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Arredouani A. GLP-1 receptor agonists, are we witnessing the emergence of a paradigm shift for neuro-cardio-metabolic disorders? Pharmacol Ther 2025; 269:108824. [PMID: 39983843 DOI: 10.1016/j.pharmthera.2025.108824] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 02/07/2025] [Accepted: 02/14/2025] [Indexed: 02/23/2025]
Abstract
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as groundbreaking therapeutic agents in managing a spectrum of metabolic disorders, demonstrating remarkable efficacy across multiple organ systems and disease states. These compounds are not only well-established in the treatment of type 2 diabetes (T2D) and obesity-conditions for which they have received widespread approval-but also exhibit promising potential in addressing cardiovascular disease (CVD) and Metabolic dysfunction-associated steatotic liver disease (MASLD). Recent investigations have begun to illuminate the utility of GLP-1RAs in the management of type 1 diabetes (T1D), as well as neurodegenerative disorders such as Alzheimer's and Parkinson's disease and various behavioral disorders. A plethora of clinical trials have consistently validated the capacity of GLP-1RAs to improve glycemic control, promote weight loss, and mitigate cardiovascular risk factors in individuals with T2D and obesity. While their application in T1D remains limited due to safety concerns-particularly regarding the risks of hypoglycemia and hyperglycemic ketoacidosis-emerging data suggest that GLP-1RAs may offer hepatoprotective benefits, potentially reducing liver fat content and decelerating the progression of MASLD. The neuroprotective attributes of GLP-1 RAs have garnered significant interest, with research indicating their potential to alleviate cognitive decline associated with neurodegenerative diseases. Furthermore, preliminary findings highlight the role of GLP-1 RAs in addressing behavioral disorders, emphasizing their extensive therapeutic promise. This comprehensive review synthesizes the current evidence supporting the diverse therapeutic applications of GLP-1RAs, positioning them as "magic drug" therapies for metabolic and neurological disorders. As ongoing research continues to explore innovative applications and combinations of GLP-1RAs, the landscape of disease management in metabolic and neurological contexts is poised for transformative advancements. This review will also critically assess safety considerations and underscore the need for personalized treatment strategies to optimize patient outcomes in these complex and often comorbid conditions.
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Affiliation(s)
- Abdelilah Arredouani
- Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation, Doha, Qatar; College of Health and Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation, Qatar.
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Duță C, Muscurel C, Dogaru CB, Stoian I. Targeting Ferroptosis in Parkinson's: Repurposing Diabetes Drugs as a Promising Treatment. Int J Mol Sci 2025; 26:1516. [PMID: 40003982 PMCID: PMC11855881 DOI: 10.3390/ijms26041516] [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: 12/31/2024] [Revised: 02/02/2025] [Accepted: 02/10/2025] [Indexed: 02/27/2025] Open
Abstract
This review explores the promising potential of repurposing type 2 diabetes (T2D) medications for the treatment of Parkinson's disease (PD), highlighting the shared pathophysiological mechanisms between these two age-related conditions, such as oxidative stress, mitochondrial dysfunction, and ferroptosis. The overlap suggests that existing diabetes drugs could target the common pathways involved in both conditions. Specifically, the review discusses how T2D medications, including metformin (Met), peroxisome-proliferator-activated receptor gamma (PPAR-γ) agonists, sodium-glucose cotransporter-2 (SGLT2) inhibitors, incretins, and dipeptidyl-peptidase 4 (DPP-4) inhibitors, can improve mitochondrial function, reduce neuroinflammation and oxidative stress, and potentially inhibit ferroptosis. The connection between ferroptosis and existing treatments, including diabetes medication, are only beginning to be explored. The limited data can be attributed also to the complexity of mechanisms involved in ferroptosis and Parkinson's disease and to the fact that the specific role of ferroptosis in Parkinson's disease pathogenesis has not been a primary focus until recent. Despite the promising preclinical evidence, clinical findings are mixed, underscoring the need for further research to elucidate these drugs' roles in neurodegeneration. Repurposing existing diabetes medications that have well-established safety profiles for Parkinson's disease treatment could significantly reduce the time and cost associated with drug development and could offer a more comprehensive approach to managing Parkinson's disease compared to treatments targeting a single mechanism.
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Affiliation(s)
| | | | - Carmen Beatrice Dogaru
- Department of Biochemistry, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (C.D.); (C.M.); (I.S.)
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Sobral MVS, Rodrigues LK, Barbosa AMP, da Rocha NC, Moulaz IR, Dos Santos JPP, Oliveira BHC, Moreira JLDML, Pacagnelli FL, Guida CM. Cardiovascular Effects of Semaglutide in Patients with Heart Failure with Preserved Ejection Fraction: A Systematic Review and Meta-Analysis. Am J Cardiovasc Drugs 2025:10.1007/s40256-025-00721-4. [PMID: 39907981 DOI: 10.1007/s40256-025-00721-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/19/2025] [Indexed: 02/06/2025]
Abstract
BACKGROUND Semaglutide has emerged as an effective medication for treating type 2 diabetes mellitus (DM). However, the cardiovascular effects and safety of this agent in patients with heart failure with preserved ejection fraction (HFpEF) are unclear. OBJECTIVE This systematic review and meta-analysis aimed to assess the clinical and laboratory effects of semaglutide compared to placebo in patients with HFpEF. METHODS We systematically searched EMBASE, PubMed, and Cochrane databases for randomized controlled trials (RCTs) and non-randomized cohorts, from inception to July 2024, comparing semaglutide versus placebo in patients with HFpEF. Statistical analyses were performed using R Studio 4.3.2. Mean difference (MD) and odds ratio (OR) with 95% confidence intervals (CIs) were pooled across trials. RESULTS This meta-analysis included three studies, two RCTs and one non-randomized cohort, reporting data on 1463 patients. The follow-up time of the studies was 52 weeks. Compared to placebo, the use of semaglutide was associated with a significant increase in the 6-min walk distance (MD 16.20; 95% CI 10.19-22.21; p < 0.01; I2 = 0%). Additionally, reductions were observed in systolic blood pressure (MD -2.22; 95% CI -3.60 to -0.83; p < 0.01; I2 = 0%), C-reactive protein level (MD 0.59; 95% CI 0.49-0.70; p < 0.01; I2 = 51%), and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) levels (MD 0.81; 95% CI 0.74-0.89; p < 0.01; I2 = 0%). CONCLUSION These findings suggest that the use of semaglutide is associated with clinical and laboratory benefits in patients with HFpEF.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - Camila Mota Guida
- Dante Pazzanese Institute of Cardiology, Av. Dante Pazzanese, Sao Paulo, 500, Brazil.
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Kim JE, Lee JW, Cha GD, Yoon JK. The Potential of Mesenchymal Stem Cell-Derived Exosomes to Treat Diabetes Mellitus. Biomimetics (Basel) 2025; 10:49. [PMID: 39851765 PMCID: PMC11760843 DOI: 10.3390/biomimetics10010049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Revised: 12/27/2024] [Accepted: 12/31/2024] [Indexed: 01/26/2025] Open
Abstract
Diabetes mellitus (DM) is a fatal metabolic disease characterized by persistent hyperglycemia. In recent studies, mesenchymal stem cell (MSC)-derived exosomes, which are being investigated clinically as a cell-free therapy for various diseases, have gained attention due to their biomimetic properties that closely resemble natural cellular communication systems. These MSC-derived exosomes inherit the regenerative and protective effects from MSCs, inducing pancreatic β-cell proliferation and inhibiting apoptosis, as well as ameliorating insulin resistance by suppressing the release of various inflammatory cytokines. Consequently, MSC-derived exosomes have attracted attention as a novel treatment for DM as an alternative to stem cell therapy. In this review, we will introduce the potential of MSC-derived exosomes for the treatment of DM by discussing the studies that have used MSC-derived exosomes to treat DM, which have shown therapeutic effects in both type 1 and type 2 DM.
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Affiliation(s)
| | | | | | - Jeong-Kee Yoon
- Department of Systems Biotechnology, Chung-Ang University, Anseong-si 17546, Gyeonggi-do, Republic of Korea (G.D.C.)
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Yang Q, Wang Z, Su J, Yang G, Liu H, Liu B, Cheng J, Dong B, Jafari H, Wang H, Zhang Y, Lei C, Dang R, Yu J. Comprehensive omics analysis of the fecal microbiome and serum metabolome in Dezhou donkey foals at the end of weaning and after weaning. Anim Sci J 2025; 96:e70021. [PMID: 39815660 DOI: 10.1111/asj.70021] [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: 10/10/2023] [Revised: 04/25/2024] [Accepted: 05/14/2024] [Indexed: 01/18/2025]
Abstract
Weaning is essential for foal growth and development. We determined the intestinal flora structure of donkey foals at the end of weaning (PreW_4d) and three stages after weaning (PostW_4d, PostW_8d, and PostW_15d) to explore the effects of weaning on intestinal development of donkey foals. The results showed that the main microbial flora in the gut of the donkey foal were Firmicutes and Bacteroides, and the proportion of Firmicutes gradually increased with weaning, which was an important reflection of the donkey foal's adaptability to the transition from lactose liquid feed to plant fiber solid feed. We also identified important microorganisms that maintain intestinal stability and boost immune, such as oscillospiraceae, Firmicutes, and lachnospiraceae. The metabolome showed that serum metabolites were mainly enriched in arachidonic acid metabolism and the tricarboxylic acid cycle (TCA cycle), which can influence energy metabolism, growth, and immunity in weaned donkey foals. We also found that the metabolite resveratrol was positively correlated with g_NK4A214_group and lactobacillus, which may have important implications for the prevention of diseases such as colon-inflammation in donkey foals. In summary, we provide a theoretical basis for studying the mechanism of intestinal microbiome and serum metabolite changes in weaning and postweaning donkey foals.
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Affiliation(s)
- Qiwen Yang
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Xianyang, Shaanxi Province, China
- National Engineering Research Center for Gelatin-based Traditional Chinese Medicine, Dong-E-E-Jiao Co. Ltd, Dong-E Country, Shandong Province, China
| | - Zhaofei Wang
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Xianyang, Shaanxi Province, China
| | - Jiangtian Su
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Xianyang, Shaanxi Province, China
| | - Ge Yang
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Xianyang, Shaanxi Province, China
| | - Haibing Liu
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Xianyang, Shaanxi Province, China
| | - Bing Liu
- National Engineering Research Center for Gelatin-based Traditional Chinese Medicine, Dong-E-E-Jiao Co. Ltd, Dong-E Country, Shandong Province, China
| | - Jie Cheng
- National Engineering Research Center for Gelatin-based Traditional Chinese Medicine, Dong-E-E-Jiao Co. Ltd, Dong-E Country, Shandong Province, China
| | - Boying Dong
- National Engineering Research Center for Gelatin-based Traditional Chinese Medicine, Dong-E-E-Jiao Co. Ltd, Dong-E Country, Shandong Province, China
| | - Halima Jafari
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Xianyang, Shaanxi Province, China
| | - Hua Wang
- National Engineering Research Center for Gelatin-based Traditional Chinese Medicine, Dong-E-E-Jiao Co. Ltd, Dong-E Country, Shandong Province, China
| | - Youxin Zhang
- National Engineering Research Center for Gelatin-based Traditional Chinese Medicine, Dong-E-E-Jiao Co. Ltd, Dong-E Country, Shandong Province, China
| | - Chuzhao Lei
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Xianyang, Shaanxi Province, China
| | - Ruihua Dang
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Xianyang, Shaanxi Province, China
| | - Jie Yu
- National Engineering Research Center for Gelatin-based Traditional Chinese Medicine, Dong-E-E-Jiao Co. Ltd, Dong-E Country, Shandong Province, China
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Krishnan G, Bagath M, Devaraj C, Soren NM. The signalling association of glucagon-like peptide-1 and its receptors in the gastrointestinal tract and GPR40 and insulin receptor in the pancreas of sheep. Gen Comp Endocrinol 2024; 358:114602. [PMID: 39226991 DOI: 10.1016/j.ygcen.2024.114602] [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: 04/08/2024] [Revised: 08/19/2024] [Accepted: 08/31/2024] [Indexed: 09/05/2024]
Abstract
The present study was aimed at gaining insight into the signalling relationship between glucagon-like peptide-1 (GLP-1) and its receptor (GLP-1R) in the regulation of glucose metabolism. Further, to assess the role of G-protein-coupled receptor 40 (GPR40) and insulin receptor (INSR) in the pancreas of sheep that were supplemented with calcium salts of long-chain fatty acids (CSFAs). An experiment was carried out over a period of 60 days with eighteen sheep, and they were fed with a standard basal diet. The sheep were divided into three groups: CSFA0 (without CSFAs), while CSFA3 and CSFA5 were supplemented with 3 % and 5 % of CSFAs, respectively. Plasma concentrations of GLP-1, insulin, glucagon, and glucose were assessed every two weeks. At the end of the experiment, sheep were slaughtered, and samples of gastrointestinal tract (GIT) epithelial tissues and pancreas were collected to assess the relative expression of mRNA of GPR40, GLP-1R, and INSR. Postprandial GLP-1 and insulin were increased by 3.7-4.1 and 1.45-1.5 times, respectively, in the CSFAs-supplemented groups compared to CSFA0. Post-feeding, glucagon and glucose levels decreased in CSFA3 and CSFA5 compared to CSFA0. The results indicated that the supplementation of LCFAs increased the expression of GLP-1R in the GIT and pancreas, as well as the mRNA of GPR40 and INSR in the pancreas. Chemosensing of LCFAs by GPR40 in the pancreas triggers signalling transduction, and enhanced GLP-1 and GLP-1R resulted in moderately increased insulin secretion and reduced glucagon levels. These combined effects, along with the glucose-lowering effect of GLP-1, effectively lowered glucose levels in normoglycemic sheep.
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Affiliation(s)
- G Krishnan
- Animal Physiology Division, ICAR-National Institute of Animal Nutrition and Physiology, Bangalore 560030, India.
| | - M Bagath
- Animal Nutrition Division, ICAR-National Institute of Animal Nutrition and Physiology, Bangalore 560030, India
| | - C Devaraj
- Bioenergetics and Environmental Sciences Division, ICAR-National Institute of Animal Nutrition and Physiology, Bangalore 560030, India
| | - N M Soren
- Animal Nutrition Division, ICAR-National Institute of Animal Nutrition and Physiology, Bangalore 560030, India
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Bui TPN. The Human Microbiome as a Therapeutic Target for Metabolic Diseases. Nutrients 2024; 16:2322. [PMID: 39064765 PMCID: PMC11280041 DOI: 10.3390/nu16142322] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Revised: 07/17/2024] [Accepted: 07/18/2024] [Indexed: 07/28/2024] Open
Abstract
The human microbiome functions as a separate organ in a symbiotic relationship with the host. Disruption of this host-microbe symbiosis can lead to serious health problems. Modifications to the composition and function of the microbiome have been linked to changes in host metabolic outcomes. Industrial lifestyles with high consumption of processed foods, alcoholic beverages and antibiotic use have significantly altered the gut microbiome in unfavorable ways. Therefore, understanding the causal relationship between the human microbiome and host metabolism will provide important insights into how we can better intervene in metabolic health. In this review, I will discuss the potential use of the human microbiome as a therapeutic target to improve host metabolism.
