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Ruggeri RM, Grossrubatscher EM, Ciocca E, Hasballa I, Jaafar S, Oldani M, Rubino M, Russo F, Isidori AM, Colao A, Faggiano A. Incretins and SGLT-2 inhibitors in diabetic patients with neuroendocrine tumors: current updates and future directions. Rev Endocr Metab Disord 2025:10.1007/s11154-025-09958-5. [PMID: 40175622 DOI: 10.1007/s11154-025-09958-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/17/2025] [Indexed: 04/04/2025]
Abstract
Neuroendocrine tumors (NET) are frequently associated with glycemic disorders, such as prediabetes or diabetes, which may result from either surgical or medical treatments or hormonal hypersecretion by the tumor itself. Moreover, pre-existing diabetes is a known risk factor for NET development, with metabolic control and antidiabetic therapies potentially influencing tumor progression. The complex interplay between diabetes and NET, which share several molecular pathways, has spurred interest in the anti-cancer effects of antidiabetic medications. This is particularly relevant as new antidiabetic drugs continue to emerge, including sodium-glucose cotransporter-2 (SGLT2) inhibitors and incretin-based therapies, such as dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 receptor (GLP-1R) agonists and dual GIP/GLP- 1 R agonists. This review explores the impact of these novel pharmacological options on NET development and progression through a comprehensive analysis of pre-clinical and clinical studies, with the purpose to evaluate safety and feasibility of introducing these drugs in the treatment of NETs patients. We conducted a comprehensive search of online databases, including PubMed, ISI Web of Science, and Scopus, for studies assessing the therapeutic effects and potential mechanisms of action of incretins and SGLT2 inhibitors in patients with NET. These novel antidiabetic drugs exhibit promising anticancer properties, potentially inhibiting tumor cell proliferation and inducing apoptosis, though concerns about certain cancer risks remain. Based on current evidence, the benefits of incretin-based therapies outweigh any potential cancer risks, leading to the proposal of tailored management algorithms for diabetes in NET patients, factoring in the diabetes aetiology, comorbidities, and life expectancy.
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Affiliation(s)
- Rosaria M Ruggeri
- Endocrinology, Department of Human Pathology of Adulthood and Childhood DETEV, University of Messina, Messina, Italy
| | | | - Eleonora Ciocca
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Iderina Hasballa
- Endocrinology Unit, Department of Internal Medicine and Medical Specialties (DIMI), University of Genoa, 16132, Genoa, Italy
| | - Simona Jaafar
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
- Endocrinology, Diabetology and Andrology Unit, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Monica Oldani
- Laboratory of Geriatric and Oncologic Neuroendocrinology Research, IRCCS, Istituto Auxologico Italiano, Milan, Italy
| | - Manila Rubino
- Onco-Endocrinology Unit, European Institute of Oncology, Milan, Italy
| | - Flaminia Russo
- Endocrinology Unit, Department of Clinical and Molecular Medicine, European Neuroendocrine Tumor Society (ENETS) Center of Excellence, Sapienza University of Rome, Sant'Andrea University Hospital, Rome, Italy
| | - Andrea M Isidori
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Annamaria Colao
- Endocrinology, Diabetology and Andrology Unit, Department of Clinical Medicine and Surgery, Federico II University of Naples, Naples, Italy
- UNESCO Chair "Education for Health and Sustainable Development", Federico II University, Naples, Italy
| | - Antongiulio Faggiano
- Endocrinology Unit, Department of Clinical and Molecular Medicine, European Neuroendocrine Tumor Society (ENETS) Center of Excellence, Sapienza University of Rome, Sant'Andrea University Hospital, Rome, Italy.
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2
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He J, Phillips L, Nisbet J, Morton A. Ketotic Hypoglycaemia Following Sleeve Gastrectomy. Clin Endocrinol (Oxf) 2025. [PMID: 40129270 DOI: 10.1111/cen.15232] [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: 08/01/2024] [Revised: 02/07/2025] [Accepted: 03/05/2025] [Indexed: 03/26/2025]
Abstract
Post-bariatric surgery hypoglycaemia is typically mediated by hyperinsulinaemia, although the exact mechanisms are incompletely understood. Two cases of non-insulin mediated, ketotic hypoglycaemia following sleeve gastrectomy are presented. After fasting for 40 and 65 h, respectively, both patients developed symptomatic hypoglycaemia, with corresponding low insulin, low c-peptide and elevated beta-hydroxybutyrate levels. Morning cortisol and IGF1 levels were normal. Potential mechanisms for ketotic hypoglycaemia following bariatric surgery include reduction in hepatic, renal and intestinal gluconeogenesis, or alternatively an underlying inborn error of metabolism such as a glycogen storage disorder unmasked by bariatric surgery. Most glycogen storage disorders present in childhood, but there have been rare case reports of glycogen storage disorders types I, III and IX diagnosed in adulthood. Neither of the above cases had other features of a glycogen storage disorder such as elevated lactate, hyperuricaemia, hypertriglyceridaemia, hepatomegaly, myopathy or an indicative family history. Both patients trialled first-line dietary management, which was inadequate in managing hypoglycaemia. Treatment with the glucagon-like peptide-1 receptor agonist semaglutide resulted in the resolution of hypoglycaemic episodes in one patient, and a significant reduction in hypoglycaemic episodes in the other patient.
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Affiliation(s)
- Jinwen He
- Mater Health, Brisbane, Australia
- Department of Medicine, University of Queensland, Brisbane, Australia
| | - Liza Phillips
- Mater Health, Brisbane, Australia
- Department of Medicine, University of Queensland, Brisbane, Australia
| | | | - Adam Morton
- Mater Health, Brisbane, Australia
- Department of Medicine, University of Queensland, Brisbane, Australia
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3
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Movahednasab M, Dianat-Moghadam H, Khodadad S, Nedaeinia R, Safabakhsh S, Ferns G, Salehi R. GLP-1-based therapies for type 2 diabetes: from single, dual and triple agonists to endogenous GLP-1 production and L-cell differentiation. Diabetol Metab Syndr 2025; 17:60. [PMID: 39962520 PMCID: PMC11834518 DOI: 10.1186/s13098-025-01623-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: 09/22/2024] [Accepted: 02/02/2025] [Indexed: 02/20/2025] Open
Abstract
Glucagon-like peptide-1 (GLP-1) is an incretin peptide hormone mainly secreted by enteroendocrine intestinal L-cells. GLP-1 is also secreted by α-cells of the pancreas and the central nervous system (CNS). GLP-1 secretion is stimulated by nutrient intake and exerts its effects on glucose homeostasis by stimulating insulin secretion, gastric emptying confiding the food intake, and β-cell proliferation. The insulinotropic effects of GLP-1, and the reduction of its effects in type 2 diabetes mellitus (T2DM), have made GLP-1 an attractive option for the treatment of T2DM. Furthermore, GLP-1-based medications such as GLP-1 receptor agonists and dipeptidyl peptidase-4 inhibitors, have been shown to improve diabetes control in preclinical and clinical trials with human subjects. Importantly, increasing the endogenous production of GLP-1 by different mechanisms or by increasing the number of intestinal L-cells that tend to produce this hormone may be another effective therapeutic approach to managing T2DM. Herein, we briefly describe therapeutic agents/compounds that enhance GLP-1 function. Then, we will discuss the approaches that can increase the endogenous production of GLP-1 through various stimuli. Finally, we introduce the potential of L-cell differentiation as an attractive future therapeutic approach to increase GLP-1 production as an attractive therapeutic alternative for T2DM.
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Affiliation(s)
- Maedeh Movahednasab
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
- Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Non-Communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Hassan Dianat-Moghadam
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
- Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Non-Communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Sana Khodadad
- Department of Genetics and Molecular Biology, School of Medicine, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Reza Nedaeinia
- Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Non-Communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Saeid Safabakhsh
- Micronesian Institute for Disease Prevention and Research, 736 Route 4, Suite 103, Sinajana, GU, 96910, USA
| | - Gordon Ferns
- Division of Medical Education, Brighton & Sussex Medical School, Falmer, Brighton, Sussex, BN1 9PH, UK
| | - Rasoul Salehi
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.
- Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Non-Communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran.
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4
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Infante M, Silvestri F, Padilla N, Pacifici F, Pastore D, Pinheiro MM, Caprio M, Tesauro M, Fabbri A, Novelli G, Alejandro R, De Lorenzo A, Ricordi C, Della-Morte D. Unveiling the Therapeutic Potential of the Second-Generation Incretin Analogs Semaglutide and Tirzepatide in Type 1 Diabetes and Latent Autoimmune Diabetes in Adults. J Clin Med 2025; 14:1303. [PMID: 40004833 PMCID: PMC11856673 DOI: 10.3390/jcm14041303] [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: 11/30/2024] [Revised: 01/31/2025] [Accepted: 02/08/2025] [Indexed: 02/27/2025] Open
Abstract
Type 1 diabetes mellitus (T1D) is a chronic autoimmune disease caused by the immune-mediated destruction of insulin-producing pancreatic beta cells, resulting in the lifelong need for exogenous insulin. Over the last few years, overweight and obesity have recently emerged as growing health issues also afflicting patients with T1D. In this context, the term "double diabetes" has been coined to indicate patients with T1D who have a family history of type 2 diabetes mellitus (T2D) and/or patients with T1D who are affected by insulin resistance and/or overweight/obesity and/or metabolic syndrome. At the same time, the use of second-generation incretin analogs semaglutide and tirzepatide has substantially increased on a global scale over the last few years, given the remarkable clinical benefits of these drugs (in terms of glucose control and weight loss) in patients with T2D and/or overweight/obesity. Although the glucagon-like peptide-1 (GLP-1) receptor agonists and the novel dual GIP (glucose-dependent insulinotropic polypeptide)/GLP-1 receptor agonist tirzepatide are currently not approved for the treatment of T1D, a growing body of evidence over the last few years has shown that these medications may serve as valid add-on treatments to insulin with substantial efficacy in improving glucose control, promoting weight loss, preserving residual beta-cell function and providing other beneficial metabolic effects in patients with T1D, double diabetes and latent autoimmune diabetes in adults (LADA). This manuscript aims to comprehensively review the currently available literature (mostly consisting of real-world studies) regarding the safety and therapeutic use (for different purposes) of semaglutide and tirzepatide in patients with T1D (at different stages of the disease), double diabetes and LADA.
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Affiliation(s)
- Marco Infante
- Section of Diabetes & Metabolic Disorders, UniCamillus, Saint Camillus International University of Health Sciences, Via di Sant’Alessandro 8, 00131 Rome, Italy
- Division of Cellular Transplantation, Diabetes Research Institute (DRI), Department of Surgery, University of Miami Miller School of Medicine, 1450 NW 10th Ave., Miami, FL 33136, USA; (N.P.); (R.A.); (C.R.)
| | - Francesca Silvestri
- Pediatric Endocrinology Outpatient Clinic, Via dell’Alpinismo 24, 00135 Rome, Italy;
| | - Nathalia Padilla
- Division of Cellular Transplantation, Diabetes Research Institute (DRI), Department of Surgery, University of Miami Miller School of Medicine, 1450 NW 10th Ave., Miami, FL 33136, USA; (N.P.); (R.A.); (C.R.)
| | - Francesca Pacifici
- Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Open University, Via di Val Cannuta 247, 00166 Rome, Italy; (F.P.); (D.P.); (M.C.); (D.D.-M.)
- Interdisciplinary Center for Advanced Studies on Lab-on-Chip and Organ on-Chip Applications (IC-LOC), University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy
| | - Donatella Pastore
- Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Open University, Via di Val Cannuta 247, 00166 Rome, Italy; (F.P.); (D.P.); (M.C.); (D.D.-M.)
- Interdisciplinary Center for Advanced Studies on Lab-on-Chip and Organ on-Chip Applications (IC-LOC), University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy
| | - Marcelo Maia Pinheiro
- UNIVAG, Centro Universitário de Várzea Grande, Av. Dom Orlando Chaves, 2655-Cristo Rei, Várzea Grande 78118-000, MT, Brazil;
| | - Massimiliano Caprio
- Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Open University, Via di Val Cannuta 247, 00166 Rome, Italy; (F.P.); (D.P.); (M.C.); (D.D.-M.)
| | - Manfredi Tesauro
- Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; (M.T.); (A.F.)
| | - Andrea Fabbri
- Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; (M.T.); (A.F.)
| | - Giuseppe Novelli
- Genetics Section, Department of Biomedicine and Prevention, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy;
- Department of Pharmacology, Reno School of Medicine, University of Nevada, 1664 N. Virginia Street, Reno, NV 89557, USA
| | - Rodolfo Alejandro
- Division of Cellular Transplantation, Diabetes Research Institute (DRI), Department of Surgery, University of Miami Miller School of Medicine, 1450 NW 10th Ave., Miami, FL 33136, USA; (N.P.); (R.A.); (C.R.)
| | - Antonino De Lorenzo
- Section of Clinical Nutrition and Nutrigenomics, Department of Biomedicine and Prevention, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy;
| | - Camillo Ricordi
- Division of Cellular Transplantation, Diabetes Research Institute (DRI), Department of Surgery, University of Miami Miller School of Medicine, 1450 NW 10th Ave., Miami, FL 33136, USA; (N.P.); (R.A.); (C.R.)
| | - David Della-Morte
- Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Open University, Via di Val Cannuta 247, 00166 Rome, Italy; (F.P.); (D.P.); (M.C.); (D.D.-M.)
- Interdisciplinary Center for Advanced Studies on Lab-on-Chip and Organ on-Chip Applications (IC-LOC), University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy
- Section of Clinical Nutrition and Nutrigenomics, Department of Biomedicine and Prevention, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy;
- Department of Neurology, Evelyn F. McKnight Brain Institute, University of Miami Miller School of Medicine, 1120 NW 14th Street, Miami, FL 33136, USA
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5
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Młynarska E, Czarnik W, Dzieża N, Jędraszak W, Majchrowicz G, Prusinowski F, Stabrawa M, Rysz J, Franczyk B. Type 2 Diabetes Mellitus: New Pathogenetic Mechanisms, Treatment and the Most Important Complications. Int J Mol Sci 2025; 26:1094. [PMID: 39940862 PMCID: PMC11817707 DOI: 10.3390/ijms26031094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Revised: 01/19/2025] [Accepted: 01/22/2025] [Indexed: 02/16/2025] Open
Abstract
Type 2 diabetes mellitus (T2DM), a prevalent chronic disease affecting over 400 million people globally, is driven by genetic and environmental factors. The pathogenesis involves insulin resistance and β-cell dysfunction, mediated by mechanisms such as the dedifferentiation of β-cells, mitochondrial dysfunction, and oxidative stress. Treatment should be based on non-pharmacological therapy. Strategies such as increased physical activity, dietary modifications, cognitive-behavioral therapy are important in maintaining normal glycemia. Advanced therapies, including SGLT2 inhibitors and GLP-1 receptor agonists, complement these treatments and offer solid glycemic control, weight control, and reduced cardiovascular risk. Complications of T2DM, such as diabetic kidney disease, retinopathy, and neuropathy, underscore the need for early diagnosis and comprehensive management to improve patient outcomes and quality of life.
