theresa Maitz
- Department of Medicine, Lehigh Valley Health Network, Allentown, PA, USA
| | - David Egeler
- Department of Medicine, Lehigh Valley Health Network, Allentown, PA, USA
| | - Anila Mehta
- Department of Medicine, Carle Foundation Hospital, Urbana, IL, USA
| | - Mark Nyaeme
- Department of Medicine, Carle Foundation Hospital, Urbana, IL, USA
| | - Adrija Hajra
- Department of Medicine, Jacobi Medical Center, Bronx, NY, USA
| | - Akshay Goel
- Department of Cardiology, Westchester Medical Center and New York Medical College, Valhalla, NY, USA
| | - Jayakumar Sreenivasan
- Department of Cardiology, Westchester Medical Center and New York Medical College, Valhalla, NY, USA
| | - Neel Patel
- Department of Cardiology, Kansas University Medical Center, Kansas City, KS, USA
| | - Wilbert S Aronow
- Department of Cardiology, Westchester Medical Center and New York Medical College, Valhalla, NY, USA
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Rathore A, Gupta N, Kahn C, Kadariya D. Euglycemic diabetic ketoacidosis caused by empagliflozin complicated by failure to thrive in a geriatric patient. Arch Clin Cases 2023; 10:89-92. [PMID: 37313125 PMCID: PMC10258732 DOI: 10.22551/2023.39.1002.10248] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/15/2023] Open
Abstract
Euglycemic diabetic ketoacidosis (euDKA) is a rare but deadly complication of sodium-glucose cotransport-2 (SGLT-2) inhibitors. Primarily indicated for the treatment of Type 2 Diabetes Mellitus, the incidence of euDKA is expected to rise as SGLT-2 inhibitors become a mainstay therapy for diabetics with heart failure. Diagnosis of euDKA can be difficult given the presence of normoglycemia and is especially challenging among geriatric patients that are complicated by additional comorbidities. We present a case of an elderly male with multiple comorbidities who presented for dehydration and altered mentation from a nursing home facility. Laboratory investigations showed signs of acute renal failure, uremia, electrolyte abnormalities, and severe metabolic acidosis due to high levels of plasma beta-hydroxybutyrate. He was admitted to the medical intensive care unit (ICU) for further management. A presumptive diagnosis of euDKA was strongly suspected due to his laboratory data and medication reconciliation which revealed the recent initiation of empagliflozin. The patient was promptly started on a standardized treatment protocol for DKA with continuous infusion of regular insulin with strict glucose monitoring, along with intravenous fluids, and a small dose of sodium bicarbonate infusion as per current standard guidelines. With the rapid improvement in symptoms and metabolic derangements, the diagnosis was confirmed. Geriatric patients from nursing home facilities are a high-risk cohort who if not properly cared for by nursing staff can develop dehydration, malnutrition and worsening frailty including sarcopenia that exposes them to increased risk of medication side effects, such as euDKA. Clinicians should consider euDKA in their differential diagnosis in elderly patients with overt or relative insulinopenia who are receiving SGLT-2 inhibitors when presenting with acute changes in health and mentation.
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Affiliation(s)
- Azeem Rathore
- Department of Medicine, University of Florida College of Medicine, Jacksonville FL, USA
| | - Nidhi Gupta
- Department of Medicine, Division of Endocrinology, University of Florida College of Medicine, Jacksonville FL, USA
| | - Cameron Kahn
- Department of Medicine, University of Florida College of Medicine, Jacksonville FL, USA
| | - Dinesh Kadariya
- Department of Medicine, Division of Cardiology, University of Florida College of Medicine, Jacksonville FL, USA
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Adherence to Oral Antidiabetic Drugs in Patients with Type 2 Diabetes: Systematic Review and Meta-Analysis. J Clin Med 2023; 12:jcm12051981. [PMID: 36902770 PMCID: PMC10004070 DOI: 10.3390/jcm12051981] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 02/27/2023] [Accepted: 02/28/2023] [Indexed: 03/06/2023] Open
Abstract
Poor adherence to oral antidiabetic drugs (OADs) in patients with type 2 diabetes (T2D) can lead to therapy failure and risk of complications. The aim of this study was to produce an adherence proportion to OADs and estimate the association between good adherence and good glycemic control in patients with T2D. We searched in MEDLINE, Scopus, and CENTRAL databases to find observational studies on therapeutic adherence in OAD users. We calculated the proportion of adherent patients to the total number of participants for each study and pooled study-specific adherence proportions using random effect models with Freeman-Tukey transformation. We also calculated the odds ratio (OR) of having good glycemic control and good adherence and pooled study-specific OR with the generic inverse variance method. A total of 156 studies (10,041,928 patients) were included in the systematic review and meta-analysis. The pooled proportion of adherent patients was 54% (95% confidence interval, CI: 51-58%). We observed a significant association between good glycemic control and good adherence (OR: 1.33; 95% CI: 1.17-1.51). This study demonstrated that adherence to OADs in patients with T2D is sub-optimal. Improving therapeutic adherence through health-promoting programs and prescription of personalized therapies could be an effective strategy to reduce the risk of complications.
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Muacevic A, Adler JR, Dhillon GS, Shah P. Empagliflozin-Associated Euglycemic Diabetic Ketoacidosis in a Patient With Type 2 Diabetes Mellitus. Cureus 2023; 15:e33892. [PMID: 36819400 PMCID: PMC9934848 DOI: 10.7759/cureus.33892] [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] [Accepted: 01/16/2023] [Indexed: 01/19/2023] Open
Abstract
Euglycemic diabetic ketoacidosis (euDKA) is an uncommon condition, which is characterized by an elevated anion gap metabolic acidosis with ketonemia/ketonuria, in the presence of normal blood glucose levels. Common risk factors for the development of this condition include pregnancy, prolonged fasting, acute pancreatitis, and bariatric surgery. Sodium-glucose cotransporter-2 (SGLT-2) inhibitors have been identified as a rare cause of euDKA. A recent literature review on PubMed found only 86 case reports of euDKA secondary to SGLT inhibitors published in the medical literature up to December 2022. Here, we present the case of a 43-year-old man who was taking empagliflozin, an SGLT-2 inhibitor. The patient was found to have euDKA, which was likely an adverse effect of his medication.
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23
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Dobrică EC, Banciu ML, Kipkorir V, Khazeei Tabari MA, Cox MJ, Simhachalam Kutikuppala LV, Găman MA. Diabetes and skin cancers: Risk factors, molecular mechanisms and impact on prognosis. World J Clin Cases 2022; 10:11214-11225. [PMID: 36387789 PMCID: PMC9649529 DOI: 10.12998/wjcc.v10.i31.11214] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 08/20/2022] [Accepted: 09/21/2022] [Indexed: 02/05/2023] Open
Abstract
Diabetes and skin cancers have emerged as threats to public health worldwide. However, their association has been less intensively studied. In this narrative review, we explore the common risk factors, molecular mechanisms, and prognosis of the association between cutaneous malignancies and diabetes. Hyperglycemia, oxidative stress, low-grade chronic inflammation, genetic, lifestyle, and environmental factors partially explain the crosstalk between skin cancers and this metabolic disorder. In addition, diabetes and its related complications may interfere with the appropriate management of cutaneous malignancies. Antidiabetic medication seems to exert an antineoplastic effect, however, future large, observation studies with a prospective design are needed to clarify its impact on the risk of malignancy in diabetes. Screening for diabetes in skin cancers, as well as close follow-up for the development of cutaneous malignancies in subjects suffering from diabetes, is warranted.
