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Sattari M, Karimpour A, Akhavan Taheri M, Larijani B, Meshkani R, Tabatabaei-Malazy O, Panahi G. Optimized Effects of Fisetin and Hydroxychloroquine on ER Stress and Autophagy in Nonalcoholic Fatty Pancreas Disease in Mice. J Diabetes Res 2025; 2025:2795127. [PMID: 40260275 PMCID: PMC12011465 DOI: 10.1155/jdr/2795127] [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: 08/14/2024] [Accepted: 03/21/2025] [Indexed: 04/23/2025] Open
Abstract
Background: Fat accumulation in the pancreas, known as nonalcoholic fatty pancreatic disease (NAFPD), is associated with obesity and may lead to prediabetes and Type 2 diabetes. Reducing endoplasmic reticulum stress and enhancing autophagy could offer therapeutic benefits. This study examines the effects of fisetin (FSN) and hydroxychloroquine (HCQ) on NAFPD. Method: Forty-eight Male C57BL/6 J mice were assigned to a standard chow diet (SCD) or a high-fat diet (HFD) for 16 weeks. The HFD group was divided into five subgroups; each group contains eight mice: HFD, HFD + V (vehicle), HFD + FSN, HFD + HCQ, and HFD + FSN + HCQ. FSN was given daily at 80 mg/kg, and HCQ was injected IP at 50 mg/kg twice weekly for more 8 weeks. Insulin resistance was assessed through OGTT and HOMA-IR. Histological analysis of pancreatic tissue was conducted, and the protein and mRNA levels of molecules associated with ER stress and autophagy were assessed using PCR and immunoblotting techniques. Result: FSN and HCQ significantly reduced weight gain, pancreatic adipocyte accumulation, and insulin resistance caused by HFD in obese mice, with the combination of the two compounds producing even more pronounced effects. Additionally, the HFD increased the expression of UPR markers ATF4 and CHOP, a response that was further intensified by HCQ. In contrast, FSN attenuated the UPR by regulating GRP78 levels. Furthermore, the HFD resulted in a significant decrease in the LC3II/LC3I ratio and an accumulation of p62 protein due to reduced p-AMPK levels. Following treatment with FSN, these alterations were reversed, leading to decreased mTOR expression and increased levels of autophagy markers such as ATG5 and Beclin1. Conclusion: Our study reveals that FSN and HCQ effectively combat HFD-induced NAFPD, improving insulin sensitivity and addressing pancreatic fat deposition linked to metabolic syndrome. While HCQ may cause endoplasmic reticulum stress, FSN offers protective effects, supporting their combined use for better treatment outcomes.
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Affiliation(s)
- Mahboobe Sattari
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
- Department of Clinical Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Amin Karimpour
- Department of Clinical Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Students' Scientific Research Center (SSRC), Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Akhavan Taheri
- Anatomical Sciences Research Center, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Bagher Larijani
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Reza Meshkani
- Department of Clinical Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Ozra Tabatabaei-Malazy
- Non-Communicable Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Ghodratollah Panahi
- Department of Clinical Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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Zhang C, Li J, Wang L, Ma J, Li X, Wu Y, Ren Y, Yang Y, Song H, Li J, Yang Y. Terazosin, a repurposed GPR119 agonist, ameliorates mitophagy and β-cell function in NAFPD by inhibiting MST1-Foxo3a signalling pathway. Cell Prolif 2025; 58:e13764. [PMID: 39413003 PMCID: PMC11882769 DOI: 10.1111/cpr.13764] [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: 03/04/2024] [Revised: 09/25/2024] [Accepted: 09/28/2024] [Indexed: 10/18/2024] Open
Abstract
GPR119 agonists are being developed to safeguard the function of pancreatic β-cells, especially in the context of non-alcoholic fatty pancreas disease (NAFPD) that is closely associated with β-cell dysfunction. This study aims to employ a drug repurposing strategy to screen GPR119 agonists and explore their potential molecular mechanisms for enhancing β-cell function in the context of NAFPD. MIN6 cells were stimulated with palmitic acid (PA), and a NAFPD model was established in GPR119-/- mice fed with a high-fat diet (HFD). Terazosin, identified through screening, was utilized to assess its impact on enhancing β-cell function via the MST1-Foxo3a pathway and mitophagy. Terazosin selectively activated GPR119, leading to increased cAMP and ATP synthesis, consequently enhancing insulin secretion. Terazosin administration improved high blood glucose, obesity, and impaired pancreatic β-cell function in NAFPD mice. It inhibited the upregulation of MST1-Foxo3a expression in pancreatic tissue and enhanced damaged mitophagy clearance, restoring autophagic flux, and improving mitochondrial quantity and structure in β-cells. Nevertheless, GPR119 deficiency negated the positive impact of terazosin on pancreatic β-cell function in NAFPD mice and abolished its inhibitory effect on the MST1-Foxo3a pathway. Terazosin activates GPR119 on the surface of pancreatic β-cells, enhancing mitophagy and alleviating β-cell dysfunction in the context of NAFPD by suppressing the MST1-Foxo3a signalling pathway. Terazosin could be considered a priority treatment for patients with concomitant NAFPD and hypertension.