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Affiliation(s)
- Ewelina Młynarska
- Department of Nephrocardiology, Medical University of Lodz, Ul. Zeromskiego 113, 90-549 Lodz, Poland
| | - Witold Czarnik
- Department of Nephrocardiology, Medical University of Lodz, Ul. Zeromskiego 113, 90-549 Lodz, Poland
| | - Natasza Dzieża
- Department of Nephrocardiology, Medical University of Lodz, Ul. Zeromskiego 113, 90-549 Lodz, Poland
| | - Weronika Jędraszak
- Department of Nephrocardiology, Medical University of Lodz, Ul. Zeromskiego 113, 90-549 Lodz, Poland
| | - Gabriela Majchrowicz
- Department of Nephrocardiology, Medical University of Lodz, Ul. Zeromskiego 113, 90-549 Lodz, Poland
| | - Filip Prusinowski
- Department of Nephrocardiology, Medical University of Lodz, Ul. Zeromskiego 113, 90-549 Lodz, Poland
| | - Magdalena Stabrawa
- Department of Nephrocardiology, Medical University of Lodz, Ul. Zeromskiego 113, 90-549 Lodz, Poland
| | - Jacek Rysz
- Department of Nephrology, Hypertension and Family Medicine, Medical University of Lodz, Ul. Zeromskiego 113, 90-549 Lodz, Poland
| | - Beata Franczyk
- Department of Nephrocardiology, Medical University of Lodz, Ul. Zeromskiego 113, 90-549 Lodz, Poland
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6
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Wu J, Tang L, Zheng F, Chen X, Li L. A review of the last decade: pancreatic cancer and type 2 diabetes. Arch Physiol Biochem 2024; 130:660-668. [PMID: 37646618 DOI: 10.1080/13813455.2023.2252204] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 08/04/2023] [Accepted: 08/21/2023] [Indexed: 09/01/2023]
Abstract
Pancreatic cancer (PC) is a prevalent gastrointestinal tumour known for its high degree of malignancy, resulting in a mere 10% five-year survival rate for most patients. Over the past decade, a growing body of research has shed light on the intricate bidirectional association between PC and Type 2 diabetes (T2DM). The collection of PC- and T2DM-related articles is derived from two comprehensive databases, namely WOS (Web of Science Core Collection) and CNKI (China National Knowledge Infrastructure). This article discusses the last 10 years of research trends in PC and T2DM and explores their potential regulatory relationship as well as related medications.
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Affiliation(s)
- Jiaqi Wu
- Nanfang Hospital, Southern Medical University, Guangzhou, China
- School of Nursing, Southern Medical University, Guangzhou, China
| | - Liang Tang
- Department of General Medicine, Zhuzhou Central Hospital, Zhuzhou, China
| | - Feng Zheng
- Department of Anatomy, University of Otago, Dunedin, New Zealand
| | - Xun Chen
- Department of the Trauma center, Zhuzhou Central Hospital, Zhuzhou, China
- Department of hepatobiliary surgery, Zhuzhou Central Hospital, Zhuzhou, China
| | - Lei Li
- Department of Pathology, University of Otago, Dunedin, New Zealand
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7
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Li X, Zhang X, Xie X, Dong T, Lv C, Guan R, Zhang W, Ji G, Chen F, Wang S, Wang X. Novel Phenoxyalkanoic Acid Derivatives as Free Fatty Acid Receptor 4 Agonists for Treating Type 2 Diabetes Mellitus. Int J Mol Sci 2024; 25:11476. [PMID: 39519029 PMCID: PMC11547093 DOI: 10.3390/ijms252111476] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2024] [Revised: 10/20/2024] [Accepted: 10/21/2024] [Indexed: 11/16/2024] Open
Abstract
Diabetes mellitus (DM) is a common metabolic disease that poses a severe threat to human health. Despite a range of therapeutic approaches, there remains a lack of effective and safe therapies with the existing drugs. Therefore, there is an urgent need to develop novel, effective, and safe therapeutic strategies for DM. Free fatty acid receptor 4 (FFAR4), also known as GPR120, is a member of the G protein-coupled receptor family, which has received considerable attention as an attractive new therapeutic target for treating DM. In the present study, based on the structure of TUG-891, which has excellent activity and selectivity, a series of novel FFAR4 agonists was designed by replacing the phenylpropanoic acid β position carbon atom with an oxygen atom, while replacing the linking oxymethylene with an amide-linking group. The target compounds were evaluated for FFAR4 agonistic activity, and the preferred compounds were evaluated for selectivity, oral glucose tolerance in normal ICR mice, antidiabetic activity in diet-induced obese (DIO) mice, pharmacokinetic properties in ICR mice and molecular modeling studies. The results showed that compound 10f possessed excellent FFAR4 agonistic activity and selectivity, significantly improved glucose tolerance in normal ICR mice, lowered blood glucose and promoted insulin secretion in a dose-dependent manner in DIO mice, and showed favorable pharmacokinetic properties. These results indicate that compound 10f may be a promising compound that deserves further structure-activity relationship and pharmacological studies for the development of antidiabetic drugs.
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Affiliation(s)
- Xu Li
- National Key Laboratory of Macromolecular Drug Development and Manufacturing, School of Pharmaceutical Sciences and Food Engineering, Liaocheng University, 1 Hunan Street, Liaocheng 252059, China; (X.L.); (X.Z.); (X.X.); (T.D.); (C.L.); (R.G.); (W.Z.); (F.C.)
| | - Xinmeng Zhang
- National Key Laboratory of Macromolecular Drug Development and Manufacturing, School of Pharmaceutical Sciences and Food Engineering, Liaocheng University, 1 Hunan Street, Liaocheng 252059, China; (X.L.); (X.Z.); (X.X.); (T.D.); (C.L.); (R.G.); (W.Z.); (F.C.)
| | - Xueyuan Xie
- National Key Laboratory of Macromolecular Drug Development and Manufacturing, School of Pharmaceutical Sciences and Food Engineering, Liaocheng University, 1 Hunan Street, Liaocheng 252059, China; (X.L.); (X.Z.); (X.X.); (T.D.); (C.L.); (R.G.); (W.Z.); (F.C.)
| | - Taimin Dong
- National Key Laboratory of Macromolecular Drug Development and Manufacturing, School of Pharmaceutical Sciences and Food Engineering, Liaocheng University, 1 Hunan Street, Liaocheng 252059, China; (X.L.); (X.Z.); (X.X.); (T.D.); (C.L.); (R.G.); (W.Z.); (F.C.)
| | - Chengxu Lv
- National Key Laboratory of Macromolecular Drug Development and Manufacturing, School of Pharmaceutical Sciences and Food Engineering, Liaocheng University, 1 Hunan Street, Liaocheng 252059, China; (X.L.); (X.Z.); (X.X.); (T.D.); (C.L.); (R.G.); (W.Z.); (F.C.)
| | - Ranran Guan
- National Key Laboratory of Macromolecular Drug Development and Manufacturing, School of Pharmaceutical Sciences and Food Engineering, Liaocheng University, 1 Hunan Street, Liaocheng 252059, China; (X.L.); (X.Z.); (X.X.); (T.D.); (C.L.); (R.G.); (W.Z.); (F.C.)
| | - Wenyue Zhang
- National Key Laboratory of Macromolecular Drug Development and Manufacturing, School of Pharmaceutical Sciences and Food Engineering, Liaocheng University, 1 Hunan Street, Liaocheng 252059, China; (X.L.); (X.Z.); (X.X.); (T.D.); (C.L.); (R.G.); (W.Z.); (F.C.)
| | - Guoxia Ji
- School of Chemistry and Chemical Engineering, Liaocheng University, 1 Hunan Street, Liaocheng 252059, China;
| | - Fanghui Chen
- National Key Laboratory of Macromolecular Drug Development and Manufacturing, School of Pharmaceutical Sciences and Food Engineering, Liaocheng University, 1 Hunan Street, Liaocheng 252059, China; (X.L.); (X.Z.); (X.X.); (T.D.); (C.L.); (R.G.); (W.Z.); (F.C.)
| | - Shiben Wang
- National Key Laboratory of Macromolecular Drug Development and Manufacturing, School of Pharmaceutical Sciences and Food Engineering, Liaocheng University, 1 Hunan Street, Liaocheng 252059, China; (X.L.); (X.Z.); (X.X.); (T.D.); (C.L.); (R.G.); (W.Z.); (F.C.)
| | - Xuekun Wang
- National Key Laboratory of Macromolecular Drug Development and Manufacturing, School of Pharmaceutical Sciences and Food Engineering, Liaocheng University, 1 Hunan Street, Liaocheng 252059, China; (X.L.); (X.Z.); (X.X.); (T.D.); (C.L.); (R.G.); (W.Z.); (F.C.)
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8
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Hamed K, Alosaimi MN, Ali BA, Alghamdi A, Alkhashi T, Alkhaldi SS, Altowarqi NA, Alzahrani H, Alshehri AM, Alkhaldi RK, Alqahtani KW, Alharbi NH, Alhulayfi HF, Sharifi SY, Dighriri IM. Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists: Exploring Their Impact on Diabetes, Obesity, and Cardiovascular Health Through a Comprehensive Literature Review. Cureus 2024; 16:e68390. [PMID: 39355484 PMCID: PMC11444311 DOI: 10.7759/cureus.68390] [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: 09/01/2024] [Indexed: 10/03/2024] Open
Abstract
Glucagon-like peptide-1 receptor agonists (GLP-1-RAs) are a novel class of medications promising for treating type 2 diabetes mellitus (T2DM) and obesity-related conditions such as cardiovascular disease (CVD) and non-alcoholic fatty liver disease (NAFLD). This comprehensive literature review examines available research on these medications, focusing on their mechanisms of action, clinical effectiveness, safety profiles, and socioeconomic implications. A comprehensive search was performed using the PubMed, EMBASE, and Cochrane Library databases. Although initially developed for glucose management, these drugs have also demonstrated efficacy in promoting weight loss and reducing the risk of CVD. GLP-1-RAs function similarly to naturally occurring incretins. They stimulate insulin secretion in response to glucose levels, inhibit glucagon release, delay stomach emptying, and generate a sense of fullness via brain pathways. Head-to-head clinical studies have indicated that GLP-1-RAs outperform conventional antidiabetic medicines in terms of glycemic management and weight reduction. According to cardiovascular outcome studies, various drugs in this category have been found to reduce the frequency of severe adverse cardiovascular events. A common side effect is gastrointestinal toxicity, which can be mitigated by gradually increasing the dose. Personalized treatment is likely because the effectiveness, safety, and dose regimens of currently available GLP-1-RAs differ. GLP-1-RAs are a superior choice for patients with T2DM, especially those who already have CVD or require weight-control support. The high cost of these drugs creates hurdles to access and fair healthcare. Current research mainly focuses on increasing therapeutic uses and producing orally delivered medicines with greater potency and bioavailability. Integrating GLP-1-RAs into clinical practice can enhance patient outcomes and reduce the community burden of cardiometabolic disease.
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Affiliation(s)
- Khalid Hamed
- Department of Clinical Toxicology, Umm Al-Qura University, Mecca, SAU
| | | | - Bashaer A Ali
- Department of Pharmacy, Nahdi Medical Company, Jeddah, SAU
| | | | | | | | | | | | | | | | - Khalid W Alqahtani
- Department of Pharmacy, Dr. Sulaiman Al Habib Medical Group, Riyadh, SAU
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9
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Liu QK. Mechanisms of action and therapeutic applications of GLP-1 and dual GIP/GLP-1 receptor agonists. Front Endocrinol (Lausanne) 2024; 15:1431292. [PMID: 39114288 PMCID: PMC11304055 DOI: 10.3389/fendo.2024.1431292] [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: 05/11/2024] [Accepted: 07/08/2024] [Indexed: 08/10/2024] Open
Abstract
Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are two incretins that bind to their respective receptors and activate the downstream signaling in various tissues and organs. Both GIP and GLP-1 play roles in regulating food intake by stimulating neurons in the brain's satiety center. They also stimulate insulin secretion in pancreatic β-cells, but their effects on glucagon production in pancreatic α-cells differ, with GIP having a glucagonotropic effect during hypoglycemia and GLP-1 exhibiting glucagonostatic effect during hyperglycemia. Additionally, GIP directly stimulates lipogenesis, while GLP-1 indirectly promotes lipolysis, collectively maintaining healthy adipocytes, reducing ectopic fat distribution, and increasing the production and secretion of adiponectin from adipocytes. Together, these two incretins contribute to metabolic homeostasis, preventing both hyperglycemia and hypoglycemia, mitigating dyslipidemia, and reducing the risk of cardiovascular diseases in individuals with type 2 diabetes and obesity. Several GLP-1 and dual GIP/GLP-1 receptor agonists have been developed to harness these pharmacological effects in the treatment of type 2 diabetes, with some demonstrating robust effectiveness in weight management and prevention of cardiovascular diseases. Elucidating the underlying cellular and molecular mechanisms could potentially usher in the development of new generations of incretin mimetics with enhanced efficacy and fewer adverse effects. The treatment guidelines are evolving based on clinical trial outcomes, shaping the management of metabolic and cardiovascular diseases.
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Affiliation(s)
- Qiyuan Keith Liu
- MedStar Medical Group, MedStar Montgomery Medical Center, Olney, MD, United States
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10
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Moon JH, Choe HJ, Lim S. Pancreatic beta-cell mass and function and therapeutic implications of using antidiabetic medications in type 2 diabetes. J Diabetes Investig 2024; 15:669-683. [PMID: 38676410 PMCID: PMC11143426 DOI: 10.1111/jdi.14221] [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: 01/21/2024] [Revised: 03/23/2024] [Accepted: 04/09/2024] [Indexed: 04/28/2024] Open
Abstract
Nowadays, the focus of diabetes treatment has switched from lowering the glucose level to preserving glycemic homeostasis and slowing the disease progression. The main pathophysiology of both type 1 diabetes and long-standing type 2 diabetes is pancreatic β-cell mass loss and dysfunction. According to recent research, human pancreatic β-cells possess the ability to proliferate in response to elevated insulin demands. It has been demonstrated that in insulin-resistant conditions in humans, such as obesity or pregnancy, the β-cell mass increases. This ability could be helpful in developing novel treatment approaches to restore a functional β-cell mass. Treatment strategies aimed at boosting β-cell function and mass may be a useful tool for managing diabetes mellitus and stopping its progression. This review outlines the processes of β-cell failure and detail the many β-cell abnormalities that manifest in people with diabetes mellitus. We also go over standard techniques for determining the mass and function of β-cells. Lastly, we provide the therapeutic implications of utilizing antidiabetic drugs in controlling the mass and function of pancreatic β-cells.
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Affiliation(s)
- Joon Ho Moon
- Department of Internal MedicineSeoul National University College of MedicineSeongnamSouth Korea
- Department of Internal MedicineSeoul National University Bundang HospitalSeongnamSouth Korea
| | - Hun Jee Choe
- Department of Internal MedicineHallym University Dongtan Sacred Heart HospitalHwaseongSouth Korea
| | - Soo Lim
- Department of Internal MedicineSeoul National University College of MedicineSeongnamSouth Korea
- Department of Internal MedicineSeoul National University Bundang HospitalSeongnamSouth Korea
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11
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Athar F, Karmani M, Templeman N. Metabolic hormones are integral regulators of female reproductive health and function. Biosci Rep 2024; 44:BSR20231916. [PMID: 38131197 PMCID: PMC10830447 DOI: 10.1042/bsr20231916] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 11/29/2023] [Accepted: 12/21/2023] [Indexed: 12/23/2023] Open
Abstract
The female reproductive system is strongly influenced by nutrition and energy balance. It is well known that food restriction or energy depletion can induce suppression of reproductive processes, while overnutrition is associated with reproductive dysfunction. However, the intricate mechanisms through which nutritional inputs and metabolic health are integrated into the coordination of reproduction are still being defined. In this review, we describe evidence for essential contributions by hormones that are responsive to food intake or fuel stores. Key metabolic hormones-including insulin, the incretins (glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1), growth hormone, ghrelin, leptin, and adiponectin-signal throughout the hypothalamic-pituitary-gonadal axis to support or suppress reproduction. We synthesize current knowledge on how these multifaceted hormones interact with the brain, pituitary, and ovaries to regulate functioning of the female reproductive system, incorporating in vitro and in vivo data from animal models and humans. Metabolic hormones are involved in orchestrating reproductive processes in healthy states, but some also play a significant role in the pathophysiology or treatment strategies of female reproductive disorders. Further understanding of the complex interrelationships between metabolic health and female reproductive function has important implications for improving women's health overall.