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Affiliation(s)
- Elena-Codruta Dobrică
- Doctoral School, University of Medicine and Pharmacy of Craiova, Craiova 200349, Romania
| | - Madalina Laura Banciu
- Department of Dermatology, "Elias" University Emergency Hospital, Bucharest 011461, Romania
| | - Vincent Kipkorir
- Department of Human Anatomy, University of Nairobi, College of Health Sciences, Nairobi 00100, Kenya
| | | | - Madeleine Jemima Cox
- University of New South Wales, University of New South Wales, Sydney 2052, Australia
| | | | - Mihnea-Alexandru Găman
- Faculty of Medicine, "Carol Davila" University of Medicine and Pharmacy, Bucharest 050474, Romania
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24
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Koullias ES, Koskinas J. Pharmacotherapy for Non-alcoholic Fatty Liver Disease Associated with Diabetes Mellitus Type 2. J Clin Transl Hepatol 2022; 10:965-971. [PMID: 36304499 PMCID: PMC9547270 DOI: 10.14218/jcth.2021.00564] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 04/14/2022] [Accepted: 04/27/2022] [Indexed: 12/04/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) and diabetes mellitus type 2 commonly coexist as a manifestation of metabolic syndrome. The presence of diabetes promotes the progression of simple fatty liver to non-alcoholic steatohepatitis (NASH) and cirrhosis, and the presence of NAFLD increases the risk of diabetic complications. This coexistence affects a large part of the population, imposing a great burden on health care systems worldwide. Apart from diet modification and exercise, recent advances in the pharmacotherapy of diabetes offer new prospects regarding liver steatosis and steatohepatitis improvement, enriching the existing algorithm and supporting a multifaceted approach to diabetic patients with fatty liver disease. These agents mainly include members of the families of glucagon-like peptide-1 analogues and the sodium-glucose co-transporter-2 inhibitors. In addition, agents acting on more than one receptor simultaneously are presently under study, in an attempt to further enhance our available options.
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Affiliation(s)
- Emmanouil S. Koullias
- Correspondence to: Emmanouil S. Koullias, 2nd Department of Internal Medicine, National and Kapodistrian University of Athens, Ampelokipoi, Athens, Greece. ORCID: https://orcid.org/0000-0002-4037-7123. Tel: +69-4-5631-395, E-mail:
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25
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Suplotovа LA, Kulmametova DS, Fedorova AI, Dushina TS, Makarova OB. Effect of sodium-glucose cotransporter type 2 inhibitors on non-alcoholic fatty liver disease. MEDITSINSKIY SOVET = MEDICAL COUNCIL 2022:83-89. [DOI: 10.21518/2079-701x-2022-16-15-83-89] [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 is one of the most common liver diseases, morphologically representing a whole spectrum of pathological conditions, from steatosis and steatohepatitis to fibrosis, the clinical outcomes of which can be liver cirrhosis and hepatocellular carcinoma. The frequency of adverse outcomes in the course of non-alcoholic fatty liver disease significantly increases against the background of type 2 diabetes mellitus, which is probably due to the pathogenetic synergy of non-alcoholic fatty liver disease and type 2 diabetes mellitus associated with metabolic syndrome. The commonality of pathogenetic links, as a result, suggests the unidirectionality of therapeutic approaches. In this connection, a search was made for studies and meta-analyses in large electronic databases (MEDLINE, Scopus, UpToDate, CyberLeninka) in order to study modern methods of pharmacotherapy for non-alcoholic fatty liver disease and type 2 diabetes mellitus. The results of a number of experimental and clinical studies evaluating the effect of hypoglycemic drugs of the group of sodium-glucose cotransporter type 2 inhibitors on non-alcoholic fatty liver disease demonstrate a wide range of intrahepatic effects that affect the manifestations of liver steatosis and fibrosis through the regulation of oxidative stress, endoplasmic reticulum stress, effects on intrahepatic inflammation, autophagy and apoptosis, as well as indirectly affecting hepatic metabolism, by reducing body weight. In addition, today gliflozins are rushing to occupy a completely new therapeutic niche, demonstrating anticarcinogenic effects in experimental studies. Thus, the pleiotropic effect of inhibitors of the sodium-glucose cotransporter type 2 suggests a potential hepatoprotective effect in the treatment of non-alcoholic fatty liver disease and its outcomes.
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26
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Kamel AS, Wahid A, Abdelkader NF, Ibrahim WW. Boosting amygdaloid GABAergic and neurotrophic machinery via dapagliflozin-enhanced LKB1/AMPK signaling in anxious demented rats. Life Sci 2022; 310:121002. [PMID: 36191679 DOI: 10.1016/j.lfs.2022.121002] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 09/19/2022] [Accepted: 09/22/2022] [Indexed: 11/18/2022]
Abstract
Anxiety is a neuropsychiatric disturbance that is commonly manifested in various dementia forms involving Alzheimer's disease (AD). The mechanisms underlying AD-associated anxiety haven't clearly recognized the role of energy metabolism in anxiety represented by the amygdala's autophagic sensors; liver kinase B1 (LKB1)/adenosine monophosphate kinase (AMPK). Dapagliflozin (DAPA), a SGLT2 inhibitor, acts as an autophagic activator through LKB1 activation in several diseases including AD. Herein, the propitious yet undetected anxiolytic potential of DAPA as an autophagic enhancer was investigated in AD animal model with emphasis on amygdala's GABAergic neurotransmission and brain-derived neurotrophic factor (BDNF). Alzheimer's disease was induced by ovariectomy (OVX) along with seventy-days-D-galactose (D-Gal) administration (150 mg/kg/day, i.p). On the 43rd day of D-Gal injection, OVX/D-Gal-subjected rats received DAPA (1 mg/kg/day, p.o) alone or with dorsomorphin the AMPK inhibitor (DORSO, 25 μg/rat, i.v.). In the amygdala, LKB1/AMPK were activated by DAPA inducing GABAB2 receptor stimulation; an effect that was abrogated by DORSO. Dapagliflozin also replenished the amygdala GABA, NE, and 5-HT levels along with glutamate suppression. Moreover, DAPA triggered BDNF production with consequent activation of its receptor, TrkB through activating GABAB2-related downstream phospholipase C/diacylglycerol/protein kinase C (PLC/DAG/PKC) signaling. This may promote GABAA expression, verifying the crosstalk between GABAA and GABAB2. The DAPA's anxiolytic effect was visualized by improved behavioral traits in elevated plus maze together with amendment of amygdala' histopathological abnormalities. Thus, the present study highlighted DAPA's anxiolytic effect which was attributed to GABAB2 activation and its function to induce BDNF/TrkB and GABAA expression through PLC/DAG/PKC pathway in AMPK-dependent manner.
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Affiliation(s)
- Ahmed S Kamel
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Egypt
| | - Ahmed Wahid
- Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Alexandria University, Egypt
| | - Noha F Abdelkader
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Egypt.
| | - Weam W Ibrahim
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Egypt
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27
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Khunti K, Jabbour S, Cos X, Mudaliar S, Mende C, Bonaca M, Fioretto P. Sodium-glucose co-transporter-2 inhibitors in patients with type 2 diabetes: Barriers and solutions for improving uptake in routine clinical practice. Diabetes Obes Metab 2022; 24:1187-1196. [PMID: 35238129 PMCID: PMC9313799 DOI: 10.1111/dom.14684] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 02/22/2022] [Accepted: 02/28/2022] [Indexed: 02/06/2023]
Abstract
Recent advances in type 2 diabetes (T2D) research have highlighted the benefits of sodium-glucose co-transporter-2 (SGLT-2) inhibitors, including cardiovascular and renal protection. However, uptake rates of these drugs remain low in patients with T2D, particularly in subpopulations most likely to benefit from them. This review considers the potential barriers to prescribing SGLT-2 inhibitors in T2D in clinical practice and outlines potential multidisciplinary recommendations to overcome these barriers. Safety concerns and a lack of clarity in and divergence of guidelines around the introduction of SGLT-2 inhibitors into treatment regimens may represent a barrier to uptake from the clinicians' perspective, including a general lack of understanding of the benefits associated with SGLT-2 inhibitors. Patient characteristics, such as socioeconomic status, may influence uptake because of the cost of SGLT-2 inhibitors, especially in the United States, where health insurance coverage could be a concern. SGLT-2 inhibitor prescription rates vary between clinical specialty (endocrinology, primary care, cardiology, and nephrology) and country, with cardiologists the lowest prescribers, and endocrinologists the highest. Primary care practitioners may experience more challenges in following SGLT-2 inhibitor-related guidelines than diabetes specialists as there may be fewer opportunities for education on how this drug class improves cardiovascular and renal outcomes in patients with T2D. Uptake rates appear to vary between countries because of differences in guidelines and health insurance systems. The amendment of SGLT-2 inhibitor-related guidelines for more multidisciplinary use and the implementation of patient and clinician education may encourage uptake of these drugs, potentially improving long-term health outcomes among patients with T2D.