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Affiliation(s)
- Chenglei Zhang
- School of Basic Medical SciencesNingxia Medical UniversityYinchuanNingxiaChina
- Medical LaboratoryGeneral Hospital of Ningxia Medical UniversityYinchuanNingxiaChina
| | - Jiarui Li
- School of Basic Medical SciencesNingxia Medical UniversityYinchuanNingxiaChina
| | - Lijuan Wang
- School of Basic Medical SciencesNingxia Medical UniversityYinchuanNingxiaChina
- Department of EndocrinologyGeneral Hospital of Ningxia Medical UniversityYinchuanNingxiaChina
| | - Jie Ma
- School of Basic Medical SciencesNingxia Medical UniversityYinchuanNingxiaChina
| | - Xin Li
- School of Basic Medical SciencesNingxia Medical UniversityYinchuanNingxiaChina
| | - Yuanyuan Wu
- Department of Oncology, Cancer HospitalGeneral Hospital of Ningxia Medical UniversityYinchuanNingxiaChina
| | - Yanru Ren
- Day‐Care UnitGeneral Hospital of Ningxia Medical UniversityYinchuanNingxiaChina
| | - Yanhui Yang
- School of Basic Medical SciencesNingxia Medical UniversityYinchuanNingxiaChina
| | - Hui Song
- School of Basic Medical SciencesNingxia Medical UniversityYinchuanNingxiaChina
| | - Jianning Li
- School of Basic Medical SciencesNingxia Medical UniversityYinchuanNingxiaChina
| | - Yi Yang
- School of Basic Medical SciencesNingxia Medical UniversityYinchuanNingxiaChina
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Ye J, Wang JG, Liu RQ, Shi Q, Wang WX. Association between intra-pancreatic fat deposition and diseases of the exocrine pancreas: A narrative review. World J Gastroenterol 2025; 31:101180. [PMID: 39811515 PMCID: PMC11684206 DOI: 10.3748/wjg.v31.i2.101180] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Revised: 10/26/2024] [Accepted: 11/19/2024] [Indexed: 12/18/2024] Open
Abstract
Intrapancreatic fat deposition (IPFD) has garnered increasing attention in recent years. The prevalence of IPFD is relatively high and associated with factors such as obesity, age, and sex. However, the pathophysiological mechanisms underlying IPFD remain unclear, with several potential contributing factors, including oxidative stress, alterations in the gut microbiota, and hormonal imbalances. IPFD was found to be highly correlated with the occurrence and prognosis of exocrine pancreatic diseases. Although imaging techniques remain the primary diagnostic approach for IPFD, an expanding array of biomarkers and clinical scoring systems have been identified for screening purposes. Currently, effective treatments for IPFD are not available; however, existing medications, such as glucagon-like peptide-1 receptor agonists, and new therapeutic approaches explored in animal models have shown considerable potential for managing this disease. This paper reviews the pathogenesis of IPFD, its association with exocrine pancreatic diseases, and recent advancements in its diagnosis and treatment, emphasizing the significant clinical relevance of IPFD.
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Affiliation(s)
- Jing Ye
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
| | - Jian-Guo Wang
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
| | - Rong-Qiang Liu
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
| | - Qiao Shi
- Department of Pancreatic Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
| | - Wei-Xing Wang
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
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Takai T, Asahara SI, Ikushiro H, Kobayashi K, Yano T, Kido Y, Ogawa W. Protective effect of CK2 against endoplasmic reticulum stress in pancreatic β cells. Diabetol Int 2025; 16:131-144. [PMID: 39877448 PMCID: PMC11769914 DOI: 10.1007/s13340-024-00775-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Accepted: 10/21/2024] [Indexed: 01/31/2025]
Abstract
Endoplasmic reticulum (ER) stress due to obesity or systemic insulin resistance is an important pathogenic factor that could lead to pancreatic β-cell failure. We have previously reported that CCAAT/enhancer-binding protein β (C/EBPβ) is highly induced by ER stress in pancreatic β cells. Moreover, its accumulation hampers the response of these cells to ER stress by inhibiting the induction of the molecular chaperone 78 kDa glucose-regulated protein (GRP78). We also demonstrated that C/EBPβ is phosphorylated by CK2, which is reportedly associated with the ER stress signal. In the present study, we aimed to clarify the mechanisms underlying the effect of CK2 on pancreatic β cells using a CK2-specific inhibitor, CX4945, and shRNA-mediated knockdown and overexpression of CK2β, the regulatory subunit of CK2. The results indicate that CK2 was activated in MIN6 cells under ER stress and in pancreatic β cells of a diabetic mouse model. Under normal conditions, CK2 interacted with FL-ATF6α in MIN6 cells and regulated the expression of GRP78 and ERAD-associated proteins. Mechanistically, CK2 activation in MIN6 cells upon the overexpression of the CK2β subunit reduced ER stress signals and the accumulation of unfolded proteins via an increase in GRP78 and ERAD-associated protein levels. These results highlight the important role of CK2 in protecting against ER stress-induced apoptosis by regulating GRP78 and ERAD proteins. CK2 contributed to the clearance of unfolded or misfolded proteins in MIN6 cells under both normal and ER stress conditions. Therefore, CK2 activation could be a promising novel approach for preventing type 2 diabetes. Supplementary Information The online version contains supplementary material available at 10.1007/s13340-024-00775-w.
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Affiliation(s)
- Tomoko Takai
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe, 650-0017 Japan
| | - Shun-ichiro Asahara
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe, 650-0017 Japan
| | - Hiroko Ikushiro
- Department of Biochemistry, Faculty of Medicine, Osaka Medical and Pharmaceutical University, Takatsuki, Japan
| | - Kenta Kobayashi
- Section of Viral Vector Development, National Institute for Physiological Sciences, National Institute of Natural Sciences, Okazaki, Japan
| | - Takato Yano
- Department of Biochemistry, Faculty of Medicine, Osaka Medical and Pharmaceutical University, Takatsuki, Japan
| | - Yoshiaki Kido
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe, 650-0017 Japan
| | - Wataru Ogawa
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe, 650-0017 Japan
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Tsiampali C, Vachliotis ID, Goulas A, Polyzos SA. Animal studies on glucagon-like peptide-1 receptor agonists and related polyagonists in nonalcoholic fatty liver disease. Hormones (Athens) 2024; 23:611-619. [PMID: 38472647 PMCID: PMC11519281 DOI: 10.1007/s42000-024-00541-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2024] [Accepted: 02/28/2024] [Indexed: 03/14/2024]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a prevalent metabolic liver disease closely associated with the epidemics of obesity and type 2 diabetes mellitus (T2DM), but without licensed pharmacological treatment to date. As glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) are approved anti-diabetic and anti-obesity medications, they were also considered a potential therapeutic option for NAFLD. Preclinical studies suggest that GLP-1RAs have a beneficial effect on major NAFLD histological outcomes, i.e., hepatic steatosis and inflammation, through multiple intrahepatic mechanisms, including increased fatty acid β-oxidation, activation of autophagy, suppression of inflammation, and oxidative stress. Data on hepatic fibrosis are limited or inconclusive, although some studies reported improvement in indices of fibrosis or prevention of fibrosis initiation or reduction of collagen deposition. Whether the positive impact of GLP-1RAs on hepatic histology is indirect, i.e., through their action on extrahepatic tissues, or whether their action is direct, i.e., through activating GLP-1R on the hepatocytes, is still a controversial issue. Alongside GLP-1RAs, newly emerging peptide polyagonists (i.e., synthetic molecules that combine the amino acid sequences of more than one peptide, thus having the ability to bind more than one receptor) are now being investigated in NAFLD with high expectations. This review summarizes the existing knowledge derived from animal studies on the effects of GLP-1RAs and GLP-1RA related peptide polyagonists on NAFLD in an attempt to illuminate areas of uncertainty and provide the groundwork for future animal and clinical research in the field.