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Affiliation(s)
- Faria Athar
- Department of Biology, University of Victoria, Victoria, British Columbia V8P 5C2, Canada
| | - Muskan Karmani
- Department of Biology, University of Victoria, Victoria, British Columbia V8P 5C2, Canada
| | - Nicole M. Templeman
- Department of Biology, University of Victoria, Victoria, British Columbia V8P 5C2, Canada
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12
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Gupta P, Ekbbal R. Liraglutide Improves Diabetic Cardiomyopathy by Downregulation of Cardiac Inflammatory and Apoptosis Markers. Curr Drug Res Rev 2024; 16:289-299. [PMID: 37966282 DOI: 10.2174/0125899775243787231103075804] [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: 01/31/2023] [Revised: 09/28/2023] [Accepted: 10/09/2023] [Indexed: 11/16/2023]
Abstract
BACKGROUND Diabetic cardiomyopathy is one of the leading causes of mortality for people with diabetes worldwide. The majority of the formalistic alterations in the heart associated with diabetic cardiomyopathy have been found to be primarily caused by the ongoing oxidative stress brought on by hyperglycemia, which leads to the dysfunctional reactions of apoptosis and inflammation. Liraglutide, a long-acting counterpart of glucagon-like peptide-1, has been demonstrated to have a number of therapeutic applications in medicine and other biological processes. METHODS The PubMed database was searched using the terms liraglutide, DCM, and all associated inflammatory markers. RESULTS There has been a lot of research on liraglutide's potential to protect the heart from cardiomyopathy brought on by diabetes. Liraglutide's therapeutic actions as an antioxidant, antihyperglycemic, anti-apoptotic, and anti-inflammatory medicine may help to lessen diabetic cardiomyopathy. CONCLUSION The most recent studies on the effects of liraglutide therapy on DCM are presented in this review, along with an explanation of the underlying mechanisms.
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Affiliation(s)
- Polly Gupta
- Department of Pharmaceutical Sciences, IIMT College of Medical Sciences (Pharmacy), IIMT University, Meerut, UP, India
| | - Rustam Ekbbal
- Department of Pharmacology, IIMT College of Medical Sciences (Pharmacy), IIMT University, Meerut, UP, India
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13
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Abstract
Glucagon-like peptide-1 receptor analogs (GLP-1 RAs) have been an innovative and instrumental drug class in the management of both type 2 diabetes and obesity. Tirzepatide is a novel agent that acts as an agonist for both GLP-1 receptors and gastric inhibitory polypeptide (GIP) receptors, another incretin that lowers glucose and appetite. Although previous studies showed a lack of therapeutic benefit for GIP agonists, current studies show that the glucose lowering and weight loss effects of tirzepatide are at least as effective as GLP-1 RAs with a similar adverse effect profile. Some studies, though not conclusive, predict that tirzepatide may in fact be more potent than GLP-1 RAs at reducing weight. A thorough review of the studies that led to tirzepatide's approval allows for comparisons between tirzepatide and GLP-1 RAs; it also allows for predictions of tirzepatide's eventual place in therapy - an agent used preferentially over GLP-1 RAs in patients with or without diabetes desiring to lose weight.
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Affiliation(s)
- John Andraos
- College of Pharmacy, Western University of Health Sciences, 91766, Pomona, CA, USA.
| | | | - Shawn R Smith
- College of Pharmacy, Western University of Health Sciences, 91766, Pomona, CA, USA
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14
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Vignesh R, Aradhyam GK. Calnuc-derived nesfatin-1-like peptide is an activator of tumor cell proliferation and migration. FEBS Lett 2023; 597:2288-2300. [PMID: 37539786 DOI: 10.1002/1873-3468.14712] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2023] [Revised: 06/28/2023] [Accepted: 07/11/2023] [Indexed: 08/05/2023]
Abstract
Calnuc (nucleobindin-1, nucb1) is a Ca2+ -binding protein involved in the etiology of many human diseases. To understand the functions of calnuc, we have identified a nesfatin-1-like peptide (NLP) in its N terminus that is proteolyzed by a convertase enzyme in the secretory granules of cells. Mutational studies confirm the presence of a proteolytic cleavage site for proprotein convertase subtilisin/kexin type 1 (PCSK1). We demonstrate that NLP regulates Gαq-mediated intracellular Ca2+ dynamics, likely via a G-protein-coupled receptor. NLP treatment to carcinoma cell lines (SCC131 cells) promotes the expression of regulators of cell cycle, proliferation, and clonogenicity by the AKT/mTOR pathway. NLP is causative of augmented migration and epithelial-mesenchymal transition (EMT), illustrating its metastatic propensity and establishing its tumor promotion ability.
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Affiliation(s)
- Ravichandran Vignesh
- Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, Tamil Nadu, India
| | - Gopala Krishna Aradhyam
- Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, Tamil Nadu, India
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15
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Castro MC, Villagarcía HG, Schinella G, Massa ML, Francini F. Mechanism of preventive effects of exendin-4 and des-fluoro-sitagliptin in a murine model of fructose-induced prediabetes. Biochim Biophys Acta Mol Cell Biol Lipids 2023:159363. [PMID: 37429413 DOI: 10.1016/j.bbalip.2023.159363] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 06/23/2023] [Accepted: 07/05/2023] [Indexed: 07/12/2023]
Abstract
Protective effects of exendin-4 (glucagon-like peptide-1 -GLP-1- receptor agonist) and des-fluoro-sitagliptin (dipeptidyl peptidase-4 inhibitor) on fructose-induced hepatic disturbances were evaluated in prediabetic rats. Complementary, a possible direct effect of exendin-4 in human hepatoblastoma-derived cell line HepG2 incubated with fructose in presence/absence of exendin-9-39 (GLP-1 receptor antagonist) was investigated. In vivo, after 21 days of fructose rich diet, we determined: glycemia, insulinemia, and triglyceridemia; hepatic fructokinase, AMP-deaminase, and G-6-P dehydrogenase (G-6-P DH) activities; carbohydrate-responsive element-binding protein (ChREBP) expression; triglyceride content and lipogenic gene expression (glycerol-3-phosphate acyltransferase -GPAT-, fatty acid synthase -FAS-, sterol regulatory element-binding protein-1c -SREBP-1c); oxidative stress and inflammatory markers expression. In HepG2 cells we measured fructokinase activity and triglyceride content. Hypertriglyceridemia, hyperinsulinemia, enhanced liver fructokinase, AMP-deaminase, and G-6-P DH activities, increased ChREBP and lipogenic genes expression, enhanced triglyceride level, oxidative stress and inflammatory markers recorded in fructose fed animals, were prevented by co-administration of either exendin-4 or des-fluoro-sitagliptin. Exendin-4 prevented fructose-induced increase in fructokinase activity and triglyceride contain in HepG2 cells. These effects were blunted co-incubating with exendin-9-39. The results demonstrated for the first time that exendin-4/des-fluro-sitagliptin prevented fructose-induced endocrine-metabolic oxidative stress and inflammatory changes probably acting on the purine degradation pathway. Exendin 9-39 blunted in vitro protective exendin-4 effects, thereby suggesting a direct effect of this compound on hepatocytes through GLP-1 receptor. Direct effect on fructokinase and AMP-deaminase activities, with a key role in the pathogenesis of liver dysfunction induced by fructose, suggests purine degradation pathway constitute a potential therapeutic objective for GLP-1 receptor agonists.
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Affiliation(s)
- María Cecilia Castro
- Centro de Endocrinología Experimental y Aplicada - CENEXA (UNLP-CONICET CCT LA PLATA CEAS CICPBA), Facultad de Ciencias Médicas, Universidad Nacional de La Plata, Street 60 and 120, La Plata 1900, Argentina.
| | - Hernán Gonzalo Villagarcía
- Centro de Endocrinología Experimental y Aplicada - CENEXA (UNLP-CONICET CCT LA PLATA CEAS CICPBA), Facultad de Ciencias Médicas, Universidad Nacional de La Plata, Street 60 and 120, La Plata 1900, Argentina.
| | - Guillermo Schinella
- Facultad de Ciencias Médicas, Universidad Nacional de La Plata, Street 60 and 120, La Plata 1900, Argentina; Instituto de Ciencias de la Salud, UNAJ-CICPBA, Street Avenue Calchaqui 6200, Florencio Varela 1888, Argentina.
| | - María Laura Massa
- Centro de Endocrinología Experimental y Aplicada - CENEXA (UNLP-CONICET CCT LA PLATA CEAS CICPBA), Facultad de Ciencias Médicas, Universidad Nacional de La Plata, Street 60 and 120, La Plata 1900, Argentina.
| | - Flavio Francini
- Centro de Endocrinología Experimental y Aplicada - CENEXA (UNLP-CONICET CCT LA PLATA CEAS CICPBA), Facultad de Ciencias Médicas, Universidad Nacional de La Plata, Street 60 and 120, La Plata 1900, Argentina.
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16
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Rasalam R, Abdo S, Deed G, O'Brien R, Overland J. Early type 2 diabetes treatment intensification with glucagon-like peptide-1 receptor agonists in primary care: An Australian perspective on guidelines and the global evidence. Diabetes Obes Metab 2023; 25:901-915. [PMID: 36541153 DOI: 10.1111/dom.14953] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2022] [Revised: 12/03/2022] [Accepted: 12/17/2022] [Indexed: 12/24/2022]
Abstract
Early and intensive management of type 2 diabetes has been shown to delay disease progression, reduce the risk of cardiorenal complications and prolong time to treatment failure. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are being increasingly recognized for their potential in early disease management, with recent guideline updates recommending second-line use of this injectable drug class alongside oral glucose-lowering drugs. GLP-1RAs target at least six of the eight core defects implicated in the pathogenesis of type 2 diabetes and offer significant glycaemic and weight-related improvements over other second-line agents in head-to-head trials. In addition, placebo-controlled clinical trials have shown cardiovascular protection with GLP-1RA use. Even so, this therapeutic class is underused in primary care, largely owing to clinical inertia and patient-related barriers to early intensification with GLP-1RAs. Fortunately, clinicians can overcome barriers to treatment acceptance through patient education and training, and management of treatment expectations. In this review we comment on global and Australian guideline updates and evidence in support of early intensification with this therapeutic class, and provide clinicians with practical advice for GLP-1RA use in primary care.
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Affiliation(s)
- Roy Rasalam
- College of Medicine, James Cook University, Townsville, Queensland, Australia
| | - Sarah Abdo
- Department of Diabetes and Endocrinology, Bankstown-Lidcombe Hospital, Sydney, New South Wales, Australia
- School of Medicine, Western Sydney University, Campbelltown, New South Wales, Australia
| | - Gary Deed
- Monash University, Melbourne, Victoria, Australia
- HealthcarePlus Medical, Carindale, Queensland, Australia
| | - Richard O'Brien
- Austin Clinical School, University of Melbourne, Heidelberg, Victoria, Australia
- Department of Endocrinology, Austin Health, Heidelberg, Victoria, Australia
| | - Jane Overland
- Total Diabetes Care, Sydney, New South Wales, Australia
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17
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Jacenik D, Lebish EJ, Beswick EJ. MK2 Promotes the Development and Progression of Pancreatic Neuroendocrine Tumors Mediated by Macrophages and Metabolomic Factors. Int J Mol Sci 2022; 23:13561. [PMID: 36362348 PMCID: PMC9658113 DOI: 10.3390/ijms232113561] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Revised: 10/31/2022] [Accepted: 11/02/2022] [Indexed: 09/24/2023] Open
Abstract
Cases of pancreatic neuroendocrine tumors (PNETs) are growing in number, and new treatment options are needed in order to improve patient outcomes. The mitogen-activated protein kinase-activated protein kinase 2 (MK2) is a crucial regulator of cytokine/chemokine production. The significance of MK2 expression and signaling pathway mediated by MK2 in PNETs has not been investigated. To characterize the impact of MK2 on PNET growth, we used the RipTag2 transgenic murine model of PNETs, and we developed a primary PNET cell line for both in vitro and in vivo studies. In the transgenic murine model of PNETs, we found that MK2 inhibition improves survival of mice and prevents PNET progression. MK2 blockade abolished cytokine/chemokine production, which was related to macrophage function. A role for MK2 in the regulation of metabolic factor secretion in PNETs was identified, making this the first study to identify a potential role for the MK2 pathway in regulation of tumor metabolism. Moreover, using an in vitro approach and allograft model of PNETs, we were able to show that macrophages with MK2 depletion exhibit increased cytotoxicity against PNET cells and substantially decreased production of pro-inflammatory cytokines and chemokines, as well as metabolic factors. Taken together, our work identifies MK2 as a potent driver of immune response and metabolic effectors in PNETs, suggesting it is a potential therapeutic target for patients with PNETs.
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Affiliation(s)
- Damian Jacenik
- Department of Cytobiochemistry, Faculty of Biology and Environmental Protection, University of Lodz, 90-236 Lodz, Poland
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, University of Utah, Salt Lake City, UT 84132, USA
| | - Eric J. Lebish
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, University of Utah, Salt Lake City, UT 84132, USA
| | - Ellen J. Beswick
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, University of Utah, Salt Lake City, UT 84132, USA
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18
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Ni X, Zhang L, Feng X, Tang L. New Hypoglycemic Drugs: Combination Drugs and Targets Discovery. Front Pharmacol 2022; 13:877797. [PMID: 35865956 PMCID: PMC9295075 DOI: 10.3389/fphar.2022.877797] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Accepted: 05/10/2022] [Indexed: 01/02/2023] Open
Abstract
New hypoglycemic drugs, including glucagon-like peptide 1 receptor agonists (GLP-1RA), dipeptidyl peptidase-4 inhibitors (DPP-4i) and sodium-glucose cotransporter 2 inhibitors (SGLT-2i), which brings more options for the treatment of type 2 diabetes (T2DM). They are generally well tolerated, although caution is required in rare cases. Clinical trials have show good glycemic control with combination therapy with new hypoglycemic drugs in prediabetes and T2DM (mostly traditional stepwise therapy), but early combination therapy appears to have faster, more, and longer-lasting benefits. With the widespread clinical application of oral semaglutide, it is time to develop combinations drugs containing new hypoglycemic drugs, especially SGLT-2i and/or GLP-1RA, to control the risk of prediabetes and newly diagnosed T2DM and its cardiovascular complications, while improving patient compliance. Clinical and preclinical studies support that SGLT-2i exerts its protective effect on heart failure through indirect and direct effects. How this comprehensive protective effect regulates the dynamic changes of heart genes needs further study. We provide ideas for the development of heart failure drugs from the perspective of "clinical drug-mechanism-intensive disease treatment." This will help to accelerate the development of heart failure drugs, and to some extent guide the use of heart failure drugs.