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Affiliation(s)
- Thi Phuong Nam Bui
- Department of Experimental Vascular Medicine, Amsterdam University Medical Center, 1105 AZ Amsterdam, The Netherlands
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8
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Abiola JO, Oluyemi AA, Idowu OT, Oyinloye OM, Ubah CS, Owolabi OV, Somade OT, Onikanni SA, Ajiboye BO, Osunsanmi FO, Nash O, Omotuyi OI, Oyinloye BE. Potential Role of Phytochemicals as Glucagon-like Peptide 1 Receptor (GLP-1R) Agonists in the Treatment of Diabetes Mellitus. Pharmaceuticals (Basel) 2024; 17:736. [PMID: 38931402 PMCID: PMC11206448 DOI: 10.3390/ph17060736] [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: 04/07/2024] [Revised: 05/28/2024] [Accepted: 06/03/2024] [Indexed: 06/28/2024] Open
Abstract
Currently, there is no known cure for diabetes. Different pharmaceutical therapies have been approved for the management of type 2 diabetes mellitus (T2DM), some are in clinical trials and they have been classified according to their route or mechanism of action. Insulin types, sulfonylureas, biguanides, alpha-glucosidase inhibitors, thiazolidinediones, meglitinides, sodium-glucose cotransporter type 2 inhibitors, and incretin-dependent therapies (glucagon-like peptide-1 receptor agonists: GLP-1R, and dipeptidyl peptidase 4 inhibitors: DPP-4). Although some of the currently available drugs are effective in the management of T2DM, the side effects resulting from prolonged use of these drugs remain a serious challenge. GLP-1R agonists are currently the preferred medications to include when oral metformin alone is insufficient to manage T2DM. Medicinal plants now play prominent roles in the management of various diseases globally because they are readily available and affordable as well as having limited and transient side effects. Recently, studies have reported the ability of phytochemicals to activate glucagon-like peptide-1 receptor (GLP-1R), acting as an agonist just like the GLP-1R agonist with beneficial effects in the management of T2DM. Consequently, we propose that careful exploration of phytochemicals for the development of novel therapeutic candidates as GLP-1R agonists will be a welcome breakthrough in the management of T2DM and the co-morbidities associated with T2DM.
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Affiliation(s)
- Julianah Ore Abiola
- Phytomedicine, Biochemical Toxicology and Biotechnology Research Laboratories, Department of Biochemistry, College of Sciences, Afe Babalola University, Ado-Ekiti 360001, Nigeria; (J.O.A.)
- Center for Genomics Research and Innovation, National Biotechnology Development Agency, Abuja 09004, Nigeria
- Institute of Drug Research and Development, S.E. Bogoro Center, Afe Babalola University, Ado-Ekiti 360001, Nigeria
| | - Ayoola Abidemi Oluyemi
- Institute of Drug Research and Development, S.E. Bogoro Center, Afe Babalola University, Ado-Ekiti 360001, Nigeria
| | - Olajumoke Tolulope Idowu
- Industrial Chemistry Unit, Department of Chemical Sciences, College of Sciences, Afe Babalola University, Ado-Ekiti 360001, Nigeria
| | - Oluwatoyin Mary Oyinloye
- Department of Mathematics, Science and Technology Education, Faculty of Education, University of Zululand, Kwadlangezwa 3886, South Africa
| | - Chukwudi Sunday Ubah
- Department of Epidemiology and Biostatistics, College of Public Health, Temple University, Philadelphia, PA 19121, USA
| | - Olutunmise Victoria Owolabi
- Medical Biochemistry Unit, College of Medicine and Health Sciences, Afe Babalola University, Ado-Ekiti 360001, Nigeria
| | - Oluwatobi T. Somade
- Phytomedicine, Biochemical Toxicology and Biotechnology Research Laboratories, Department of Biochemistry, College of Sciences, Afe Babalola University, Ado-Ekiti 360001, Nigeria; (J.O.A.)
- Department of Biochemistry, College of Biosciences, Federal University of Agriculture, Abeokuta 111101, Nigeria
| | - Sunday Amos Onikanni
- Phytomedicine, Biochemical Toxicology and Biotechnology Research Laboratories, Department of Biochemistry, College of Sciences, Afe Babalola University, Ado-Ekiti 360001, Nigeria; (J.O.A.)
- College of Medicine, Graduate Institute of Biomedical Sciences, China Medical University, Taichung 40402, Taiwan
| | - Basiru Olaitan Ajiboye
- Institute of Drug Research and Development, S.E. Bogoro Center, Afe Babalola University, Ado-Ekiti 360001, Nigeria
- Phytomedicine and Molecular Toxicology Research Laboratory, Department of Biochemistry, Federal University Oye-Ekiti, Oye-Ekiti 371104, Nigeria
| | - Foluso Oluwagbemiga Osunsanmi
- Biotechnology and Structural Biology (BSB) Group, Department of Biochemistry and Microbiology, University of Zululand, Kwadlangezwa 3886, South Africa
| | - Oyekanmi Nash
- Center for Genomics Research and Innovation, National Biotechnology Development Agency, Abuja 09004, Nigeria
| | - Olaposi Idowu Omotuyi
- Institute of Drug Research and Development, S.E. Bogoro Center, Afe Babalola University, Ado-Ekiti 360001, Nigeria
- Department of Pharmacology and Toxicology, College of Pharmacy, Afe Babalola University, Ado-Ekiti 360001, Nigeria
| | - Babatunji Emmanuel Oyinloye
- Phytomedicine, Biochemical Toxicology and Biotechnology Research Laboratories, Department of Biochemistry, College of Sciences, Afe Babalola University, Ado-Ekiti 360001, Nigeria; (J.O.A.)
- Institute of Drug Research and Development, S.E. Bogoro Center, Afe Babalola University, Ado-Ekiti 360001, Nigeria
- Biotechnology and Structural Biology (BSB) Group, Department of Biochemistry and Microbiology, University of Zululand, Kwadlangezwa 3886, South Africa
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Heckmann ND, Palmer R, Mayfield CK, Gucev G, Lieberman JR, Hong K. Glucagon-Like Peptide Receptor-1 Agonists Used for Medically-Supervised Weight Loss in Patients With Hip and Knee Osteoarthritis: Critical Considerations for the Arthroplasty Surgeon. Arthroplast Today 2024; 27:101327. [PMID: 39071832 PMCID: PMC11282421 DOI: 10.1016/j.artd.2024.101327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 12/08/2023] [Accepted: 01/27/2024] [Indexed: 07/30/2024] Open
Abstract
Patients with morbid obesity and concomitant hip or knee osteoarthritis represent a challenging patient demographic to treat as these patients often present earlier in life, have more severe symptoms, and have worse surgical outcomes following total hip and total knee arthroplasty. Previously, bariatric and metabolic surgeries represented one of the few weight loss interventions that morbidly obese patients could undergo prior to total joint arthroplasty. However, data regarding the reduction in complications with preoperative bariatric surgery remain mixed. Glucagon-like peptide receptor-1 (GLP-1) agonists have emerged as an effective treatment option for obesity in patients with and without diabetes mellitus. Furthermore, recent data suggest these medications may serve as potential anti-inflammatory and disease-modifying agents for numerous chronic conditions, including osteoarthritis. This review will discuss the GLP-1 agonists and GLP-1/glucose-dependent insulinotropic polypeptide dual agonists currently available, along with GLP-1/glucose-dependent insulinotropic polypeptide/glucagon triple agonists presently being developed to address the obesity epidemic. Furthermore, this review will address the potential problem of GLP-1-related delayed gastric emptying and its impact on the timing of elective total joint arthroplasty. The review aims to provide arthroplasty surgeons with a primer for implementing this class of medication in their current and future practice, including perioperative instructions and perioperative safety considerations when treating patients taking these medications.
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Affiliation(s)
- Nathanael D. Heckmann
- Department of Orthopaedic Surgery, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA
| | - Ryan Palmer
- Department of Orthopaedic Surgery, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA
| | - Cory K. Mayfield
- Department of Orthopaedic Surgery, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA
| | - Gligor Gucev
- Department of Anesthesiology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA
| | - Jay R. Lieberman
- Department of Orthopaedic Surgery, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA
| | - Kurt Hong
- Center for Clinical Nutrition, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA
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Xia X, Lin Q, Zhou Z, Chen Y. An imbalanced GLP-1R/GIPR co-agonist peptide with a site-specific N-terminal PEGylation to maximize metabolic benefits. iScience 2024; 27:109377. [PMID: 38510128 PMCID: PMC10951637 DOI: 10.1016/j.isci.2024.109377] [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: 09/27/2023] [Revised: 01/18/2024] [Accepted: 02/27/2024] [Indexed: 03/22/2024] Open
Abstract
Glycemic and body weight control gained from GLP-1R agonists remains an unmet need for diabetes and obesity treatment, leading to the development of GLP-1R/GIPR co-agonists. An imbalance in GLP-1R/GIPR agonism may extensively maximize the glucose- and weight-lowering effects. Hence, we prepared a potent and imbalanced GLP-1R/GIPR co-agonist, and refined its action time through a site-specific N-terminal PEGylation strategy. The pharmacological efficacy of these resulting long-acting co-agonists was interrogated both in vitro and in vivo. The results showed that peptide 1 possessed potent and imbalanced receptor-stimulating potency favoring GIP activity, but its hypoglycemic action was disrupted probably resulting from its short half-life. After PEGylation to improve the pharmacokinetics, the pharmacological effects were amplified compared to native peptide 1. Among the resulting derivatives, D-5K exhibited significant glycemic, HbA1c, body-weight, and food-intake control, outperforming GLP-1R mono-agonists. Based on its excellent pharmacological profiles, D-5K may hold the great therapeutic potential for diabetes and obesity treatment.
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Affiliation(s)
- Xuan Xia
- Department of Oncology, NHC Key Laboratory of Cancer Proteomics, State Local Joint Engineering Laboratory for Anticancer Drugs, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
- Department of Oncology, NHC Key Laboratory of Cancer Proteomics, State Local Joint Engineering Laboratory for Anticancer Drugs, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Qianmeng Lin
- Department of Oncology, NHC Key Laboratory of Cancer Proteomics, State Local Joint Engineering Laboratory for Anticancer Drugs, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
- Department of Oncology, NHC Key Laboratory of Cancer Proteomics, State Local Joint Engineering Laboratory for Anticancer Drugs, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Zhan Zhou
- Research Center for Molecular Metabolomics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Yongheng Chen
- Department of Oncology, NHC Key Laboratory of Cancer Proteomics, State Local Joint Engineering Laboratory for Anticancer Drugs, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
- Department of Oncology, NHC Key Laboratory of Cancer Proteomics, State Local Joint Engineering Laboratory for Anticancer Drugs, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
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Cui J, Wang M, Zhang W, Sun J, Zhang Y, Zhao L, Hong Z, Li D, Huang YX, Zhang N, Chen Y. Enhancing insulin sensitivity in type 2 diabetes mellitus using apelin-loaded small extracellular vesicles from Wharton's jelly-derived mesenchymal stem cells: a novel therapeutic approach. Diabetol Metab Syndr 2024; 16:84. [PMID: 38622732 PMCID: PMC11020616 DOI: 10.1186/s13098-024-01332-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Accepted: 04/09/2024] [Indexed: 04/17/2024] Open
Abstract
BACKGROUND Type 2 diabetes mellitus (T2DM), characterized by β-cell dysfunction and insulin resistance (IR), presents considerable treatment challenges. Apelin is an adipocyte-derived factor that shows promise in improving IR; however, it is limited by poor targeting and a short half-life. In the present study, engineered small extracellular vesicles (sEVs) derived from Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs) loaded with apelin were used to address the limitations of the therapeutic application of apelin. METHODS WJ-MSCs were transduced to obtain engineered sEVs loaded with overexpressed apelin (apelin-MSC-sEVs) and the control sEVs (MSC-sEVs). T2DM mice were injected with apelin-MSC-sEVs and MSC-sEVs, and blood glucose monitoring, glucose and insulin tolerance tests, confocal microscopy, and immunocytochemical analysis were performed. IR models of 3T3-L1 adipocytes were employed to detect GLUT4 expression in each group using western blotting; the affected pathways were determined by measuring the changes in Akt and AMPK signaling and phosphorylation. RESULTS Upon successful engineering, WJ-MSCs demonstrated significant overexpression of apelin. The genetic modification did not adversely impact the characteristics of sEVs, ranging from surface protein markers, morphology, to particle size, but generated apelin-overexpressed sEVs. Apelin-MSC-sEVs treatment resulted in notable enhancement of Akt and AMPK pathway activities within 3T3-L1 adipocytes and adipose tissues of T2DM mice. Furthermore, the apelin-loaded sEVs significantly reduced plasma glucose levels, increased pancreatic β-cell proliferation, improved insulin and glucose tolerance, and modulated pro-inflammatory cytokine profiles, compared to mice treated with the control sEVs. CONCLUSION Our study developed novel genetically engineered apelin-loaded sEVs derived from WJ-MSCs, and demonstrated their potent role in augmenting insulin sensitivity and regulating inflammatory responses, highlighting their therapeutic promise in T2DM management. The findings open new avenues for the development of clinically viable treatments for T2DM in humans using the apelin-loaded sEVs.
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Affiliation(s)
- Jing Cui
- The Fifth School of Clinical Medicine, Navy Clinical College, Anhui Medical University, Hefei, Anhui, China
- Department of Cardiology, The Sixth Medical Center of Chinese People's Liberation Army General Hospital, Beijing, China·, China
| | - Mingkun Wang
- The Fifth School of Clinical Medicine, Navy Clinical College, Anhui Medical University, Hefei, Anhui, China
| | - Wenhong Zhang
- The Fifth School of Clinical Medicine, Navy Clinical College, Anhui Medical University, Hefei, Anhui, China
- Department of Cardiology, The Sixth Medical Center of Chinese People's Liberation Army General Hospital, Beijing, China·, China
| | - Jiachen Sun
- Department of Dermatology, Peking University Third Hospital, Beijing, China
| | - Yan Zhang
- Department of Cardiology, The Sixth Medical Center of Chinese People's Liberation Army General Hospital, Beijing, China·, China
| | - Li Zhao
- Department of Cardiology, The Sixth Medical Center of Chinese People's Liberation Army General Hospital, Beijing, China·, China
| | - Zhibo Hong
- Department of Cardiology, The Sixth Medical Center of Chinese People's Liberation Army General Hospital, Beijing, China·, China
| | - Dongtao Li
- Department of Cardiology, The Sixth Medical Center of Chinese People's Liberation Army General Hospital, Beijing, China·, China
| | - Yi Xiong Huang
- Department of Cardiology, The Sixth Medical Center of Chinese People's Liberation Army General Hospital, Beijing, China·, China
| | - Ningkun Zhang
- Department of Cardiology, The Sixth Medical Center of Chinese People's Liberation Army General Hospital, Beijing, China·, China.
| | - Yu Chen
- The Fifth School of Clinical Medicine, Navy Clinical College, Anhui Medical University, Hefei, Anhui, China.