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Affiliation(s)
- Chara Tsiampali
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece
| | - Ilias D Vachliotis
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece
| | - Antonis Goulas
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece
| | - Stergios A Polyzos
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece.
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Della Pepa G, Salamone D, Testa R, Bozzetto L, Costabile G. Intrapancreatic fat deposition and nutritional treatment: the role of various dietary approaches. Nutr Rev 2024; 82:1820-1834. [PMID: 38153345 DOI: 10.1093/nutrit/nuad159] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2023] Open
Abstract
Ectopic fat accumulation in various organs and tissues, such as the liver, muscle, kidney, heart, and pancreas, is related to impaired capacity of adipose tissue to accumulate triglycerides, as a consequence of overnutrition and an unhealthy lifestyle. Ectopic fat promotes organ dysfunction and is a key factor in the development and progression of cardiometabolic diseases. Interest in intrapancreatic fat deposition (IPFD) has developed in the last few years, particularly in relation to improvement in methodological techniques for detection of fat in the pancreas, and to growing evidence for the role that IPFD might have in glucose metabolism disorders and cardiometabolic disease. Body weight reduction represents the main option for reducing fat, and the evidence consistently shows that hypocaloric diets are effective in reducing IPFD. Changes in diet composition, independently of changes in energy intake, might offer a more feasible and safe alternative treatment to energy restriction. This current narrative review focused particularly on the possible beneficial role of the diet and its nutrient content, in hypocaloric and isocaloric conditions, in reducing IPFD in individuals with high cardiometabolic risk, highlighting the possible effects of differences in calorie quantity and calorie quality. This review also describes plausible mechanisms by which the various dietary approaches could modulate IPFD.
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Affiliation(s)
- Giuseppe Della Pepa
- Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy
- Cardiometabolic Risk Unit, Institute of Clinical Physiology, National Research Council-CNR, Pisa, Italy
| | - Dominic Salamone
- Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy
| | - Roberta Testa
- Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy
| | - Lutgarda Bozzetto
- Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy
| | - Giuseppina Costabile
- Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy
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Warrayat A, Ali A, Waked J, Tocci D, Speth RC. Assessment of the therapeutic potential of salubrinal for ME/CFS and long-COVID. Trends Mol Med 2024:S1471-4914(24)00268-5. [PMID: 39438198 DOI: 10.1016/j.molmed.2024.10.001] [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: 08/04/2024] [Revised: 09/30/2024] [Accepted: 10/01/2024] [Indexed: 10/25/2024]
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic debilitating condition with no cure that shares commonality with long-COVID. This review examines current understanding of long-COVID symptoms, characteristics of the affected population, the connection with ME/CFS, and the potential for salubrinal, an agent known for its influence on cellular stress pathways, to mitigate these disorders It also describes the historical development and mechanism of action of salubrinal, to mitigate endoplasmic reticulum (ER)/cellular stress responses, that could potentially contribute to symptom improvement in both ME/CFS and long-COVID patients. Further research and clinical trials are warranted to advance our understanding of the potential role of salubrinal in improving the quality of life for individuals with long-COVID-related ME/CFS symptoms as well as ME/CFS patients.
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Affiliation(s)
- Aseel Warrayat
- Barry and Judy Silverman College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA
| | - Ayah Ali
- Barry and Judy Silverman College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA
| | - Joulin Waked
- Barry and Judy Silverman College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA
| | - Darcy Tocci
- Barry and Judy Silverman College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA
| | - Robert C Speth
- Department of Pharmaceutical Sciences, Barry and Judy Silverman College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA; Department of Pharmacology and Physiology, School of Medicine, Georgetown University, Washington, DC 20007, USA.
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Habas E, Farfar K, Habas E, Rayani A, Elzouki AN. Extended Review and Updates of Nonalcoholic Fatty Pancreas Disease. SAUDI JOURNAL OF MEDICINE & MEDICAL SCIENCES 2024; 12:284-291. [PMID: 39539795 PMCID: PMC11556510 DOI: 10.4103/sjmms.sjmms_526_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 11/12/2023] [Revised: 07/29/2024] [Accepted: 08/01/2024] [Indexed: 11/16/2024]
Abstract
Non-alcoholic fatty pancreatic disease (NAFPD), also known as pancreatic steatosis, is a benign condition characterized by deposition of lipids in the pancreas and is associated with insulin resistance, malnutrition, obesity, metabolic syndrome, aging, and absence of heavy alcohol intake or infection. Similar to nonalcoholic fatty liver disease, NAFPD is a phenotypic entity that includes fat buildup in the pancreas, pancreatic inflammation, and subsequent fibrosis. The extent to which pancreatic fat infiltration is clinically important remains unclear. Despite these clinical associations, most of the clinical effects of NAFPD are not known. NAFPD may be identified by transabdominal and elastography ultrasound, computed tomography scan, or magnetic resonance imaging modalities, but a confirmatory diagnosis can only be made through tissue histology. In addition to complications such as acute and chronic pancreatitis, NAFPD may progress to pancreatic ductal adenocarcinoma. However, further research is required to fully understand the associations, pathophysiology, and effects of NAFPD. This review provides a narrative synthesis of the current literature on the epidemiology, pathophysiology, complications, diagnostic and imaging tools, and management of NAFPD.