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Affiliation(s)
| | | | - Xiaojun Feng
- Department of Pharmacy, The First Affiliated Hospital of University of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China (USTC), Hefei, China
| | - Liqin Tang
- Department of Pharmacy, The First Affiliated Hospital of University of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China (USTC), Hefei, China
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19
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Sun T, Zhang B, Ru QJ, Chen XM, Lv BD. Tocopheryl quinone improves non-alcoholic steatohepatitis (NASH) associated dysmetabolism of glucose and lipids by upregulating the expression of glucagon-like peptide 1 (GLP-1) via restoring the balance of intestinal flora in rats. PHARMACEUTICAL BIOLOGY 2021; 59:723-731. [PMID: 34139927 PMCID: PMC8871605 DOI: 10.1080/13880209.2021.1916542] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/07/2023]
Abstract
CONTEXT Glucagon-like peptide 1 (GLP-1) and α-tocopheryl quinone can promote the growth of intestinal flora and affect the pathogenesis of non-alcoholic steatohepatitis (NASH). OBJECTIVE This study determines the molecular mechanism of the effect of tocopheryl quinone in the treatment of high cholesterol and cholate diet (HFCC)-induced NASH. MATERIALS AND METHODS Thirty-two male Sprague Dawley (SD) rats grouped as lean control (LC), LC + tocopheryl quinone (1 mL of 3 × 106 dpm tocopheryl quinone via i.p. injection), HFCC (5.1 kcal/g of fat diet), and HFCC + tocopheryl quinone. Profiles of intestinal flora were assessed by 16S ribosomal ribonucleic acid-based analysis. Levels and activity of GLP-1, interleukin 6 (IL-6) and tumour necrosis factor alpha (TNF-α) in intestinal tissues were detected by immunohistochemistry (IHC), Western blot and enzyme-linked immunosorbent assay (ELISA). RESULTS HFCC rats presented higher levels of cholesterol, low-density lipoprotein (LDL) and high-density lipoprotein (HDL), while tocopheryl quinone reversed the effects of HFCC. HFCC dysregulated malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), Vitamin E, 12-hydroxyeicosatetraenoic acid (12-HETE), 13-hydroxyoctadecadienoic acid (13-HODE) and nuclear factor kappa B (NF-κB), and the effects of HFCC were reversed by the treatment of tocopheryl quinone. Also, GLP-1 in the HFCC group was down-regulated while the IL-6 and TNF-α activity and endotoxins were all up-regulated. HFCC significantly decreased the number and diversity of bacteria, whereas tocopheryl quinone substantially restored the balance of intestinal flora and promoted the growth of both Bacteroides and Lactobacilli in vitro. DISCUSSION AND CONCLUSIONS α-Tocopheryl quinone relieves HFCC-induced NASH via regulating oxidative stress, GLP-1 expression, intestinal flora imbalance, and the metabolism of glucose and lipids.
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Affiliation(s)
- Tao Sun
- The Second Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, PR China
- Department of Hepatology, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, PR China
| | - Bing Zhang
- Department of Traditional Chinese Medicine, Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, PR China
| | - Qing-jing Ru
- Department of Hepatology, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, PR China
| | - Xiao-mei Chen
- Department of Hepatology, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, PR China
| | - Bo-dong Lv
- The Second Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, PR China
- CONTACT Bo-dong Lv The Second Clinical Medical College of Zhejiang Chinese Medicine University, No.318 Chaowang Road, Gongshu District, Hangzhou310005, PR China
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20
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Mukherjee N, Lin L, Contreras CJ, Templin AT. β-Cell Death in Diabetes: Past Discoveries, Present Understanding, and Potential Future Advances. Metabolites 2021; 11:796. [PMID: 34822454 PMCID: PMC8620854 DOI: 10.3390/metabo11110796] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 11/15/2021] [Accepted: 11/18/2021] [Indexed: 12/19/2022] Open
Abstract
β-cell death is regarded as a major event driving loss of insulin secretion and hyperglycemia in both type 1 and type 2 diabetes mellitus. In this review, we explore past, present, and potential future advances in our understanding of the mechanisms that promote β-cell death in diabetes, with a focus on the primary literature. We first review discoveries of insulin insufficiency, β-cell loss, and β-cell death in human diabetes. We discuss findings in humans and mouse models of diabetes related to autoimmune-associated β-cell loss and the roles of autoreactive T cells, B cells, and the β cell itself in this process. We review discoveries of the molecular mechanisms that underlie β-cell death-inducing stimuli, including proinflammatory cytokines, islet amyloid formation, ER stress, oxidative stress, glucotoxicity, and lipotoxicity. Finally, we explore recent perspectives on β-cell death in diabetes, including: (1) the role of the β cell in its own demise, (2) methods and terminology for identifying diverse mechanisms of β-cell death, and (3) whether non-canonical forms of β-cell death, such as regulated necrosis, contribute to islet inflammation and β-cell loss in diabetes. We believe new perspectives on the mechanisms of β-cell death in diabetes will provide a better understanding of this pathological process and may lead to new therapeutic strategies to protect β cells in the setting of diabetes.
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Affiliation(s)
- Noyonika Mukherjee
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA;
- Lilly Diabetes Center of Excellence, Indiana Biosciences Research Institute, Indianapolis, IN 46202, USA; (L.L.); (C.J.C.)
| | - Li Lin
- Lilly Diabetes Center of Excellence, Indiana Biosciences Research Institute, Indianapolis, IN 46202, USA; (L.L.); (C.J.C.)
| | - Christopher J. Contreras
- Lilly Diabetes Center of Excellence, Indiana Biosciences Research Institute, Indianapolis, IN 46202, USA; (L.L.); (C.J.C.)
- Department of Medicine, Roudebush Veterans Affairs Medical Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Andrew T. Templin
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA;
- Lilly Diabetes Center of Excellence, Indiana Biosciences Research Institute, Indianapolis, IN 46202, USA; (L.L.); (C.J.C.)
- Department of Medicine, Roudebush Veterans Affairs Medical Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Center for Diabetes and Metabolic Diseases, School of Medicine, Indiana University, Indianapolis, IN 46202, USA
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21
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Przezak A, Bielka W, Pawlik A. Incretins in the Therapy of Diabetic Kidney Disease. Int J Mol Sci 2021; 22:ijms222212312. [PMID: 34830194 PMCID: PMC8617946 DOI: 10.3390/ijms222212312] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Revised: 11/09/2021] [Accepted: 11/12/2021] [Indexed: 12/17/2022] Open
Abstract
Diabetic kidney disease is a microvascular complication that occurs in patients with diabetes. It is strongly associated with increased risk of kidney replacement therapy and all-cause mortality. Incretins are peptide hormones derived from the gastrointestinal tract, that besides causing enhancement of insulin secretion after oral glucose intake, participate in many other metabolic processes. Antidiabetic drug classes, such as dipeptidyl peptidase 4 inhibitors and glucagon-like peptide receptor agonists, which way of action is based on incretins facility, not only show glucose-lowering properties but also have nephroprotective functions. The aim of this article is to present the latest information about incretin-based therapy and its influence on diabetic kidney disease appearance and progression, point its potential mechanisms of kidney protection and focus on future therapeutic possibilities bound with these two antidiabetic drug classes.
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Chueire VB, Muscelli E. Effect of free fatty acids on insulin secretion, insulin sensitivity and incretin effect - a narrative review. ARCHIVES OF ENDOCRINOLOGY AND METABOLISM 2021; 65:24-31. [PMID: 33320449 PMCID: PMC10528699 DOI: 10.20945/2359-3997000000313] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Accepted: 09/26/2020] [Indexed: 11/23/2022]
Abstract
Deleterious effects of free fatty acids, FFAs, on insulin sensitivity are observed in vivo studies in humans. Mechanisms include impaired insulin signaling, oxidative stress, inflammation, and mitochondrial dysfunction, but the effects on insulin secretion are less well known. Our aim was to review the relationship of increased FFAs with insulin resistance, secretion and mainly with the incretin effect in humans. Narrative review. Increased endogenous or administered FFAs induce insulin resistance. FFAs effects on insulin secretion are debatable; inhibition and stimulation have been reported, depending on the type and duration of lipids exposition and the study subjects. Chronically elevated FFAs seem to decrease insulin biosynthesis, glucose-stimulated insulin secretion and β-cell glucose sensitivity. Lipids infusion decreases the response to incretins with unchanged incretin levels in volunteers with normal glucose tolerance. In contrast, FFAs reduction by acipimox did not restore the incretin effect in type-2 diabetes, probably due to the dysfunctional β-cell. Possible mechanisms of FFAs excess on incretin effect include reduction of the expression and levels of GLP-1 (glucagon like peptide-1) receptor, reduction of connexin-36 expression thus the coordinated secretory activity in response to GLP-1, and GIP (glucose-dependent insulinotropic polypeptide) receptors downregulation in islets cells. Increased circulating FFAs impair insulin sensitivity. Effects on insulin secretion are complex and controversial. Deleterious effects on the incretin-induced potentiation of insulin secretion were reported. More investigation is needed to better understand the extent and mechanisms of β-cell impairment and insulin resistance induced by increased FFAs and how to prevent them.
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Affiliation(s)
- Valeria Bahdur Chueire
- Departamento de Endocrinologia, Hospital da Pontifícia Universidade Católica de Campinas, Campinas, SP, Brasil,
| | - Elza Muscelli
- Departamento de Clínica Médica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, SP, Brasil
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Nugraheni M, Purwanti S, Ekawatiningsih P. Impact of Analog Rice Derived from Different Composite Flours from Tubers, Germinated Legumes, and Cereals on Improving Serum Markers in Alloxan-Induced Diabetic Rats. Prev Nutr Food Sci 2021; 26:296-306. [PMID: 34737990 PMCID: PMC8531424 DOI: 10.3746/pnf.2021.26.3.296] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 06/07/2021] [Accepted: 06/23/2021] [Indexed: 11/29/2022] Open
Abstract
This study aimed to evaluate the consumption of four types of analog rice made from different composite flours in alloxan-induced diabetic rats. Forty-two male Wistar rats were divided into seven groups and fed different food for six weeks: normal standard food (NSF), diabetic standard food (DSF), diabetic commercial rice (DCR), and diabetic analog rice (DAR) I∼IV. Total phenolic, dietary fiber, and resistant starch contents were evaluated in every analog and commercial type of rice. The parameters studied were fasting blood glucose, homeostatic model assessment (HOMA) insulin resistance (IR), HOMA β, lipid profile, atherogenic indexes (AI), weight changes, serum insulin and antioxidant activities. Total phenol, dietary fiber, and resistant starch were higher for analog rice IV than the other three analog rice. In addition, analog rice IV had a greater ability to lower fasting blood glucose, total cholesterol, triglycerides, and low-density lipoprotein levels. High density lipoprotein levels increased in all groups fed analog rice, and all diabetic rats fed four types of analog rice had improved weight, antioxidant activity, serum insulin levels, HOMA IR, HOMA β, and AI. Commercial rice consumption did not improve glucose or lipids profiles, antioxidant activity, serum insulin level, HOMA IR, HOMA β, or AI in diabetic mice. These results show that the four types of analog rice significantly improved serum markers in diabetic rats.
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Affiliation(s)
- Mutiara Nugraheni
- Culinary Art Vocational Education, Faculty of Engineering, Yogyakarta State University, Yogyakarta 55281, Indonesia
| | - Sutriyati Purwanti
- Culinary Art Vocational Education, Faculty of Engineering, Yogyakarta State University, Yogyakarta 55281, Indonesia
| | - Prihastuti Ekawatiningsih
- Culinary Art Vocational Education, Faculty of Engineering, Yogyakarta State University, Yogyakarta 55281, Indonesia
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Takahashi Y, Kamata A, Nishimura M, Nishihira J. Effect of one-week administration of dipeptidyl peptidase-IV inhibitory peptides from chum salmon milt on postprandial blood glucose level: a randomised, placebo-controlled, double-blind, crossover, pilot clinical trial. Food Funct 2021; 12:8544-8551. [PMID: 34328151 DOI: 10.1039/d1fo00592h] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Salmon milt peptide (SMP), an unused fish processing byproduct, exhibits strong inhibitory activity against dipeptidyl peptidase-IV (DPP-IV) and a suppressive effect on postprandial hyperglycaemia in Sprague-Dawley rats. Herein, we conducted a randomised, placebo-controlled, double-blind, crossover study of healthy Japanese subjects to investigate the effect of glucose loading on postprandial blood glucose levels after one week of administering continuous or single dose of 500 mg of SMP. The primary and secondary outcomes of reduced blood glucose and insulin levels were not met in the 14 subjects included in the analysis. This may be due to the ineffectiveness of SMP in insulin resistance due to its DPP-IV inhibitory activity. Therefore, we conducted a SMP subgroup analysis based on the homeostasis model assessment of insulin resistance (HOMA-IR); the group with normal HOMA-IR (<1.6) had a significantly lower area under the curve and blood glucose at 60 min after glucose loading than the group with HOMA-IR ≥1.6. These results suggest that SMP is effective in subjects without insulin resistance. There were no adverse events associated with the test food, and SMP was considered safe. This report is the first to investigate the effect of a food ingredient with DPP-IV inhibitory activity in a clinical trial.
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Affiliation(s)
- Yoshinori Takahashi
- Central Research Institute, Maruha Nichiro Corporation, 16-2, Wadai, Tsukuba, Ibaraki 300-4295, Japan.
| | - Akira Kamata
- Central Research Institute, Maruha Nichiro Corporation, 16-2, Wadai, Tsukuba, Ibaraki 300-4295, Japan.
| | - Mie Nishimura
- Department of Medical Management and Informatics, Hokkaido Information University, 59-2, Nishi-nopporo, Ebetsu, Hokkaido, 069-8585, Japan.
| | - Jun Nishihira
- Department of Medical Management and Informatics, Hokkaido Information University, 59-2, Nishi-nopporo, Ebetsu, Hokkaido, 069-8585, Japan.
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Brown E, Heerspink HJL, Cuthbertson DJ, Wilding JPH. SGLT2 inhibitors and GLP-1 receptor agonists: established and emerging indications. Lancet 2021; 398:262-276. [PMID: 34216571 DOI: 10.1016/s0140-6736(21)00536-5] [Citation(s) in RCA: 295] [Impact Index Per Article: 73.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Revised: 02/12/2021] [Accepted: 02/24/2021] [Indexed: 12/21/2022]
Abstract
SGLT2 inhibitors and GLP-1 receptor agonists are used in patients with type 2 diabetes as glucose lowering therapies, with additional benefits of weight loss and blood pressure reduction. Data from cardiovascular outcome trials have highlighted that these drugs confer protection against major cardiovascular disease in those with established atherosclerotic cardiovascular disease, reduce the risk of admission to hospital for heart failure, and reduce cardiovascular and all-cause mortality. Ongoing research using hard renal endpoints such as end stage kidney disease rather than surrogate markers might clarify the renoprotective benefits of both agents. When used for glucose lowering, SGLT2 inhibitors are most effective if the estimated glomerular filtration rate is more than 60 ml per min per 1·73m2 at initiation and should be avoided where there is a risk of diabetic ketoacidosis. GLP-1 receptor agonists are contraindicated in those with a history of medullary thyroid cancer and used with caution in patients with a history of pancreatitis of a known cause. These drugs are now second-line, or even arguably first-line, glucose lowering therapies in patients with cardiorenal disease, irrespective of glycaemic control. If an SGLT2 inhibitor or GLP-1 receptor agonist is considered suitable in patients with type 2 diabetes, treatment should be prioritised according to existing evidence: GLP-1 receptor agonists should be considered in patients at a high risk of, or with established, cardiovascular disease and SGLT2 inhibitors considered for patients with heart failure (with reduced ejection fraction) or chronic kidney disease (with or without established cardiovascular disease). There is now compelling data on the benefits of these drugs for a range of other clinical indications even without type 2 diabetes, including for GLP-1 receptor agonists in patients with obesity and overweight with weight-related comorbidities.