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Affiliation(s)
- Kamlesh Khunti
- Diabetes Research Centre, College of Medicine, Biological Sciences and PsychologyUniversity of LeicesterLeicesterUK
- NIHR Applied Research Collaboration ‐ East MidlandsLeicesterUK
| | - Serge Jabbour
- Thomas Jefferson UniversityPhiladelphiaPennsylvaniaUSA
| | - Xavier Cos
- Sant Marti de Provençals Primary Care CentresBarcelonaSpain
- Institut Català de la Salut. IDIAP Jordi Gol. DAP_Cat Study Group CIBERDEMUniversitat Autonoma de BarcelonaBarcelonaSpain
| | - Sunder Mudaliar
- Department of MedicineUniversity of California, San Diego School of MedicineSan DiegoCaliforniaUSA
- Veterans Affairs Medical CenterSan DiegoCaliforniaUSA
| | - Christian Mende
- Department of MedicineUniversity of California San DiegoLa JollaCaliforniaUSA
| | - Marc Bonaca
- Department of Medicine, Division of CardiologyUniversity of Colorado School of Medicine, Aurora CO; CPC Clinical ResearchAuroraColoradoUSA
| | - Paola Fioretto
- Department of MedicineUniversity of Padua, Unite of Medical Clinic 3, Hospital of PaduaPaduaItaly
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28
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MacDonald TL, Pattamaprapanont P, Cooney EM, Nava RC, Mitri J, Hafida S, Lessard SJ. Canagliflozin Prevents Hyperglycemia-Associated Muscle Extracellular Matrix Accumulation and Improves the Adaptive Response to Aerobic Exercise. Diabetes 2022; 71:881-893. [PMID: 35108373 PMCID: PMC9044131 DOI: 10.2337/db21-0934] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Accepted: 01/27/2022] [Indexed: 02/03/2023]
Abstract
Chronic hyperglycemia is associated with low response to aerobic exercise training in rodent models and humans, including reduced aerobic exercise capacity and impaired oxidative remodeling in skeletal muscle. Here, we investigated whether glucose lowering with the sodium-glucose cotransporter 2 inhibitor (SGLT2i), canagliflozin (Cana; 30 mg/kg/day), could restore exercise training response in a model of hyperglycemia (low-dose streptozotocin [STZ]). Cana effectively prevented increased blood glucose in STZ-treated mice. After 6 weeks of voluntary wheel running, Cana-treated mice displayed improvements in aerobic exercise capacity, higher capillary density in striated muscle, and a more oxidative fiber-type in skeletal muscle. In contrast, these responses were blunted or absent in STZ-treated mice. Recent work implicates glucose-induced accumulation of skeletal muscle extracellular matrix (ECM) and hyperactivation of c-Jun N-terminal kinase (JNK)/SMAD2 mechanical signaling as potential mechanisms underlying poor exercise response. In line with this, muscle ECM accretion was prevented by Cana in STZ-treated mice. JNK/SMAD2 signaling with acute exercise was twofold higher in STZ compared with control but was normalized by Cana. In human participants, ECM accumulation was associated with increased JNK signaling, low VO2peak, and impaired metabolic health (oral glucose tolerance test-derived insulin sensitivity). These data demonstrate that hyperglycemia-associated impairments in exercise adaptation can be ameliorated by cotherapy with SGLT2i.
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Affiliation(s)
- Tara L. MacDonald
- Research Division, Joslin Diabetes Center, Boston, MA
- Harvard Medical School, Boston, MA
| | | | | | - Roberto C. Nava
- Research Division, Joslin Diabetes Center, Boston, MA
- Harvard Medical School, Boston, MA
| | - Joanna Mitri
- Research Division, Joslin Diabetes Center, Boston, MA
- Harvard Medical School, Boston, MA
| | - Samar Hafida
- Research Division, Joslin Diabetes Center, Boston, MA
- Harvard Medical School, Boston, MA
| | - Sarah J. Lessard
- Research Division, Joslin Diabetes Center, Boston, MA
- Harvard Medical School, Boston, MA
- Corresponding author: Sarah J. Lessard,
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29
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Dasari D, Bhat A, Mangali S, Ghatage T, Lahane GP, Sriram D, Dhar A. Canagliflozin and Dapagliflozin Attenuate Glucolipotoxicity-Induced Oxidative Stress and Apoptosis in Cardiomyocytes via Inhibition of Sodium-Glucose Cotransporter-1. ACS Pharmacol Transl Sci 2022; 5:216-225. [PMID: 35434529 PMCID: PMC9003386 DOI: 10.1021/acsptsci.1c00207] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Indexed: 12/19/2022]
Abstract
Sodium-dependent glucose cotransporter 2 inhibitors (SGLT2) are recently approved drugs for the treatment of diabetes that regulate blood glucose levels by inhibiting reabsorption of glucose and sodium in the proximal tubules of the kidney. SGLT2 inhibitors have also shown cardiovascular (CV) benefits in diabetic patients. However, the therapeutic efficacy of SGLT2 inhibitors with respect to CV disease needs further investigation. Thus, the aim of the present study was to examine the effects of SGLT2 inhibitors, canagliflozin (CANA) and dapagliflozin (DAPA) in vitro under glucolipotoxic condition by treating cultured cardiomyocytes (H9C2) with high glucose (HG) and high lipid, palmitic acid (PA), to investigate whether inhibition of sodium glucose cotransporter could prevent any harmful effects of glucolipotoxicity in these cells. SGLT1 expression was measured by immunofluorescence staining and quantitative polymerase chain reaction. Oxidative stress and apoptosis were measured by flow cytometry. Hypertrophy was measured by hematoxylin and eosin (H&E) and crystal violet staining. A significant increase in SGLT1 expression was observed in HG- and PA-treated cardiomyocytes. Also, a significant increase in reactive oxygen species generation and apoptosis was observed in HG+PA-treated cultured cardiomyocytes. HG- and PA-treated cardiomyocytes developed significant structural alterations. All these effects of HG and PA were attenuated by CANA and DAPA. In conclusion, our study demonstrates upregulation of SGLT1 induces oxidative stress and apoptosis in cultured cardiomyocytes. Thus, inhibition of SGLT1 may be used as a possible approach for the treatment of CVD in diabetic patients.
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Affiliation(s)
- Deepika Dasari
- Department of Pharmacy, Birla Institute of Technology and Sciences (BITS) Pilani, Hyderabad Campus, Jawahar Nagar, Shameerpet, Hyderabad, Telangana 500078, India
| | - Audesh Bhat
- Department of Molecular Biology, Central University of Jammu, Bagla Suchani, Jammu and Kashmir 181143, India
| | - Sureshbabu Mangali
- Department of Pharmacy, Birla Institute of Technology and Sciences (BITS) Pilani, Hyderabad Campus, Jawahar Nagar, Shameerpet, Hyderabad, Telangana 500078, India
| | - Trupti Ghatage
- Department of Pharmacy, Birla Institute of Technology and Sciences (BITS) Pilani, Hyderabad Campus, Jawahar Nagar, Shameerpet, Hyderabad, Telangana 500078, India
| | - Ganesh Panditrao Lahane
- Department of Pharmacy, Birla Institute of Technology and Sciences (BITS) Pilani, Hyderabad Campus, Jawahar Nagar, Shameerpet, Hyderabad, Telangana 500078, India.,Department of Molecular Biology, Central University of Jammu, Bagla Suchani, Jammu and Kashmir 181143, India
| | - Dharmarajan Sriram
- Department of Pharmacy, Birla Institute of Technology and Sciences (BITS) Pilani, Hyderabad Campus, Jawahar Nagar, Shameerpet, Hyderabad, Telangana 500078, India
| | - Arti Dhar
- Department of Pharmacy, Birla Institute of Technology and Sciences (BITS) Pilani, Hyderabad Campus, Jawahar Nagar, Shameerpet, Hyderabad, Telangana 500078, India
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30
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SGLT2 Inhibitors in Type 2 Diabetes Mellitus and Heart Failure-A Concise Review. J Clin Med 2022; 11:jcm11061470. [PMID: 35329796 PMCID: PMC8952302 DOI: 10.3390/jcm11061470] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2022] [Revised: 02/28/2022] [Accepted: 03/06/2022] [Indexed: 01/25/2023] Open
Abstract
The incidence of both diabetes mellitus type 2 and heart failure is rapidly growing, and the diseases often coexist. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are a new antidiabetic drug class that mediates epithelial glucose transport at the renal proximal tubules, inhibiting glucose absorption—resulting in glycosuria—and therefore improving glycemic control. Recent trials have proven that SGLT2i also improve cardiovascular and renal outcomes, including reduced cardiovascular mortality and fewer hospitalizations for heart failure. Reduced preload and afterload, improved vascular function, and changes in tissue sodium and calcium handling may also play a role. The expected paradigm shift in treatment strategies was reflected in the most recent 2021 guidelines published by the European Society of Cardiology, recommending dapagliflozin and empagliflozin as first-line treatment for heart failure patients with reduced ejection fraction. Moreover, the recent results of the EMPEROR-Preserved trial regarding empagliflozin give us hope that there is finally an effective treatment for patients with heart failure with preserved ejection fraction. This review aims to assess the efficacy and safety of these new anti-glycemic oral agents in the management of diabetic and heart failure patients.
