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Anastasiou IΑ, Argyrakopoulou G, Dalamaga M, Kokkinos A. Dual and Triple Gut Peptide Agonists on the Horizon for the Treatment of Type 2 Diabetes and Obesity. An Overview of Preclinical and Clinical Data. Curr Obes Rep 2025; 14:34. [PMID: 40210807 PMCID: PMC11985575 DOI: 10.1007/s13679-025-00623-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/21/2025] [Indexed: 04/12/2025]
Abstract
PURPOSE OF REVIEW The development of long-acting incretin receptor agonists represents a significant advance in the fight against the concurrent epidemics of type 2 diabetes mellitus (T2DM) and obesity. The aim of the present review is to examine the cellular processes underlying the actions of these new, highly significant classes of peptide receptor agonists. We further explore the potential actions of multi-agonist drugs as well as the mechanisms through which gut-brain communication can be used to achieve long-term weight loss without negative side effects. RECENT FINDINGS Several unimolecular dual-receptor agonists have shown promising clinical efficacy studies when used alone or in conjunction with approved glucose-lowering medications. We also describe the development of incretin-based pharmacotherapy, starting with exendin- 4 and ending with the identification of multi-incretin hormone receptor agonists, which appear to be the next major step in the fight against T2DM and obesity. We discuss the multi-agonists currently in clinical trials and how each new generation of these drugs improves their effectiveness. Since most glucose-dependent insulinotropic polypeptide (GIP) receptor: glucagon-like peptide- 1 receptor (GLP- 1) receptor: glucagon receptor triagonists compete in efficacy with bariatric surgery, the success of these agents in preclinical models and clinical trials suggests a bright future for multi-agonists in the treatment of metabolic diseases. To fully understand how these treatments affect body weight, further research is needed.
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Affiliation(s)
- Ioanna Α Anastasiou
- Diabetes Center, First Department of Propaedeutic Internal Medicine, Medical School, Laiko General Hospital, National and Kapodistrian University of Athens, 11527, Athens, Greece
- Department of Pharmacology, National and Kapodistrian University of Athens, 11527, Athens, Greece
| | | | - Maria Dalamaga
- Department of Biological Chemistry, National and Kapodistrian University of Athens, 11527, Athens, Greece
| | - Alexander Kokkinos
- Diabetes Center, First Department of Propaedeutic Internal Medicine, Medical School, Laiko General Hospital, National and Kapodistrian University of Athens, 11527, Athens, Greece.
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2
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Stefater-Richards MA, Jhe G, Zhang YJ. GLP-1 Receptor Agonists in Pediatric and Adolescent Obesity. Pediatrics 2025; 155:e2024068119. [PMID: 40031990 DOI: 10.1542/peds.2024-068119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Accepted: 12/11/2024] [Indexed: 03/05/2025] Open
Abstract
Obesity remains highly prevalent among children in the United States and is associated with an ever-increasing burden of obesity-related diseases. Effective pediatric obesity prevention and treatment will require both societal interventions and health care system innovation. One recent advancement is the approval of glucagon-like peptide-1 receptor agonists (GLP-1RAs) for use in adolescents. GLP-1RAs are notable for their effectiveness in weight management and in their ability to ameliorate obesity-related diseases. GLP-1RAs can be an important part of a comprehensive treatment plan for pediatric patients seeking obesity care, and we will review the pediatric clinician's considerations for their effective use. We discuss the history of obesity pharmacology and development of GLP-1RAs. We review the indications for use and common adverse reactions. We highlight the importance of mental health care for obesity treatment, with a focus on disordered eating behaviors and their intersection with obesity and pharmacologic treatment of obesity. Nutrition remains an important issue for obesity prevention and management, and we highlight nutritional concerns during GLP-1RA therapy. Finally, we discuss health inequities in obesity, the dangers of perpetuating these inequities if GLP-1RA access remains biased, and the opportunities for improvement.