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Affiliation(s)
- Emily Brown
- Department of Metabolic and Cardiovascular Medicine, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK; Liverpool University Hospitals NHS Foundation Trust, Longmoor Lane, Liverpool, UK
| | - Hiddo J L Heerspink
- Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Centre Groningen, Groningen, Netherlands
| | - Daniel J Cuthbertson
- Department of Metabolic and Cardiovascular Medicine, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK; Liverpool University Hospitals NHS Foundation Trust, Longmoor Lane, Liverpool, UK.
| | - John P H Wilding
- Department of Metabolic and Cardiovascular Medicine, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK; Liverpool University Hospitals NHS Foundation Trust, Longmoor Lane, Liverpool, UK
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Agrawal P, Gautam A, Pursnani N, Farooqui M, Kalra S. Papulonodular Lesions in a Patient of Diabetes Mellitus Receiving Sitagliptin and Metformin. Indian J Endocrinol Metab 2021; 25:356-358. [PMID: 35136746 PMCID: PMC8793959 DOI: 10.4103/ijem.ijem_270_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 07/29/2021] [Accepted: 08/06/2021] [Indexed: 11/07/2022] Open
Affiliation(s)
- Prabhat Agrawal
- P.G. Department of Medicine, S.N. Medical College, Agra, Uttar Pradesh, India
| | - Ashish Gautam
- P.G. Department of Medicine, S.N. Medical College, Agra, Uttar Pradesh, India
| | - Nikhil Pursnani
- P.G. Department of Medicine, S.N. Medical College, Agra, Uttar Pradesh, India
| | - Maaz Farooqui
- P.G. Department of Medicine, Hind Institute of Medical Sciences, Ataria, Sitapur, Uttar Pradesh, India
| | - S.K. Kalra
- Consultant Physician, Agra, Uttar Pradesh, India
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Novel Approaches to Restore Pancreatic Beta-Cell Mass and Function. Handb Exp Pharmacol 2021; 274:439-465. [PMID: 34114119 DOI: 10.1007/164_2021_474] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Beta-cell dysfunction and beta-cell death are critical events in the development of type 2 diabetes mellitus (T2DM). Therefore, the goals of modern T2DM management have shifted from merely restoring normoglycemia to maintaining or regenerating beta-cell mass and function. In this review we summarize current and novel approaches to achieve these goals, ranging from lifestyle interventions to N-methyl-D-aspartate receptor (NMDAR) antagonism, and discuss the mechanisms underlying their effects on beta-cell physiology and glycemic control. Notably, timely intervention seems critical, but not always strictly required, to maximize the effect of any approach on beta-cell recovery and disease progression. Conventional antidiabetic medications are not disease-modifying in the sense that the disease does not progress or reoccur while on treatment or thereafter. More invasive approaches, such as bariatric surgery, are highly effective in restoring normoglycemia, but are reserved for a rather small proportion of obese individuals and sometimes associated with serious adverse events. Finally, we recapitulate the broad range of effects mediated by peripheral NMDARs and discuss recent evidence on the potential of NMDAR antagonists to be developed as a novel class of antidiabetic drugs. In the future, a more refined assessment of disease risk or disease subtype might enable more targeted therapies to prevent or treat diabetes.
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Shandilya A, Mehan S. Dysregulation of IGF-1/GLP-1 signaling in the progression of ALS: potential target activators and influences on neurological dysfunctions. Neurol Sci 2021; 42:3145-3166. [PMID: 34018075 DOI: 10.1007/s10072-021-05328-6] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Accepted: 05/17/2021] [Indexed: 12/31/2022]
Abstract
The prominent causes for motor neuron diseases like ALS are demyelination, immune dysregulation, and neuroinflammation. Numerous research studies indicate that the downregulation of IGF-1 and GLP-1 signaling pathways plays a significant role in the progression of ALS pathogenesis and other neurological disorders. In the current review, we discussed the dysregulation of IGF-1/GLP-1 signaling in neurodegenerative manifestations of ALS like a genetic anomaly, oligodendrocyte degradation, demyelination, glial overactivation, immune deregulation, and neuroexcitation. In addition, the current review reveals the IGF-1 and GLP-1 activators based on the premise that the restoration of abnormal IGF-1/GLP-1 signaling could result in neuroprotection and neurotrophic effects for the clinical-pathological presentation of ALS and other brain diseases. Thus, the potential benefits of IGF-1/GLP-1 signal upregulation in the development of disease-modifying therapeutic strategies may prevent ALS and associated neurocomplications.
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Affiliation(s)
- Ambika Shandilya
- Neuropharmacology Division, Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, 142001, India
| | - Sidharth Mehan
- Neuropharmacology Division, Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, 142001, India.
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Ahn SM, Hyung WJ. Beneficial effects of proximal intestinal bypass reconstruction on glucose metabolism in a type 2 diabetes animal model: a possible reconstruction strategy for diabetic gastric cancer patients. Ann Surg Treat Res 2021; 100:218-227. [PMID: 33854991 PMCID: PMC8019988 DOI: 10.4174/astr.2021.100.4.218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 01/13/2021] [Accepted: 01/15/2021] [Indexed: 11/30/2022] Open
Abstract
Purpose Proximal intestinal bypass (PIB), such as Billroth II or Roux-en-Y gastrojejunostomy after curative distal gastrectomy for gastric cancer induces beneficial effects on glycemic control in patients with type 2 diabetes. We aimed to characterize the long-term evolution of pancreatic beta cells and insulin signaling in target tissue after a PIB procedure. Methods Zucker diabetic fatty rats were randomly assigned to the PIB, sham-operated PIB pair-fed, and ad libitum fed groups. Oral glucose tolerance (GT) and plasma insulin levels were measured periodically at 16 weeks postoperatively. Histomorphometric analyses were performed to evaluate changes in islet architectures and intranuclear pancreatic duodenal homeobox 1 (PDX1) expression in beta cells. Insulin signaling changes in visceral adipocytes were measured by the phosphorylated Akt/Akt ratio. Results Contrary to the progressively deteriorating GT and plasma insulin levels in sham-operated animals, these were preserved in PIB animals (P < 0.01) at 16 weeks postoperatively. The proportion of the islets having asteroid-like expanding projection was higher in PIB animals than in sham-operated animals (P < 0.01). PIB animals had 3-fold wider fractional area of beta cells (P < 0.01) and 3-fold higher proportion of beta-cell nuclear PDX1 expression (P < 0.01) than sham-operated animals. PIB animals had significantly higher levels of Akt phosphorylation in the visceral adipocytes (P < 0.05). The PIB did not substantially affect weight and food intake postoperatively. Conclusion The PIB preserved the plasma insulin levels and the wider beta-cell area over time and facilitated insulin signaling in the visceral fats. It could be considered as a possible reconstruction strategy for diabetic gastric cancer patients.
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Affiliation(s)
- Soo Min Ahn
- Department Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Woo Jin Hyung
- Gastric Cancer Center, Yonsei Cancer Center, Yonsei University Health System, Seoul, Korea
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Carli M, Kolachalam S, Longoni B, Pintaudi A, Baldini M, Aringhieri S, Fasciani I, Annibale P, Maggio R, Scarselli M. Atypical Antipsychotics and Metabolic Syndrome: From Molecular Mechanisms to Clinical Differences. Pharmaceuticals (Basel) 2021; 14:238. [PMID: 33800403 PMCID: PMC8001502 DOI: 10.3390/ph14030238] [Citation(s) in RCA: 122] [Impact Index Per Article: 30.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 03/02/2021] [Accepted: 03/03/2021] [Indexed: 12/15/2022] Open
Abstract
Atypical antipsychotics (AAPs) are commonly prescribed medications to treat schizophrenia, bipolar disorders and other psychotic disorders. However, they might cause metabolic syndrome (MetS) in terms of weight gain, dyslipidemia, type 2 diabetes (T2D), and high blood pressure, which are responsible for reduced life expectancy and poor adherence. Importantly, there is clear evidence that early metabolic disturbances can precede weight gain, even if the latter still remains the hallmark of AAPs use. In fact, AAPs interfere profoundly with glucose and lipid homeostasis acting mostly on hypothalamus, liver, pancreatic β-cells, adipose tissue, and skeletal muscle. Their actions on hypothalamic centers via dopamine, serotonin, acetylcholine, and histamine receptors affect neuropeptides and 5'AMP-activated protein kinase (AMPK) activity, thus producing a supraphysiological sympathetic outflow augmenting levels of glucagon and hepatic glucose production. In addition, altered insulin secretion, dyslipidemia, fat deposition in the liver and adipose tissues, and insulin resistance become aggravating factors for MetS. In clinical practice, among AAPs, olanzapine and clozapine are associated with the highest risk of MetS, whereas quetiapine, risperidone, asenapine and amisulpride cause moderate alterations. The new AAPs such as ziprasidone, lurasidone and the partial agonist aripiprazole seem more tolerable on the metabolic profile. However, these aspects must be considered together with the differences among AAPs in terms of their efficacy, where clozapine still remains the most effective. Intriguingly, there seems to be a correlation between AAP's higher clinical efficacy and increase risk of metabolic alterations. Finally, a multidisciplinary approach combining psychoeducation and therapeutic drug monitoring (TDM) is proposed as a first-line strategy to avoid the MetS. In addition, pharmacological treatments are discussed as well.
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Affiliation(s)
- Marco Carli
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy; (S.K.); (B.L.); (A.P.); (M.B.); (S.A.)
| | - Shivakumar Kolachalam
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy; (S.K.); (B.L.); (A.P.); (M.B.); (S.A.)
| | - Biancamaria Longoni
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy; (S.K.); (B.L.); (A.P.); (M.B.); (S.A.)
| | - Anna Pintaudi
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy; (S.K.); (B.L.); (A.P.); (M.B.); (S.A.)
| | - Marco Baldini
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy; (S.K.); (B.L.); (A.P.); (M.B.); (S.A.)
| | - Stefano Aringhieri
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy; (S.K.); (B.L.); (A.P.); (M.B.); (S.A.)
| | - Irene Fasciani
- Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (I.F.); (R.M.)
| | - Paolo Annibale
- Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany;
| | - Roberto Maggio
- Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (I.F.); (R.M.)
| | - Marco Scarselli
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy; (S.K.); (B.L.); (A.P.); (M.B.); (S.A.)
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Yao M, Zhang J, Li Z, Bai X, Ma J, Li Y. Liraglutide Protects Nucleus Pulposus Cells Against High-Glucose Induced Apoptosis by Activating PI3K/Akt/ mTOR/Caspase-3 and PI3K/Akt/GSK3β/Caspase-3 Signaling Pathways. Front Med (Lausanne) 2021; 8:630962. [PMID: 33681258 PMCID: PMC7933515 DOI: 10.3389/fmed.2021.630962] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Accepted: 01/25/2021] [Indexed: 12/11/2022] Open
Abstract
Background and Objective: Diabetes mellitus (DM) is reportedly a significant risk factor for intervertebral disc degeneration (IDD). Incretin system and particularly glucagon-like peptide 1 (GLP-1) because of its glucose-lowering effects has become an important target in therapeutic strategies of type 2 diabetes (T2D). Liraglutide is a GLP-1 receptor (GLP-1R) agonist with glucoregulatory and insulinotropic functions as well as regulatory functions on cell proliferation, differentiation, and apoptosis. However, little is known on the roles and signaling pathways of apoptosis protecting effects of liraglutide in IDD. This study aimed to investigate the potential protective effects of liraglutide against high glucose-induced apoptosis of nucleus pulposus cells (NPCs) and the possible involved signaling pathways. Methods: The human NPCs were incubated with 100 nM liraglutide alone or in combination with LY294002 (PI3K inhibitor), rapamycin (mTOR inhibitor), and SB216763 (GSK3β inhibitor) in a high glucose culture for 48 h. The four groups were assessed further for apoptosis and genes expressions. The apoptotic effect was evaluated by flow cytometry and further confirmed by cell death detection enzyme-linked immunoassay plus (ELISAPLUS). The gene and protein expression levels were assessed by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting techniques. The results were comparatively assessed between the four groups. Results: The results confirmed the presence of GLP-1R in the NPCs indicating that liraglutide inhibited the high glucose-induced apoptosis, which was blocked by silencing GLP-1R with siRNA. Moreover, liraglutide stimulated the phosphorylation of Akt, mTOR and GSK3β. Treatment with LY294002 significantly increased the apoptosis of NPCs and reduced the levels of their downstream substrates (p-AKT, p-mTOR, and p-GSK3β). Further assessments revealed that activation of mTOR and GSK3β was almost completely inhibited by rapamycin and SB216763, respectively, which significantly increased the caspase-3 levels. Conclusion: Liraglutide could protect NPCs against high glucose-induced apoptosis by activating the PI3K/AKT/mTOR/caspase-3 and PI3K/AKT/GSK3β/caspase-3 signaling pathways.
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Affiliation(s)
- Mingyan Yao
- Department of Endocrinology, The Third Hospital of Hebei Medical University, Shijiazhuang, China.,Department of Endocrinology, Baoding No.1 Central Hospital, Baoding, China
| | - Jing Zhang
- Department of Cardiology, Affiliated Hospital of Hebei University, Baoding, China
| | - Zhihong Li
- Department of Endocrinology, Baoding No.1 Central Hospital, Baoding, China
| | - Xiaoliang Bai
- Department of Orthopedics, Baoding No.1 Central Hospital, Baoding, China
| | - Jinhui Ma
- Department of Endocrinology, Affiliated Hospital of Hebei University, Baoding, China
| | - Yukun Li
- Department of Endocrinology, The Third Hospital of Hebei Medical University, Shijiazhuang, China
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Continuous stimulation of dual-function peptide PGLP-1-VP inhibits the morbidity and mortality of NOD mice through anti-inflammation and immunoregulation. Sci Rep 2021; 11:3593. [PMID: 33574570 PMCID: PMC7878925 DOI: 10.1038/s41598-021-83201-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2020] [Accepted: 02/01/2021] [Indexed: 12/17/2022] Open
Abstract
Multiple animal and human studies have shown that administration of GLP-1RA can enhance β-cell recovery, reduce insulin dosage, reduce HbA1c content in the blood, reduce the risk of hypoglycemia and reduce inflammation. In the NOD mouse model, peptide VP treatment can prevent and treat type 1 diabetes through immunomodulation. Therefore, we designed a new dual-functional PGLP-1-VP, which is expected to combine the anti-inflammatory effect of PGLP-1 and the immunomodulatory effect of VP peptide. In streptozotocin-induced hyperglycemic mice model, we demonstrated that PGLP-1-VP can act as a GLP-1R agonist to improve hyperglycemia and increase insulin sensitivity. In the NOD mouse model, PGLP-1-VP treatment reduced morbidity, mortality, and pancreatic inflammation, and showed superior effect to PGLP-1 or VP treatment alone, confirming that PGLP-1-VP may act as a dual-function peptide. PGLP-1-VP provided immunomodulatory effect through increasing Th2 cell percentage and balancing the ratio of Th2/Th1 in spleen and PLN, similar to P277 and VP. Additionally, PGLP-1-VP and PGLP-1 act the anti-inflammation by increasing Treg cells and TGF-β1 content like DPP-IV inhibitor. Taken together, our data shows that the dual-functional PGLP-1-VP reduces morbidity and mortality in the NOD model, suggesting a potential role in preventing and treating type 1 diabetes.
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Aghahoseini F, Alihemmati A, Hosseini L, Badalzadeh R. Vildagliptin ameliorates renal injury in type 2 diabetic rats by suppressing oxidative stress. J Diabetes Metab Disord 2021; 19:701-707. [PMID: 33553010 DOI: 10.1007/s40200-020-00548-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2020] [Revised: 05/08/2020] [Accepted: 05/16/2020] [Indexed: 12/27/2022]
Abstract
Purpose Vildagliptin has been shown to prevent microvascular complications during diabetes. The aim of this research was to evaluate the antioxidant effects of vildagliptin in diabetic nephropathy. Methods The diabetes was induced in the animals by high-fat diet and intraperitoneal injection of 35 mg/kg streptozotocin. After diagnosis of diabetes, the vildagliptin (6 mg/kg/day) was orally administered for one month. The biochemical parameters of blood urea nitrogen, creatinine, insulin, and serum albumin were measured. The levels of stress oxidative markers were detected using spectrophotometry. Results Treatment with vildagliptin significantly diminished blood glucose, oxidative stress, and reduced creatinine as well as increased insulin secretion. In addition, the vildagliptin improved renal glomerular and tubule interstitial damages and reduced vascular lesions. Conclusions The treatment with vildagliptin can be useful in controlling the renal complications of type 2 diabetes mellitus through inhibiting lipid peroxidation and increasing the antioxidant enzymes.