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31
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Euglycemic Diabetic Ketoacidosis after Discontinuing SGLT2 Inhibitor. Case Rep Endocrinol 2022; 2022:4101975. [PMID: 35282610 PMCID: PMC8906987 DOI: 10.1155/2022/4101975] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 01/23/2022] [Accepted: 02/16/2022] [Indexed: 12/13/2022] Open
Abstract
Background Sodium glucose cotransporter-2 (SGLT2) inhibitors have been proven to be very effective in the management of type II diabetes. These medications can cause adverse drug reactions such as genital mycotic infections. Another critical adverse drug reaction is euglycemic diabetic ketoacidosis (EDKA) under the setting of other contributing risk factors for developing diabetic ketoacidosis. Case Presentation. We report a case of a 45-year-old gentleman with type 2 diabetes mellitus on empagliflozin, metformin, and glimepiride who presented with abdominal pain, fatigue, and vomiting. Of note, he started a ketogenic diet three days before his presentation and self-stopped his antidiabetic medications two days before his presentation. The patient was found to have euglycemic diabetic ketoacidosis and was treated as per the protocol. He was discharged on metformin and pioglitazone. Two weeks following discharge, canagliflozin was added. Conclusion Euglycemic diabetic ketoacidosis could still be precipitated despite discontinuation of SGLT2I under a ketogenic diet. Discussion related to the initiation of a ketogenic diet should occur between the care provider and the patient.
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32
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Barreto YB, Alencar AM. Random-walk model of the sodium-glucose transporter SGLT2 with stochastic steps and inhibition. JOURNAL OF PHYSICS. CONDENSED MATTER : AN INSTITUTE OF PHYSICS JOURNAL 2022; 34:184004. [PMID: 35090150 DOI: 10.1088/1361-648x/ac4fea] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Accepted: 01/28/2022] [Indexed: 06/14/2023]
Abstract
Random-walk models are frequently used to model distinct natural phenomena such as diffusion processes, stock-market fluctuations, and biological systems. Here, we present a random-walk model to describe the dynamics of glucose uptake by the sodium-glucose transporter of type 2, SGLT2. Our starting point is the canonical alternating-access model, which suggests the existence of six states for the transport cycle. We propose the inclusion of two new states to this canonical model. The first state is added to implement the recent discovery that the Na+ion can exit before the sugar is released into the proximal tubule epithelial cells. The resulting model is a seven-state mechanism with stochastic steps. Then we determined the transition probabilities between these seven states and used them to write a set of master equations to describe the time evolution of the system. We showed that our model converges to the expected equilibrium configuration and that the binding of Na+and glucose to SGLT2 in the inward-facing conformation must be necessarily unordered. After that, we added another state to implement inhibition in the model. Our results reproduce the experimental dependence of glucose uptake on the inhibitor concentration and they reveal that the inhibitors act by decreasing the number of available SGLT2s, which increases the chances of glucose escaping reabsorption.
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Affiliation(s)
- Yan B Barreto
- Instituto de Física, Universidade de São Paulo, 05508-090 São Paulo, São Paulo, Brazil
| | - Adriano M Alencar
- Instituto de Física, Universidade de São Paulo, 05508-090 São Paulo, São Paulo, Brazil
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33
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Буйваленко АВ, Покровская ЕВ. [Interaction between the gut microbiota and oral antihyperglycemic drugs]. PROBLEMY ENDOKRINOLOGII 2022; 68:66-71. [PMID: 35488758 PMCID: PMC9764270 DOI: 10.14341/probl12835] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 12/21/2021] [Accepted: 12/27/2021] [Indexed: 06/14/2023]
Abstract
The gut microbiome is the largest microbial habitat in the human body. The main functions include obtaining energy from complex food fibers, maturation and formation of the immune system, intestinal angiogenesis, restoration of epithelial damage to the intestine, development of the nervous system, protection against pathogens, etc. It is also known that a number of drugs can cause changes in the composition of the intestinal microflora, and intestinal bacteria, in turn, produce a number of enzymes and metabolites that can chemically change the structure of drugs, leading to more side effects, and in some cases to positive changes. In this review we present current evidence supporting the effects of microbiota in host-drug interactions, in particular, the reciprocal effects of gut microbiota and oral hypoglycemic drugs on each other. Gaining and evaluating knowledge in this area will help pave the way for the development of new microbiota-based strategies that can be used in the future to improve treatment outcomes for type 2 diabetes mellitus (T2D).
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34
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Katsenos AP, Davri AS, Simos YV, Nikas IP, Bekiari C, Paschou SA, Peschos D, Konitsiotis S, Vezyraki P, Tsamis KI. New treatment approaches for Alzheimer's disease: preclinical studies and clinical trials centered on antidiabetic drugs. Expert Opin Investig Drugs 2022; 31:105-123. [PMID: 34941464 DOI: 10.1080/13543784.2022.2022122] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) represent two major chronic diseases that affect a large percentage of the population and share common pathogenetic mechanisms, including oxidative stress and inflammation. Considering their common mechanistic aspects, and given the current lack of effective therapies for AD, accumulating research has focused on the therapeutic potential of antidiabetic drugs in the treatment or prevention of AD. AREAS COVERED This review examines the latest preclinical and clinical evidence on the potential of antidiabetic drugs as candidates for AD treatment. Numerous approved drugs for T2DM, including insulin, metformin, glucagon-like peptide-1 receptor agonists (GLP-1 RA), and sodium glucose cotransporter 2 inhibitors (SGLT2i), are in the spotlight and may constitute novel approaches for AD treatment. EXPERT OPINION Among other pharmacologic agents, GLP-1 RA and SGLT2i have so far exhibited promising results as novel treatment approaches for AD, while current research has centered on deciphering their action on the central nervous system (CNS). Further investigation is crucial to reveal the most effective pharmacological agents and their optimal combinations, maximize their beneficial effects on neurons, and find ways to increase their distribution to the CNS.
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Affiliation(s)
- Andreas P Katsenos
- Department of Physiology, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece.,Nanomedicine and Nanobiotechnology Research Group, University of Ioannina, Greece
| | - Athena S Davri
- Department of Physiology, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece
| | - Yannis V Simos
- Department of Physiology, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece.,Nanomedicine and Nanobiotechnology Research Group, University of Ioannina, Greece
| | - Ilias P Nikas
- School of Medicine, European University Cyprus, Nicosia, Cyprus
| | - Chryssa Bekiari
- Laboratory of Anatomy and Histology, school of Veterinary Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Stavroula A Paschou
- Endocrine Unit and Diabetes Centre, Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Dimitrios Peschos
- Department of Physiology, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece.,Nanomedicine and Nanobiotechnology Research Group, University of Ioannina, Greece
| | | | - Patra Vezyraki
- Department of Physiology, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece
| | - Konstantinos I Tsamis
- Department of Physiology, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece.,Nanomedicine and Nanobiotechnology Research Group, University of Ioannina, Greece.,Department of Neurology, University Hospital of Ioannina, Ioannina, Greece
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Ge V, Subramaniam A, Banakh I, Wang WC, Tiruvoipati R. Management of sodium-glucose cotransporter 2 inhibitors during the perioperative period: A retrospective comparative study. J Perioper Pract 2021; 31:391-398. [PMID: 32894998 DOI: 10.1177/1750458920948693] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
PURPOSE Current guidelines recommend withholding sodium-glucose cotransporter 2 inhibitors perioperatively due to concerns of euglycaemic diabetic ketoacidosis. However, such guidelines are largely based on case reports and small case series, many extrapolated from non-surgical patients. The aim was to investigate whether withholding sodium-glucose cotransporter 2 inhibitors as per current perioperative guidelines was associated with a reduction in serious adverse events, including euglycaemic diabetic ketoacidosis. METHODS Instances of perioperative management of sodium-glucose cotransporter 2 inhibitors, over a four-year period were classified into two categories: those where sodium-glucose cotransporter 2 inhibitors were withheld as per guidelines and those where sodium-glucose cotransporter 2 inhibitors were administered in the perioperative period. The primary outcome was 'total major perioperative complications': a composite of serious adverse events including euglycaemic diabetic ketoacidosis, diabetic ketoacidosis, acute kidney injury, urosepsis and death. RESULTS Eighty-two instances in 64 patients were included. Withholding sodium-glucose cotransporter 2 inhibitors was associated with an increased incidence of total major perioperative complications and poorer glycaemic control postoperatively. Multivariable logistic regression analysis revealed that withholding sodium-glucose cotransporter 2 inhibitors perioperatively (OR = 13.15; 95% CI = 1.8-138.9) and preoperative urea (OR 1.85 (95% CI = 1.17-3.43) were independently associated with an increase in total major postoperative complications. CONCLUSION Withholding sodium-glucose cotransporter 2 inhibitors as per current guidelines was associated with an increase in postoperative complications and reduced glycaemic control.