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Affiliation(s)
- Elmukhtar Habas
- Department of Medicine, Hamad Medical Corporation, Doha, Qatar
- Department of Medicine, College of Medicine, Qatar University, Doha, Qatar
| | - Kalifa Farfar
- Department of Medicine, Alwakra General Hospital, Alwakra, Qatar
| | - Eshrak Habas
- Department of Medicine, Tripoli Central Hospital, Tripoli, Libya
| | - Amnna Rayani
- Tripoli Children Hospital, Medical College, Tripoli University, Tripoli, Libya
| | - Abdul-Naser Elzouki
- Department of Medicine, Hamad Medical Corporation, Doha, Qatar
- Department of Medicine, College of Medicine, Qatar University, Doha, Qatar
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Pang C, Dong P, Yang J, Fan Z, Cheng Z, Zhan H. Non-alcoholic fatty pancreas disease: an updated review. JOURNAL OF PANCREATOLOGY 2024; 7:212-221. [DOI: 10.1097/jp9.0000000000000157] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2025] Open
Abstract
Ectopic accumulation of fat can cause a variety of metabolic diseases, and the emerging non-alcoholic fatty pancreas disease (NAFPD) is increasingly being recognized by clinicians as a cause for concern. NAFPD is a disease caused by abnormal accumulation of adipose tissue in the pancreas, which is related to obesity. The main feature of NAFPD is death of acinar cells, which are then replaced by adipose cells. However, the underlying molecular mechanisms have not been fully explored. Obesity, aging, and metabolic syndrome are independent risk factors for the occurrence and development of NAFPD. Studies have shown that NAFPD leads to insulin resistance and pancreatic dysfunction, increases the risk of diabetes mellitus, worsens the severity of pancreatitis, and is significantly correlated with pancreatic cancer and postoperative pancreatic fistula. There is no standard treatment for NAFPD; exercise, a balanced diet, and lifestyle can help reduce pancreatic fat; however, other treatment modalities such as drugs and bariatric surgery are still being explored. The specific pathological mechanism of NAFPD remains unclear, and its potential association with various clinical diseases requires further study. This review summarizes the etiology, diagnosis, clinical consequences, and potential therapeutic strategies of NAFPD.
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Affiliation(s)
- Chaoyu Pang
- Division of Pancreatic Surgery, Department of General Surgery, Qilu Hospital, Shandong University, Jinan 250012, China
| | - Peng Dong
- Division of Pancreatic Surgery, Department of General Surgery, Qilu Hospital, Shandong University, Jinan 250012, China
| | - Jian Yang
- Division of Pancreatic Surgery, Department of General Surgery, Qilu Hospital, Shandong University, Jinan 250012, China
| | - Zhiyao Fan
- Division of Pancreatic Surgery, Department of General Surgery, Qilu Hospital, Shandong University, Jinan 250012, China
| | - Zhiqiang Cheng
- Division of Colorectal Surgery, Department of General Surgery, Qilu Hospital, Shandong University, Jinan 250012, China
| | - Hanxiang Zhan
- Division of Pancreatic Surgery, Department of General Surgery, Qilu Hospital, Shandong University, Jinan 250012, China
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Liu J, Luo Y, Zhu YR, Wu ZT, Hou Y, Xu YJ, Li L, Ma CW. Correlation between type 2 diabetes mellitus remission and intrapancreatic fat deposition. World J Clin Cases 2024; 12:4536-4542. [PMID: 39070807 PMCID: PMC11235486 DOI: 10.12998/wjcc.v12.i21.4536] [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: 03/21/2024] [Revised: 05/09/2024] [Accepted: 06/13/2024] [Indexed: 06/30/2024] Open
Abstract
BACKGROUND Intrapancreatic fat deposition (IPFD) exerts a significant negative impact on patients with type 2 diabetes mellitus (T2DM), accelerates disease deterioration, and may lead to impaired β-cell quality and function. AIM To investigate the correlation between T2DM remission and IPFD. METHODS We enrolled 80 abdominally obese patients with T2DM admitted to our institution from January 2019 to October 2023, including 40 patients with weight loss-induced T2DM remission (research group) and 40 patients with short-term intensive insulin therapy-induced T2DM remission (control group). We comparatively analyzed improvements in IPFD [differential computed tomography (CT) values of the spleen and pancreas and average CT value of the pancreas]; levels of fasting blood glucose (FBG), 2-h postprandial blood glucose (2hPBG), and insulin; and homeostasis model assessment of insulin resistance (HOMA-IR) scores. Correlation analysis was performed to explore the association between T2DM remission and IPFD. RESULTS After treatment, the differential CT values of the spleen and pancreas, FBG, 2hPBG, and HOMA-IR in the research group were significantly lower than those before treatment and in the control group, and the average CT value of the pancreas and insulin levels were significantly higher. Correlation analysis revealed that the greater the T2DM remission, the lower the amount of IPFD. CONCLUSION T2DM remission and IPFD are inversely correlated.