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Affiliation(s)
- Margaret A Stefater-Richards
- Division of Endocrinology, Boston Children's Hospital, Boston, Massachusetts
- Department of Pediatrics, Harvard Medical School, Boston, Massachusetts
| | - Grace Jhe
- Division of Adolescent/Young Adult Medicine, Boston Children's Hospital, Boston, Massachusetts
- Department of Psychiatry and Behavioral Sciences, Boston Children's Hospital, Boston, Massachusetts
- Department of Psychiatry, Harvard Medical School, Boston, Massachusetts
| | - Yanjia Jason Zhang
- Department of Pediatrics, Harvard Medical School, Boston, Massachusetts
- Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, Massachusetts
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts
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3
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Athar F, Karmani M, Templeman N. Metabolic hormones are integral regulators of female reproductive health and function. Biosci Rep 2024; 44:BSR20231916. [PMID: 38131197 PMCID: PMC10830447 DOI: 10.1042/bsr20231916] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 11/29/2023] [Accepted: 12/21/2023] [Indexed: 12/23/2023] Open
Abstract
The female reproductive system is strongly influenced by nutrition and energy balance. It is well known that food restriction or energy depletion can induce suppression of reproductive processes, while overnutrition is associated with reproductive dysfunction. However, the intricate mechanisms through which nutritional inputs and metabolic health are integrated into the coordination of reproduction are still being defined. In this review, we describe evidence for essential contributions by hormones that are responsive to food intake or fuel stores. Key metabolic hormones-including insulin, the incretins (glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1), growth hormone, ghrelin, leptin, and adiponectin-signal throughout the hypothalamic-pituitary-gonadal axis to support or suppress reproduction. We synthesize current knowledge on how these multifaceted hormones interact with the brain, pituitary, and ovaries to regulate functioning of the female reproductive system, incorporating in vitro and in vivo data from animal models and humans. Metabolic hormones are involved in orchestrating reproductive processes in healthy states, but some also play a significant role in the pathophysiology or treatment strategies of female reproductive disorders. Further understanding of the complex interrelationships between metabolic health and female reproductive function has important implications for improving women's health overall.
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Affiliation(s)
- Faria Athar
- Department of Biology, University of Victoria, Victoria, British Columbia V8P 5C2, Canada
| | - Muskan Karmani
- Department of Biology, University of Victoria, Victoria, British Columbia V8P 5C2, Canada
| | - Nicole M. Templeman
- Department of Biology, University of Victoria, Victoria, British Columbia V8P 5C2, Canada
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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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Folli F, Finzi G, Manfrini R, Galli A, Casiraghi F, Centofanti L, Berra C, Fiorina P, Davalli A, La Rosa S, Perego C, Higgins PB. Mechanisms of action of incretin receptor based dual- and tri-agonists in pancreatic islets. Am J Physiol Endocrinol Metab 2023; 325:E595-E609. [PMID: 37729025 PMCID: PMC10874655 DOI: 10.1152/ajpendo.00236.2023] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Revised: 09/15/2023] [Accepted: 09/16/2023] [Indexed: 09/22/2023]
Abstract
Simultaneous activation of the incretin G-protein-coupled receptors (GPCRs) via unimolecular dual-receptor agonists (UDRA) has emerged as a new therapeutic approach for type 2 diabetes. Recent studies also advocate triple agonism with molecules also capable of binding the glucagon receptor. In this scoping review, we discuss the cellular mechanisms of action (MOA) underlying the actions of these novel and therapeutically important classes of peptide receptor agonists. Clinical efficacy studies of several UDRAs have demonstrated favorable results both as monotherapies and when combined with approved hypoglycemics. Although the additive insulinotropic effects of dual glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic peptide receptor (GIPR) agonism were anticipated based on the known actions of either glucagon-like peptide-1 (GLP-1) or glucose-dependent insulinotropic peptide (GIP) alone, the additional benefits from GCGR were largely unexpected. Whether additional synergistic or antagonistic interactions among these G-protein receptor signaling pathways arise from simultaneous stimulation is not known. The signaling pathways affected by dual- and tri-agonism require more trenchant investigation before a comprehensive understanding of the cellular MOA. This knowledge will be essential for understanding the chronic efficacy and safety of these treatments.