- Department of Cardiology, The Sixth Medical Center of Chinese People's Liberation Army General Hospital, Beijing, China·, China.
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12
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Salvadori M, Rosso G. Update on the gut microbiome in health and diseases. World J Methodol 2024; 14:89196. [PMID: 38577200 PMCID: PMC10989414 DOI: 10.5662/wjm.v14.i1.89196] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Revised: 12/18/2023] [Accepted: 01/27/2024] [Indexed: 03/07/2024] Open
Abstract
The Human Microbiome Project, Earth Microbiome Project, and next-generation sequencing have advanced novel genome association, host genetic linkages, and pathogen identification. The microbiome is the sum of the microbes, their genetic information, and their ecological niche. This study will describe how millions of bacteria in the gut affect the human body in health and disease. The gut microbiome changes in relation with age, with an increase in Bacteroidetes and Firmicutes. Host and environmental factors affecting the gut microbiome are diet, drugs, age, smoking, exercise, and host genetics. In addition, changes in the gut microbiome may affect the local gut immune system and systemic immune system. In this study, we discuss how the microbiome may affect the metabolism of healthy subjects or may affect the pathogenesis of metabolism-generating metabolic diseases. Due to the high number of publications on the argument, from a methodologically point of view, we decided to select the best papers published in referred journals in the last 3 years. Then we selected the previously published papers. The major goals of our study were to elucidate which microbiome and by which pathways are related to healthy and disease conditions.
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Affiliation(s)
- Maurizio Salvadori
- Department of Renal Transplantation, Careggi University Hospital, Florence 50139, Tuscany, Italy
| | - Giuseppina Rosso
- Division of Nephrology, San Giovanni di Dio Hospital, Florence 50143, Toscana, Italy
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13
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Paradiž Leitgeb E, Kerčmar J, Križančić Bombek L, Pohorec V, Skelin Klemen M, Slak Rupnik M, Gosak M, Dolenšek J, Stožer A. Exendin-4 affects calcium signalling predominantly during activation and activity of beta cell networks in acute mouse pancreas tissue slices. Front Endocrinol (Lausanne) 2024; 14:1315520. [PMID: 38292770 PMCID: PMC10826511 DOI: 10.3389/fendo.2023.1315520] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Accepted: 12/22/2023] [Indexed: 02/01/2024] Open
Abstract
Tight control of beta cell stimulus-secretion coupling is crucial for maintaining homeostasis of energy-rich nutrients. While glucose serves as a primary regulator of this process, incretins augment beta cell function, partly by enhancing cytosolic [Ca2+] dynamics. However, the details of how precisely they affect beta cell recruitment during activation, their active time, and functional connectivity during plateau activity, and how they influence beta cell deactivation remain to be described. Performing functional multicellular Ca2+ imaging in acute mouse pancreas tissue slices enabled us to systematically assess the effects of the GLP-1 receptor agonist exendin-4 (Ex-4) simultaneously in many coupled beta cells with high resolution. In otherwise substimulatory glucose, Ex-4 was able to recruit approximately a quarter of beta cells into an active state. Costimulation with Ex-4 and stimulatory glucose shortened the activation delays and accelerated beta cell activation dynamics. More specifically, active time increased faster, and the time required to reach half-maximal activation was effectively halved in the presence of Ex-4. Moreover, the active time and regularity of [Ca2+]IC oscillations increased, especially during the first part of beta cell response. In contrast, subsequent addition of Ex-4 to already active cells did not significantly enhance beta cell activity. Network analyses further confirmed increased connectivity during activation and activity in the presence of Ex-4, with hub cell roles remaining rather stable in both control experiments and experiments with Ex-4. Interestingly, Ex-4 demonstrated a biphasic effect on deactivation, slightly prolonging beta cell activity at physiological concentrations and shortening deactivation delays at supraphysiological concentrations. In sum, costimulation by Ex-4 and glucose increases [Ca2+]IC during beta cell activation and activity, indicating that the effect of incretins may, to an important extent, be explained by enhanced [Ca2+]IC signals. During deactivation, previous incretin stimulation does not critically prolong cellular activity, which corroborates their low risk of hypoglycemia.
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Affiliation(s)
- Eva Paradiž Leitgeb
- Institute of Physiology, Faculty of Medicine, University of Maribor, Maribor, Slovenia
| | - Jasmina Kerčmar
- Institute of Physiology, Faculty of Medicine, University of Maribor, Maribor, Slovenia
| | | | - Vilijem Pohorec
- Institute of Physiology, Faculty of Medicine, University of Maribor, Maribor, Slovenia
| | - Maša Skelin Klemen
- Institute of Physiology, Faculty of Medicine, University of Maribor, Maribor, Slovenia
| | - Marjan Slak Rupnik
- Institute of Physiology, Faculty of Medicine, University of Maribor, Maribor, Slovenia
- Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
- Alma Mater Europaea-European Center Maribor, Maribor, Slovenia
| | - Marko Gosak
- Institute of Physiology, Faculty of Medicine, University of Maribor, Maribor, Slovenia
- Alma Mater Europaea-European Center Maribor, Maribor, Slovenia
- Faculty of Natural Sciences and Mathematics, University of Maribor, Maribor, Slovenia
| | - Jurij Dolenšek
- Institute of Physiology, Faculty of Medicine, University of Maribor, Maribor, Slovenia
- Faculty of Natural Sciences and Mathematics, University of Maribor, Maribor, Slovenia
| | - Andraž Stožer
- Institute of Physiology, Faculty of Medicine, University of Maribor, Maribor, Slovenia
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14
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Inabu Y, Horike H, Yamano H, Taguchi Y, Okada S, Etoh T, Shiotsuka Y, Fujino R, Takahashi H. Effect of feeding sodium butyrate to beef female cows during pre- and post-partum period on concentrations of glucagon-like peptides in plasma and colostrum. Anim Sci J 2024; 95:e13961. [PMID: 38769804 DOI: 10.1111/asj.13961] [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: 12/18/2023] [Revised: 04/13/2024] [Accepted: 04/24/2024] [Indexed: 05/22/2024]
Abstract
The objective of this study was to evaluate the effect of feeding beef cows with sodium butyrate during the late pregnancy and early post-partum periods on concentrations of glucagon-like peptide (GLP)-1 and 2 in plasma, colostrum, and transition milk. Twelve Japanese Black female cows were fed concentrate feed without (CON; n = 6) or with (BUTY; n = 6) sodium butyrate supplementation at 1.1% of dietary dry matter from -60 d relative to the expected parturition date to 4 d after parturition. Plasma total cholesterol concentration was higher for the BUTY than for the CON (P = 0.04). In addition, plasma GLP-1 concentration was higher for the BUTY than for the CON at 3 d after calving (P < 0.05). This study showed for the first time that GLP-1 is present in the colostrum of Japanese Black cows at higher concentrations as compared to in plasma (P < 0.01). On the other hand, no treatment effect was observed for concentrations of metabolite and hormone in colostrum and transition milk. In summary, feeding beef cows with sodium butyrate during the late gestation and early post-partum period likely increases plasma GLP-1 concentrations post-partum without affecting the components of colostrum and transition milk.
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Affiliation(s)
- Yudai Inabu
- Kuju Agricultural Research Center, Graduate School of Agriculture, Kyushu University, Oita, Japan
- Graduate School of Integrated Sciences for Life, Hiroshima University, Higashi-Hiroshima, Japan
| | - Hiroshi Horike
- Kuju Agricultural Research Center, Graduate School of Agriculture, Kyushu University, Oita, Japan
| | - Haruki Yamano
- Kuju Agricultural Research Center, Graduate School of Agriculture, Kyushu University, Oita, Japan
| | - Yutaka Taguchi
- Kuju Agricultural Research Center, Graduate School of Agriculture, Kyushu University, Oita, Japan
| | - Shunnosuke Okada
- Kuju Agricultural Research Center, Graduate School of Agriculture, Kyushu University, Oita, Japan
| | - Tetsuji Etoh
- Kuju Agricultural Research Center, Graduate School of Agriculture, Kyushu University, Oita, Japan
| | - Yuji Shiotsuka
- Kuju Agricultural Research Center, Graduate School of Agriculture, Kyushu University, Oita, Japan
| | - Ryoichi Fujino
- Kuju Agricultural Research Center, Graduate School of Agriculture, Kyushu University, Oita, Japan
| | - Hideyuki Takahashi
- Kuju Agricultural Research Center, Graduate School of Agriculture, Kyushu University, Oita, Japan
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15
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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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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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17
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Petakh P, Kamyshna I, Kamyshnyi A. Unveiling the potential pleiotropic effects of metformin in treating COVID-19: a comprehensive review. Front Mol Biosci 2023; 10:1260633. [PMID: 37881440 PMCID: PMC10595158 DOI: 10.3389/fmolb.2023.1260633] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Accepted: 09/28/2023] [Indexed: 10/27/2023] Open
Abstract
This review article explores the potential of metformin, a medication commonly used for type 2 diabetes, as an antiviral and anti-inflammatory agent in the context of coronavirus disease 2019 (COVID-19). Metformin has demonstrated inhibitory effects on the growth of SARS-CoV-2 in cell culture models and has shown promising results in reducing viral load and achieving undetectable viral levels in clinical trials. Additionally, metformin exhibits anti-inflammatory properties by reducing the production of pro-inflammatory cytokines and modulating immune cell function, which may help prevent cytokine storms associated with severe COVID-19. The drug's ability to regulate the balance between pro-inflammatory Th17 cells and anti-inflammatory Treg cells suggests its potential in mitigating inflammation and restoring T cell functionality. Furthermore, metformin's modulation of the gut microbiota, particularly changes in bacterial taxa and the production of short-chain fatty acids, may contribute to its therapeutic effects. The interplay between metformin, bile acids, the gut microbiome, glucagon-like peptide-1 secretion, and glycemic control has implications for the management of diabetes and potential interventions in COVID-19. By refreshing the current evidence, this review highlights the potential of metformin as a therapeutic option in the management of COVID-19, while also exploring its effects on the gut microbiome and immunometabolism.
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Affiliation(s)
- Pavlo Petakh
- Department of Biochemistry and Pharmacology, Uzhhorod National University, Uzhhorod, Ukraine
- Department of Microbiology, Virology, and Immunology, I. Horbachevsky Ternopil National Medical University, Ternopil, Ukraine
| | - Iryna Kamyshna
- Department of Medical Rehabilitation, I. Horbachevsky Ternopil National Medical University, Ternopil, Ukraine
| | - Aleksandr Kamyshnyi
- Department of Microbiology, Virology, and Immunology, I. Horbachevsky Ternopil National Medical University, Ternopil, Ukraine
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18
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Emfinger CH, Clark LE, Yandell B, Schueler KL, Simonett SP, Stapleton DS, Mitok KA, Merrins MJ, Keller MP, Attie AD. Novel regulators of islet function identified from genetic variation in mouse islet Ca 2+ oscillations. eLife 2023; 12:RP88189. [PMID: 37787501 PMCID: PMC10547476 DOI: 10.7554/elife.88189] [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] [Indexed: 10/04/2023] Open
Abstract
Insufficient insulin secretion to meet metabolic demand results in diabetes. The intracellular flux of Ca2+ into β-cells triggers insulin release. Since genetics strongly influences variation in islet secretory responses, we surveyed islet Ca2+ dynamics in eight genetically diverse mouse strains. We found high strain variation in response to four conditions: (1) 8 mM glucose; (2) 8 mM glucose plus amino acids; (3) 8 mM glucose, amino acids, plus 10 nM glucose-dependent insulinotropic polypeptide (GIP); and (4) 2 mM glucose. These stimuli interrogate β-cell function, α- to β-cell signaling, and incretin responses. We then correlated components of the Ca2+ waveforms to islet protein abundances in the same strains used for the Ca2+ measurements. To focus on proteins relevant to human islet function, we identified human orthologues of correlated mouse proteins that are proximal to glycemic-associated single-nucleotide polymorphisms in human genome-wide association studies. Several orthologues have previously been shown to regulate insulin secretion (e.g. ABCC8, PCSK1, and GCK), supporting our mouse-to-human integration as a discovery platform. By integrating these data, we nominate novel regulators of islet Ca2+ oscillations and insulin secretion with potential relevance for human islet function. We also provide a resource for identifying appropriate mouse strains in which to study these regulators.
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Affiliation(s)
| | - Lauren E Clark
- Department of Biochemistry, University of Wisconsin-MadisonMadisonUnited States
| | - Brian Yandell
- Department of Statistics, University of Wisconsin-MadisonMadisonUnited States
| | - Kathryn L Schueler
- Department of Biochemistry, University of Wisconsin-MadisonMadisonUnited States
| | - Shane P Simonett
- Department of Biochemistry, University of Wisconsin-MadisonMadisonUnited States
| | - Donnie S Stapleton
- Department of Biochemistry, University of Wisconsin-MadisonMadisonUnited States
| | - Kelly A Mitok
- Department of Biochemistry, University of Wisconsin-MadisonMadisonUnited States
| | - Matthew J Merrins
- Department of Medicine, Division of Endocrinology, University of Wisconsin-MadisonMadisonUnited States
- William S. Middleton Memorial Veterans HospitalMadisonUnited States
| | - Mark P Keller
- Department of Biochemistry, University of Wisconsin-MadisonMadisonUnited States
| | - Alan D Attie
- Department of Biochemistry, University of Wisconsin-MadisonMadisonUnited States
- Department of Medicine, Division of Endocrinology, University of Wisconsin-MadisonMadisonUnited States
- Department of Chemistry, University of Wisconsin-MadisonMadisonUnited States
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19
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Rubio-Navarro A, Gómez-Banoy N, Stoll L, Dündar F, Mawla AM, Ma L, Cortada E, Zumbo P, Li A, Reiterer M, Montoya-Oviedo N, Homan EA, Imai N, Gilani A, Liu C, Naji A, Yang B, Chong ACN, Cohen DE, Chen S, Cao J, Pitt GS, Huising MO, Betel D, Lo JC. A beta cell subset with enhanced insulin secretion and glucose metabolism is reduced in type 2 diabetes. Nat Cell Biol 2023; 25:565-578. [PMID: 36928765 PMCID: PMC10449536 DOI: 10.1038/s41556-023-01103-1] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Accepted: 02/02/2023] [Indexed: 03/18/2023]
Abstract
The pancreatic islets are composed of discrete hormone-producing cells that orchestrate systemic glucose homeostasis. Here we identify subsets of beta cells using a single-cell transcriptomic approach. One subset of beta cells marked by high CD63 expression is enriched for the expression of mitochondrial metabolism genes and exhibits higher mitochondrial respiration compared with CD63lo beta cells. Human and murine pseudo-islets derived from CD63hi beta cells demonstrate enhanced glucose-stimulated insulin secretion compared with pseudo-islets from CD63lo beta cells. We show that CD63hi beta cells are diminished in mouse models of and in humans with type 2 diabetes. Finally, transplantation of pseudo-islets generated from CD63hi but not CD63lo beta cells into diabetic mice restores glucose homeostasis. These findings suggest that loss of a specific subset of beta cells may lead to diabetes. Strategies to reconstitute or maintain CD63hi beta cells may represent a potential anti-diabetic therapy.