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Affiliation(s)
- Jiang Liu
- Division of Endocrinology, Wenshan Hospital Affiliated to Kunming University of Science and Technology, Wenshan 663000, Yunnan Province, China
| | - Yue Luo
- Department of Radiological Medicine, Wenshan Hospital Affiliated to Kunming University of Science and Technology, Wenshan 663000, Yunnan Province, China
| | - Yin-Rong Zhu
- Division of Endocrinology, Wenshan Hospital Affiliated to Kunming University of Science and Technology, Wenshan 663000, Yunnan Province, China
| | - Zu-Tao Wu
- Division of Endocrinology, Wenshan Hospital Affiliated to Kunming University of Science and Technology, Wenshan 663000, Yunnan Province, China
| | - Yan Hou
- Division of Endocrinology, Wenshan Hospital Affiliated to Kunming University of Science and Technology, Wenshan 663000, Yunnan Province, China
| | - Yu-Jie Xu
- Division of Endocrinology, Wenshan Hospital Affiliated to Kunming University of Science and Technology, Wenshan 663000, Yunnan Province, China
| | - Li Li
- Division of Endocrinology, Wenshan Hospital Affiliated to Kunming University of Science and Technology, Wenshan 663000, Yunnan Province, China
| | - Cun-Wen Ma
- Department of Radiological Medicine, Wenshan Hospital Affiliated to Kunming University of Science and Technology, Wenshan 663000, Yunnan Province, China
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Petrov MS. The Pharmacological Landscape for Fatty Change of the Pancreas. Drugs 2024; 84:375-384. [PMID: 38573485 PMCID: PMC11101365 DOI: 10.1007/s40265-024-02022-7] [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] [Accepted: 03/07/2024] [Indexed: 04/05/2024]
Abstract
The quest for medications to reduce intra-pancreatic fat deposition is now quarter a century old. While no specific medication has been approved for the treatment of fatty change of the pancreas, drug repurposing shows promise in reducing the burden of the most common disorder of the pancreas. This leading article outlines the 12 classes of medications that have been investigated to date with a view to reducing intra-pancreatic fat deposition. Information is presented hierarchically-from preclinical studies to retrospective findings in humans to prospective interventional studies to randomised controlled trials. This lays the grounds for shepherding the most propitious drugs into medical practice through well-designed basic science studies and adequately powered randomised controlled trials.
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Affiliation(s)
- Maxim S Petrov
- School of Medicine, University of Auckland, Auckland, New Zealand.
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Pagkali A, Makris A, Brofidi K, Agouridis AP, Filippatos TD. Pathophysiological Mechanisms and Clinical Associations of Non-Alcoholic Fatty Pancreas Disease. Diabetes Metab Syndr Obes 2024; 17:283-294. [PMID: 38283640 PMCID: PMC10813232 DOI: 10.2147/dmso.s397643] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Accepted: 12/29/2023] [Indexed: 01/30/2024] Open
Abstract
Non-Alcoholic Fatty Pancreas disease (NAFPD), characterized by fat accumulation in pancreatic tissue, is an emerging clinical entity. However, the clinical associations, the underlying molecular drivers, and the pathophysiological mechanisms of NAFPD have not yet been characterized in detail. The NAFPD spectrum not only includes infiltration and accumulation of fat within and between pancreatic cells but also involves several inflammatory processes, dysregulation of physiological metabolic pathways, and hormonal defects. A deeper understanding of the underlying molecular mechanisms is key to correlate NAFPD with clinical entities including non-alcoholic fatty liver disease, metabolic syndrome, diabetes mellitus, atherosclerosis, as well as pancreatic cancer and pancreatitis. The aim of this review is to examine the pathophysiological mechanisms of NAFPD and to assess the possible causative/predictive risk factors of NAFPD-related clinical syndromes.
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Affiliation(s)
- Antonia Pagkali
- School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Anastasios Makris
- School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Kalliopi Brofidi
- Department of Internal Medicine, School of Medicine, University of Crete, Heraklion, Greece
| | - Aris P Agouridis
- School of Medicine, European University Cyprus, Nicosia, Cyprus
- Department of Internal Medicine, German Oncology Center, Limassol, Cyprus
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Tsiampali C, Papaioannidou P, Goulas A, Polyzos SA. The role of glucagon-like peptide-1 receptor agonists in nonalcoholic fatty liver disease. Expert Rev Clin Pharmacol 2023; 16:1063-1072. [PMID: 37864548 DOI: 10.1080/17512433.2023.2274536] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Accepted: 10/19/2023] [Indexed: 10/23/2023]
Abstract
INTRODUCTION Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent disease, associated with obesity, type 2 diabetes mellitus and dyslipidemia, which can lead to liver cirrhosis and hepatocellular carcinoma in some patients. Apart from lifestyle modifications, which are the cornerstone for its management, several drugs are under evaluation, including glucagon-like peptide-1 receptor agonists (GLP-R1RAs). In this review, we summarized major clinical data concerning the effects of GLP-1RAs on NAFLD, trying to highlight existing knowledge and to elucidate areas of uncertainty, thus providing clues to potential clinical implications and research. AREAS COVERED Selected clinical studies on GLP-R1As in NAFLD are presented in this narrative review. EXPERT OPINION There is evidence that treatment with GLP-R1As in NAFLD has beneficial effects on NAFLD, i.e. improvement in liver function tests and histological improvement in hepatic steatosis and inflammation, but not fibrosis. Further research is required toward the early use of GLP-R1Αs, i.e. in NAFLD patients without fibrosis to evaluate whether they may prevent the progression to fibrosis, or in patients with advanced disease in combination with other medications, which may have additive or even synergistic effects on NAFLD.