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Affiliation(s)
- Franco Folli
- Dipartimento di Scienze della Salute, Università degli Studi di Milano, Milan, Italy
- Unit of Diabetes, Endocrinology and Metabolism, San Paolo Hospital, ASST Santi Paolo e Carlo, Milan, Italy
| | - Giovanna Finzi
- Unit of Pathology, Department of Oncology, ASST Sette Laghi, Varese, Italy
| | - Roberto Manfrini
- Dipartimento di Scienze della Salute, Università degli Studi di Milano, Milan, Italy
- Unit of Diabetes, Endocrinology and Metabolism, San Paolo Hospital, ASST Santi Paolo e Carlo, Milan, Italy
| | - Alessandra Galli
- Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy
| | - Francesca Casiraghi
- Dipartimento di Scienze della Salute, Università degli Studi di Milano, Milan, Italy
| | - Lucia Centofanti
- Dipartimento di Scienze della Salute, Università degli Studi di Milano, Milan, Italy
| | - Cesare Berra
- IRCCS MultiMedica, Sesto San Giovanni, Milan, Italy
| | - Paolo Fiorina
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC, Università di Milano, Milan, Italy
- Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States
- Division of Endocrinology, ASST Fatebenefratelli-Sacco, Milan, Italy
| | - Alberto Davalli
- Diabetes and Endocrinology Unit, Department of Internal Medicine, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Stefano La Rosa
- Unit of Pathology, Department of Medicine and Technological Innovation, University of Insubria, Varese, Italy
| | - Carla Perego
- Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy
| | - Paul B Higgins
- Department of Life & Physical Sciences, Atlantic Technological University, Letterkenny, Ireland
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Zhang M, Zhang S, Yu Z, Yao X, Lei Z, Yan P, Wu N, Wang X, Hu Q, Liu D. Dose decision of HSK7653 oral immediate release tablets in specific populations clinical trials based on mechanistic physiologically-based pharmacokinetic model. Eur J Pharm Sci 2023; 189:106553. [PMID: 37532063 PMCID: PMC10485820 DOI: 10.1016/j.ejps.2023.106553] [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: 03/13/2023] [Revised: 07/25/2023] [Accepted: 07/30/2023] [Indexed: 08/04/2023]
Abstract
HSK7653, an oral dipeptidyl peptidase-4 inhibitor administered every 2 weeks, is a candidate for the treatment of type 2 diabetes mellitus. The major elimination pathway of HSK7653 in vivo is renal excretion, and hepatic metabolism and fecal excretion of unchanged compound contribute less to the systemic clearance of HSK7653. Considering the disposition characteristics and the potential indication population of HSK7653, evaluating the HSK7653 exposure in patients with renal impairment and geriatric populations is a prerequisite for bringing more benefits to the patients. Here, a PBPK model was developed based on in vitro experimental results, such as dissolution, permeability, and metabolism, and the in vivo renal clearance, to evaluate the effects of physiological factors and food on HSK7653 exposure in specific populations, including adult and elder individuals with renal impairment and geriatric populations. Simulation results showed that the AUC of HSK7653 increased by 46%, 82%, and 129% in adult patients with mild, moderate, and severe renal impairment, and by 56%, 78%, and 101% in patients aged 65-75, 75-85 and 85-95 years, respectively. The AUC increased in the range of 62%-83%, 98%-133%, and 153%-195% in elderly patients (65-95 years) with mild, moderate, and severe renal impairment, respectively. Moreover, two different absorption model development methods (dissolution profile method and the diffusion layer model method) predicted that food had no effect on the exposure of the same simulated population. Since the predicted AUC of HSK7653 at the 10 mg dose in various specific populations was still within the relatively flat results of the exposure-response analysis, the 10 mg dose of HSK7653 was first used to explore the exposure in the renal impairment population (CTR20221952).
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Affiliation(s)
- Miao Zhang
- Drug Clinical Trial Center, Peking University Third Hospital, Beijing, China; Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, NY, United States
| | - Shudong Zhang
- Beijing Institute for Drug Control, NMPA Key Laboratory for Research and Evaluation of Generic Drugs, Beijing Key Laboratory of Analysis and Evaluation on Chinese Medicine, Beijing, China
| | - Zhiheng Yu
- Drug Clinical Trial Center, Peking University Third Hospital, Beijing, China; Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
| | - Xueting Yao
- Drug Clinical Trial Center, Peking University Third Hospital, Beijing, China
| | - Zihan Lei
- Drug Clinical Trial Center, Peking University Third Hospital, Beijing, China
| | - Pangke Yan
- Haisco Pharmaceutical Group Co., Ltd., Chengdu, China
| | - Nan Wu
- Haisco Pharmaceutical Group Co., Ltd., Chengdu, China
| | - Xu Wang
- Haisco Pharmaceutical Group Co., Ltd., Chengdu, China
| | - Qin Hu
- Beijing Institute for Drug Control, NMPA Key Laboratory for Research and Evaluation of Generic Drugs, Beijing Key Laboratory of Analysis and Evaluation on Chinese Medicine, Beijing, China
| | - Dongyang Liu
- Drug Clinical Trial Center, Peking University Third Hospital, Beijing, China.