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Affiliation(s)
- Alfonso Rubio-Navarro
- Weill Center for Metabolic Health, Cardiovascular Research Institute, Division of Cardiology, Department of Medicine, Weill Cornell Medicine, New York, NY, USA
- Excellence Research Unit "Modeling Nature" (MNat), CTS-963-Center of Biomedical Research (CIBM), University of Granada, Granada, Spain
- Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), University Hospitals of Granada-University of Granada, Granada, Spain
| | - Nicolás Gómez-Banoy
- Weill Center for Metabolic Health, Cardiovascular Research Institute, Division of Cardiology, Department of Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Lisa Stoll
- Weill Center for Metabolic Health, Cardiovascular Research Institute, Division of Cardiology, Department of Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Friederike Dündar
- Department of Physiology and Biophysics, Applied Bioinformatics Core, Weill Cornell Medicine, New York, NY, USA
| | - Alex M Mawla
- Department of Neurobiology, Physiology and Behavior, College of Biological Sciences, University of California, Davis, CA, USA
| | - Lunkun Ma
- Weill Center for Metabolic Health, Cardiovascular Research Institute, Division of Cardiology, Department of Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Eric Cortada
- Weill Center for Metabolic Health, Cardiovascular Research Institute, Division of Cardiology, Department of Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Paul Zumbo
- Department of Physiology and Biophysics, Applied Bioinformatics Core, Weill Cornell Medicine, New York, NY, USA
| | - Ang Li
- Weill Center for Metabolic Health, Cardiovascular Research Institute, Division of Cardiology, Department of Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Moritz Reiterer
- Weill Center for Metabolic Health, Cardiovascular Research Institute, Division of Cardiology, Department of Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Nathalia Montoya-Oviedo
- Weill Center for Metabolic Health, Cardiovascular Research Institute, Division of Cardiology, Department of Medicine, Weill Cornell Medicine, New York, NY, USA
- Lipids and Diabetes Laboratory, Department of Physiological Sciences, Faculty of Medicine, National University of Colombia, Bogotá, Colombia
| | - Edwin A Homan
- Weill Center for Metabolic Health, Cardiovascular Research Institute, Division of Cardiology, Department of Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Norihiro Imai
- Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medicine, New York, NY, USA
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Aichi, Japan
| | - Ankit Gilani
- Weill Center for Metabolic Health, Cardiovascular Research Institute, Division of Cardiology, Department of Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Chengyang Liu
- Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
| | - Ali Naji
- Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
| | - Boris Yang
- Weill Center for Metabolic Health, Cardiovascular Research Institute, Division of Cardiology, Department of Medicine, Weill Cornell Medicine, New York, NY, USA
| | | | - David E Cohen
- Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Shuibing Chen
- Department of Surgery, Weill Cornell Medicine, New York, NY, USA
| | - Jingli Cao
- Cardiovascular Research Institute, Weill Cornell Medicine, New York, NY, USA
| | - Geoffrey S Pitt
- Cardiovascular Research Institute, Weill Cornell Medicine, New York, NY, USA
| | - Mark O Huising
- Department of Neurobiology, Physiology and Behavior, College of Biological Sciences, University of California, Davis, CA, USA
- Department of Physiology and Membrane Biology, School of Medicine, University of California Davis, Davis, CA, USA
| | - Doron Betel
- Department of Physiology and Biophysics, Applied Bioinformatics Core, Weill Cornell Medicine, New York, NY, USA
- Institute for Computational Biomedicine, Division of Hematology and Medical Oncology, Applied Bioinformatics Core, Weill Cornell Medicine, New York, NY, USA
| | - James C Lo
- Weill Center for Metabolic Health, Cardiovascular Research Institute, Division of Cardiology, Department of Medicine, Weill Cornell Medicine, New York, NY, USA.
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20
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Ribeiro-Silva JC, Tavares CAM, Girardi ACC. The blood pressure lowering effects of glucagon-like peptide-1 receptor agonists: A mini-review of the potential mechanisms. Curr Opin Pharmacol 2023; 69:102355. [PMID: 36857807 DOI: 10.1016/j.coph.2023.102355] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 01/10/2023] [Accepted: 01/27/2023] [Indexed: 03/03/2023]
Abstract
The incretin hormone glucagon-like peptide 1 (GLP-1) is a key component of the signaling mechanisms promoting glucose homeostasis. Clinical and experimental studies demonstrated that GLP-1 receptor agonists, including GLP-1 itself, have favorable effects on blood pressure and reduce the risk of major cardiovascular events, independently of their effect on glycemic control. GLP-1 receptors are present in the hypothalamus and brainstem, the carotid body, the vasculature, and the kidneys. These organs are involved in blood pressure regulation, have their function altered in hypertension, and are positively benefited by the treatment with GLP-1 receptor agonists. Here, we discuss the potential mechanisms whereby activation of GLP-1R signaling exerts blood pressure-lowering effects beyond glycemic control.
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Affiliation(s)
- Joao Carlos Ribeiro-Silva
- Laboratório de Genética e Cardiologia Molecular, Instituto do Coração (InCor), Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | - Caio A M Tavares
- Unidade de Cardiogeriatria, Instituto do Coração (InCor), Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil; Academic Research Organization (ARO), Hospital Israelita Albert Einstein, São Paulo, São Paulo, Brazil
| | - Adriana C C Girardi
- Laboratório de Genética e Cardiologia Molecular, Instituto do Coração (InCor), Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.
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21
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Ahn CH, Oh TJ, Min SH, Cho YM. Incretin and Pancreatic β-Cell Function in Patients with Type 2 Diabetes. Endocrinol Metab (Seoul) 2023; 38:1-9. [PMID: 36781163 PMCID: PMC10008660 DOI: 10.3803/enm.2023.103] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Accepted: 01/30/2023] [Indexed: 02/15/2023] Open
Abstract
To maintain normal glucose homeostasis after a meal, it is essential to secrete an adequate amount of insulin from pancreatic β-cells. However, if pancreatic β-cells solely depended on the blood glucose level for insulin secretion, a surge in blood glucose levels would be inevitable after the ingestion of a large amount of carbohydrates. To avoid a deluge of glucose in the bloodstream after a large carbohydrate- rich meal, enteroendocrine cells detect the amount of nutrient absorption from the gut lumen and secrete incretin hormones at scale. Since insulin secretion in response to incretin hormones occurs only in a hyperglycemic milieu, pancreatic β-cells can secrete a "Goldilocks" amount of insulin (i.e., not too much and not too little) to keep the blood glucose level in the normal range. In this regard, pancreatic β-cell sensitivity to glucose and incretin hormones is crucial for maintaining normal glucose homeostasis. In this Namgok lecture 2022, we review the effects of current anti-diabetic medications on pancreatic β-cell sensitivity to glucose and incretin hormones.
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Affiliation(s)
- Chang Ho Ahn
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Tae Jung Oh
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Se Hee Min
- Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Young Min Cho
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
- Corresponding author: Young Min Cho. Department of Internal Medicine, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea Tel: +82-2-2072-1965, Fax: +82-2-2072-7246, E-mail:
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22
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Yang X, Bao L, Zhang Y, Long J, Li Y, Wang H, Cui Y, Yan D. Novel weight loss diet attenuates dietary-induced obesity in mice and might correlate with altered gut microbiota and metabolite profiles. Front Nutr 2022; 9:987955. [DOI: 10.3389/fnut.2022.987955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Accepted: 10/27/2022] [Indexed: 11/13/2022] Open
Abstract
Although many dietary patterns have been studied for weight loss, various limitations still exist. Therefore, we designed a novel weight loss diet (NWLD) with carbohydrate, protein, and fat (energy) contents of 45%, 20%, and 35%, respectively. The saturated fatty acids: monounsaturated fatty acids:polyunsaturated fatty acids ratio was 1:2:1, and the insoluble: soluble dietary fiber ratio was 2:1. We aimed to observe the effect of NWLD on weight loss and understand the underlying metabolic mechanisms. Twenty-nine male C57BL/6J mice were selected. Nine mice were fed ordinary feed in a blank control group, and the rest were fed a high-fat diet (HFD) to establish obese mouse models. Twelve weeks later, obesity models were established, and 10 obese mice were switched to NWLD feeding. Six weeks after switching the diet, the serum, intestinal feces, and kidneys of mice were collected. Obesity-related indicators, gut microbial composition, and fecal metabolite profiles of all the mice were determined, and the correlations among these indicators were analyzed. Kidney function indicators were also assessed. The results showed that the NWLD attenuated HFD-induced weight gain, serum triglycerides (TG), and inflammatory factors, optimized the body composition without kidney function impairment. Amino acid metabolism pathways and metabolites might play key roles in this process. The findings of this research imply that NWLD could be an effective nutritional remedy for managing dietary-induced obesity.
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23
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Zaborska KE, Jordan KL, Thorson AS, Dadi PK, Schaub CM, Nakhe AY, Dickerson MT, Lynch JC, Weiss AJ, Dobson JR, Jacobson DA. Liraglutide increases islet Ca 2+ oscillation frequency and insulin secretion by activating hyperpolarization-activated cyclic nucleotide-gated channels. Diabetes Obes Metab 2022; 24:1741-1752. [PMID: 35546791 PMCID: PMC9843726 DOI: 10.1111/dom.14747] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 04/28/2022] [Accepted: 04/29/2022] [Indexed: 01/19/2023]
Abstract
AIM To determine whether hyperpolarization-activated cyclic nucleotide-gated (HCN) channels impact glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) modulation of islet Ca2+ handling and insulin secretion. METHODS The impact of liraglutide (GLP-1 analogue) on islet Ca2+ handling, HCN currents and insulin secretion was monitored with fluorescence microscopy, electrophysiology and enzyme immunoassays, respectively. Furthermore, liraglutide-mediated β-to-δ-cell cross-communication was assessed following selective ablation of either mouse islet δ or β cells. RESULTS Liraglutide increased β-cell Ca2+ oscillation frequency in mouse and human islets under stimulatory glucose conditions. This was dependent in part on liraglutide activation of HCN channels, which also enhanced insulin secretion. Similarly, liraglutide activation of HCN channels also increased β-cell Ca2+ oscillation frequency in islets from rodents exposed to a diabetogenic diet. Interestingly, liraglutide accelerated Ca2+ oscillations in a majority of islet δ cells, which showed synchronized Ca2+ oscillations equivalent to β cells; therefore, we assessed if either cell type was driving this liraglutide-mediated islet Ca2+ response. Although δ-cell loss did not impact liraglutide-mediated increase in β-cell Ca2+ oscillation frequency, β-cell ablation attenuated liraglutide-facilitated acceleration of δ-cell Ca2+ oscillations. CONCLUSION The data presented here show that liraglutide-induced stimulation of islet HCN channels augments Ca2+ oscillation frequency. As insulin secretion oscillates with β-cell Ca2+ , these findings have important implications for pulsatile insulin secretion that is probably enhanced by liraglutide activation of HCN channels and therapeutics that target GLP-1Rs for treating diabetes. Furthermore, these studies suggest that liraglutide as well as GLP-1-based therapies enhance δ-cell Ca2+ oscillation frequency and somatostatin secretion kinetics in a β-cell-dependent manner.
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Affiliation(s)
- Karolina E Zaborska
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee
| | - Kelli L Jordan
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee
| | - Ariel S Thorson
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee
| | - Prasanna K Dadi
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee
| | - Charles M Schaub
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee
| | - Arya Y Nakhe
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee
| | - Matthew T Dickerson
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee
| | - Joshua C Lynch
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee
| | - Adam J Weiss
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee
| | - Jordyn R Dobson
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee
| | - David A Jacobson
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee
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24
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Bourouh C, Courty E, Rolland L, Pasquetti G, Gromada X, Rabhi N, Carney C, Moreno M, Boutry R, Caron E, Benfodda Z, Meffre P, Kerr-Conte J, Pattou F, Froguel P, Bonnefond A, Oger F, Annicotte JS. The transcription factor E2F1 controls the GLP-1 receptor pathway in pancreatic β cells. Cell Rep 2022; 40:111170. [PMID: 35947949 DOI: 10.1016/j.celrep.2022.111170] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 04/11/2022] [Accepted: 07/15/2022] [Indexed: 11/03/2022] Open
Abstract
The glucagon-like peptide 1 (Glp-1) has emerged as a hormone with broad pharmacological potential in type 2 diabetes (T2D) treatment, notably by improving β cell functions. The cell-cycle regulator and transcription factor E2f1 is involved in glucose homeostasis by modulating β cell mass and function. Here, we report that β cell-specific genetic ablation of E2f1 (E2f1β-/-) impairs glucose homeostasis associated with decreased expression of the Glp-1 receptor (Glp1r) in E2f1β-/- pancreatic islets. Pharmacological inhibition of E2F1 transcriptional activity in nondiabetic human islets decreases GLP1R levels and blunts the incretin effect of GLP1R agonist exendin-4 (ex-4) on insulin secretion. Overexpressing E2f1 in pancreatic β cells increases Glp1r expression associated with enhanced insulin secretion mediated by ex-4. Interestingly, ex-4 induces retinoblastoma protein (pRb) phosphorylation and E2f1 transcriptional activity. Our findings reveal critical roles for E2f1 in β cell function and suggest molecular crosstalk between the E2F1/pRb and GLP1R signaling pathways.