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Affiliation(s)
- Victor Ge
- Department of Intensive Care Medicine, Peninsula Health, Melbourne, Australia
| | - Ashwin Subramaniam
- Department of Intensive Care Medicine, Peninsula Health, Melbourne, Australia
- Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Australia
| | - Iouri Banakh
- Department of Pharmacy, Peninsula Health, Melbourne, Australia
| | - Wei Chun Wang
- Cabrini Health and Monash Health, Melbourne, Australia
| | - Ravindranath Tiruvoipati
- Department of Intensive Care Medicine, Peninsula Health, Melbourne, Australia
- Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Australia
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Deger M, Kaya B, Akdogan N, Kaplan HM, Bagir E, Izol V, Aridogan IA. Protective effect of dapagliflozin against cyclosporine A-induced nephrotoxicity. Drug Chem Toxicol 2021; 45:2637-2643. [PMID: 34565275 DOI: 10.1080/01480545.2021.1979996] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
This study aimed to reveal the possible protective effect of dapagliflozin (DAPA) against acute kidney damage due to cyclosporine A (CsA). Thirty-two mice with an eight-week-old Balb\c albino strain were divided into four groups: control group, CsA group, DAPA group, and CsA + DAPA group. On day 9 of treatment, the animals were decapitated, and bilateral nephrectomy was performed. Oxidative stress and apoptosis were evaluated with caspase-3 activity, total oxidant status (TOS), total antioxidant status (TAS), malondialdehyde (MDA), myeloperoxidase (MPO), B-cell lymphoma-2 (Bcl-2), and Bcl-2-associated X protein (Bax) in the right kidney resection material. The left kidney resection material was evaluated histopathologically. CsA increased caspase-3 activity, Bax, TOS, MDA, TAS, and MPO levels, and the administration of DAPA with CsA significantly reduced this increase in levels (p < 0.001, p < 0.001, p < 0.001, p < 0.001, p < 0.001, and p < 0.001, respectively). CsA decreased Bcl-2 levels, and administration of CsA + DAPA significantly increased Bcl-2 levels compared with only CsA administration (p < 0.001). Additionally, administration of DAPA significantly reduced the histopathological findings (parenchymal inflammation, hyaline cast formation, vacuolization, and lysis of renal tubular cells) caused by CsA. DAPA reduces oxidative stress, apoptosis, and histopathological damage caused by CsA in renal tissue.
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Affiliation(s)
- Mutlu Deger
- Department of Urology, Faculty of Medicine, Çukurova University, Adana, Turkey
| | - Bulent Kaya
- Department of Nephrology, Faculty of Medicine, Çukurova University, Adana, Turkey
| | - Nebil Akdogan
- Department of Urology, Faculty of Medicine, Çukurova University, Adana, Turkey
| | - Halil Mahir Kaplan
- Department of Pharmacology, Faculty of Medicine, Cukurova University, Adana, Turkey
| | - Emine Bagir
- Department of Pathology, Faculty of Medicine, Çukurova University, Adana, Turkey
| | - Volkan Izol
- Department of Urology, Faculty of Medicine, Çukurova University, Adana, Turkey
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Youssef ME, Abd El-Fattah EE, Abdelhamid AM, Eissa H, El-Ahwany E, Amin NA, Hetta HF, Mahmoud MH, Batiha GES, Gobba N, Ahmed Gaafar AG, Saber S. Interference With the AMPKα/mTOR/NLRP3 Signaling and the IL-23/IL-17 Axis Effectively Protects Against the Dextran Sulfate Sodium Intoxication in Rats: A New Paradigm in Empagliflozin and Metformin Reprofiling for the Management of Ulcerative Colitis. Front Pharmacol 2021; 12:719984. [PMID: 34489707 PMCID: PMC8417441 DOI: 10.3389/fphar.2021.719984] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Accepted: 07/26/2021] [Indexed: 12/20/2022] Open
Abstract
Empagliflozin and metformin are widely used for the treatment of type 2 diabetes. These drugs showed marked anti-inflammatory effects in different animal models via enhancing AMPK activity. Yet, the protective anti-inflammatory effects of their combination against ulcerative colitis have not been previously investigated. The current study aimed to explore the potential of empagliflozin/metformin combination to mitigate the DSS-induced rat colitis model. The modulating effects of empagliflozin and metformin on the AMPK/mTOR/NLRP3 axis and T cell polarization were delineated. In this study, distal colons were examined for macroscopic and microscopic pathological alterations. ELISA, qRT-PCR, and immunohistochemistry techniques were applied to detect proteins and cytokines involved in AMPK/mTOR/NLRP3 axis and T Cell polarization. Oral administration of empagliflozin (10 mg/kg/day) and metformin (200 mg/kg/day) combination alleviated colitis as revealed by the reduced disease activity index, macroscopic damage index, colon weight/length ratio, and histopathologic scoring values. Interestingly, empagliflozin/metformin combination significantly enhanced AMPK phosphorylation and depressed mTOR and NLRP3 expression leading to a subsequent reduction in caspase-1 cleavage and inhibition of several inflammatory cytokines, including IL-1β, and IL-18. Reduced mTOR expression and reduced IL-6 levels led to a reduction in Th17 cell polarization and maintenance. Together, the current study reveals that the protective effects of empagliflozin and metformin against DSS-induced colitis are fundamentally mediated via enhancing AMPK phosphorylation. Since adult humans with diabetes mellitus are at greater risk for developing inflammatory bowel diseases, clinical application of empagliflozin/metformin combination represents a novel therapeutic approach for treating diabetic patients with ulcerative colitis.
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Affiliation(s)
- Mahmoud E Youssef
- Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt
| | - Eslam E Abd El-Fattah
- Department of Biochemistry, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt
| | - Amir M Abdelhamid
- Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt
| | - Hanan Eissa
- Department of Clinical Pharmacology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Eman El-Ahwany
- Department of Immunology, Theodor Bilharz Research Institute, Giza, Egypt
| | - Noha A Amin
- Department of Hematology, Theodor Bilharz Research Institute, Giza, Egypt
| | - Helal F Hetta
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, Egypt.,Department of Internal Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH, United States
| | - Mohamed H Mahmoud
- Department of Biochemistry, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Gaber El-Saber Batiha
- Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicine, Damanhour University, Damanhour, Egypt
| | - Naglaa Gobba
- Department of Pharmacology and Toxicology, College of Pharmacy, Misr University for Science and Technology, 6th of October City, Egypt
| | - Ahmed Gaafar Ahmed Gaafar
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Port-Said University, Port-Said, Egypt
| | - Sameh Saber
- Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt
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Sodium-Glucose Cotransporter-2 Inhibitor Use is Associated with a Reduced Risk of Heart Failure Hospitalization in Patients with Heart Failure with Preserved Ejection Fraction and Type 2 Diabetes Mellitus: A Real-World Study on a Diverse Urban Population. Drugs Real World Outcomes 2021; 9:53-62. [PMID: 34478119 PMCID: PMC8844327 DOI: 10.1007/s40801-021-00277-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/10/2021] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Limited evidence-based therapies exist for the management of heart failure with preserved ejection fraction (HFpEF). Sodium-glucose cotransporter-2 inhibitor (SGLT2i) use in patients with systolic heart failure (HFrEF) and type-2-diabetes mellitus (T2DM) is associated with improved cardiovascular (CV) and renal outcomes. OBJECTIVE We sought to examine whether there is an association of SGLT2i use with improved CV outcomes in patients with HFpEF. PATIENTS AND METHODS We conducted a single-center, retrospective review of patients with HFpEF and T2DM. The cohort was divided into two groups based on prescription of a SGLT2i or sitagliptin. The primary outcome was heart failure hospitalization (HFH); secondary outcomes were all-cause hospitalization and acute kidney injury (AKI). RESULTS After propensity score matching, there were 250 patients (89 in the SGLT2i group, 161 in the sitagliptin group), with a mean follow-up of 295 days. Univariate Cox regression analysis showed that the SGLT2i group had a reduced risk of HFH versus the sitagliptin group (hazard ratio (HR) 0.13; 95% confidence interval (CI) (0.05-0.36); p < 0.001). The SGLT2i group had a decreased risk of all-cause hospitalization (HR 0.48; 95% CI (0.33-0.70); p < 0.001) and SGLT2i had a lower risk of AKI (HR 0.39; 95% CI (0.20-0.74); p = 0.004). CONCLUSIONS The use of SGLT2is is associated with a reduced incidence of HFH and AKI in patients with HFpEF and T2DM.