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7
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Wu MZ, GongPan PC, Dai MY, Sun P, Huang TP, Xu YK, Xiao CF, Li J, Sun YL, Ji KL. Dimeric styrylpyrones with stimulating GLP-1 secretion activities from Alpinia kwangsiensis. Tetrahedron 2022. [DOI: 10.1016/j.tet.2022.132901] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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8
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Florentin M, Kostapanos MS, Papazafiropoulou AK. Role of dipeptidyl peptidase 4 inhibitors in the new era of antidiabetic treatment. World J Diabetes 2022; 13:85-96. [PMID: 35211246 PMCID: PMC8855136 DOI: 10.4239/wjd.v13.i2.85] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 07/29/2021] [Accepted: 01/26/2022] [Indexed: 02/06/2023] Open
Abstract
The last few years important changes have occurred in the field of diabetes treatment. The priority in the therapy of patients with diabetes is not glycemic control per se rather an overall management of risk factors, while individualization of glycemic target is suggested. Furthermore, regulatory authorities now require evidence of cardiovascular (CV) safety in order to approve new antidiabetic agents. The most novel drug classes, i.e., sodium-glucose transporter 2 inhibitors (SGLT2-i) and some glucagon-like peptide-1 receptor agonists (GLP-1 RA), have been demonstrated to reduce major adverse CV events and, thus, have a prominent position in the therapeutic algorithm of hyperglycemia. In this context, the role of previously used hypoglycemic agents, including dipeptidyl peptidase 4 (DPP-4) inhibitors, has been modified. DPP-4 inhibitors have a favorable safety profile, do not cause hypoglycemia or weight gain and do not require dose uptitration. Furthermore, they can be administered in patients with chronic kidney disease after dose modification and elderly patients with diabetes. Still, though, they have been undermined to a third line therapeutic choice as they have not been shown to reduce CV events as is the case with SGLT2-i and GLP-1 RA. Overall, DPP-4 inhibitors appear to have a place in the management of patients with diabetes as a safe class of oral glucose lowering agents with great experience in their use.
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Affiliation(s)
- Matilda Florentin
- Department of Internal Medicine, School of Medicine, University of Ioannina, Ioannina 45221, Greece
| | - Michael S Kostapanos
- Lipid Clinic, Department of General Medicine, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom
| | - Athanasia K Papazafiropoulou
- 1st Department of Internal Medicine and Diabetes Center, Tzaneio General Hospital of Piraeus, Athens 18536, Greece
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9
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Tantisattamo E, Kalantar-Zadeh K, Molnar MZ. Nutritional and dietary interventions to prolong renal allograft survival after kidney transplantation. Curr Opin Nephrol Hypertens 2022; 31:6-17. [PMID: 34750333 DOI: 10.1097/mnh.0000000000000757] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
PURPOSE OF REVIEW Diet plays an important role in slowing progression of chronic kidney disease in native and transplanted kidneys. There is limited evidence on the association on dietary intake with renal allograft function. Mechanisms of major nutrients and dietary patterns with focusing on a plant-based diet related to kidney transplant health and longevity are reviewed. RECENT FINDINGS High dietary protein intake may adversely affect renal allograft. Low protein plant-focused diets such as Dietary Approaches to Stop Hypertension, plant-dominant low-protein diet and Mediterranean diets appear associated with favorable outcomes in slowing renal allograft function decline. The mechanism may be related to a change in renal hemodynamic by decreasing glomerular hyperfiltration from low dietary protein intake and plant-based ingredients. Recent observational studies of association between dietary protein intake and kidney allograft outcomes are conflicting. Although strong evidence is still lacking, a low protein diet of 0.6-0.8 g/kg/day with at least 50% of the protein source from plant-based components in kidney transplant recipients with stable kidney allograft function should be considered as the dietary target. SUMMARY Dietary intervention with low-protein plant-focused meals may improve outcomes in kidney transplant recipients, but the evidence remains limited and further studies are warranted.