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Affiliation(s)
- Chara Tsiampali
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Paraskevi Papaioannidou
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Antonis Goulas
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Stergios A Polyzos
- First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
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Yang T, Zhang D. Research progress on the effects of novel hypoglycemic drugs in diabetes combined with myocardial ischemia/reperfusion injury. Ageing Res Rev 2023; 86:101884. [PMID: 36801379 DOI: 10.1016/j.arr.2023.101884] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 02/08/2023] [Accepted: 02/14/2023] [Indexed: 02/18/2023]
Abstract
Acute myocardial infarction (AMI) reperfusion is associated with ischemia/reperfusion (I/R) injury, which leads to enlarged myocardial infarction size, poor healing of the infarcted myocardium, and poor left ventricular remodeling, thus increasing the risk of major adverse cardiovascular events (MACEs). Diabetes increases myocardial susceptibility to I/R injury, decreases myocardial responsiveness to cardioprotective strategies, exacerbates myocardial I/R injury, and expands the infarct size of AMI, thereby increasing the incidence of malignant arrhythmias and heart failure. Currently, evidence regarding pharmacological interventions for diabetes combined with AMI and I/R injury is lacking. Traditional hypoglycemic drugs have a limited role in the prevention and treatment of diabetes combined with I/R injury. Current evidence suggests that novel hypoglycemic drugs may exert a preventive effect on diabetes combined with myocardial I/R injury, especially glucagon-like peptide-1 receptor agonists (GLP-1 RA) and sodium-dependent glucose transporter protein 2 inhibitors (SGLT2i), which may increase coronary blood flow, reduce acute thrombosis, attenuate I/R injury, decrease myocardial infarction size, inhibit structural and functional remodeling of the ischemic heart, improve cardiac function, and reduce the occurrence of MACEs of diabetes patients combined with AMI via mechanisms such as reduction of inflammatory response, inhibition of oxidative stress, and improvement of vascular endothelial function. This paper will systematically elaborate the protective role and molecular mechanisms of GLP-1 RA and SGLT2i in diabetes combined with myocardial I/R injury, aiming to provide clinical assistance.
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Affiliation(s)
- Tiangui Yang
- Department of Cardiology, Shengjing Hospital of China Medical University, China.
| | - Daqing Zhang
- Department of Cardiology, Shengjing Hospital of China Medical University, China.
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Huang P, Li Z, Peng T, Yang J, Bi L, Huang G, Qiu Y, Yang M, Ye P, Huang M, Jin H, Sun L. Evaluation of [ 18F]F-TZ3108 for PET Imaging of Metabolic-Associated Fatty Liver Disease. Mol Imaging Biol 2022; 24:909-919. [PMID: 35705779 DOI: 10.1007/s11307-022-01740-2] [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: 01/24/2022] [Revised: 04/20/2022] [Accepted: 05/06/2022] [Indexed: 12/29/2022]
Abstract
PURPOSE Sigma-1 receptor (Sig-1R), a chaperone that resides at the mitochondrion-associated endoplasmic reticulum (ER) membrane, is an ER stress biomarker. It is thought that ER stress plays a critical role in the progression of metabolic-associated fatty liver disease (MAFLD). The aim of this study was to evaluate a positron emission tomography (PET) tracer [18F]F-TZ3108 targeting Sig-1R for MAFLD. PROCEDURES The mouse model of MAFLD was established by feeding high-fat diet (HFD) for 12 weeks. Dynamic (0-60 min) PET/CT scans were performed after intravenous injection of 2-deoxy-2[18F]fluoro-D-glucose ([18F]-FDG) and [18F]F-TZ3108. Tracer kinetic modeling was performed for quantification of the PET/CT imaging of the liver. Post-PET biodistribution, the liver tissue western blotting (WB), and immunofluorescence (IF) were performed to compare the expression of Sig-1R levels in the organs harvested from both MAFLD and age-matched control mice. RESULTS The micro PET/CT imaging revealed a significantly decreased uptake of [18F]F-TZ3108 in the livers of the MAFLD group compared to the healthy controls, while the uptake of [18F]-FDG in the livers was not significantly different between the two groups. Based on the tracer kinetic modeling, the binding disassociate rate (k4) for [18F]F-TZ3108 was significantly increased in MAFLD group compared to healthy controls. The volume distribution (VT), and the non-displacement binding potential (BPND) revealed significantly decrease in MAFLD compared to healthy controls respectively. The post-PET biodistribution (%ID/g) of [18F]F-TZ3108 in the livers of MAFLD mice was significantly reduced nearly twofold than that in the livers of control mice. WB and IF experiments further confirmed the reduction of Sig-1R expression in the MAFLD group. CONCLUSIONS The expression of Sig-1R in the liver, measured by the PET tracer, [18F]F-TZ3108, was significantly decreased in mouse model of MAFLD. The [18F]F-TZ3108 PET/CT imaging may provide a novel means of visualization for ER stress in MAFLD or other diseases in vivo.
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Affiliation(s)
- Peiyi Huang
- Department of Endocrinology, The Fifth Affiliated Hospital, Sun Yat-Sen University, Zhuhai, Guangdong Province, China.,Guangdong Provincial Key Laboratory of Biomedical Imaging and Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-Sen University, Zhuhai, Guangdong Province, China
| | - Zhijun Li
- Guangdong Provincial Key Laboratory of Biomedical Imaging and Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-Sen University, Zhuhai, Guangdong Province, China
| | - Tukang Peng
- Guangdong Provincial Key Laboratory of Biomedical Imaging and Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-Sen University, Zhuhai, Guangdong Province, China
| | - Jihua Yang
- Department of Endocrinology, The Fifth Affiliated Hospital, Sun Yat-Sen University, Zhuhai, Guangdong Province, China
| | - Lei Bi
- Guangdong Provincial Key Laboratory of Biomedical Imaging and Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-Sen University, Zhuhai, Guangdong Province, China
| | - Guolong Huang
- Guangdong Provincial Key Laboratory of Biomedical Imaging and Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-Sen University, Zhuhai, Guangdong Province, China
| | - Yifan Qiu
- Guangdong Provincial Key Laboratory of Biomedical Imaging and Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-Sen University, Zhuhai, Guangdong Province, China
| | - Min Yang
- Guangdong Provincial Key Laboratory of Biomedical Imaging and Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-Sen University, Zhuhai, Guangdong Province, China
| | - Peizhen Ye
- Guangdong Provincial Key Laboratory of Biomedical Imaging and Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-Sen University, Zhuhai, Guangdong Province, China
| | - Mingxing Huang
- Department of Infectious Diseases, The Fifth Affiliated Hospital, Sun Yat-Sen University, Zhuhai, Guangdong Province, China
| | - Hongjun Jin
- Guangdong Provincial Key Laboratory of Biomedical Imaging and Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-Sen University, Zhuhai, Guangdong Province, China.
| | - Liao Sun
- Department of Endocrinology, The Fifth Affiliated Hospital, Sun Yat-Sen University, Zhuhai, Guangdong Province, China.