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Sopek Merkaš I, Slišković AM, Lakušić N. Current concept in the diagnosis, treatment and rehabilitation of patients with congestive heart failure. World J Cardiol 2021; 13:183-203. [PMID: 34367503 PMCID: PMC8326153 DOI: 10.4330/wjc.v13.i7.183] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 05/20/2021] [Accepted: 07/09/2021] [Indexed: 02/06/2023] Open
Abstract
Heart failure (HF) is a major public health problem with a prevalence of 1%-2% in developed countries. The underlying pathophysiology of HF is complex and as a clinical syndrome is characterized by various symptoms and signs. HF is classified according to left ventricular ejection fraction (LVEF) and falls into three groups: LVEF ≥ 50% - HF with preserved ejection fraction (HFpEF), LVEF < 40% - HF with reduced ejection fraction (HFrEF), LVEF 40%-49% - HF with mid-range ejection fraction. Diagnosing HF is primarily a clinical approach and it is based on anamnesis, physical examination, echocardiogram, radiological findings of the heart and lungs and laboratory tests, including a specific markers of HF - brain natriuretic peptide or N-terminal pro-B-type natriuretic peptide as well as other diagnostic tests in order to elucidate possible etiologies. Updated diagnostic algorithms for HFpEF have been recommended (H2FPEF, HFA-PEFF). New therapeutic options improve clinical outcomes as well as functional status in patients with HFrEF (e.g., sodium-glucose cotransporter-2 - SGLT2 inhibitors) and such progress in treatment of HFrEF patients resulted in new working definition of the term "HF with recovered left ventricular ejection fraction". In line with rapid development of HF treatment, cardiac rehabilitation becomes an increasingly important part of overall approach to patients with chronic HF for it has been proven that exercise training can relieve symptoms, improve exercise capacity and quality of life as well as reduce disability and hospitalization rates. We gave an overview of latest insights in HF diagnosis and treatment with special emphasize on the important role of cardiac rehabilitation in such patients.
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Affiliation(s)
- Ivana Sopek Merkaš
- Department of Cardiology, Special Hospital for Medical Rehabilitation Krapinske Toplice, Krapinske Toplice 49217, Croatia.
| | - Ana Marija Slišković
- Department of Cardiology, University Hospital Centre Zagreb, Zagreb 10000, Croatia
| | - Nenad Lakušić
- Department of Cardiology, Special Hospital for Medical Rehabilitation Krapinske Toplice, Krapinske Toplice 49217, Croatia
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Shaheer A, Kumar A, Menon P, Jallo M, Basha S. Effect of Add-On Therapy of Sodium-Glucose Cotransporter 2 Inhibitors and Dipeptidyl Peptidase 4 Inhibitors on Adipokines in Type 2 Diabetes Mellitus. J Clin Med Res 2021; 13:355-362. [PMID: 34267843 PMCID: PMC8256907 DOI: 10.14740/jocmr4510] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Accepted: 05/07/2021] [Indexed: 02/07/2023] Open
Abstract
Background Excess adiposity is associated with an increased risk of cardiovascular disease due to metabolic changes in the body. Visceral obesity increases the risk of diabetes mellitus through adipocytokines and hence the effective targeting therapies are essential to control obesity in high-risk individuals. The study's main objective was to evaluate the effect of add-on therapy of sodium-glucose cotransporter 2 (SGLT2) inhibitors and dipeptidyl peptidase 4 (DPP4) inhibitors on visceral fat-associated serum adipokines. Methods The study included 90 subjects diagnosed with type 2 diabetes mellitus. The blood samples were taken before starting first-line therapy with metformin, 12 weeks after starting metformin therapy and 12 weeks after starting add-on therapy. Serum adipokines were analyzed with enzyme-linked immunosorbent assay (ELISA). Hemoglobin A1c (HbA1c) level was estimated with high-performance liquid chromatography (HPLC). The biochemical variables were measured using Cobas® 6000 analyzer. Results The mean adiponectin level was significantly elevated with add-on therapy using SGLT2 inhibitors and DPP4 inhibitors (P < 0.001). The mean retinol binding protein 4 (RBP4), fatty acid binding protein 4 (FABP4) and visfatin levels were reduced considerably (P < 0.001). The SGLT2 inhibitors are more effective on serum FABP4 in patients with type 2 diabetes (P = 0.038). The mean fasting plasma glucose (FPG), postprandial blood glucose (PPBG) and HbA1c levels were reduced significantly with add-on therapy (P < 0.001). Lipid profile was also altered significantly with this add-on therapy (P < 0.001). Conclusions The results indicate that add-on therapy exerts a beneficial effect in type 2 diabetic patients insufficiently controlled with metformin only by altering the visceral fat-associated adipokine levels and controlling the metabolic activities.
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Affiliation(s)
- Abid Shaheer
- Department of Biomedical Sciences, Gulf Medical University, Ajman, United Arab Emirates
| | - Ashok Kumar
- Department of Biochemistry, Rajah Muthiah Medical College, Annamalai University, Chidambaram, India
| | - Palat Menon
- Clinical Department, Pathology Laboratory, Fakeeh University Hospital, Dubai, United Arab Emirates
| | - Mahir Jallo
- Department of Internal Medicine, Gulf Medical University, Ajman, United Arab Emirates
| | - Shaikh Basha
- Department of Internal Medicine, Gulf Medical University, Ajman, United Arab Emirates
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Cure E, Sirin H, Cure MC, Sahin DA. Dapagliflozin-induced long-term and severe anorexia and weight loss: An extraordinary case. Indian J Pharmacol 2021. [PMID: 34100404 DOI: 10.4103/ijp.ijp_785_19.] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Affiliation(s)
- Erkan Cure
- Department of Internal Medicine, Ota and Jinemed Hospital, Istanbul, Turkey
| | - Hakan Sirin
- Department of Urology, Basaksehir Cam ve Sakura City Hospital, Istanbul, Turkey
| | - Medine Cumhur Cure
- Department of Biochemistry, Private Kucukcekmece Hospital, Istanbul, Turkey
| | - Dursun Ali Sahin
- Department of General Surgery, Private Practise, Istanbul, Turkey
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Strain WD, Down S, Brown P, Puttanna A, Sinclair A. Diabetes and Frailty: An Expert Consensus Statement on the Management of Older Adults with Type 2 Diabetes. Diabetes Ther 2021; 12:1227-1247. [PMID: 33830409 PMCID: PMC8099963 DOI: 10.1007/s13300-021-01035-9] [Citation(s) in RCA: 86] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Accepted: 02/13/2021] [Indexed: 02/08/2023] Open
Abstract
Prognosis and appropriate treatment goals for older adults with diabetes vary greatly according to frailty. It is now recognised that changes may be needed to diabetes management in some older people. Whilst there is clear guidance on the evaluation of frailty and subsequent target setting for people living with frailty, there remains a lack of formal guidance for healthcare professionals in how to achieve these targets. The management of older adults with type 2 diabetes is complicated by comorbidities, shortened life expectancy and exaggerated consequences of adverse effects from treatment. In particular, older adults are more prone to hypoglycaemia and are more vulnerable to its consequences, including falls, fractures, hospitalisation, cardiovascular events and all-cause mortality. Thus, assessment of frailty should be a routine component of a diabetes review for all older adults, and glycaemic targets and therapeutic choices should be modified accordingly. Evidence suggests that over-treatment of older adults with type 2 diabetes is common, with many having had their regimens intensified over preceding years when they were in better health, or during more recent acute hospital admissions when their blood glucose levels might have been atypically high, and nutritional intake may vary. In addition, assistance in taking medications, as often occurs in later life following implementation of community care strategies or admittance to a care home, may dramatically improve treatment adherence, leading to a fall in glycated haemoglobin (HbA1c) levels. As a person with diabetes gets older, simplification, switching or de-escalation of the therapeutic regimen may be necessary, depending on their level of frailty and HbA1c levels. Consideration should be given, in particular, to de-escalation of therapies that may induce hypoglycaemia, such as sulphonylureas and shorter-acting insulins. We discuss the use of available glucose-lowering therapies in older adults and recommend simple glycaemic management algorithms according to their level of frailty.