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Affiliation(s)
- Ekamol Tantisattamo
- Harold Simmons Center for Kidney Disease Research and Epidemiology, Division of Nephrology, Hypertension and Kidney Transplantation, Department of Medicine, University of California Irvine School of Medicine, Orange.,Nephrology Section, Department of Medicine, Tibor Rubin Veterans Affairs Medical Center, Veterans Affairs Long Beach Healthcare System, Long Beach, California.,Multi-Organ Transplant Center, Section of Nephrology, Department of Internal Medicine, William Beaumont Hospital, Oakland University William Beaumont School of Medicine, Royal Oak, Michigan
| | - Kamyar Kalantar-Zadeh
- Harold Simmons Center for Kidney Disease Research and Epidemiology, Division of Nephrology, Hypertension and Kidney Transplantation, Department of Medicine, University of California Irvine School of Medicine, Orange.,Nephrology Section, Department of Medicine, Tibor Rubin Veterans Affairs Medical Center, Veterans Affairs Long Beach Healthcare System, Long Beach, California.,Lundquist Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California
| | - Miklos Z Molnar
- Division of Nephrology and Hypertension, Department of Medicine, University of Utah, Utah, USA
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Lamontagne-Proulx J, Coulombe K, Dahhani F, Côté M, Guyaz C, Tremblay C, Di Marzo V, Flamand N, Calon F, Soulet D. Effect of Docosahexaenoic Acid (DHA) at the Enteric Level in a Synucleinopathy Mouse Model. Nutrients 2021; 13:nu13124218. [PMID: 34959768 PMCID: PMC8703327 DOI: 10.3390/nu13124218] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 11/18/2021] [Accepted: 11/22/2021] [Indexed: 12/15/2022] Open
Abstract
The aggregation of alpha-synuclein protein (αSyn) is a hallmark of Parkinson’s disease (PD). Considerable evidence suggests that PD involves an early aggregation of αSyn in the enteric nervous system (ENS), spreading to the brain. While it has previously been reported that omega-3 polyunsaturated fatty acids (ω-3 PUFA) acts as neuroprotective agents in the brain in murine models of PD, their effect in the ENS remains undefined. Here, we studied the effect of dietary supplementation with docosahexaenoic acid (DHA, an ω-3 PUFA), on the ENS, with a particular focus on enteric dopaminergic (DAergic) neurons. Thy1-αSyn mice, which overexpress human αSyn, were fed ad libitum with a control diet, a low ω-3 PUFA diet or a diet supplemented with microencapsulated DHA and then compared with wild-type littermates. Our data indicate that Thy1-αSyn mice showed a lower density of enteric dopaminergic neurons compared with non-transgenic animals. This decrease was prevented by dietary DHA. Although we found that DHA reduced microgliosis in the striatum, we did not observe any evidence of peripheral inflammation. However, we showed that dietary intake of DHA promoted a build-up of ω-3 PUFA-derived endocannabinoid (eCB)-like mediators in plasma and an increase in glucagon-like peptide-1 (GLP-1) and the redox regulator, Nrf2 in the ENS. Taken together, our results suggest that DHA exerts neuroprotection of enteric DAergic neurons in the Thy1-αSyn mice, possibly through alterations in eCB-like mediators, GLP-1 and Nrf2.
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Affiliation(s)
- Jérôme Lamontagne-Proulx
- Centre de Recherche du CHU de Québec, Québec, QC G1V 4G2, Canada; (J.L.-P.); (K.C.); (M.C.); (C.T.); (F.C.)
- Faculté de Pharmacie, Université Laval, Québec, QC G1V 0A6, Canada;
| | - Katherine Coulombe
- Centre de Recherche du CHU de Québec, Québec, QC G1V 4G2, Canada; (J.L.-P.); (K.C.); (M.C.); (C.T.); (F.C.)
| | - Fadil Dahhani
- Centre de Recherche de l’Institut Universitaire de Cardiologie et de Pneumologie de Québec (IUCPQ), Québec, QC G1V 4G5, Canada; (F.D.); (V.D.); (N.F.)
- Canada Excellence Research in the Microbiome-Endocannabinoidome Axis in Metabolic Health (CERC-MEND), Québec, QC G1V 4G5, Canada
| | - Mélissa Côté
- Centre de Recherche du CHU de Québec, Québec, QC G1V 4G2, Canada; (J.L.-P.); (K.C.); (M.C.); (C.T.); (F.C.)
| | - Cédric Guyaz
- Faculté de Pharmacie, Université Laval, Québec, QC G1V 0A6, Canada;
| | - Cyntia Tremblay
- Centre de Recherche du CHU de Québec, Québec, QC G1V 4G2, Canada; (J.L.-P.); (K.C.); (M.C.); (C.T.); (F.C.)
- Faculté de Pharmacie, Université Laval, Québec, QC G1V 0A6, Canada;
| | - Vincenzo Di Marzo
- Centre de Recherche de l’Institut Universitaire de Cardiologie et de Pneumologie de Québec (IUCPQ), Québec, QC G1V 4G5, Canada; (F.D.); (V.D.); (N.F.)