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Affiliation(s)
- Cyril Bourouh
- Université de Lille, INSERM, CNRS, CHU Lille, Institut Pasteur de Lille, U1283 - UMR 8199 - EGID, 59000 Lille, France
| | - Emilie Courty
- Université de Lille, INSERM, CNRS, CHU Lille, Institut Pasteur de Lille, U1283 - UMR 8199 - EGID, 59000 Lille, France; Université de Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1167 - RID-AGE - Facteurs de Risque et Déterminants Moléculaires des Maladies Liées au Vieillissement, 59000 Lille, France
| | - Laure Rolland
- Université de Lille, INSERM, CNRS, CHU Lille, Institut Pasteur de Lille, U1283 - UMR 8199 - EGID, 59000 Lille, France; Université de Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1167 - RID-AGE - Facteurs de Risque et Déterminants Moléculaires des Maladies Liées au Vieillissement, 59000 Lille, France
| | - Gianni Pasquetti
- Université de Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1190 - EGID, 59000 Lille, France
| | - Xavier Gromada
- Université de Lille, INSERM, CNRS, CHU Lille, Institut Pasteur de Lille, U1283 - UMR 8199 - EGID, 59000 Lille, France
| | - Nabil Rabhi
- Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118, USA
| | - Charlène Carney
- Université de Lille, INSERM, CNRS, CHU Lille, Institut Pasteur de Lille, U1283 - UMR 8199 - EGID, 59000 Lille, France
| | - Maeva Moreno
- Université de Lille, INSERM, CNRS, CHU Lille, Institut Pasteur de Lille, U1283 - UMR 8199 - EGID, 59000 Lille, France
| | - Raphaël Boutry
- Université de Lille, INSERM, CNRS, CHU Lille, Institut Pasteur de Lille, U1283 - UMR 8199 - EGID, 59000 Lille, France
| | - Emilie Caron
- Université de Lille, INSERM, CHU Lille, U1172-LilNCog - Lille Neuroscience & Cognition - EGID - DISTALZ, 59000 Lille, France
| | - Zohra Benfodda
- Université de Nîmes, UPR CHROME, 30021 Nîmes Cedex 1, France
| | - Patrick Meffre
- Université de Nîmes, UPR CHROME, 30021 Nîmes Cedex 1, France
| | - Julie Kerr-Conte
- Université de Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1190 - EGID, 59000 Lille, France
| | - François Pattou
- Université de Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1190 - EGID, 59000 Lille, France
| | - Philippe Froguel
- Université de Lille, INSERM, CNRS, CHU Lille, Institut Pasteur de Lille, U1283 - UMR 8199 - EGID, 59000 Lille, France; Department of Metabolism, Imperial College London, Hammersmith Hospital, London W12 0NN, UK
| | - Amélie Bonnefond
- Université de Lille, INSERM, CNRS, CHU Lille, Institut Pasteur de Lille, U1283 - UMR 8199 - EGID, 59000 Lille, France; Department of Metabolism, Imperial College London, Hammersmith Hospital, London W12 0NN, UK
| | - Frédérik Oger
- Université de Lille, INSERM, CNRS, CHU Lille, Institut Pasteur de Lille, U1283 - UMR 8199 - EGID, 59000 Lille, France
| | - Jean-Sébastien Annicotte
- Université de Lille, INSERM, CNRS, CHU Lille, Institut Pasteur de Lille, U1283 - UMR 8199 - EGID, 59000 Lille, France; Université de Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1167 - RID-AGE - Facteurs de Risque et Déterminants Moléculaires des Maladies Liées au Vieillissement, 59000 Lille, France.
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25
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Merrins MJ, Corkey BE, Kibbey RG, Prentki M. Metabolic cycles and signals for insulin secretion. Cell Metab 2022; 34:947-968. [PMID: 35728586 PMCID: PMC9262871 DOI: 10.1016/j.cmet.2022.06.003] [Citation(s) in RCA: 58] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Revised: 06/01/2022] [Accepted: 06/04/2022] [Indexed: 02/03/2023]
Abstract
In this review, we focus on recent developments in our understanding of nutrient-induced insulin secretion that challenge a key aspect of the "canonical" model, in which an oxidative phosphorylation-driven rise in ATP production closes KATP channels. We discuss the importance of intrinsic β cell metabolic oscillations; the phasic alignment of relevant metabolic cycles, shuttles, and shunts; and how their temporal and compartmental relationships align with the triggering phase or the secretory phase of pulsatile insulin secretion. Metabolic signaling components are assigned regulatory, effectory, and/or homeostatic roles vis-à-vis their contribution to glucose sensing, signal transmission, and resetting the system. Taken together, these functions provide a framework for understanding how allostery, anaplerosis, and oxidative metabolism are integrated into the oscillatory behavior of the secretory pathway. By incorporating these temporal as well as newly discovered spatial aspects of β cell metabolism, we propose a much-refined MitoCat-MitoOx model of the signaling process for the field to evaluate.
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Affiliation(s)
- Matthew J Merrins
- Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Wisconsin-Madison, Madison, WI, USA; William S. Middleton Memorial Veterans Hospital, Madison, WI, USA.
| | - Barbara E Corkey
- Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
| | - Richard G Kibbey
- Departments of Internal Medicine (Endocrinology) and Cellular & Molecular Physiology, Yale University, New Haven, CT, USA.
| | - Marc Prentki
- Molecular Nutrition Unit and Montreal Diabetes Research Center, CRCHUM, and Departments of Nutrition, Biochemistry and Molecular Medicine, Université de Montréal, Montréal, ON, Canada.
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26
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Roles of cADPR and NAADP in pancreatic beta cell signalling. Cell Calcium 2022; 103:102562. [DOI: 10.1016/j.ceca.2022.102562] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Revised: 02/05/2022] [Accepted: 02/09/2022] [Indexed: 11/19/2022]
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27
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Cabrera O, Ficorilli J, Shaw J, Echeverri F, Schwede F, Chepurny OG, Leech CA, Holz GG. Intra-islet glucagon confers β-cell glucose competence for first-phase insulin secretion and favors GLP-1R stimulation by exogenous glucagon. J Biol Chem 2022; 298:101484. [PMID: 34896391 PMCID: PMC8789663 DOI: 10.1016/j.jbc.2021.101484] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 12/07/2021] [Accepted: 12/07/2021] [Indexed: 02/07/2023] Open
Abstract
We report that intra-islet glucagon secreted from α-cells signals through β-cell glucagon and GLP-1 receptors (GcgR and GLP-1R), thereby conferring to rat islets their competence to exhibit first-phase glucose-stimulated insulin secretion (GSIS). Thus, in islets not treated with exogenous glucagon or GLP-1, first-phase GSIS is abolished by a GcgR antagonist (LY2786890) or a GLP-1R antagonist (Ex[9-39]). Mechanistically, glucose competence in response to intra-islet glucagon is conditional on β-cell cAMP signaling because it is blocked by the cAMP antagonist prodrug Rp-8-Br-cAMPS-pAB. In its role as a paracrine hormone, intra-islet glucagon binds with high affinity to the GcgR, while also exerting a "spillover" effect to bind with low affinity to the GLP-1R. This produces a right shift of the concentration-response relationship for the potentiation of GSIS by exogenous glucagon. Thus, 0.3 nM glucagon fails to potentiate GSIS, as expected if similar concentrations of intra-islet glucagon already occupy the GcgR. However, 10 to 30 nM glucagon effectively engages the β-cell GLP-1R to potentiate GSIS, an action blocked by Ex[9-39] but not LY2786890. Finally, we report that the action of intra-islet glucagon to support insulin secretion requires a step-wise increase of glucose concentration to trigger first-phase GSIS. It is not measurable when GSIS is stimulated by a gradient of increasing glucose concentrations, as occurs during an oral glucose tolerance test in vivo. Collectively, such findings are understandable if defective intra-islet glucagon action contributes to the characteristic loss of first-phase GSIS in an intravenous glucose tolerance test that is diagnostic of type 2 diabetes in the clinical setting.
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Affiliation(s)
- Over Cabrera
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA.
| | - James Ficorilli
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA
| | - Janice Shaw
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA
| | | | - Frank Schwede
- Biolog Life Science Institute GmbH & Co KG, Bremen, Germany
| | - Oleg G Chepurny
- Department of Medicine, State University of New York (SUNY) Upstate Medical University, Syracuse, New York, USA
| | - Colin A Leech
- Department of Medicine, State University of New York (SUNY) Upstate Medical University, Syracuse, New York, USA
| | - George G Holz
- Department of Medicine, State University of New York (SUNY) Upstate Medical University, Syracuse, New York, USA; Department of Pharmacology, State University of New York (SUNY) Upstate Medical University, Syracuse, New York, USA.
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28
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Holter MM, Saikia M, Cummings BP. Alpha-cell paracrine signaling in the regulation of beta-cell insulin secretion. Front Endocrinol (Lausanne) 2022; 13:934775. [PMID: 35957816 PMCID: PMC9360487 DOI: 10.3389/fendo.2022.934775] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Accepted: 06/28/2022] [Indexed: 01/14/2023] Open
Abstract
As an incretin hormone, glucagon-like peptide 1 (GLP-1) lowers blood glucose levels by enhancing glucose-stimulated insulin secretion from pancreatic beta-cells. Therapies targeting the GLP-1 receptor (GLP-1R) use the classical incretin model as a physiological framework in which GLP-1 secreted from enteroendocrine L-cells acts on the beta-cell GLP-1R. However, this model has come into question, as evidence demonstrating local, intra-islet GLP-1 production has advanced the competing hypothesis that the incretin activity of GLP-1 may reflect paracrine signaling of GLP-1 from alpha-cells on GLP-1Rs on beta-cells. Additionally, recent studies suggest that alpha-cell-derived glucagon can serve as an additional, albeit less potent, ligand for the beta-cell GLP-1R, thereby expanding the role of alpha-cells beyond that of a counterregulatory cell type. Efforts to understand the role of the alpha-cell in the regulation of islet function have revealed both transcriptional and functional heterogeneity within the alpha-cell population. Further analysis of this heterogeneity suggests that functionally distinct alpha-cell subpopulations display alterations in islet hormone profile. Thus, the role of the alpha-cell in glucose homeostasis has evolved in recent years, such that alpha-cell to beta-cell communication now presents a critical axis regulating the functional capacity of beta-cells. Herein, we describe and integrate recent advances in our understanding of the impact of alpha-cell paracrine signaling on insulin secretory dynamics and how this intra-islet crosstalk more broadly contributes to whole-body glucose regulation in health and under metabolic stress. Moreover, we explore how these conceptual changes in our understanding of intra-islet GLP-1 biology may impact our understanding of the mechanisms of incretin-based therapeutics.
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Affiliation(s)
- Marlena M. Holter
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, United States
- *Correspondence: Marlena M. Holter,
| | - Mridusmita Saikia
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, United States
- Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, United States
| | - Bethany P. Cummings
- School of Medicine, Department of Surgery, Center for Alimentary and Metabolic Sciences, University of California, Davis, Sacramento, CA, United States
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29
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Ogawa Y, Kimura H, Fujimoto H, Kawashima H, Toyoda K, Mukai E, Yagi Y, Ono M, Inagaki N, Saji H. Development of novel radioiodinated exendin-4 derivatives targeting GLP-1 receptor for detection of β-cell mass. Bioorg Med Chem 2021; 52:116496. [PMID: 34808404 DOI: 10.1016/j.bmc.2021.116496] [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: 07/23/2021] [Revised: 10/15/2021] [Accepted: 11/02/2021] [Indexed: 10/19/2022]
Abstract
In subjects with type 2 diabetes mellitus (T2DM), pancreatic β-cell mass decreases; however, it is unknown to what extent this decrease contributes to the pathophysiology of T2DM. Therefore, the development of a method for noninvasive detection of β-cell mass is underway. We previously reported that glucagon-like peptide-1 receptor (GLP-1R) is a promising target molecule for β-cell imaging. In this study, we attempted to develop a probe targeting GLP-1R for β-cell imaging using single-photon emission computed tomography (SPECT). For this purpose, we selected exendin-4 as the lead compound and radiolabeled lysine at residue 12 in exendin-4 or additional lysine at the C-terminus using [123I]iodobenzoylation. To evaluate in vitro receptor specificity, binding assay was performed using dispersed mouse islet cells. Biodistribution study was performed in normal ddY mice. Ex vivo autoradiography was performed in transgenic mice expressing green fluorescent protein under control of the mouse insulin I gene promoter. Additionally, SPECT imaging was performed in normal ddY mice. The affinity of novel synthesized derivatives toward pancreatic β-cells was not affected by iodobenzoylation. The derivatives accumulated in the pancreas after intravenous administration specifically via GLP-1R expressed on the pancreatic β-cells. Extremely high signal-to-noise ratio was observed during evaluation of biodistribution of [123I]IB12-Ex4. SPECT images using normal mice showed that [123I]IB12-Ex4 accumulated in the pancreas with high contrast between the pancreas and background. These results indicate that [123I]IB12-Ex4 for SPECT is useful for clinical applications because of its preferable kinetics in vivo.
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Affiliation(s)
- Yu Ogawa
- Department of Patho-Functional Bioanalysis, Kyoto University Graduate School of Pharmaceutical Sciences, 46-29, Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan
| | - Hiroyuki Kimura
- Department of Patho-Functional Bioanalysis, Kyoto University Graduate School of Pharmaceutical Sciences, 46-29, Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan; Department of Analytical and Bioinorganic Chemistry, Division of Analytical and Physical Chemistry, Kyoto Pharmaceutical University, 5 Nakauchi-cho, Misasagi, Yamashina-ku, Kyoto 607-8414, Japan.
| | - Hiroyuki Fujimoto
- Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
| | - Hidekazu Kawashima
- Department of Patho-Functional Bioanalysis, Kyoto University Graduate School of Pharmaceutical Sciences, 46-29, Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan; Radioisotope Research Center, Kyoto Pharmaceutical University, 1 Misasagi-shichono-cho, Yamashina-ku, Kyoto 607-8412, Japan
| | - Kentaro Toyoda
- Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
| | - Eri Mukai
- Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
| | - Yusuke Yagi
- Department of Patho-Functional Bioanalysis, Kyoto University Graduate School of Pharmaceutical Sciences, 46-29, Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan; Department of Analytical and Bioinorganic Chemistry, Division of Analytical and Physical Chemistry, Kyoto Pharmaceutical University, 5 Nakauchi-cho, Misasagi, Yamashina-ku, Kyoto 607-8414, Japan
| | - Masahiro Ono
- Department of Patho-Functional Bioanalysis, Kyoto University Graduate School of Pharmaceutical Sciences, 46-29, Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan
| | - Nobuya Inagaki
- Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
| | - Hideo Saji
- Department of Patho-Functional Bioanalysis, Kyoto University Graduate School of Pharmaceutical Sciences, 46-29, Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
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30
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Maltan L, Najjar H, Tiffner A, Derler I. Deciphering Molecular Mechanisms and Intervening in Physiological and Pathophysiological Processes of Ca 2+ Signaling Mechanisms Using Optogenetic Tools. Cells 2021; 10:3340. [PMID: 34943850 PMCID: PMC8699489 DOI: 10.3390/cells10123340] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 11/17/2021] [Accepted: 11/22/2021] [Indexed: 11/16/2022] Open
Abstract
Calcium ion channels are involved in numerous biological functions such as lymphocyte activation, muscle contraction, neurotransmission, excitation, hormone secretion, gene expression, cell migration, memory, and aging. Therefore, their dysfunction can lead to a wide range of cellular abnormalities and, subsequently, to diseases. To date various conventional techniques have provided valuable insights into the roles of Ca2+ signaling. However, their limited spatiotemporal resolution and lack of reversibility pose significant obstacles in the detailed understanding of the structure-function relationship of ion channels. These drawbacks could be partially overcome by the use of optogenetics, which allows for the remote and well-defined manipulation of Ca2+-signaling. Here, we review the various optogenetic tools that have been used to achieve precise control over different Ca2+-permeable ion channels and receptors and associated downstream signaling cascades. We highlight the achievements of optogenetics as well as the still-open questions regarding the resolution of ion channel working mechanisms. In addition, we summarize the successes of optogenetics in manipulating many Ca2+-dependent biological processes both in vitro and in vivo. In summary, optogenetics has significantly advanced our understanding of Ca2+ signaling proteins and the used tools provide an essential basis for potential future therapeutic application.