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Affiliation(s)
- Fariba Aghahoseini
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Alireza Alihemmati
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Anatomical Sciences, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Leila Hosseini
- Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Reza Badalzadeh
- Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Chronic Kidney Disease Research Center, and Department of Physiology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
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Combination therapy with Exendin-4 and islet transplantation as a synergistic treatment for diabetic nephropathy in rats. Life Sci 2021; 271:119207. [PMID: 33571517 DOI: 10.1016/j.lfs.2021.119207] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 01/30/2021] [Accepted: 02/05/2021] [Indexed: 11/24/2022]
Abstract
OBJECTIVE To explore the improvement and mechanism of combination therapy with Exendin-4 (Ex4) and islet transplantation (IT) on the rat model with diabetic nephropathy (DN). MAIN METHODS The DN rat model was established by injecting streptozotocin (STZ), supplemented by high-fat and high-glucose feeding. Forty DN rats were assigned to four groups treated with saline, Ex4, IT, and Ex4 combined with IT, respectively, using the healthy rat as normal control. The glomerular filtration barrier (GFB) and renal functions were assessed via the histopathological examination and urinalysis, respectively. Then general indexes, renal fibrosis-related factors, CTGF, TGF-β1, and the anti-renal fibrosis factor, HGF, PI3K/Akt/MTOR signaling pathway-related factors were investigated via immunohistochemical staining and western blotting method. KEY FINDING Body weight, blood glucose level, %HbAlc and other diabetes-related factors were all significantly decreased in combination therapy group compare to all other three DN rat groups. After combination or mono treatment of Ex4 and IT, the GFB structure of DN model rats were all obviously improved compared with saline-treated ones. The 24 h-urine proteins and thickness glomerular basilemma in combination group were obviously down-regulated. The pathological change of podocytes, oxidative stress-related factors, the expression levels of HGF, CTGF and TGF-β1 were all obviously improved in combination group. Furthermore, combined treatment also effectively improved the oxidative stress related indicators, and down-regulated PI3K/Akt/MTOR signaling pathway compare to saline or any mono treatment group. CONCLUSIONS Combined Ex4 with IT exhibited promising improvement on DN via inhibiting oxidative stress, fibrosis and down-regulating the PI3K/Akt/MTOR signaling pathway in DN rats.
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Yang H, Wang S, Ye Y, Xie M, Li Y, Jin H, Li J, Gao L. GLP-1 preserves β cell function via improvement on islet insulin signaling in high fat diet feeding mice. Neuropeptides 2021; 85:102110. [PMID: 33307381 DOI: 10.1016/j.npep.2020.102110] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Revised: 11/17/2020] [Accepted: 11/18/2020] [Indexed: 10/22/2022]
Abstract
BACKGROUND Numerous studies have shown that Glucagon like peptide-1 (GLP-1) treatment can protect β cell function, but the exact mechanism remains unclear. We hypothesized that GLP-1 may protect β cell function via its action on insulin signaling pathway. METHODS Mice were fed with high fat diet (HFD, 20 weeks) in the presence or absence of GLP-1 receptor agonist (exenatide) treatment. The islet structure was demonstrated by HE staining. Immunofluorescence antibodies targeting insulin and glucagon were used to illustrate α and β cell distribution. The insulin and glucagon abundance was measured by ELISA using pancreatic homogenates. The molecules involved in insulin signaling pathway (IRc, IRS1, IRS2, mTOR) in islet were examined with immunohistochemistry and immunoblotting. The effect of IRS1 silencing on mTOR and apoptosis were examined on NIT cells(β cell line)with immunoblotting and flow cytometry. RESULTS HE and immunofluorescence staining demonstrated that the normal structure of islet was deformed in HFD mice but preserved by exenatide. Insulin and glucagon contents were increased in islet and blood stream of HFD mice (HFD vs. Control, p<0.05) but resumed by exenatide. Meanwhile the expressions of IRc, IRS-1, mTOR from insulin signaling pathway and β cell apoptosis in the pancreas were significantly reduced (p<0.05) by HFD but reversed by exenatide. CONCLUSION Exenatide improved insulin signaling pathway that was suppressed by HFD in mice islet. Our results reveal a novel mechanism of the protective effects of GLP-1 on β cell function.
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Affiliation(s)
- Heng Yang
- Department of Endocrinology, Renmin Hospital of Wuhan University, 430060, China
| | - Shuo Wang
- Department of Endocrinology, Renmin Hospital of Wuhan University, 430060, China
| | - Yingchun Ye
- Department of Endocrinology, Renmin Hospital of Wuhan University, 430060, China
| | - Min Xie
- Department of Endocrinology, Renmin Hospital of Wuhan University, 430060, China
| | - Yubin Li
- Department of Endocrinology, Renmin Hospital of Wuhan University, 430060, China
| | - Hong Jin
- Department of Endocrinology, Renmin Hospital of Wuhan University, 430060, China
| | - Jing Li
- Department of Endocrinology, Renmin Hospital of Wuhan University, 430060, China
| | - Ling Gao
- Department of Endocrinology, Renmin Hospital of Wuhan University, 430060, China.
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Abstract
Glucagon-like peptide-1 (GLP-1) is an enterohormone with a key role in several processes controlling body homeostasis, including glucose homeostasis and food intake regulation. It is secreted by the intestinal cells in response to nutrients, such as glucose, fat and amino acids. In the present review, we analyse the effect of protein on GLP-1 secretion and clearance. We review the literature on the GLP-1 secretory effects of protein and protein hydrolysates, and the mechanisms through which they exert these effects. We also review the studies on protein from different sources that has inhibitory effects on dipeptidyl peptidase-4 (DPP4), the enzyme responsible for GLP-1 inactivation, with particular emphasis on specific sources and treatments, and the gaps there still are in knowledge. There is evidence that the protein source and the hydrolytic processing applied to them can influence the effects on GLP-1 signalling. The gastrointestinal digestion of proteins, for example, significantly changes their effectiveness at modulating this enterohormone secretion in both in vivo and in vitro studies. Nevertheless, little information is available regarding human studies and more research is required to understand their potential as regulators of glucose homeostasis.
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Li Y, Wang Y, Zhang L, Yan Z, Shen J, Chang Y, Wang J. ι-Carrageenan Tetrasaccharide from ι-Carrageenan Inhibits Islet β Cell Apoptosis Via the Upregulation of GLP-1 to Inhibit the Mitochondrial Apoptosis Pathway. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2021; 69:212-222. [PMID: 33353303 DOI: 10.1021/acs.jafc.0c06456] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
ι-Carrageenan performs diversified biological activities but has low bioavailability. ι-Carrageenan tetrasaccharide (ιCTs), a novel marine oligosaccharide prepared by the marine enzyme Cgi82A, was investigated for its effects on insulin resistance in high-fat and high-sucrose diet mice. Oral administration of ιCTs (ιCTs-L 30.0 mg/kg·bw, ιCTs-H 90.0 mg/kg·bw) decreased fasting blood glucose by 35.1% ± 1.41 (P < 0.01) and 27.4% ± 0.420 (P < 0.05), and enhanced glucose tolerance. Besides, ιCTs-L ameliorated islet vacuolization, decreased the β cell apoptosis by 21.8% ± 0.200 (P < 0.05), and promoted insulin secretion by 5.41% ± 0.0173 (P < 0.01) through pancreatic hematoxylin and eosin (H&E) staining, TUNEL staining, and insulin-glucagon immunostaining analysis. Interestingly, ιCTs-L and ιCTs-H treatment increased the incretin GLP-1 content in serum by 22.1% ± 0.402 (P < 0.01) and 10.7% ± 0.0935 (P < 0.05) respectively, through regulating the bile acid levels, which contributed to the inhibition of β cell apoptosis. Mechanically, ιCTs upregulated the expression of the GLP-1 receptor (GLP-1R) and protein kinase A (PKA) in the GLP-1/cAMP/PKA signaling pathway, and further inhibited the expression of cytochrome C and caspase 3 in the mitochondrial apoptotic pathway. In conclusion, this study suggested that ιCTs alleviated insulin resistance by GLP-1-mediated inhibition of β cell apoptosis and proposed a new strategy for developing potential functional foods that prevent insulin resistance.
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Affiliation(s)
- Yanqi Li
- College of Food Science and Engineering, Ocean University of China, Qingdao 266003, China
| | - Yanchao Wang
- College of Food Science and Engineering, Ocean University of China, Qingdao 266003, China
| | - Lei Zhang
- College of Food Science and Engineering, Ocean University of China, Qingdao 266003, China
| | - Ziyi Yan
- College of Food Science and Engineering, Ocean University of China, Qingdao 266003, China
| | - Jingjing Shen
- College of Food Science and Engineering, Ocean University of China, Qingdao 266003, China
| | - Yaoguang Chang
- College of Food Science and Engineering, Ocean University of China, Qingdao 266003, China
| | - Jingfeng Wang
- College of Food Science and Engineering, Ocean University of China, Qingdao 266003, China
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Li D, Zou H, Yin P, Li W, He J, Wang S, Huang L, Shao S, Chen Y, Yang Y, Yu X. Durability of glycaemic control in type 2 diabetes: A systematic review and meta-analysis for its association with body weight changes. Diabetes Obes Metab 2021; 23:208-217. [PMID: 33016522 DOI: 10.1111/dom.14217] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 08/26/2020] [Accepted: 09/20/2020] [Indexed: 10/23/2022]
Abstract
AIMS To analyse quantitatively the association between the durability of glycaemic control and body weight changes during treatment. MATERIALS AND METHODS This study adhered to an appropriate methodology according to Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines. Studies with follow-ups >12 months, and final and intermediate assessments of haemoglobin A1c (HbA1c) and body weight were included. Four outcomes assessing therapeutic durability were extracted and synthesized using Stata statistical software, including changes in HbA1c, goal-achievement rate, failure rate and coefficient of failure (CoF). RESULTS After 8.9 months of treatment, HbA1c levels declined from 8.03% [95% confidence interval (CI), 7.91-8.15; I2 = 99.2%] to 7.15% (95% CI, 7.02-7.27; I2 = 99.4%) and then gradually increased up to 7.72% (95% CI, 7.50-7.94; I2 = 99.0%) 5 years later. The goal-achievement rate decreased from 54.8% (after 1 year of treatment) to 19.4% 5 years later. The CoF was 0.123 ± 0.022%/year (P < .001). After stratification, the CoFs were 0.224 ± 0.025%/year (P < .001) for weight gain, 0.137 ± 0.034%/year (P < .001) for neutral weight and -0.024 ± 0.032%/year (P = .450) for weight loss. After stratification by treatment approaches, the CoFs were 0.45%/year for insulin, 0.43%/year for sulphonylurea, 0.34%/year for thiazolidinediones, 0.29%/year for metformin, 0.16% for glucagon-like polypeptide-1 receptor agonists, 0.12% for surgery, -0.03% for sodium-glucose cotransporter-2 inhibitors and -0.21% for dipeptidyl peptidase-IV inhibitors. CONCLUSION Modest weight loss with a goal of 2-3% of body weight should be recommended to improve therapeutic durability and prevent beta-cell deterioration.
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Affiliation(s)
- Danpei Li
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - HuaJie Zou
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ping Yin
- Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wenjun Li
- Computer Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Junyu He
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shuyun Wang
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Li Huang
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shiying Shao
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yong Chen
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yan Yang
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xuefeng Yu
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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EGLP-1 lowers body weight better than exendin-4 by reducing food intake and increasing basal energy expenditure in diet-induced obese mice. Exp Cell Res 2020; 399:112454. [PMID: 33359447 DOI: 10.1016/j.yexcr.2020.112454] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2020] [Revised: 11/07/2020] [Accepted: 12/18/2020] [Indexed: 12/17/2022]
Abstract
It is well known that GLP-1 activates GLP-1R to reduce body weight by inhibiting eating. GLP-1 is cleaved by the neutral endopeptidase (NEP) 24.11 into a pentapeptide GLP-1 (32-36) amide, which increases basal energy expenditure and inhibits weight gain in obese mice. It is well known that GLP-1 analogs can reduce weight by suppressing eating. However, there are few reports of reducing weight through the dual effects of inhibiting eating and increasing basic energy. Here, we report the peptide EGLP-1, a GLP-1 analogue, which can reduce food intake and increase basal energy expenditure. In C2C12 myotubes, EGLP-1 can increase both phosphorylation of acetyl CoA carboxylase (ACC) and the ratio between phosphorylation of ACC and the total expression of ACC (pACC/ACC). In diet-induced obese mice, EGLP-1 is more effective than exendin-4 in reducing body weight, reducing fat mass and improving hepatic steatosis. At the same time, EGLP-1 can improve hyperglycemia, reduce food intake, and improve insulin resistance, just like exendin-4. In addition, EGLP-1, not exendin-4, can improve physiological parameters associated with lipid metabolism and increase oxygen consumption by increasing uncoupling proteins 3 (UCP3) expression and pACC/ACC ratio in skeletal muscle. Taken together, this data showed that EGLP-1 is able to reduce body weight by reducing food intake and increasing basal energy expenditure, suggesting it may be more effective in treating diabetic and non-diabetic overweight or obese people than pure GLP-1R agonist exendin-4.
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Boer GA, Holst JJ. Incretin Hormones and Type 2 Diabetes-Mechanistic Insights and Therapeutic Approaches. BIOLOGY 2020; 9:biology9120473. [PMID: 33339298 PMCID: PMC7766765 DOI: 10.3390/biology9120473] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Revised: 12/09/2020] [Accepted: 12/10/2020] [Indexed: 02/06/2023]
Abstract
Simple Summary When we ingest a meal, our intestine secretes hormones that are released into the bloodstream. Amongst these hormones are the incretins hormones which stimulate the release of insulin from the pancreas which is essential for the regulation of in particular postprandial glucose concentrations. In patients with type 2 diabetes, the effect of the incretins is diminished. This is thought to contribute importantly to the pathophysiology of the disease. However, in pharmacological amounts, the incretins may still influence insulin secretion and metabolism. Much research has therefore been devoted to the development of incretin-based therapies for type 2 diabetes. These therapies include compounds that strongly resemble the incretins, hereby stimulating their effects as well as inhibitors of the enzymatic degradation of the hormones, thereby increasing the concentration of incretins in the blood. Both therapeutic approaches have been implemented successfully, but research is still ongoing aimed at the development of further optimized therapies. Abstract Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are secreted from the gut upon nutrient stimulation and regulate postprandial metabolism. These hormones are known as classical incretin hormones and are responsible for a major part of postprandial insulin release. The incretin effect is severely reduced in patients with type 2 diabetes, but it was discovered that administration of GLP-1 agonists was capable of normalizing glucose control in these patients. Over the last decades, much research has been focused on the development of incretin-based therapies for type 2 diabetes. These therapies include incretin receptor agonists and inhibitors of the incretin-degrading enzyme dipeptidyl peptidase-4. Especially the development of diverse GLP-1 receptor agonists has shown immense success, whereas studies of GIP monotherapy in patients with type 2 diabetes have consistently been disappointing. Interestingly, both GIP-GLP-1 co-agonists and GIP receptor antagonists administered in combination with GLP-1R agonists appear to be efficient with respect to both weight loss and control of diabetes, although the molecular mechanisms behind these effects remain unknown. This review describes our current knowledge of the two incretin hormones and the development of incretin-based therapies for treatment of type 2 diabetes.