- Canada Excellence Research in the Microbiome-Endocannabinoidome Axis in Metabolic Health (CERC-MEND), Québec, QC G1V 4G5, Canada
- Faculté de Médecine, Université Laval, Québec, QC G1V 0A6, Canada
- Institut sur la Nutrition et les Aliments Fonctionnels (INAF) et Centre NUTRISS, Université Laval, Québec, QC G1V 0A6, Canada
| | - Nicolas Flamand
- Centre de Recherche de l’Institut Universitaire de Cardiologie et de Pneumologie de Québec (IUCPQ), Québec, QC G1V 4G5, Canada; (F.D.); (V.D.); (N.F.)
- Canada Excellence Research in the Microbiome-Endocannabinoidome Axis in Metabolic Health (CERC-MEND), Québec, QC G1V 4G5, Canada
- Faculté de Médecine, Université Laval, Québec, QC G1V 0A6, Canada
| | - Frédéric Calon
- Centre de Recherche du CHU de Québec, Québec, QC G1V 4G2, Canada; (J.L.-P.); (K.C.); (M.C.); (C.T.); (F.C.)
- Faculté de Pharmacie, Université Laval, Québec, QC G1V 0A6, Canada;
- Laboratoire International Associé OptiNutriBrain, (NutriNeuro France-INAF Canada), Québec, QC G1V 0A6, Canada
| | - Denis Soulet
- Centre de Recherche du CHU de Québec, Québec, QC G1V 4G2, Canada; (J.L.-P.); (K.C.); (M.C.); (C.T.); (F.C.)
- Faculté de Pharmacie, Université Laval, Québec, QC G1V 0A6, Canada;
- Institut sur la Nutrition et les Aliments Fonctionnels (INAF) et Centre NUTRISS, Université Laval, Québec, QC G1V 0A6, Canada
- Correspondence: ; Tel.: +1-418-654-2296
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11
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Sun EW, Martin AM, de Fontgalland D, Sposato L, Rabbitt P, Hollington P, Wattchow DA, Colella AD, Chataway T, Wewer Albrechtsen NJ, Spencer NJ, Young RL, Keating DJ. Evidence for Glucagon Secretion and Function Within the Human Gut. Endocrinology 2021; 162:6127286. [PMID: 33534908 DOI: 10.1210/endocr/bqab022] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2020] [Indexed: 11/19/2022]
Abstract
Glucagon is secreted by pancreatic α cells in response to hypoglycemia and increases hepatic glucose output through hepatic glucagon receptors (GCGRs). There is evidence supporting the notion of extrapancreatic glucagon but its source and physiological functions remain elusive. Intestinal tissue samples were obtained from patients undergoing surgical resection of cancer. Mass spectrometry analysis was used to detect glucagon from mucosal lysate. Static incubations of mucosal tissue were performed to assess glucagon secretory response. Glucagon concentration was quantitated using a highly specific sandwich enzyme-linked immunosorbent assay. A cholesterol uptake assay and an isolated murine colonic motility assay were used to assess the physiological functions of intestinal GCGRs. Fully processed glucagon was detected by mass spectrometry in human intestinal mucosal lysate. High glucose evoked significant glucagon secretion from human ileal tissue independent of sodium glucose cotransporter and KATP channels, contrasting glucose-induced glucagon-like peptide 1 (GLP-1) secretion. The GLP-1 receptor agonist Exendin-4 attenuated glucose-induced glucagon secretion from the human ileum. GCGR blockade significantly increased cholesterol uptake in human ileal crypt culture and markedly slowed ex vivo colonic motility. Our findings describe the human gut as a potential source of extrapancreatic glucagon and demonstrate a novel enteric glucagon/GCGR circuit with important physiological functions beyond glycemic regulation.