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Affiliation(s)
| | | | | | - Isabella Derler
- Institute of Biophysics, JKU Life Science Center, Johannes Kepler University Linz, A-4020 Linz, Austria; (L.M.); (H.N.); (A.T.)
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31
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Barone M, D'Amico F, Fabbrini M, Rampelli S, Brigidi P, Turroni S. Over-feeding the gut microbiome: A scoping review on health implications and therapeutic perspectives. World J Gastroenterol 2021; 27:7041-7064. [PMID: 34887627 PMCID: PMC8613651 DOI: 10.3748/wjg.v27.i41.7041] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 07/02/2021] [Accepted: 10/14/2021] [Indexed: 02/06/2023] Open
Abstract
The human gut microbiome has gained increasing attention over the past two decades. Several findings have shown that this complex and dynamic microbial ecosystem can contribute to the maintenance of host health or, when subject to imbalances, to the pathogenesis of various enteric and non-enteric diseases. This scoping review summarizes the current knowledge on how the gut microbiota and microbially-derived compounds affect host metabolism, especially in the context of obesity and related disorders. Examples of microbiome-based targeted intervention strategies that aim to restore and maintain an eubiotic layout are then discussed. Adjuvant therapeutic interventions to alleviate obesity and associated comorbidities are traditionally based on diet modulation and the supplementation of prebiotics, probiotics and synbiotics. However, these approaches have shown only moderate ability to induce sustained changes in the gut microbial ecosystem, making the development of innovative and tailored microbiome-based intervention strategies of utmost importance in clinical practice. In this regard, the administration of next-generation probiotics and engineered microbiomes has shown promising results, together with more radical intervention strategies based on the replacement of the dysbiotic ecosystem by means of fecal microbiota transplantation from healthy donors or with the introduction of synthetic communities specifically designed to achieve the desired therapeutic outcome. Finally, we provide a perspective for future translational investigations through the implementation of bioinformatics approaches, including machine and deep learning, to predict health risks and therapeutic outcomes.
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Affiliation(s)
- Monica Barone
- Microbiomics Unit, Department of Medical and Surgical Sciences, University of Bologna, Bologna 40138, Italy
- Unit of Microbiome Science and Biotechnology, Department of Pharmacy and Biotechnology, University of Bologna, Bologna 40126, Italy
| | - Federica D'Amico
- Microbiomics Unit, Department of Medical and Surgical Sciences, University of Bologna, Bologna 40138, Italy
- Unit of Microbiome Science and Biotechnology, Department of Pharmacy and Biotechnology, University of Bologna, Bologna 40126, Italy
| | - Marco Fabbrini
- Microbiomics Unit, Department of Medical and Surgical Sciences, University of Bologna, Bologna 40138, Italy
- Unit of Microbiome Science and Biotechnology, Department of Pharmacy and Biotechnology, University of Bologna, Bologna 40126, Italy
| | - Simone Rampelli
- Unit of Microbiome Science and Biotechnology, Department of Pharmacy and Biotechnology, University of Bologna, Bologna 40126, Italy
| | - Patrizia Brigidi
- Microbiomics Unit, Department of Medical and Surgical Sciences, University of Bologna, Bologna 40138, Italy
| | - Silvia Turroni
- Unit of Microbiome Science and Biotechnology, Department of Pharmacy and Biotechnology, University of Bologna, Bologna 40126, Italy
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Shepard BD, Ecelbarger CM. Sodium Glucose Transporter, Type 2 (SGLT2) Inhibitors (SGLT2i) and Glucagon-Like Peptide 1-Receptor Agonists: Newer Therapies in Whole-Body Glucose Stabilization. Semin Nephrol 2021; 41:331-348. [PMID: 34715963 DOI: 10.1016/j.semnephrol.2021.06.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Diabetes is a worldwide epidemic that is increasing rapidly to become the seventh leading cause of death in the world. The increased incidence of this disease mirrors a similar uptick in obesity and metabolic syndrome, and, collectively, these conditions can cause deleterious effects on a number of organ systems including the renal and cardiovascular systems. Historically, treatment of type 2 diabetes has focused on decreasing hyperglycemia and glycated hemoglobin levels. However, it now is appreciated that there is more to the puzzle. Emerging evidence has indicated that newer classes of diabetes drugs, sodium-glucose co-transporter 2 inhibitors and glucagon-like peptide 1-receptor agonists, improve cardiovascular and renal function, while appropriately managing hyperglycemia. In this review, we highlight the recent clinical and preclinical studies that have shed light on sodium-glucose co-transporter 2 inhibitors and glucagon-like peptide 1-receptor agonists and their ability to stabilize blood glucose levels while offering whole-body protection in diabetic and nondiabetic patient populations.
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Affiliation(s)
- Blythe D Shepard
- Department of Human Science, Georgetown University Medical Center, Washington, DC
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33
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Gao Y, Li X, Huang Y, Chen J, Qiu M. Bitter Melon and Diabetes Mellitus. FOOD REVIEWS INTERNATIONAL 2021. [DOI: 10.1080/87559129.2021.1923733] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- Ya Gao
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, PR China
- University of the Chinese Academy of Sciences, Beijing, PR China
- Yunnan Key Laboratory of Natural Medicinal Chemistry, Chinese Academy of Sciences, Kunming, PR China
| | - Xian Li
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, PR China
- University of the Chinese Academy of Sciences, Beijing, PR China
- Yunnan Key Laboratory of Natural Medicinal Chemistry, Chinese Academy of Sciences, Kunming, PR China
| | - Yanjie Huang
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, PR China
- University of the Chinese Academy of Sciences, Beijing, PR China
- Yunnan Key Laboratory of Natural Medicinal Chemistry, Chinese Academy of Sciences, Kunming, PR China
| | - Jianchao Chen
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, PR China
| | - Minghua Qiu
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, PR China
- University of the Chinese Academy of Sciences, Beijing, PR China
- Yunnan Key Laboratory of Natural Medicinal Chemistry, Chinese Academy of Sciences, Kunming, PR China
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34
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Iworima DG, Rieck S, Kieffer TJ. Process parameter development for the scaled generation of stem cell-derived pancreatic endocrine cells. Stem Cells Transl Med 2021; 10:1459-1469. [PMID: 34387389 PMCID: PMC8550703 DOI: 10.1002/sctm.21-0161] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 06/28/2021] [Accepted: 07/05/2021] [Indexed: 12/20/2022] Open
Abstract
Diabetes is a debilitating disease characterized by high blood glucose levels. The global prevalence of this disease has been projected to reach 700 million adults by the year 2045. Type 1 diabetes represents about 10% of the reported cases of diabetes. Although islet transplantation can be a highly effective method to treat type 1 diabetes, its widespread application is limited by the paucity of cadaveric donor islets. The use of pluripotent stem cells as an unlimited cell source to generate insulin‐producing cells for implant is a promising alternative for treating diabetes. However, to be clinically relevant, it is necessary to manufacture these stem cell‐derived cells at sufficient scales. Significant advances have been made in differentiation protocols used to generate stem cell‐derived cells capable of reversing diabetes in animal models and for testing in clinical trials. We discuss the potential of both stem cell‐derived pancreatic progenitors and more matured insulin‐producing cells to treat diabetes. We discuss the need for rigorous bioprocess parameter optimization and identify some critical process parameters and strategies that may influence the critical quality attributes of the cells with the goal of facilitating scalable manufacturing of human pluripotent stem cell‐derived pancreatic endocrine cells.
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Affiliation(s)
- Diepiriye G Iworima
- School of Biomedical Engineering, University of British Columbia, Vancouver, British Columbia, Canada.,Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia, Canada
| | | | - Timothy J Kieffer
- School of Biomedical Engineering, University of British Columbia, Vancouver, British Columbia, Canada.,Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia, Canada.,Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada
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35
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Spyrou N, Vallianou N, Kadillari J, Dalamaga M. The interplay of obesity, gut microbiome and diet in the immune check point inhibitors therapy era. Semin Cancer Biol 2021; 73:356-376. [PMID: 33989733 DOI: 10.1016/j.semcancer.2021.05.008] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 03/22/2021] [Accepted: 05/06/2021] [Indexed: 12/13/2022]
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Ramzy A, Kieffer TJ. Altered islet prohormone processing: A cause or consequence of diabetes? Physiol Rev 2021; 102:155-208. [PMID: 34280055 DOI: 10.1152/physrev.00008.2021] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Peptide hormones are first produced as larger precursor prohormones that require endoproteolytic cleavage to liberate the mature hormones. A structurally conserved but functionally distinct family of nine prohormone convertase enzymes (PCs) are responsible for cleavage of protein precursors of which PC1/3 and PC2 are known to be exclusive to neuroendocrine cells and responsible for prohormone cleavage. Differential expression of PCs within tissues define prohormone processing; whereas glucagon is the major product liberated from proglucagon via PC2 in pancreatic α-cells, proglucagon is preferentially processed by PC1/3 in intestinal L cells to produce glucagon-like peptides 1 and 2 (GLP-1, GLP-2). Beyond our understanding of processing of islet prohormones in healthy islets, there is convincing evidence that proinsulin, proIAPP, and proglucagon processing is altered during prediabetes and diabetes. There is predictive value of elevated circulating proinsulin or proinsulin : C-peptide ratio for progression to type 2 diabetes and elevated proinsulin or proinsulin : C-peptide is predictive for development of type 1 diabetes in at risk groups. After onset of diabetes, patients have elevated circulating proinsulin and proIAPP and proinsulin may be an autoantigen in type 1 diabetes. Further, preclinical studies reveal that α-cells have altered proglucagon processing during diabetes leading to increased GLP-1 production. We conclude that despite strong associative data, current evidence is inconclusive on the potential causal role of impaired prohormone processing in diabetes, and suggest that future work should focus on resolving the question of whether altered prohormone processing is a causal driver or merely a consequence of diabetes pathology.
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Affiliation(s)
- Adam Ramzy
- Laboratory of Molecular and Cellular Medicine, Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada
| | - Timothy J Kieffer
- Laboratory of Molecular and Cellular Medicine, Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada.,Department of Surgery, University of British Columbia, Vancouver, BC, Canada.,School of Biomedical Engineering, University of British Columbia, Vancouver, BC, Canada
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Augestad IL, Dekens D, Karampatsi D, Elabi O, Zabala A, Pintana H, Larsson M, Nyström T, Paul G, Darsalia V, Patrone C. Normalisation of glucose metabolism by exendin-4 in the chronic phase after stroke promotes functional recovery in male diabetic mice. Br J Pharmacol 2021; 179:677-694. [PMID: 33973246 PMCID: PMC8820185 DOI: 10.1111/bph.15524] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 03/30/2021] [Accepted: 04/27/2021] [Indexed: 01/25/2023] Open
Abstract
BACKGROUND AND PURPOSE Glucagon-like peptide-1 (GLP-1) receptor activation decreases stroke risk in people with Type 2 diabetes (T2D), while animal studies have shown the efficacy of this strategy to counteract stroke-induced acute brain damage. However, whether GLP-1 receptor activation also improves recovery in the chronic phase after stroke is unknown. We investigated whether post-acute, chronic administration of the GLP-1 receptor agonist, exendin-4, improves post-stroke recovery and examined possible underlying mechanisms in T2D and non-T2D mice. EXPERIMENTAL APPROACH We induced stroke via transient middle cerebral artery occlusion (tMCAO) in T2D/obese mice (8 months of high-fat diet) and age-matched controls. Exendin-4 was administered for 8 weeks from Day 3 post-tMCAO. We assessed functional recovery by weekly upper-limb grip strength tests. Insulin sensitivity and glycaemia were evaluated at 4 and 8 weeks post-tMCAO. Neuronal survival, stroke-induced neurogenesis, neuroinflammation, atrophy of GABAergic parvalbumin+ interneurons, post-stroke vascular remodelling and fibrotic scar formation were investigated by immunohistochemistry. KEY RESULTS Exendin-4 normalised T2D-induced impairment of forepaw grip strength recovery in correlation with normalised glycaemia and insulin sensitivity. Moreover, exendin-4 counteracted T2D-induced atrophy of parvalbumin+ interneurons and decreased microglia activation. Finally, exendin-4 normalised density and pericyte coverage of micro-vessels and restored fibrotic scar formation in T2D mice. In non-T2D mice, the exendin-4-mediated recovery was minor. CONCLUSION AND IMPLICATIONS Chronic GLP-1 receptor activation mediates post-stroke functional recovery in T2D mice by normalising glucose metabolism and improving neuroplasticity and vascular remodelling in the recovery phase. The results warrant clinical trial of GLP-1 receptor agonists for rehabilitation after stroke in T2D.