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Affiliation(s)
- Geke Aline Boer
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark;
- NNF Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark
| | - Jens Juul Holst
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark;
- NNF Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark
- Correspondence: ; Tel.: +45-2875-7518
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Mikov M, Pavlović N, Stanimirov B, Đanić M, Goločorbin-Kon S, Stankov K, Al-Salami H. DPP-4 Inhibitors: Renoprotective Potential and Pharmacokinetics in Type 2 Diabetes Mellitus Patients with Renal Impairment. Eur J Drug Metab Pharmacokinet 2020; 45:1-14. [PMID: 31385198 DOI: 10.1007/s13318-019-00570-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The continuously increasing incidence of diabetes worldwide has attracted the attention of the scientific community and driven the development of a novel class of antidiabetic drugs that can be safely and effectively used in diabetic patients. Of particular interest in this context are complications associated with diabetes, such as renal impairment, which is the main cause of high cardiovascular morbidity and mortality in diabetic patients. Intensive control of glucose levels and other risk factors associated with diabetes and metabolic syndrome provides the foundations for both preventing and treating diabetic nephropathy. Dipeptidyl peptidase-4 (DPP-4) inhibitors represent a highly promising novel class of oral agents used in the treatment of type 2 diabetes mellitus that may be successfully combined with currently available antidiabetic therapeutics in order to achieve blood glucose goals. Beyond glycemic control, emerging evidence suggests that DPP-4 inhibitors may have desirable off-target effects, including renoprotection. All type 2 diabetes mellitus patients with impaired renal function require dose adjustment of any DPP-4 inhibitor administered except for linagliptin, for which renal excretion is a minor elimination pathway. Thus, linagliptin is the drug most frequently chosen to treat type 2 diabetes mellitus patients with renal failure.
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Affiliation(s)
- Momir Mikov
- Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, University of Novi Sad, Novi Sad, Vojvodina, Serbia.
| | - Nebojša Pavlović
- Department of Pharmacy, Faculty of Medicine, University of Novi Sad, Novi Sad, Vojvodina, Serbia
| | - Bojan Stanimirov
- Department of Biochemistry, Faculty of Medicine, University of Novi Sad, Novi Sad, Vojvodina, Serbia
| | - Maja Đanić
- Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, University of Novi Sad, Novi Sad, Vojvodina, Serbia
| | - Svetlana Goločorbin-Kon
- Department of Pharmacy, Faculty of Medicine, University of Novi Sad, Novi Sad, Vojvodina, Serbia
| | - Karmen Stankov
- Department of Biochemistry, Faculty of Medicine, University of Novi Sad, Novi Sad, Vojvodina, Serbia
| | - Hani Al-Salami
- Biotechnology and Drug Development Research Laboratory, School of Pharmacy and Biomedical Sciences, Biosciences Research Precinct, Curtin Health Innovation Research Institute, Curtin University, Perth, WA, Australia
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Suetomi R, Ohta Y, Akiyama M, Matsumura T, Taguchi A, Yamamoto K, Kamatani T, Tanizawa Y. Adrenomedullin has a cytoprotective role against endoplasmic reticulum stress for pancreatic β-cells in autocrine and paracrine manners. J Diabetes Investig 2020; 11:823-833. [PMID: 31989791 PMCID: PMC7378419 DOI: 10.1111/jdi.13218] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2019] [Revised: 01/19/2020] [Accepted: 01/20/2020] [Indexed: 01/06/2023] Open
Abstract
AIMS/INTRODUCTION Pancreatic β-cells are sensitive to endoplasmic reticulum (ER) stress, which has a major role in the context of β-cell death. Adrenomedullin (ADM) has been shown to exert a cytoprotective effect under various pathophysiological conditions. Several studies have suggested that thiazolidinediones have protective effects on β-cells. During the course to elucidate the molecular mechanisms by which pioglitazone prevents β-cell death, ADM emerged as a candidate. Here, we studied the regulation of ADM expression, including the effects of pioglitazone, and its role in pancreatic islets. MATERIALS AND METHODS We analyzed ADM expression in islet cell lines treated with pioglitazone. The effects of ER stress on ADM and ADM receptor expressions were investigated by analyzing thapsigargin-treated MIN6 cells and islets isolated from Wfs1-/- and db/db mice. To study the anti-apoptotic effect of ADM, ER stress-exposed MIN6 cells were treated with ADM peptides or transfected with ADM expression plasmid. RESULTS Pioglitazone increased the production and secretion of ADM in islets through peroxisome-proliferator activated receptor-γ-dependent mechanisms. Thapsigargin treatment increased expressions of both ADM and ADM receptor, composed of Ramp2, Ramp3 and Crlr, in MIN6 cells. ADM and ADM receptor expressions were also increased in isolated islets from Wfs1-/- and db/db mice. ADM peptides and ADM overexpression protected MIN6 cells from thapsigargin-induced apoptosis. CONCLUSIONS ER stress stimulates ADM production and secretion in islets. ADM signaling might protect β-cells from ER stress-induced apoptosis, and might be one of the self-protective mechanisms. β-Cell protection by pioglitazone is partly through induction of ADM. ADM-based therapy could be a novel strategy for treating diabetes.
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Affiliation(s)
- Risa Suetomi
- Division of Endocrinology, Metabolism, Hematological Science and TherapeuticsDepartment of Bio‐Signal AnalysisGraduate School of MedicineYamaguchi UniversityUbeJapan
| | - Yasuharu Ohta
- Division of Endocrinology, Metabolism, Hematological Science and TherapeuticsDepartment of Bio‐Signal AnalysisGraduate School of MedicineYamaguchi UniversityUbeJapan
- Department of Diabetes ResearchSchool of MedicineYamaguchi UniversityUbeJapan
| | - Masaru Akiyama
- Division of Endocrinology, Metabolism, Hematological Science and TherapeuticsDepartment of Bio‐Signal AnalysisGraduate School of MedicineYamaguchi UniversityUbeJapan
| | - Takuro Matsumura
- Division of Endocrinology, Metabolism, Hematological Science and TherapeuticsDepartment of Bio‐Signal AnalysisGraduate School of MedicineYamaguchi UniversityUbeJapan
| | - Akihiko Taguchi
- Division of Endocrinology, Metabolism, Hematological Science and TherapeuticsDepartment of Bio‐Signal AnalysisGraduate School of MedicineYamaguchi UniversityUbeJapan
| | - Kaoru Yamamoto
- Division of Endocrinology, Metabolism, Hematological Science and TherapeuticsDepartment of Bio‐Signal AnalysisGraduate School of MedicineYamaguchi UniversityUbeJapan
| | - Takashi Kamatani
- Division of Endocrinology, Metabolism, Hematological Science and TherapeuticsDepartment of Bio‐Signal AnalysisGraduate School of MedicineYamaguchi UniversityUbeJapan
| | - Yukio Tanizawa
- Division of Endocrinology, Metabolism, Hematological Science and TherapeuticsDepartment of Bio‐Signal AnalysisGraduate School of MedicineYamaguchi UniversityUbeJapan
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Clough TJ, Baxan N, Coakley EJ, Rivas C, Zhao L, Leclerc I, Martinez-Sanchez A, Rutter GA, Long NJ. Synthesis and in vivo behaviour of an exendin-4-based MRI probe capable of β-cell-dependent contrast enhancement in the pancreas. Dalton Trans 2020; 49:4732-4740. [PMID: 32207493 PMCID: PMC7116436 DOI: 10.1039/d0dt00332h] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Global rates of diabetes mellitus are increasing, and treatment of the disease consumes a growing proportion of healthcare spending across the world. Pancreatic β-cells, responsible for insulin production, decline in mass in type 1 and, to a more limited degree, in type 2 diabetes. However, the extent and rate of loss in both diseases differs between patients resulting in the need for the development of novel diagnostic tools, which could quantitatively assess changes in mass of β-cells over time and potentially lead to earlier diagnosis and improved treatments. Exendin-4, a potent analogue of glucagon-like-peptide 1 (GLP-1), binds to the receptor GLP-1R, whose expression is enriched in β-cells. GLP-1R has thus been used in the past as a means of targeting probes for a wide variety of imaging modalities to the endocrine pancreas. However, exendin-4 conjugates designed specifically for MRI contrast agents are an under-explored area. In the present work, the synthesis and characterization of an exendin-4-dota(ga)-Gd(iii) complex, GdEx, is reported, along with its in vivo behaviour in healthy and in β-cell-depleted C57BL/6J mice. Compared to the ubiquitous probe, [Gd(dota)]-, GdEx shows selective uptake by the pancreas with a marked decrease in accumulation observed after the loss of β-cells elicited by deleting the microRNA processing enzyme, DICER. These results open up pathways towards the development of other targeted MRI contrast agents based on similar chemistry methodology.
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Affiliation(s)
- Thomas J Clough
- Department of Chemistry, Molecular Sciences Research Hub, Imperial College London, White City Campus, Wood Lane, London, W12 0BZ, UK.
| | - Nicoleta Baxan
- Biological Imaging Centre, Faculty of Medicine, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK
| | - Emma J Coakley
- Department of Chemistry, Molecular Sciences Research Hub, Imperial College London, White City Campus, Wood Lane, London, W12 0BZ, UK.
| | - Charlotte Rivas
- Department of Chemistry, Molecular Sciences Research Hub, Imperial College London, White City Campus, Wood Lane, London, W12 0BZ, UK.
| | - Lan Zhao
- Biological Imaging Centre, Faculty of Medicine, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK and National Heart and Lung Institute, Faculty of Medicine, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK
| | - Isabelle Leclerc
- Section of Cell Biology and Functional Genomics, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK.
| | - Aida Martinez-Sanchez
- Section of Cell Biology and Functional Genomics, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK.
| | - Guy A Rutter
- Section of Cell Biology and Functional Genomics, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK. and Lee Kong Chain School of Medicine, Nan Yang Technological University, 11 Mandalay Road, 308232 Singapore
| | - Nicholas J Long
- Department of Chemistry, Molecular Sciences Research Hub, Imperial College London, White City Campus, Wood Lane, London, W12 0BZ, UK.
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Drug discovery approaches targeting the incretin pathway. Bioorg Chem 2020; 99:103810. [PMID: 32325333 DOI: 10.1016/j.bioorg.2020.103810] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Revised: 02/20/2020] [Accepted: 03/29/2020] [Indexed: 12/20/2022]
Abstract
Incretin pathway plays an important role in the development of diabetes medications. Interventions in DPP-4 and GLP-1 receptor have shown remarkable efficacy in experimental and clinical studies and imperatively become one of the most promising therapeutic approaches in the T2DM drug discovery pipeline. Herein, we analyzed the actionmechanismsof DPP-4 and GLP-1 receptor targeting the incretin pathway in T2DM treatment. We gave an insight into the structural requirements for the potent DPP-4 inhibitors and revealed a classification of DPP-4 inhibitors by stressing on the binding modes of these ligands to the enzyme. We then reviewed the drug discovery strategies for the development of peptide and non-peptide GLP-1 receptor agonists (GLP-1 RAs). Furthermore, the drug design strategies for DPP-4 inhibitors and GLP-1R agonists were detailed accurately. This review might provide an efficient evidence for the highly potent and selective DPP-4 inhibitors and the GLP-1 RAs, as novel medicines for patients suffering from T2DM.
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Wang W, Wu RD, Chen P, Xu XJ, Shi XZ, Huang LH, Shao ZL, Guo W. Liraglutide combined with human umbilical cord mesenchymal stem cell transplantation inhibits beta-cell apoptosis via mediating the ASK1/JNK/BAX pathway in rats with type 2 diabetes. Diabetes Metab Res Rev 2020; 36:e3212. [PMID: 31411368 DOI: 10.1002/dmrr.3212] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2018] [Revised: 06/15/2019] [Accepted: 08/09/2019] [Indexed: 12/13/2022]
Abstract
OBJECTIVE Accumulating evidence suggests an association between beta-cell apoptosis and the ASK1/JNK/BAX pathway. The aim of this study was to investigate the effects of a combined therapy of liraglutide and human umbilical cord mesenchymal stem cells (hUC-MSCs) on the glucose metabolism and islet beta-cell apoptosis, and further explore its relationship to the ASK1/JNK/BAX pathway. METHOD Type 2 diabetes mellitus (T2DM) rat model was induced by a high-sugar and high-fat diet and intraperitoneal injection of low-dose streptozotocin (STZ) (30 mg/kg). Three days after STZ injection, diabetic rats were randomly treated with subcutaneous injection of liraglutide (200 μg/kg/12 h) for 8 weeks and or hUC-MSCs (1 × 106 /rat) at the first and fifth weeks. Diabetes-related physical and biochemical parameters, pancreatic histopathological changes, immunohistochemical staining, quantitative real-time polymerase chain reaction, and western blot were used to measure the expression of apoptosis signal-regulating kinase 1 (ASK1), Jun N-terminal kinase (JNK), Bcl-2 associated X protein (BAX), and B-cell lymphoma-2 (Bcl-2). RESULTS Eight weeks after liraglutide or human umbilical cord mesenchymal stem cell administration, FPG, HbA1c , glucagon, body weight, and pancreatic ASK1, JNK, and BAX mRNA and proteins were significantly decreased, and the levels of serum C-p, INS and GLP-1, ratio of insulin positive area, and Bcl-2 expression were significantly increased in three treatment groups compared with T2DM group (P<.05). CONCLUSION Liraglutide combined with hUC-MSCs improve glucose metabolism and inhibit islet beta-cell apoptosis in a ASK1/JNK/BAX pathway-dependent manner.
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Affiliation(s)
- Wei Wang
- Fuzong Clinical Medical College, Fujian Medical University, Fuzhou, China
- Department of Endocrinology, Fuzhou General Hospital, Fuzhou, China
| | - Rong Dan Wu
- Fuzong Clinical Medical College, Fujian Medical University, Fuzhou, China
- Department of Endocrinology, Fuzhou General Hospital, Fuzhou, China
| | - Pin Chen
- Fuzong Clinical Medical College, Fujian Medical University, Fuzhou, China
- Department of Endocrinology, Fuzhou General Hospital, Fuzhou, China
| | - Xiang Jin Xu
- Fuzong Clinical Medical College, Fujian Medical University, Fuzhou, China
- Department of Endocrinology, Fuzhou General Hospital, Fuzhou, China
| | - Xiao Zhi Shi
- Fuzong Clinical Medical College, Fujian Medical University, Fuzhou, China
- Department of Endocrinology, Fuzhou General Hospital, Fuzhou, China
| | - Li Hong Huang
- Fuzong Clinical Medical College, Fujian Medical University, Fuzhou, China
- Department of Endocrinology, Fuzhou General Hospital, Fuzhou, China
| | - Zhu Lin Shao
- Department of Endocrinology, Fuzhou General Hospital, Fuzhou, China
| | - Wen Guo
- Department of Endocrinology, Fuzhou General Hospital, Fuzhou, China
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Grandl G, Novikoff A, DiMarchi R, Tschöp MH, Müller TD. Gut Peptide Agonism in the Treatment of Obesity and Diabetes. Compr Physiol 2019; 10:99-124. [PMID: 31853954 DOI: 10.1002/cphy.c180044] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Obesity is a global healthcare challenge that gives rise to devastating diseases such as the metabolic syndrome, type-2 diabetes (T2D), and a variety of cardiovascular diseases. The escalating prevalence of obesity has led to an increased interest in pharmacological options to counteract excess weight gain. Gastrointestinal hormones such as glucagon, amylin, and glucagon-like peptide-1 (GLP-1) are well recognized for influencing food intake and satiety, but the therapeutic potential of these native peptides is overall limited by a short half-life and an often dose-dependent appearance of unwanted effects. Recent clinical success of chemically optimized GLP-1 mimetics with improved pharmacokinetics and sustained action has propelled pharmacological interest in using bioengineered gut hormones to treat obesity and diabetes. In this article, we summarize the basic biology and signaling mechanisms of selected gut peptides and discuss how they regulate systemic energy and glucose metabolism. Subsequently, we focus on the design and evaluation of unimolecular drugs that combine the beneficial effects of selected gut hormones into a single entity to optimize the beneficial impact on systems metabolism. © 2020 American Physiological Society. Compr Physiol 10:99-124, 2020.