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Affiliation(s)
- W David Strain
- University of Exeter Medical School, and Royal Devon and Exeter Hospital, Exeter, UK.
| | - Su Down
- Somerset Foundation Trust, Somerset, UK
| | | | | | - Alan Sinclair
- The Foundation for Diabetes Research in Older People (fDROP) and King's College, London, UK
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Kabel AM, Salama SA. Effect of taxifolin/dapagliflozin combination on colistin-induced nephrotoxicity in rats. Hum Exp Toxicol 2021; 40:1767-1780. [PMID: 33882723 DOI: 10.1177/09603271211010906] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Colistin is an antimicrobial agent that is used in resistant gram-negative infections. Its most common dose-limiting adverse effect is nephrotoxicity. The objective of our study was to explore the possible effects of each of taxifolin and dapagliflozin alone and in combination on colistin-induced nephrotoxicity in rats. Sixty male rats were randomized into six groups: Control; colistin; colistin + taxifolin; colistin + dapagliflozin; colistin + carboxymethyl cellulose (CMC) and colistin + taxifolin + dapagliflozin. Dapagliflozin, taxifolin, and CMC were given daily for 7 days, 4 hours before colistin injection. Kidney weight/body weight ratio and renal function tests were determined. Renal tissue nerve growth factor-β (NGF-β), transforming growth factor beta 1 (TGF-β1), proinflammatory cytokines, nuclear factor (erythroid-derived 2)-like 2 (Nrf2), toll-like receptor 4 (TLR4), nuclear factor kappa B (NF-κB) p65, signal transducer and activator of transcription 3 (STAT3), oxidative stress parameters, beclin-1 and c-Jun NH2-terminal kinase (JNK) activities were measured. Kidneys were examined histopathologically and immunohistochemically. Taxifolin and/or dapagliflozin induced significant improvement in the renal functions and oxidative stress parameters with significant increase in tissue Nrf2, STAT3 and NGF-β accompanied with significant decrease in kidney weight/body weight ratio, tissue proinflammatory cytokines, TGF-β1, NF-κB (p65), TLR4, beclin-1 and JNK activities and improved the histopathological picture when compared to rats treated with colistin alone. This improvement was significant with taxifolin/dapagliflozin combination compared to rats treated with each of these agents alone. So, we concluded that the combined use of taxifolin and dapagliflozin may confer a therapeutic tool for attenuation of colistin-induced nephrotoxicity.
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Affiliation(s)
- A M Kabel
- Department of Pharmacology, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - S A Salama
- Division of Biochemistry, Department of Pharmacology, College of Pharmacy, Taif University, Taif, Saudi Arabia
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Cure E, Sirin H, Cure MC, Sahin DA. Dapagliflozin-induced long-term and severe anorexia and weight loss: An extraordinary case. Indian J Pharmacol 2021; 53:174-175. [PMID: 34100404 PMCID: PMC8265413 DOI: 10.4103/ijp.ijp_785_19] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Affiliation(s)
- Erkan Cure
- Department of Internal Medicine, Ota and Jinemed Hospital, Istanbul, Turkey
- Address for correspondence: Dr. Erkan Cure, Department of Internal Medicine, Ota and Jinemed Hospital, Muradiye Mahallesi Nuzhetiye Cad, Deryadil Sokagi No: 1, 34357 Besiktas, Istanbul, Turkey. E-mail:
| | - Hakan Sirin
- Department of Urology, Basaksehir Cam ve Sakura City Hospital, Istanbul, Turkey
| | - Medine Cumhur Cure
- Department of Biochemistry, Private Kucukcekmece Hospital, Istanbul, Turkey
| | - Dursun Ali Sahin
- Department of General Surgery, Private Practise, Istanbul, Turkey
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Dąbrowski M. Diabetes, Antidiabetic Medications and Cancer Risk in Type 2 Diabetes: Focus on SGLT-2 Inhibitors. Int J Mol Sci 2021; 22:1680. [PMID: 33562380 PMCID: PMC7915237 DOI: 10.3390/ijms22041680] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 01/31/2021] [Accepted: 02/03/2021] [Indexed: 12/14/2022] Open
Abstract
In the last decade, cancer became the leading cause of death in the population under 65 in the European Union. Diabetes is also considered as a factor increasing risk of cancer incidence and mortality. Type 2 diabetes is frequently associated with being overweight and obese, which also plays a role in malignancy. Among biological mechanisms linking diabetes and obesity with cancer hyperglycemia, hyperinsulinemia, insulin resistance, increased levels of growth factors, steroid and peptide hormones, oxidative stress and increased activity of pro-inflammatory cytokines are listed. Antidiabetic medications can modulate cancer risk through directly impacting metabolism of cancer cells as well as indirectly through impact on risk factors of malignancy. Some of them are considered beneficial (metformin and thiazolidinedions-with the exception of bladder cancer); on the other hand, excess of exogenous insulin may be potentially harmful, while other medications seem to have neutral impact on cancer risk. Inhibitors of the sodium-glucose cotransporter-2 (SGLT-2) are increasingly used in the treatment of type 2 diabetes. However, their association with cancer risk is unclear. The aim of this review was to analyze the anticancer potential of this class of drugs, as well as risks of site-specific malignancies associated with their use.
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Affiliation(s)
- Mariusz Dąbrowski
- College of Medical Sciences, University of Rzeszów, Al. Rejtana 16C, 35-959 Rzeszów, Poland
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Ergun-Longmire B, Clemente E, Vining-Maravolo P, Roberts C, Buth K, Greydanus DE. Diabetes education in pediatrics: How to survive diabetes. Dis Mon 2021; 67:101153. [PMID: 33541707 DOI: 10.1016/j.disamonth.2021.101153] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Diabetes mellitus is the most common abnormal carbohydrate metabolism disorder affecting millions of people worldwide. It is characterized by hyperglycemia as a result of ß-cell destruction or dysfunction by both genetic and environmental factors. Over time chronic hyperglycemia leads to microvascular (i.e., retinopathy, nephropathy and neuropathy) and macrovascular (i.e., ischemic heart disease, peripheral vascular disease, and cerebrovascular disease) complications of diabetes. Diabetes complication trials showed the importance of achieving near-normal glycemic control to prevent and/or reduce diabetes-related morbidity and mortality. There is a staggering rate of increased incidence of diabetes in youth, raising concerns for future generations' health, quality of life and its enormous economic burden. Despite advancements in the technology, diabetes management remains cumbersome. Training individuals with diabetes to gain life-long survival skills requires a comprehensive and ongoing diabetes education by a multidisciplinary team. Diabetes education and training start at the time of diagnosis of diabetes and should be continuous throughout the course of disease. The goal is to empower the individuals and families to gain diabetes self-management skills. Diabetes education must be individualized depending on the individual's age, education, family dynamics, and support. In this article, we review the history of diabetes, etiopathogenesis and clinical presentation of both type 1 and type 2 diabetes in children as well as adolescents. We then focus on diabetes management with education methods and materials.