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Affiliation(s)
- Ingrid Lovise Augestad
- NeuroCardioMetabol Group, Department of Clinical Science and Education, Södersjukhuset, Internal Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Doortje Dekens
- NeuroCardioMetabol Group, Department of Clinical Science and Education, Södersjukhuset, Internal Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Dimitra Karampatsi
- NeuroCardioMetabol Group, Department of Clinical Science and Education, Södersjukhuset, Internal Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Osama Elabi
- Translational Neurology Group, Department of Clinical Sciences, Wallenberg Neuroscience Center, Wallenberg Center for Molecular Medicine, Lund University, Lund, Sweden
| | - Alexander Zabala
- NeuroCardioMetabol Group, Department of Clinical Science and Education, Södersjukhuset, Internal Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Hiranya Pintana
- NeuroCardioMetabol Group, Department of Clinical Science and Education, Södersjukhuset, Internal Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Martin Larsson
- NeuroCardioMetabol Group, Department of Clinical Science and Education, Södersjukhuset, Internal Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Thomas Nyström
- NeuroCardioMetabol Group, Department of Clinical Science and Education, Södersjukhuset, Internal Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Gesine Paul
- Translational Neurology Group, Department of Clinical Sciences, Wallenberg Neuroscience Center, Wallenberg Center for Molecular Medicine, Lund University, Lund, Sweden
| | - Vladimer Darsalia
- NeuroCardioMetabol Group, Department of Clinical Science and Education, Södersjukhuset, Internal Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Cesare Patrone
- NeuroCardioMetabol Group, Department of Clinical Science and Education, Södersjukhuset, Internal Medicine, Karolinska Institutet, Stockholm, Sweden
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38
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Lamos EM, Kristan M, Siamashvili M, Davis SN. Effects of anti-diabetic treatments in type 2 diabetes and fatty liver disease. Expert Rev Clin Pharmacol 2021; 14:837-852. [PMID: 33882758 DOI: 10.1080/17512433.2021.1917374] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Introduction: Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) are significant non-communicable diseases that often affect individuals concurrently. In individuals with both T2DM and NAFLD, there is evidence that anti-diabetic therapies may demonstrate potential combined beneficial metabolic and reduced hepatic inflammatory effects.Areas covered: A PubMed and Google Scholar search was performed to find relevant literature. Included studies focused on individuals with T2DM and NAFLD receiving anti-diabetic treatments including bariatric surgery, insulin sensitizers, incretin mimetics, and SGLT2 inhibitors. Additional articles highlight investigational treatments.Expert opinion: In individuals with T2DM and NAFLD, 5-10% weight loss or bariatric surgery if unable to lose weight or maintain weight loss are appropriate. GLP-1 receptor agonists and SGLT2 inhibitors result in weight loss, appear safe and may provide beneficial hepatic outcomes. Whether their effects are related to favorable weight changes or intrinsic hepatic effects is unclear. Thiazolidinediones have advantageous anti-hyperglycemic and hepatic effects but individuals must be monitored for weight gain and edema. Metformin and DPP-4 inhibitor beneficial hepatic effects remain debated. There are opportunities to standardize markers and imaging of NAFLD. Studies powered to evaluate the possible cardiovascular benefits of anti-diabetic therapies in individuals with T2DM and NAFLD are needed.
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Affiliation(s)
- Elizabeth M Lamos
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Megan Kristan
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Maka Siamashvili
- Department of Medicine, University of Maryland Medical Center, Baltimore, MD, USA
| | - Stephen N Davis
- Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
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Quintilhano DL, Miksza DR, de Souza Galia WB, Ramalho MORC, Lucena CF, Valle MMR, Graciano MFR, de Souza HM, Bertolini GL. Insulin secretion decline in Walker-256 tumor-bearing rats is early, follows the course of cachexia, and is not improved by lixisenatide. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2021; 394:697-705. [PMID: 33128591 DOI: 10.1007/s00210-020-02006-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Accepted: 10/19/2020] [Indexed: 12/13/2022]
Abstract
Lixisenatide, a glucagon-like peptide-1 receptor agonist, is used to stimulate insulin secretion in patients with type 2 diabetes mellitus. However, its effect on insulin secretion in cancer patients, particularly during the cachexia course, has not yet been evaluated. The purpose of this study was to investigate the lixisenatide effect on INS secretion decline during the cachexia course (2, 6, and 12 days of tumor) in pancreatic islets isolated from Walker-256 tumor-bearing rats. Pancreatic islets of healthy and tumor-bearing rats were incubated in the presence or absence of lixisenatide (10 nM). Tumor-bearing rats showed reduction of body weight and fat and muscle mass, characterizing the development of cachexia, as well as reduction of insulinemia and INS secretion stimulated by glucose (5.6, 8.3, 11.1, 16.7, and 20 mM) on days 2, 6, and/or 12 of tumor. Lixisenatide increased the 16.7 mM glucose-stimulated insulin secretion, but not by 5.6 mM glucose, in the islets of healthy rats, without changing the insulin intracellular content. However, lixisenatide did not prevent the decreased 16.7 mM glucose-stimulated insulin secretion in the pancreatic islets of rats with 2, 6, and 12 days of tumor and neither the decreased insulin intracellular content of rats with 12 days of tumor. In consistency, in vivo treatment with lixisenatide (50 μg kg-1, SC, once daily, for 6 days) visually increased insulinemia of healthy fasted rats, but did not prevent hypoinsulinemia of tumor-bearing rats. In conclusion, Walker-256 tumor-bearing rats showed early decline (2 days of tumor) of insulin secretion, which followed the cachexia course (6 and 12 days of tumor) and was not improved by lixisenatide, evidencing that this insulin secretagogue, used to treat type 2 diabetes, does not have beneficial effect in cancer bearing-rats.
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Affiliation(s)
- Débora Luiza Quintilhano
- Department of Physiological Sciences, State University of Londrina, Londrina, PR, 86051-990, Brazil
| | - Daniele Romani Miksza
- Department of Physiological Sciences, State University of Londrina, Londrina, PR, 86051-990, Brazil
| | | | | | - Camila Ferraz Lucena
- Department of Physiology and Biophysics, University of São Paulo, Sao Paulo, PR, 05508-900, Brazil
| | | | | | - Helenir Medri de Souza
- Department of Physiological Sciences, State University of Londrina, Londrina, PR, 86051-990, Brazil
| | - Gisele Lopes Bertolini
- Department of Physiological Sciences, State University of Londrina, Londrina, PR, 86051-990, Brazil.
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Shuai H, Xu Y, Ahooghalandari P, Tengholm A. Glucose-induced cAMP elevation in β-cells involves amplification of constitutive and glucagon-activated GLP-1 receptor signalling. Acta Physiol (Oxf) 2021; 231:e13611. [PMID: 33369112 PMCID: PMC8047901 DOI: 10.1111/apha.13611] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2020] [Revised: 12/17/2020] [Accepted: 12/19/2020] [Indexed: 01/02/2023]
Abstract
Aim cAMP typically signals downstream of Gs‐coupled receptors and regulates numerous cell functions. In β‐cells, cAMP amplifies Ca2+‐triggered exocytosis of insulin granules. Glucose‐induced insulin secretion is associated with Ca2+‐ and metabolism‐dependent increases of the sub‐plasma‐membrane cAMP concentration ([cAMP]pm) in β‐cells, but potential links to canonical receptor signalling are unclear. The aim of this study was to clarify the role of glucagon‐like peptide‐1 receptors (GLP1Rs) for glucose‐induced cAMP signalling in β‐cells. Methods Total internal reflection microscopy and fluorescent reporters were used to monitor changes in cAMP, Ca2+ and ATP concentrations as well as insulin secretion in MIN6 cells and mouse and human β‐cells. Insulin release from mouse and human islets was also measured with ELISA. Results The GLP1R antagonist exendin‐(9‐39) (ex‐9) prevented both GLP1‐ and glucagon‐induced elevations of [cAMP]pm, consistent with GLP1Rs being involved in the action of glucagon. This conclusion was supported by lack of unspecific effects of the antagonist in a reporter cell‐line. Ex‐9 also suppressed IBMX‐ and glucose‐induced [cAMP]pm elevations. Depolarization with K+ triggered Ca2+‐dependent [cAMP]pm elevation, an effect that was amplified by high glucose. Ex‐9 inhibited both the Ca2+ and glucose‐metabolism‐dependent actions on [cAMP]pm. The drug remained effective after minimizing paracrine signalling by dispersing the islets and it reduced basal [cAMP]pm in a cell‐line heterologously expressing GLP1Rs, indicating that there is constitutive GLP1R signalling. The ex‐9‐induced reduction of [cAMP]pm in glucose‐stimulated β‐cells was paralleled by suppression of insulin secretion. Conclusion Agonist‐independent and glucagon‐stimulated GLP1R signalling in β‐cells contributes to basal and glucose‐induced cAMP production and insulin secretion.
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Affiliation(s)
- Hongyan Shuai
- School of Basic Medicine Sciences Dali University Yunnan China
- Department of Medical Cell Biology Biomedical Centre Uppsala University Uppsala Sweden
| | - Yunjian Xu
- Department of Medical Cell Biology Biomedical Centre Uppsala University Uppsala Sweden
| | - Parvin Ahooghalandari
- Department of Medical Cell Biology Biomedical Centre Uppsala University Uppsala Sweden
| | - Anders Tengholm
- Department of Medical Cell Biology Biomedical Centre Uppsala University Uppsala Sweden
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Lee CB, Chae SU, Jo SJ, Jerng UM, Bae SK. The Relationship between the Gut Microbiome and Metformin as a Key for Treating Type 2 Diabetes Mellitus. Int J Mol Sci 2021; 22:ijms22073566. [PMID: 33808194 PMCID: PMC8037857 DOI: 10.3390/ijms22073566] [Citation(s) in RCA: 69] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 03/22/2021] [Accepted: 03/27/2021] [Indexed: 02/08/2023] Open
Abstract
Metformin is the first-line pharmacotherapy for treating type 2 diabetes mellitus (T2DM); however, its mechanism of modulating glucose metabolism is elusive. Recent advances have identified the gut as a potential target of metformin. As patients with metabolic disorders exhibit dysbiosis, the gut microbiome has garnered interest as a potential target for metabolic disease. Henceforth, studies have focused on unraveling the relationship of metabolic disorders with the human gut microbiome. According to various metagenome studies, gut dysbiosis is evident in T2DM patients. Besides this, alterations in the gut microbiome were also observed in the metformin-treated T2DM patients compared to the non-treated T2DM patients. Thus, several studies on rodents have suggested potential mechanisms interacting with the gut microbiome, including regulation of glucose metabolism, an increase in short-chain fatty acids, strengthening intestinal permeability against lipopolysaccharides, modulating the immune response, and interaction with bile acids. Furthermore, human studies have demonstrated evidence substantiating the hypotheses based on rodent studies. This review discusses the current knowledge of how metformin modulates T2DM with respect to the gut microbiome and discusses the prospect of harnessing this mechanism in treating T2DM.
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Affiliation(s)
- Chae Bin Lee
- College of Pharmacy and Integrated Research Institute of Pharmaceutical Sciences, The Catholic University of Korea, Bucheon 14662, Korea; (C.B.L.); (S.U.C.); (S.J.J.)
| | - Soon Uk Chae
- College of Pharmacy and Integrated Research Institute of Pharmaceutical Sciences, The Catholic University of Korea, Bucheon 14662, Korea; (C.B.L.); (S.U.C.); (S.J.J.)
| | - Seong Jun Jo
- College of Pharmacy and Integrated Research Institute of Pharmaceutical Sciences, The Catholic University of Korea, Bucheon 14662, Korea; (C.B.L.); (S.U.C.); (S.J.J.)
| | - Ui Min Jerng
- Department of Internal Medicine, College of Korean Medicine, Sangji University, Wonju 26339, Korea;
| | - Soo Kyung Bae
- College of Pharmacy and Integrated Research Institute of Pharmaceutical Sciences, The Catholic University of Korea, Bucheon 14662, Korea; (C.B.L.); (S.U.C.); (S.J.J.)
- Correspondence: ; Tel.: +82-2-2164-4054
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Marroqui L, Martinez-Pinna J, Castellano-Muñoz M, Dos Santos RS, Medina-Gali RM, Soriano S, Quesada I, Gustafsson JA, Encinar JA, Nadal A. Bisphenol-S and Bisphenol-F alter mouse pancreatic β-cell ion channel expression and activity and insulin release through an estrogen receptor ERβ mediated pathway. CHEMOSPHERE 2021; 265:129051. [PMID: 33250229 DOI: 10.1016/j.chemosphere.2020.129051] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Revised: 11/17/2020] [Accepted: 11/18/2020] [Indexed: 06/12/2023]
Abstract
Bisphenol-S (BPS) and Bisphenol-F (BPF) are current Bisphenol-A (BPA) substitutes. Here we used pancreatic β-cells from wild type (WT) and estrogen receptor β (ERβ) knockout (BERKO) mice to investigate the effects of BPS and BPF on insulin secretion, and the expression and activity of ion channels involved in β-cell function. BPS or BPF rapidly increased insulin release and diminished ATP-sensitive K+ (KATP) channel activity. Similarly, 48 h treatment with BPS or BPF enhanced insulin release and decreased the expression of several ion channel subunits in β-cells from WT mice, yet no effects were observed in cells from BERKO mice. PaPE-1, a ligand designed to preferentially trigger extranuclear-initiated ER pathways, mimicked the effects of bisphenols, suggesting the involvement of extranuclear-initiated ERβ pathways. Molecular dynamics simulations indicated differences in ERβ ligand-binding domain dimer stabilization and solvation free energy among different bisphenols and PaPE-1. Our data suggest a mode of action involving ERβ whose activation alters three key cellular events in β-cell, namely ion channel expression and activity, and insulin release. These results may help to improve the hazard identification of bisphenols.
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Affiliation(s)
- Laura Marroqui
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universitas Miguel Hernández, Elche, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Spain
| | - Juan Martinez-Pinna
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universitas Miguel Hernández, Elche, Spain; Departamento de Fisiología, Genética y Microbiología, Universidad de Alicante, Alicante, Spain
| | - Manuel Castellano-Muñoz
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Spain
| | - Reinaldo S Dos Santos
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universitas Miguel Hernández, Elche, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Spain
| | - Regla M Medina-Gali
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universitas Miguel Hernández, Elche, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Spain
| | - Sergi Soriano
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universitas Miguel Hernández, Elche, Spain; Departamento de Fisiología, Genética y Microbiología, Universidad de Alicante, Alicante, Spain
| | - Ivan Quesada
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universitas Miguel Hernández, Elche, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Spain
| | - Jan-Ake Gustafsson
- Department of Cell Biology and Biochemistry, Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX, USA; Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden
| | - José A Encinar
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universitas Miguel Hernández, Elche, Spain
| | - Angel Nadal
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universitas Miguel Hernández, Elche, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Spain.