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Affiliation(s)
- Gerald Grandl
- Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München - German Research Center for Environmental Health (GmbH), Neuherberg, Germany.,German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Aaron Novikoff
- Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München - German Research Center for Environmental Health (GmbH), Neuherberg, Germany.,German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Richard DiMarchi
- Department of Chemistry, Indiana University, Bloomington, Indiana, USA
| | - Matthias H Tschöp
- German Center for Diabetes Research (DZD), Neuherberg, Germany.,Division of Metabolic Diseases, Technische Universität München, Munich, Germany
| | - Timo D Müller
- Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München - German Research Center for Environmental Health (GmbH), Neuherberg, Germany.,German Center for Diabetes Research (DZD), Neuherberg, Germany.,Department of Pharmacology and Experimental Therapy, Institute of Experimental and Clinical Pharmacology and Toxicology, Eberhard Karls University Hospitals and Clinics, Tübingen, Germany
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Antwi K, Nicolas G, Fani M, Heye T, Pattou F, Grossman A, Chanson P, Reubi JC, Perren A, Gloor B, Vogt DR, Wild D, Christ E. 68Ga-Exendin-4 PET/CT Detects Insulinomas in Patients With Endogenous Hyperinsulinemic Hypoglycemia in MEN-1. J Clin Endocrinol Metab 2019; 104:5843-5852. [PMID: 31298706 DOI: 10.1210/jc.2018-02754] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Accepted: 07/08/2019] [Indexed: 01/15/2023]
Abstract
CONTEXT Surgical intervention is advised in patients with multiple endocrine neoplasia type-1 (MEN-1) and nonfunctioning pancreatic neuroendocrine tumors (PanNETs) with a size ≥20 mm. Functioning PanNETs, such as in patients with endogenous hyperinsulinemic hypoglycemia (EHH) due to (one or multiple) insulinomas, should be treated surgically independent of size. Preoperative localization of insulinomas is critical for surgery. OBJECTIVE To evaluate the feasibility and sensitivity of 68Ga-DOTA-exendin-4 positron emission tomography (PET)/CT in the detection of clinically relevant lesions in patients with MEN-1 and EHH in combination with MRI. DESIGN Post hoc subgroup analysis of a larger prospective imaging study with 52 patients with EHH. PATIENTS Six of 52 consecutive patients with EHH and genetically proven MEN-1 mutation were included. INTERVENTIONS All patients received one 68Ga-DOTA-exendin-4 PET/CT and one MRI scan within 3 to 4 days. Thereafter, surgery was performed based on all imaging results. MAIN OUTCOME MEASURES Lesion-based sensitivity of PET/CT and MRI for detection of clinically relevant lesions was calculated. Readers were unaware of other results. The reference standard was surgery with histology and treatment outcome. True positive (i.e., clinically relevant lesions) was defined as PanNETs ≥20 mm or insulinoma. RESULTS In six patients, 37 PanNETs were confirmed by histopathology. Sensitivity (95% CI) in the detection of clinically relevant lesions for combined PET/CT plus MRI, MRI, and PET/CT was 92.3% (64% to 99.8%), 38.5% (13.9% to 68.4%), and 84.6% (54.6% to 98.1%), respectively (P = 0.014 for the comparison of PET/CT plus MRI vs MRI). Postsurgery, EHH resolved in all patients. CONCLUSION 68Ga-DOTA-exendin-4 PET/CT is feasible in patients with MEN-1 and EHH. The combination with MRI is superior to MRI alone in the detection of insulinomas and may guide the surgical strategy.
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Affiliation(s)
- Kwadwo Antwi
- Clinic of Radiology and Nuclear Medicine, University Hospital Basel, Basel, Switzerland
| | - Guillaume Nicolas
- Clinic of Radiology and Nuclear Medicine, University Hospital Basel, Basel, Switzerland
- Center for Neuroendocrine and Endocrine Tumors, University Hospital Basel, Basel, Switzerland
| | - Melpomeni Fani
- Clinic of Radiology and Nuclear Medicine, University Hospital Basel, Basel, Switzerland
| | - Tobias Heye
- Clinic of Radiology and Nuclear Medicine, University Hospital Basel, Basel, Switzerland
| | - Francois Pattou
- Department of General and Endocrine Surgery, Lille University Hospital, Lille France
| | - Ashley Grossman
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom
- Neuroendocrine Unit, Royal Free Hospital, London, United Kingdom
| | - Philippe Chanson
- Assistance Publique-Hôpitaux de Paris, Service d'Endocrinologie et des Maladies de la Reproduction, Hôpital Bicêtre, Le Kremlin-Bicêtre, France
- UMR S-1185, Université Paris Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France
| | | | - Aurel Perren
- Department of Pathology, University of Bern, Bern, Switzerland
| | - Beat Gloor
- Department of Visceral Surgery, University Hospital of Bern, Inselspital, Bern, Switzerland
| | - Deborah R Vogt
- Clinical Trial Unit, Department of Clinical Research, University Hospital Basel, University of Basel, Basel, Switzerland
| | - Damian Wild
- Clinic of Radiology and Nuclear Medicine, University Hospital Basel, Basel, Switzerland
- Center for Neuroendocrine and Endocrine Tumors, University Hospital Basel, Basel, Switzerland
| | - Emanuel Christ
- Center for Neuroendocrine and Endocrine Tumors, University Hospital Basel, Basel, Switzerland
- Division of Endocrinology, Diabetology and Metabolism, University Hospital Basel, Basel, Switzerland
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Lee JM, Yoo IK, Lee JM, Kim SH, Choi HS, Kim ES, Keum B, Seo YS, Jeen YT, Chun HJ, Lee HS, Um SH, Kim CD. Dipeptidyl-peptidase-4 (DPP-4) inhibitor ameliorates 5-flurouracil induced intestinal mucositis. BMC Cancer 2019; 19:1016. [PMID: 31664952 PMCID: PMC6819400 DOI: 10.1186/s12885-019-6231-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Accepted: 10/01/2019] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Chemotherapy-induced alimentary mucositis (AM) is difficult to prevent and treatment is rarely effective. Recent study have been showed that glucagon-like peptide (GLP)-1 and GLP-2 has protective in chemotherapy-induced AM. While the DPP-4 enzyme degrades this GLP-1, the DPP-4 inhibitor blocks the degradation process and raises the concentration of GLP-1. This study aimed to assess the role of DPP-4 inhibitor, a well-known hypoglycemic agent, on chemotherapy-induced AM. METHODS Twenty-four 6-week-old male C57BL/6 mice were divided into 4 groups: control, 5-fluorouracil (5-FU), DPP-4 inhibitor, and saline (DPP-4i), and DPP-4 inhibitor and 5-FU (DPP-4i + 5-FU). Mucositis was induced by intraperitoneal injection of 5-FU (400 mg/kg). DPP-4 inhibitor (50 mg/kg) was administered orally for four days starting the day before 5-FU administration. Post 72 h of 5-FU injection, mice were sacrificed and body weight change, diarrhea score, villus height, villus/crypt ratio, histologic characteristics including goblet cell count, and mRNA expression of inflammatory cytokines tumor necrosis factor (TNF)-α and interleukin (IL)-6, were assessed. RESULTS Daily body weight change was not statistically significant between the 5-FU and the DPP-4i + 5-FU group (P = 0.571). Diarrhea score was significantly different between these two groups (P = 0.033). In the 5-FU group, the villus height was not maintained well, the epithelial lining was irregular, and inflammatory cell infiltration was observed. Goblet cell count in the DPP-4i + 5-FU group was significantly higher than in the 5-FU group (P = 0.007). However, in the DPP-4i + 5-FU group, the villus height, epithelial lining, and crypt structure were better maintained than in the 5-FU group. Compared with the control group, mRNA expression of TNF-α was significantly up-regulated in the 5-FU group. Moreover, mRNA expression of TNF-α in the DPP-4i + 5-FU group was down-regulated compared to the 5-FU group. However, IL-6 in the 5-FU group was significantly down-regulated compared to the control, there was no significant difference in expression of IL-6 between the 5-FU and DPP4i + 5-FU group. CONCLUSION DPP-4 inhibitor can improve 5-FU induced AM and, therefore, has potential as an alternative treatment for chemotherapy-induced AM.
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Affiliation(s)
- Jung Min Lee
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, South Korea.,Division of Gastroenterology and Hepatology, Department of Internal Medicine, Wonkwang University Sanbon Medical Center, Gunpo, South Korea
| | - In Kyung Yoo
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, South Korea
| | - Jae Min Lee
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, South Korea
| | - Seung Han Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, South Korea
| | - Hyuk Soon Choi
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, South Korea
| | - Eun Sun Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, South Korea
| | - Bora Keum
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, South Korea
| | - Yeon Seok Seo
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, South Korea
| | - Yoon Tae Jeen
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, South Korea
| | - Hoon Jai Chun
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, South Korea.
| | - Hong Sik Lee
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, South Korea
| | - Soon Ho Um
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, South Korea
| | - Chang Duck Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, South Korea
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Fiorentino TV, Casiraghi F, Davalli AM, Finzi G, La Rosa S, Higgins PB, Abrahamian GA, Marando A, Sessa F, Perego C, Guardado-Mendoza R, Kamath S, Ricotti A, Fiorina P, Daniele G, Paez AM, Andreozzi F, Bastarrachea RA, Comuzzie AG, Gastaldelli A, Chavez AO, Di Cairano ES, Frost P, Luzi L, Dick EJ, Halff GA, DeFronzo RA, Folli F. Exenatide regulates pancreatic islet integrity and insulin sensitivity in the nonhuman primate baboon Papio hamadryas. JCI Insight 2019; 4:93091. [PMID: 31536476 DOI: 10.1172/jci.insight.93091] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Accepted: 09/05/2019] [Indexed: 12/20/2022] Open
Abstract
The glucagon-like peptide-1 receptor agonist exenatide improves glycemic control by several and not completely understood mechanisms. Herein, we examined the effects of chronic intravenous exenatide infusion on insulin sensitivity, β cell and α cell function and relative volumes, and islet cell apoptosis and replication in nondiabetic nonhuman primates (baboons). At baseline, baboons received a 2-step hyperglycemic clamp followed by an l-arginine bolus (HC/A). After HC/A, baboons underwent a partial pancreatectomy (tail removal) and received a continuous exenatide (n = 12) or saline (n = 12) infusion for 13 weeks. At the end of treatment, HC/A was repeated, and the remnant pancreas (head-body) was harvested. Insulin sensitivity increased dramatically after exenatide treatment and was accompanied by a decrease in insulin and C-peptide secretion, while the insulin secretion/insulin resistance (disposition) index increased by about 2-fold. β, α, and δ cell relative volumes in exenatide-treated baboons were significantly increased compared with saline-treated controls, primarily as the result of increased islet cell replication. Features of cellular stress and secretory dysfunction were present in islets of saline-treated baboons and absent in islets of exenatide-treated baboons. In conclusion, chronic administration of exenatide exerts proliferative and cytoprotective effects on β, α, and δ cells and produces a robust increase in insulin sensitivity in nonhuman primates.
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Affiliation(s)
- Teresa Vanessa Fiorentino
- Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy.,Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
| | - Francesca Casiraghi
- Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.,Department of Biomedical Sciences for Health, University of Milan, Milan, Italy
| | - Alberto M Davalli
- Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.,Department of Medicine, Endocrinology Unit, Ospedale San Raffaele, Milan, Italy
| | - Giovanna Finzi
- Unit of Pathology, Ospedale di Circolo and Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Stefano La Rosa
- Service of Clinical Pathology, Institute of Pathology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Paul B Higgins
- Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, Texas, USA
| | - Gregory A Abrahamian
- Department of Surgery, Transplant Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
| | - Alessandro Marando
- Unit of Pathology, Ospedale di Circolo and Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Fausto Sessa
- Unit of Pathology, Ospedale di Circolo and Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Carla Perego
- Department of Pharmacology and Biomolecular Science, University of Milan, Milan, Italy
| | - Rodolfo Guardado-Mendoza
- Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
| | - Subhash Kamath
- Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
| | - Andrea Ricotti
- Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
| | - Paolo Fiorina
- Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, Division of Health Science, Harvard University, Boston, Massachusetts, USA
| | - Giuseppe Daniele
- Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
| | - Ana M Paez
- Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
| | - Francesco Andreozzi
- Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy.,Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
| | - Raul A Bastarrachea
- Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, Texas, USA
| | - Anthony G Comuzzie
- Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, Texas, USA
| | - Amalia Gastaldelli
- Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.,Institute of Clinical Physiology, National Research Council, Pisa, Italy
| | - Alberto O Chavez
- Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
| | - Eliana S Di Cairano
- Department of Pharmacology and Biomolecular Science, University of Milan, Milan, Italy
| | - Patrice Frost
- Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, Texas, USA
| | - Livio Luzi
- Department of Biomedical Sciences for Health, University of Milan, Milan, Italy.,Metabolism Research Centre, IRCCS Policlinico San Donato, Milan, Italy
| | - Edward J Dick
- Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, Texas, USA
| | - Glenn A Halff
- Department of Surgery, Transplant Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
| | - Ralph A DeFronzo
- Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
| | - Franco Folli
- Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.,Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, Texas, USA.,Department of Health Science, University of Milan, Milan, Italy
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Srivastava S, Pandey H, Singh SK, Tripathi YB. Anti-oxidant, anti-apoptotic, anti-hypoxic and anti-inflammatory conditions induced by PTY-2 against STZ-induced stress in islets. Biosci Trends 2019; 13:382-393. [PMID: 31597821 DOI: 10.5582/bst.2019.01181] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
The earlier assessment of Pueraria tuberosa (PT) has shown anti-diabetic effects through enhancing incretin action and DPP-IV (Dipeptidyl peptidase-IV) inhibition. The aim of this work was to further explore the protective role of aqueous extract of Pueraria tuberosa tuber (PTY-2) against streptozotocin (STZ) induced islet stress in rats. Diabetes was induced by STZ (65 mg/kg body weight) in charles foster male rats. After 60 days of STZ administration, animals with blood glucose levels > 200 g/dL were considered as diabetic. All the rats were later divided into three groups: Group-1 (STZ untreated normal rats), Group-2 (Diabetic control), and Group-3 (PTY-2 [50 mg/100 g bw treatment for next 10 days to diabetic rats). The rats were then sacrificed after the 10th day of treatment accordingly. STZ treatment led to an increase in expression of Matrix metalloproteinases-9 (MMP-9), Tumour necrosis factor-α (Tnf-α), Hypoxia inducible factor-α (HIF-1α), Vascular endothelial growth factor (VEGF), Interleukin-6 (IL-6), Protein kinase C-ε (PKC-ε), Nuclear factor kappa-light-chain-enhancer of activated B-cells (NFkB), and Caspase-3. Reverse Transcriptase-PCR (RT-PCR), Immunohistochemistry and Western-Blot analysis showed an increase in the expressions of Superoxide Dismutase (SOD) and Nephrin, and a decrease in the expressions of NFkB, PKC-ε, TNF-α, MMP-9, HIF-1α, VEGF, Caspase-3 and IL-6 after 10 days of PTY-2 treatment. The results showed that PTY-2 favorably changed all the expressions via anti-oxidant, anti-apoptotic, anti-hypoxic and anti-inflammatory pathways, making itself as a protective agent against STZ induced islet stress. Further evaluation of PTY-2 might be helpful in establishing its role in the management of diabetes mellitus.
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Affiliation(s)
- Shivani Srivastava
- Department of Medicinal Chemistry, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India
| | - Harsh Pandey
- Department of Medicinal Chemistry, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India
| | - Surya Kumar Singh
- Department of Endocrinology and Metabolism, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India
| | - Yamini Bhusan Tripathi
- Department of Medicinal Chemistry, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India
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