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Affiliation(s)
- Emily W Sun
- Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Bedford Park, SA, Australia
| | - Alyce M Martin
- Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Bedford Park, SA, Australia
| | | | - Luigi Sposato
- Department of Surgery, Flinders Medical Centre, Bedford Park, SA, Australia
| | - Philippa Rabbitt
- Department of Surgery, Flinders Medical Centre, Bedford Park, SA, Australia
| | - Paul Hollington
- Department of Surgery, Flinders Medical Centre, Bedford Park, SA, Australia
| | - David A Wattchow
- Department of Surgery, Flinders Medical Centre, Bedford Park, SA, Australia
| | - Alexander D Colella
- Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Bedford Park, SA, Australia
| | - Tim Chataway
- Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Bedford Park, SA, Australia
| | | | - Nick J Spencer
- Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Bedford Park, SA, Australia
| | - Richard L Young
- Adelaide Medical School and NHMRC Centre of Research Excellence in Translating Nutritional Science to Good Health, University of Adelaide, Adelaide, SA, Australia
- Nutrition, Diabetes and Metabolism, Lifelong Health, South Australia Health and Medical Research Institute, Adelaide, SA, Australia
| | - Damien J Keating
- Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Bedford Park, SA, Australia
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12
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Vastagh C, Farkas I, Scott MM, Liposits Z. Networking of glucagon-like peptide-1 axons with GnRH neurons in the basal forebrain of male mice revealed by 3DISCO-based immunocytochemistry and optogenetics. Brain Struct Funct 2020; 226:105-120. [PMID: 33169188 PMCID: PMC7817561 DOI: 10.1007/s00429-020-02167-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Accepted: 10/17/2020] [Indexed: 12/25/2022]
Abstract
Glucagon-like peptide-1 (GLP-1) regulates reproduction centrally, although, the neuroanatomical basis of the process is unknown. Therefore, the putative networking of the central GLP-1 and gonadotropin-releasing hormone (GnRH) systems was addressed in male mice using whole mount immunocytochemistry and optogenetics. Enhanced antibody penetration and optical clearing procedures applied to 500–1000 µm thick basal forebrain slices allowed the simultaneous visualization of the two distinct systems in the basal forebrain. Beaded GLP-1-IR axons innervated about a quarter of GnRH neurons (23.2 ± 1.4%) forming either single or multiple contacts. GnRH dendrites received a more intense GLP-1 innervation (64.6 ± 0.03%) than perikarya (35.4 ± 0.03%). The physiological significance of the innervation was examined by optogenetic activation of channelrhodopsin-2 (ChR2)-expressing axons of preproglucagon (GCG) neurons upon the firing of GnRH neurons by patch clamp electrophysiology in acute brain slices of triple transgenic mice (Gcg-cre/ChR2/GFP-GnRH). High-frequency laser beam stimulation (20 Hz, 10 ms pulse width, 3 mW laser power) of ChR2-expressing GCG axons in the mPOA increased the firing rate of GnRH neurons (by 75 ± 17.3%, p = 0.0007). Application of the GLP-1 receptor antagonist, Exendin-3-(9-39) (1 μM), prior to the photo-stimulation, abolished the facilitatory effect. In contrast, low-frequency trains of laser pulses (0.2 Hz, 60 pulses) had no effect on the spontaneous postsynaptic currents of GnRH neurons. The findings indicate a direct wiring of GLP-1 neurons with GnRH cells which route is excitatory for the GnRH system. The pathway may relay metabolic signals to GnRH neurons and synchronize metabolism with reproduction.
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Affiliation(s)
- Csaba Vastagh
- Laboratory of Endocrine Neurobiology, Institute of Experimental Medicine, Szigony u. 43, 1083, Budapest, Hungary
| | - Imre Farkas
- Laboratory of Reproductive Neurobiology, Institute of Experimental Medicine, Budapest, Hungary
| | - Michael M Scott
- Department of Pharmacology, School of Medicine, University of Virginia, Charlottesville, VA, USA
| | - Zsolt Liposits
- Laboratory of Endocrine Neurobiology, Institute of Experimental Medicine, Szigony u. 43, 1083, Budapest, Hungary.
- Department of Neuroscience, Faculty of Information Technology and Bionics, Pázmány Péter Catholic University, Budapest, Hungary.
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13
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Ho HJ, Komai M, Shirakawa H. Beneficial Effects of Vitamin K Status on Glycemic Regulation and Diabetes Mellitus: A Mini-Review. Nutrients 2020; 12:nu12082485. [PMID: 32824773 PMCID: PMC7469006 DOI: 10.3390/nu12082485] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 08/12/2020] [Accepted: 08/13/2020] [Indexed: 12/16/2022] Open
Abstract
Type 2 diabetes mellitus is a chronic disease that is characterized by hyperglycemia, insulin resistance, and dysfunctional insulin secretion. Glycemic control remains a crucial contributor to the progression of type 2 diabetes mellitus as well as the prevention or delay in the onset of diabetes-related complications. Vitamin K is a fat-soluble vitamin that plays an important role in the regulation of the glycemic status. Supplementation of vitamin K may reduce the risk of diabetes mellitus and improve insulin sensitivity. This mini-review summarizes the recent insights into the beneficial effects of vitamin K and its possible mechanism of action on insulin sensitivity and glycemic status, thereby suppressing the progression of diabetes mellitus.