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Chabosseau P, Rutter GA, Millership SJ. Importance of Both Imprinted Genes and Functional Heterogeneity in Pancreatic Beta Cells: Is There a Link? Int J Mol Sci 2021; 22:1000. [PMID: 33498234 PMCID: PMC7863946 DOI: 10.3390/ijms22031000] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 01/12/2021] [Accepted: 01/14/2021] [Indexed: 02/02/2023] Open
Abstract
Diabetes mellitus now affects more than 400 million individuals worldwide, with significant impacts on the lives of those affected and associated socio-economic costs. Although defects in insulin secretion underlie all forms of the disease, the molecular mechanisms which drive them are still poorly understood. Subsets of specialised beta cells have, in recent years, been suggested to play critical roles in "pacing" overall islet activity. The molecular nature of these cells, the means through which their identity is established and the changes which may contribute to their functional demise and "loss of influence" in both type 1 and type 2 diabetes are largely unknown. Genomic imprinting involves the selective silencing of one of the two parental alleles through DNA methylation and modified imprinted gene expression is involved in a number of diseases. Loss of expression, or loss of imprinting, can be shown in mouse models to lead to defects in beta cell function and abnormal insulin secretion. In the present review we survey the evidence that altered expression of imprinted genes contribute to loss of beta cell function, the importance of beta cell heterogeneity in normal and disease states, and hypothesise whether there is a direct link between the two.
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Affiliation(s)
| | | | - Steven J. Millership
- Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, Du Cane Road, London W12 0NN, UK; (P.C.); (G.A.R.)
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Sun Y, Tao Q, Wu X, Zhang L, Liu Q, Wang L. The Utility of Exosomes in Diagnosis and Therapy of Diabetes Mellitus and Associated Complications. Front Endocrinol (Lausanne) 2021; 12:756581. [PMID: 34764939 PMCID: PMC8576340 DOI: 10.3389/fendo.2021.756581] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Accepted: 10/01/2021] [Indexed: 12/12/2022] Open
Abstract
Diabetes mellitus and the associated complications are metabolic diseases with high morbidity that result in poor quality of health and life. The lack of diagnostic methods for early detection results in patients losing the best treatment opportunity. Oral hypoglycemics and exogenous insulin replenishment are currently the most common therapeutic strategies, which only yield temporary glycemic control rather than curing the disease and its complications. Exosomes are nanoparticles containing bioactive molecules reflecting individual physiological status, regulating metabolism, and repairing damaged tissues. They function as biomarkers of diabetes mellitus and diabetic complications. Considering that exosomes are bioactive molecules, can be obtained from body fluid, and have cell-type specificity, in this review, we highlight the multifold effects of exosomes in the pathology and therapy of diabetes mellitus and diabetic complications.
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Affiliation(s)
- Yaoxiang Sun
- Department of Clinical Laboratory, Yixing People's Hospital, Yixing, China
| | - Qing Tao
- Center for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, China
| | - Xueqin Wu
- Department of Clinical Laboratory, Yixing People's Hospital, Yixing, China
| | - Ling Zhang
- Department of Clinical Laboratory, Yixing People's Hospital, Yixing, China
| | - Qi Liu
- Department of Clinical Laboratory, Yixing People's Hospital, Yixing, China
| | - Lei Wang
- Center for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, China
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Inabu Y, Haisan J, Oba M, Sugino T. Effects of feeding a moderate- or high-energy close-up diet to cows on response of newborn calves to milk replacer feeding and intravenous injection of glucagon-like peptide 1. Domest Anim Endocrinol 2021; 74:106528. [PMID: 32810655 DOI: 10.1016/j.domaniend.2020.106528] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Revised: 04/22/2020] [Accepted: 07/17/2020] [Indexed: 11/30/2022]
Abstract
In this study, we investigated the effects of feeding a moderate- or high-energy close-up diet to close-up cows on response of newborn calves to intravenously (i.v.) injected glucagon-like peptide 1 (GLP-1). Newborn Holstein heifer calves (n = 37) from cows fed with a moderate-energy [M, 1.54 Mcal/kg of dry matter (DM) NEl; 14% starch; n = 17] or high-energy (H, 1.63 Mcal/kg of DM NEl; 26% starch; n = 20) diet in the last 28 d prepartum were assigned to one of two treatment groups, which were i.v. injected with saline (MC and HC, n = 9 and 10, respectively) or GLP-1 solution at 1.0 μg/kg BW (MG and HG, n = 8 and 10, respectively) immediately after milk replacer (MR; 26% CP, 16% fat) feeding. Blood samples were obtained through a jugular vein catheter at -10, 0, 10, 20, 30, 40, 50, 60, 90, and 120 min relative to MR feeding at 2, 10, and 20 d after birth, and plasma glucose, insulin, and GLP-1 concentrations were measured. Plasma GLP-1 concentration tended to increase starting from 30 min after MR feeding in the MC relative to the HC group at 10 (0.77 ng/mL vs 0.69 ng/mL for MC and HC, respectively; P = 0.10) and 20 d after birth (0.47 ng/mL vs 0.35 ng/mL for MC and HC, respectively; P = 0.07). Plasma glucose and insulin concentrations after MR feeding did not differ between MC and HC groups at 2 and 20 d after birth but were higher (P < 0.05) in MC (158 mg/dL and 3.64 ng/mL for glucose and insulin, respectively) than in HC (143 mg/dL and 2.46 ng/mL for glucose and insulin, respectively) calves at 10 d after birth. The elevation in plasma glucose concentration after MR feeding was suppressed by direct glucose-lowering action of i.v. injected GLP-1 at 2, 10, and 20 d after birth in M and H calves; this direct glucose-lowering action by GLP-1 was greater (P < 0.05) for H than for M calves at 20 d after birth. These results indicate that feeding a high-energy close-up diet to cows affects glucose status in their female offspring via suppression of postprandial plasma concentrations of GLP-1 and insulin as well as the alteration in the glucose-lowering action of GLP-1 after feeding depending on the day after birth.
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Affiliation(s)
- Y Inabu
- The Research Center for Animal Science, Graduate School of Biosphere Science, Hiroshima University, Higashi-Hiroshima 739-8528, Japan
| | - J Haisan
- Department of Agricultural Food and Nutritional Science, University of Alberta, Edmonton, AB T6G 2P5, Canada
| | - M Oba
- Department of Agricultural Food and Nutritional Science, University of Alberta, Edmonton, AB T6G 2P5, Canada
| | - T Sugino
- The Research Center for Animal Science, Graduate School of Biosphere Science, Hiroshima University, Higashi-Hiroshima 739-8528, Japan.
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Xie H, Yepuri N, Meng Q, Dhawan R, Leech CA, Chepurny OG, Holz GG, Cooney RN. Therapeutic potential of α7 nicotinic acetylcholine receptor agonists to combat obesity, diabetes, and inflammation. Rev Endocr Metab Disord 2020; 21:431-447. [PMID: 32851581 PMCID: PMC7572644 DOI: 10.1007/s11154-020-09584-3] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/21/2020] [Indexed: 12/12/2022]
Abstract
The cholinergic anti-inflammatory reflex (CAIR) represents an important homeostatic regulatory mechanism for sensing and controlling the body's response to inflammatory stimuli. Vagovagal reflexes are an integral component of CAIR whose anti-inflammatory effects are mediated by acetylcholine (ACh) acting at α7 nicotinic acetylcholine receptors (α7nAChR) located on cells of the immune system. Recently, it is appreciated that CAIR and α7nAChR also participate in the control of metabolic homeostasis. This has led to the understanding that defective vagovagal reflex circuitry underlying CAIR might explain the coexistence of obesity, diabetes, and inflammation in the metabolic syndrome. Thus, there is renewed interest in the α7nAChR that mediates CAIR, particularly from the standpoint of therapeutics. Of special note is the recent finding that α7nAChR agonist GTS-21 acts at L-cells of the distal intestine to stimulate the release of two glucoregulatory and anorexigenic hormones: glucagon-like peptide-1 (GLP-1) and peptide YY (PYY). Furthermore, α7nAChR agonist PNU 282987 exerts trophic factor-like actions to support pancreatic β-cell survival under conditions of stress resembling diabetes. This review provides an overview of α7nAChR function as it pertains to CAIR, vagovagal reflexes, and metabolic homeostasis. We also consider the possible usefulness of α7nAChR agonists for treatment of obesity, diabetes, and inflammation.
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Affiliation(s)
- Han Xie
- Departments of Surgery, State University of New York (SUNY), Upstate Medical University, 750 E Adams St., Suite 8141, Syracuse, NY, 13210, USA
| | - Natesh Yepuri
- Departments of Surgery, State University of New York (SUNY), Upstate Medical University, 750 E Adams St., Suite 8141, Syracuse, NY, 13210, USA
| | - Qinghe Meng
- Departments of Surgery, State University of New York (SUNY), Upstate Medical University, 750 E Adams St., Suite 8141, Syracuse, NY, 13210, USA
| | - Ravi Dhawan
- Departments of Surgery, State University of New York (SUNY), Upstate Medical University, 750 E Adams St., Suite 8141, Syracuse, NY, 13210, USA
| | - Colin A Leech
- Departments of Surgery, State University of New York (SUNY), Upstate Medical University, 750 E Adams St., Suite 8141, Syracuse, NY, 13210, USA
| | - Oleg G Chepurny
- Departments of Medicine, State University of New York (SUNY), Upstate Medical University, Syracuse, NY, USA
| | - George G Holz
- Departments of Medicine, State University of New York (SUNY), Upstate Medical University, Syracuse, NY, USA
| | - Robert N Cooney
- Departments of Surgery, State University of New York (SUNY), Upstate Medical University, 750 E Adams St., Suite 8141, Syracuse, NY, 13210, USA.
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Engineered protein switches for exogenous control of gene expression. Biochem Soc Trans 2020; 48:2205-2212. [DOI: 10.1042/bst20200441] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 09/28/2020] [Accepted: 09/30/2020] [Indexed: 02/02/2023]
Abstract
There is an ongoing need in the synthetic biology community for novel ways to regulate gene expression. Protein switches, which sense biological inputs and respond with functional outputs, represent one way to meet this need. Despite the fact that there is already a large pool of transcription factors and signaling proteins available, the pool of existing switches lacks the substrate specificities and activities required for certain applications. Therefore, a large number of techniques have been applied to engineer switches with novel properties. Here we discuss some of these techniques by broadly organizing them into three approaches. We show how novel switches can be created through mutagenesis, domain swapping, or domain insertion. We then briefly discuss their use as biosensors and in complex genetic circuits.
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Abstract
Observational findings achieved during the past two decades suggest that the intestinal microbiota may contribute to the metabolic health of the human host and, when aberrant, to the pathogenesis of various common metabolic disorders including obesity, type 2 diabetes, non-alcoholic liver disease, cardio-metabolic diseases and malnutrition. However, to gain a mechanistic understanding of how the gut microbiota affects host metabolism, research is moving from descriptive microbiota census analyses to cause-and-effect studies. Joint analyses of high-throughput human multi-omics data, including metagenomics and metabolomics data, together with measures of host physiology and mechanistic experiments in humans, animals and cells hold potential as initial steps in the identification of potential molecular mechanisms behind reported associations. In this Review, we discuss the current knowledge on how gut microbiota and derived microbial compounds may link to metabolism of the healthy host or to the pathogenesis of common metabolic diseases. We highlight examples of microbiota-targeted interventions aiming to optimize metabolic health, and we provide perspectives for future basic and translational investigations within the nascent and promising research field.
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He J, Chu Y. Small-molecule GLP-1 secretagogs: challenges and recent advances. Drug Discov Today 2020; 25:S1359-6446(20)30308-1. [PMID: 32835725 DOI: 10.1016/j.drudis.2020.08.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Revised: 07/05/2020] [Accepted: 08/06/2020] [Indexed: 12/14/2022]
Abstract
Glucagon-like peptide-1 (GLP-1) is a potent anti-hyperglycemic hormone that is an alternative treatment choice for patients with type 2 diabetes mellitus (T2DM). The glucose-dependent mechanism of GLP-1 is particularly important because it does not stimulate insulin secretion and cause hypoglycemia when plasma glucose concentrations are in the normal fasting range. Although several peptide drugs of GLP-1 analogs are clinically available, research on the small molecules that stimulate GLP-1 secretion is still struggling. In this review, we summarize recent updates in the discovery of small-molecule GLP-1 secretagogs targeting the G-protein-coupled receptor (GPCR) family. We also discuss the challenges and strategies for the study and describe the latest developments.
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Affiliation(s)
- Jie He
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Yong Chu
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China.
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Martins FL, Bailey MA, Girardi ACC. Endogenous Activation of Glucagon-Like Peptide-1 Receptor Contributes to Blood Pressure Control: Role of Proximal Tubule Na +/H + Exchanger Isoform 3, Renal Angiotensin II, and Insulin Sensitivity. Hypertension 2020; 76:839-848. [PMID: 32755467 DOI: 10.1161/hypertensionaha.120.14868] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
The pharmacological administration of GLP-1R (glucagon-like peptide-1 receptor) agonists reduces blood pressure (BP) in type 2 diabetes mellitus and nondiabetic patients. This study tested the hypothesis that endogenous GLP-1R signaling influences the regulation of BP. To this end, SHRs (spontaneously hypertensive rats) and Wistar rats were treated with the GLP-1R antagonist Ex9 (exendin-9) or vehicle for 4 weeks. Rats receiving the GLP-1R agonist Ex4 (exenatide) were used as an additional control. We found that blockade of baseline GLP-1R signaling by Ex9 increased systolic BP in both SHR and Wistar rats, compared with vehicle-treated animals, while Ex4 only reduced systolic BP in SHR. Higher systolic BP induced by Ex9 was accompanied by reduced lithium clearance and lower levels of NHE3 (Na+/H+ exchanger isoform 3) phosphorylation at the serine 552, indicative of increased proximal tubule sodium reabsorption. Additionally, urinary AGT (angiotensinogen) and renal cortical concentration of Ang II (angiotensin II) were enhanced by Ex9. Conversely, Ex4 decreased both urinary AGT and cortical Ang II but exclusively in SHRs. Moreover, both SHR and Wistar rats treated with Ex9 displayed hyperinsulinemia as compared with vehicle-treated rats, whereas Ex4 reduced fasting insulin concentration in SHR. Collectively, these results suggest that endogenous GLP-1R signaling exerts a physiologically relevant effect on BP control, which may be attributable, in part, to its tonic actions on the proximal tubule NHE3-mediated sodium reabsorption, intrarenal renin-angiotensin system, and insulin sensitivity. The possible role of impaired GLP-1R signaling in the pathogenesis of hypertension warrants further investigation.
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Affiliation(s)
- Flavia L Martins
- From the Heart Institute (InCor), Medical School, University of São Paulo, Brazil (F.L.M., A.C.C.G.)
| | - Matthew A Bailey
- Centre for Cardiovascular Science, Queen's Medical Research Institute, The University of Edinburgh, United Kingdom (M.A.B.)
| | - Adriana C C Girardi
- From the Heart Institute (InCor), Medical School, University of São Paulo, Brazil (F.L.M., A.C.C.G.)
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