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Flessa C, Kyrou I, Nasiri‐Ansari N, Kaltsas G, Kassi E, Randeva HS. Endoplasmic reticulum stress in nonalcoholic (metabolic associated) fatty liver disease (NAFLD/MAFLD). J Cell Biochem 2022; 123:1585-1606. [PMID: 35490371 DOI: 10.1002/jcb.30247] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 03/09/2022] [Accepted: 03/28/2022] [Indexed: 02/06/2023]
Affiliation(s)
- Christina‐Maria Flessa
- Department of Biological Chemistry, Medical School National and Kapodistrian University of Athens Athens Greece
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM) University Hospitals Coventry and Warwickshire NHS Trust Coventry UK
| | - Ioannis Kyrou
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM) University Hospitals Coventry and Warwickshire NHS Trust Coventry UK
- Division of Translational and Experimental Medicine, Metabolic and Vascular Health, Warwick Medical School University of Warwick Coventry UK
- Centre for Sport, Exercise and Life Sciences, Research Institute for Health & Wellbeing Coventry University Coventry UK
- Aston Medical School, College of Health and Life Sciences Aston University Birmingham UK
- Department of Food Science & Human Nutrition Agricultural University of Athens Athens Greece
| | - Narjes Nasiri‐Ansari
- Department of Biological Chemistry, Medical School National and Kapodistrian University of Athens Athens Greece
| | - Gregory Kaltsas
- Endocrine Unit, 1st Department of Propaedeutic and Internal Medicine, Laiko Hospital National and Kapodistrian University of Athens Athens Greece
| | - Eva Kassi
- Department of Biological Chemistry, Medical School National and Kapodistrian University of Athens Athens Greece
- Endocrine Unit, 1st Department of Propaedeutic and Internal Medicine, Laiko Hospital National and Kapodistrian University of Athens Athens Greece
| | - Harpal S. Randeva
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM) University Hospitals Coventry and Warwickshire NHS Trust Coventry UK
- Division of Translational and Experimental Medicine, Metabolic and Vascular Health, Warwick Medical School University of Warwick Coventry UK
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Liraglutide + PYY3-36 Combination Therapy Mimics Effects of Roux-en-Y Bypass on Early NAFLD Whilst Lacking-Behind in Metabolic Improvements. J Clin Med 2022; 11:jcm11030753. [PMID: 35160204 PMCID: PMC8836549 DOI: 10.3390/jcm11030753] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 01/27/2022] [Accepted: 01/28/2022] [Indexed: 02/04/2023] Open
Abstract
Background: Treatment options for NAFLD are still limited. Bariatric surgery, such as Roux-en-Y gastric bypass (RYGB), has been shown to improve metabolic and histologic markers of NAFLD. Glucagon-like-peptide-1 (GLP-1) analogues lead to improvements in phase 2 clinical trials. We directly compared the effects of RYGB with a treatment using liraglutide and/or peptide tyrosine tyrosine 3-36 (PYY3-36) in a rat model for early NAFLD. Methods: Obese male Wistar rats (high-fat diet (HFD)-induced) were randomized into the following treatment groups: RYGB, sham-operation (sham), liraglutide (0.4 mg/kg/day), PYY3-36 (0.1 mg/kg/day), liraglutide+PYY3-36, and saline. After an observation period of 4 weeks, liver samples were histologically evaluated, ELISAs and RNA sequencing + RT-qPCRs were performed. Results: RYGB and liraglutide+PYY3-36 induced a similar body weight loss and, compared to sham/saline, marked histological improvements with significantly less steatosis. However, only RYGB induced significant metabolic improvements (e.g., adiponectin/leptin ratio 18.8 ± 11.8 vs. 2.4 ± 1.2 in liraglutide+PYY3-36- or 1.4 ± 0.9 in sham-treated rats). Furthermore, RNA sequencing revealed a high number of differentially regulated genes in RYGB treated animals only. Conclusions: The combination therapy of liraglutide+PYY3-36 partly mimics the positive effects of RYGB on weight reduction and on hepatic steatosis, while its effects on metabolic function lack behind RYGB.
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Zhang CL, Wang JJ, Li JN, Yang Y. Nonalcoholic fatty pancreas disease: An emerging clinical challenge. World J Clin Cases 2021; 9:6624-6638. [PMID: 34447810 PMCID: PMC8362510 DOI: 10.12998/wjcc.v9.i23.6624] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 05/20/2021] [Accepted: 06/01/2021] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty pancreas disease (NAFPD) is an emerging disease that has gained an increasing amount of attention in recent years. It describes fat accumulation in the pancreas with insignificant alcohol consumption, but the pathogenesis is largely unknown. A wide range of terms have been used to describe the phenomenon of pancreatic fat accumulation, but NAFPD remains an under-recognized and non-independent disorder. Obesity, age, sex, race, and unhealthy lifestyle are established independent risk factors for NAFPD, which is strongly associated with metabolic syndrome, type 2 diabetes, pancreatitis, pancreatic fistula, pancreatic cancer, and nonalcoholic fatty liver disease. At present, imaging techniques are common diagnostic aids, but uniform criteria and consensus are lacking. Therapeutically, healthy diet, weight loss, and exercise are the mainstays to reduce pancreatic fat accumulation. It can be seen that there is a limited understanding of NAFPD at this stage and further exploration is needed. Previous studies have revealed that NAFPD may directly affect diagnosis and clinical decision-making. Therefore, exploring the pathophysiological mechanism and clinical associations of NAFPD is a major challenge for researchers and clinicians.