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Affiliation(s)
- Berrin Ergun-Longmire
- Associate Professor, Department of Pediatric and Adolescent Medicine, Western Michigan University, Homer Stryker M.D. School of Medicine, Kalamazoo, MI, USA.
| | - Ethel Clemente
- Department of Pediatric and Adolescent Medicine, Western Michigan University, Homer Stryker M.D. School of Medicine, Kalamazoo, MI, USA
| | - Patricia Vining-Maravolo
- Department of Pediatric and Adolescent Medicine, Western Michigan University, Homer Stryker M.D. School of Medicine, Kalamazoo, MI, USA
| | - Cheryl Roberts
- Department of Pediatric and Adolescent Medicine, Western Michigan University, Homer Stryker M.D. School of Medicine, Kalamazoo, MI, USA
| | - Koby Buth
- Western Michigan University, Homer Stryker M.D. School of Medicine, Kalamazoo, MI, USA
| | - Donald E Greydanus
- Professor, Department of Pediatric and Adolescent Medicine, Western Michigan University, Homer Stryker M.D. School of Medicine, Kalamazoo, MI United States
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Yabiku K. Efficacy of Sodium-Glucose Cotransporter 2 Inhibitors in Patients With Concurrent Type 2 Diabetes Mellitus and Non-Alcoholic Steatohepatitis: A Review of the Evidence. Front Endocrinol (Lausanne) 2021; 12:768850. [PMID: 34950104 PMCID: PMC8688740 DOI: 10.3389/fendo.2021.768850] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Accepted: 11/19/2021] [Indexed: 12/12/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most prevalent liver disease worldwide, and more than half of individuals diagnosed with type 2 diabetes concurrently present with NAFLD. There is a bidirectional pathological relationship between the two conditions, whereby NAFLD increases the risk of type 2 diabetes, and type 2 diabetes contributes to and accelerates the progression of NAFLD. Furthermore, over 30% of patients with NAFLD progress to non-alcoholic liver steatohepatitis (NASH), which then increases the risk of cirrhosis and hepatocellular carcinoma. Despite its high prevalence and the potential clinical implications, the underlying pathogenesis of NAFLD has yet to be fully elucidated, and there is no consensus regarding standard diagnosis and treatment for either NALFD or NASH. As patients with both NASH and type 2 diabetes have impaired hepatic function owing to chronic inflammation and the resulting structural changes caused by hepatic fat accumulation, they face reduced options for antidiabetic treatment. SGLT-2 inhibitors inhibit glucose reabsorption in the proximal tubule, with increased excretion of glucose in urine and decreased glucose levels in plasma, and their glycemia-lowering effect is insulin-independent. Several other beneficial effects have been reported for SGLT-2 inhibitors, including reduced risks of cardiovascular and renal diseases, improved blood pressure control, body weight reduction, and reductions in liver fat content. Experimental studies in mouse models have suggested that SGLT-2 inhibitors may have beneficial modulatory effects on NAFLD/NASH. Several trials in patients with type 2 diabetes have also suggested that these drugs may be useful in treating both type 2 diabetes and NAFLD or NASH. However, further research is needed to identify the mechanisms by which SGLT-2 inhibitors affect fatty liver and steatohepatitis. In this state-of-the-art review, we explore the literature on the efficacy of SGLT-2 inhibitors in patients with type 2 diabetes and NASH, and present arguments for and against the use of SGLT-2 inhibitors in this patient population.
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Stover KR, Hugh E, Sherman JJ, Malinowski SS, Berdahl GJ, Riche DM. Infectious complications of newer agents in the fight against diabetes. Nurse Pract 2020; 45:17-24. [PMID: 33093391 DOI: 10.1097/01.npr.0000718508.65708.a1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
Infectious complications have been reported with antidiabetic medications. Glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors have been associated with upper respiratory tract infections and urinary tract infections. Sodium-glucose cotransporter 2 inhibitors have been associated with lower limb amputations, urinary tract infections, genital mycotic infections, and Fournier gangrene.
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Development and Validation of Rapid RP-HPLC and Green Second-Derivative UV Spectroscopic Methods for Simultaneous Quantification of Metformin and Remogliflozin in Formulation Using Experimental Design. SEPARATIONS 2020. [DOI: 10.3390/separations7040059] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Recently, a new formulation containing metformin HCl (MFH) and remogliflozin etabonate (RGE) has been approved for the management of diabetes mellitus. However, only one analytical method has been reported for the simultaneous determination of both the analytes. Therefore, the current study was designed to develop simple UV derivative spectroscopic and rapid RP-HPLC methods for simultaneous determination of MFH and RGE. The chromatographic separation of MFH and RGE was performed using a monolithic C18 column with an optimized chromatographic conditions carried out by full factorial Box–Behnken design model. The spectroscopic technique was based on the determination of peak amplitude of second-order derivative UV spectra at zero crossings. Further, both the methods were validated and compared statistically using Student’s-t-test and F-test, and employed for the concurrent estimation of MFH and RGE in laboratory mixed solutions and formulations. Perturbation plots and response surface models showed the effect of chromatographic parameters and the final chromatographic condition was selected from 47 solutions suggested by the desirability function. Further, UV spectroscopic and HPLC procedures showed good linearity in the range of 1–24 µg/mL and 2–150 µg/mL for RGE and 2–30 µg/mL and 5–200 µg/mL for MFH, respectively. The average percent assay was found to be 99.51% and 99.80% for MFH and 99.60% and 100.07% for RGE by spectroscopic and HPLC methods, respectively. The proposed methods were simple, accurate, precise, and rapid. Therefore, they can be used for regular quality control of MFH and RGE formulations and dissolution studies as well.
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Zhuang Y, Song J, Ying M, Li M. Efficacy and safety of dapagliflozin plus saxagliptin vs monotherapy as added to metformin in patients with type 2 diabetes: A meta-analysis. Medicine (Baltimore) 2020; 99:e21409. [PMID: 32791755 PMCID: PMC7386974 DOI: 10.1097/md.0000000000021409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
BACKGROUND This study aim at evaluating the efficacy and safety of dapagliflozin plus saxagliptin vs monotherapy as added to metformin in patients with type 2 diabetes mellitus (T2DM). METHOD PubMed, Cochrane library, Embase, CNKI and Wanfang databases were searched up to 31 December 2019. Randomized controlled trials (RCTs) applicable in dapagliflozin plus saxagliptin vs monotherapy as added to metformin in the treatment of T2DM were included. The outcomes included changes in HbA1c, FPG, body weight, SBP, DBP and adverse reactions. Fixed or random effects model were used to assess these outcomes. RESULTS In this study, 8 RCTs involved 7346 patients were included. Compared with dapagliflozin plus metformin(DM) group, patients treated with dapagliflozin plus saxagliptin add on to metformin(DSM) could significantly increase the adjusted mean change levels of HbA1c, FPG, SBP and DBP(P < .00001, SMD = -4.88, 95%CI = -6.93∼-2.83; P < .00001, SMD = -6.50, 95%CI = -8.55∼-4.45; P < .00001, SMD = -0.97, 95%CI = -1.15∼-0.78; P < .00001, SMD = -2.00, 95%CI = -2.20∼-1.80), but no major difference in body weight loss showed(P = .12, SMD = 0.92, 95%CI = -0.22∼2.06). Furthermore, DSM therapy displayed better effects than saxagliptin plus metformin(SM) in the adjusted mean change levels of HbA1c, FPG, body weight and SBP(P < .00001, SMD = -7.75, 95%CI = -8.84∼-6.66; P < .00001, SMD = -7.75, 95%CI = -8.84∼-6.66; P = .04, SMD = -3.40, 95%CI = -6.64∼-0.17; P = .04, SMD = -7.75, 95%CI = -8.84∼-6.66), whereas no obvious difference in lowering DBP(P = .18, SMD = -16.35, 95%CI = -40.12∼7.41). Additionally, compared with DM and SM groups, there were no remarkable difference in the incidence of nausea, influenza, headache, diarrhea, urinary tract infection and renal failure for patients taking DSM, but the incidence of genital infection and hypoglycemia were higher in DSM group. CONCLUSIONS Patients taking the DSM therapy had better effects in reducing the level of HbA1c, FPG, body weight, SBP and DBP than the DM and SM therapy. However, patients treated with DSM therapy are more likely to have hypoglycemia and genital infection. Dapagliflozin plus saxagliptin may be a suitable therapy strategy for patients with T2DM inadequately controlled with metformin, and this will provide a clinical reference for the treatment of T2DM.
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Affiliation(s)
| | | | - Miaofa Ying
- Department of Pharmacy, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Mingxing Li
- Department of Pharmacy, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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