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Affiliation(s)
- Cheng-Lei Zhang
- Department of Clinical Laboratory, General Hospital of Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
- The Institute of Endocrinology, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Jing-Jiao Wang
- Department of Stomatology, General Hospital of Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Jian-Ning Li
- The Institute of Endocrinology, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
- School of Basic Medical Sciences, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Yi Yang
- The Institute of Endocrinology, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
- School of Basic Medical Sciences, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
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A bilayer microneedle for therapeutic peptide delivery towards the treatment of diabetes in db/db mice. J Drug Deliv Sci Technol 2021. [DOI: 10.1016/j.jddst.2021.102336] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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Hupa-Breier KL, Dywicki J, Hartleben B, Wellhöner F, Heidrich B, Taubert R, Mederacke YSE, Lieber M, Iordanidis K, Manns MP, Wedemeyer H, Hardtke-Wolenski M, Jaeckel E. Dulaglutide Alone and in Combination with Empagliflozin Attenuate Inflammatory Pathways and Microbiome Dysbiosis in a Non-Diabetic Mouse Model of NASH. Biomedicines 2021; 9:biomedicines9040353. [PMID: 33808404 PMCID: PMC8066839 DOI: 10.3390/biomedicines9040353] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 03/22/2021] [Accepted: 03/25/2021] [Indexed: 12/15/2022] Open
Abstract
Dysregulation of glucose homeostasis plays a major role in the pathogenesis of non-alcoholic steatohepatitis (NASH) as it activates proinflammatory and profibrotic processes. Beneficial effects of antiglycemic treatments such as GLP-1 agonist or SGLT-2 inhibitor on NASH in patients with diabetes have already been investigated. However, their effect on NASH in a non-diabetic setting remains unclear. With this aim, we investigated the effect of long-acting GLP1-agonist dulaglutide and SGLT-2 inhibitor empagliflozin and their combination in a non-diabetic mouse model of NASH. C57BL/6 mice received a high-fat-high-fructose (HFHC) diet with a surplus of cholesterol for 16 weeks. After 12 weeks of diet, mice were treated with either dulaglutide, empagliflozin or their combination. Dulaglutide alone and in combination with empagliflozin led to significant weight loss, improved glucose homeostasis and diminished anti-inflammatory and anti-fibrotic pathways. Combination of dulaglutide and empagliflozin further decreased MoMFLy6CHigh and CD4+Foxp3+ T cells. No beneficial effects for treatment with empagliflozin alone could be shown. While no effect of dulaglutide or its combination with empaglifozin on hepatic steatosis was evident, these data demonstrate distinct anti-inflammatory effects of dulaglutide and their combination with empagliflozin in a non-diabetic background, which could have important implications for further treatment of NASH.
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Affiliation(s)
- Katharina Luise Hupa-Breier
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, 30625 Hannover, Germany; (J.D.); (F.W.); (B.H.); (R.T.); (Y.S.M.); (M.L.); (K.I.); (M.P.M.); (H.W.); (M.H.-W.); (E.J.)
- Correspondence: ; Tel.: +49-(0)-511-532-6992
| | - Janine Dywicki
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, 30625 Hannover, Germany; (J.D.); (F.W.); (B.H.); (R.T.); (Y.S.M.); (M.L.); (K.I.); (M.P.M.); (H.W.); (M.H.-W.); (E.J.)
| | - Björn Hartleben
- Department of Pathology, Hannover Medical School, 30625 Hannover, Germany;
| | - Freya Wellhöner
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, 30625 Hannover, Germany; (J.D.); (F.W.); (B.H.); (R.T.); (Y.S.M.); (M.L.); (K.I.); (M.P.M.); (H.W.); (M.H.-W.); (E.J.)
| | - Benjamin Heidrich
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, 30625 Hannover, Germany; (J.D.); (F.W.); (B.H.); (R.T.); (Y.S.M.); (M.L.); (K.I.); (M.P.M.); (H.W.); (M.H.-W.); (E.J.)
| | - Richard Taubert
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, 30625 Hannover, Germany; (J.D.); (F.W.); (B.H.); (R.T.); (Y.S.M.); (M.L.); (K.I.); (M.P.M.); (H.W.); (M.H.-W.); (E.J.)
| | - Young-Seon Elisabeth Mederacke
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, 30625 Hannover, Germany; (J.D.); (F.W.); (B.H.); (R.T.); (Y.S.M.); (M.L.); (K.I.); (M.P.M.); (H.W.); (M.H.-W.); (E.J.)
| | - Maren Lieber
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, 30625 Hannover, Germany; (J.D.); (F.W.); (B.H.); (R.T.); (Y.S.M.); (M.L.); (K.I.); (M.P.M.); (H.W.); (M.H.-W.); (E.J.)
| | - Konstantinos Iordanidis
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, 30625 Hannover, Germany; (J.D.); (F.W.); (B.H.); (R.T.); (Y.S.M.); (M.L.); (K.I.); (M.P.M.); (H.W.); (M.H.-W.); (E.J.)
| | - Michael P. Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, 30625 Hannover, Germany; (J.D.); (F.W.); (B.H.); (R.T.); (Y.S.M.); (M.L.); (K.I.); (M.P.M.); (H.W.); (M.H.-W.); (E.J.)
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, 30625 Hannover, Germany; (J.D.); (F.W.); (B.H.); (R.T.); (Y.S.M.); (M.L.); (K.I.); (M.P.M.); (H.W.); (M.H.-W.); (E.J.)
| | - Matthias Hardtke-Wolenski
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, 30625 Hannover, Germany; (J.D.); (F.W.); (B.H.); (R.T.); (Y.S.M.); (M.L.); (K.I.); (M.P.M.); (H.W.); (M.H.-W.); (E.J.)
- Department of Gastroenterology and Hepatology, Essen University Hospital, University Duisburg-Essen, 45147 Essen, Germany
| | - Elmar Jaeckel
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, 30625 Hannover, Germany; (J.D.); (F.W.); (B.H.); (R.T.); (Y.S.M.); (M.L.); (K.I.); (M.P.M.); (H.W.); (M.H.-W.); (E.J.)
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