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Affiliation(s)
- Hsin-Jung Ho
- Laboratory of Nutrition, Graduate School of Agricultural Science, Tohoku University, Sendai 980-8572, Japan; (M.K.); (H.S.)
- Correspondence: ; Tel.: +81-11-706-3395
| | - Michio Komai
- Laboratory of Nutrition, Graduate School of Agricultural Science, Tohoku University, Sendai 980-8572, Japan; (M.K.); (H.S.)
| | - Hitoshi Shirakawa
- Laboratory of Nutrition, Graduate School of Agricultural Science, Tohoku University, Sendai 980-8572, Japan; (M.K.); (H.S.)
- International Education and Research Center for Food Agricultural Immunology, Graduate School of Agricultural Science, Tohoku University, Sendai 980-8572, Japan
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14
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Duszka K, Gregor A, Reichel MW, Baierl A, Fahrngruber C, König J. Visual stimulation with food pictures in the regulation of hunger hormones and nutrient deposition, a potential contributor to the obesity crisis. PLoS One 2020; 15:e0232099. [PMID: 32330183 PMCID: PMC7182185 DOI: 10.1371/journal.pone.0232099] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Accepted: 04/07/2020] [Indexed: 12/11/2022] Open
Abstract
Food cues affect hunger and nutritional choices. Omnipresent stimulation with palatable food contributes to the epidemics of obesity. The objective of the study was to investigate the impact of food cues on appetite-related hormones and to assess the functionality of the secreted hormones on macronutrient uptake in healthy subjects. Additionally, we aimed at verifying differences in the response of total and active ghrelin to stimulation with food pictures and to a meal followed by the stimulation. We were also interested in the identification of factors contributing to response to food cues. We recruited healthy, non-obese participants for two independent cross-over studies. During the first study, the subjects were presented random non-food pictures on the first day and pictures of foods on the second day of the study. Throughout the second study, following the picture session, the participants were additionally asked to drink a milkshake. Concentrations of blood glucose, triglycerides and hunger-related hormones were measured. The results showed that concentrations of several hormones measured in the blood are interdependent. In the case of ghrelin and gastric inhibitory peptide (GIP) as well as ghrelin and glucagon-like peptide-1 (GLP-1), this co-occurrence relies on the visual cues. Regulation of total ghrelin concentration following food stimulation is highly individual and responders showed upregulated total ghrelin, while the concentration of active ghrelin decreases following a meal. Protein content and colour intensity of food pictures reversely correlated with participants’ rating of the pictures. We conclude that observation of food pictures influences the concentration of several appetite-related hormones. The close link of visual clues to physiological responses is likely of clinical relevance. Additionally, the protein content of displayed foods and green colour intensity in pictures may serve as a predictor of subjective attractiveness of the presented meal.
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Affiliation(s)
- Kalina Duszka
- Department of Nutritional Sciences, University of Vienna, Vienna, Austria
- * E-mail:
| | - András Gregor
- Department of Nutritional Sciences, University of Vienna, Vienna, Austria
| | | | - Andreas Baierl
- Department of Statistics and Operations Research, University of Vienna, Vienna, Austria
| | | | - Jürgen König
- Department of Nutritional Sciences, University of Vienna, Vienna, Austria
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15
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Drug discovery approaches targeting the incretin pathway. Bioorg Chem 2020; 99:103810. [PMID: 32325333 DOI: 10.1016/j.bioorg.2020.103810] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Revised: 02/20/2020] [Accepted: 03/29/2020] [Indexed: 12/20/2022]
Abstract
Incretin pathway plays an important role in the development of diabetes medications. Interventions in DPP-4 and GLP-1 receptor have shown remarkable efficacy in experimental and clinical studies and imperatively become one of the most promising therapeutic approaches in the T2DM drug discovery pipeline. Herein, we analyzed the actionmechanismsof DPP-4 and GLP-1 receptor targeting the incretin pathway in T2DM treatment. We gave an insight into the structural requirements for the potent DPP-4 inhibitors and revealed a classification of DPP-4 inhibitors by stressing on the binding modes of these ligands to the enzyme. We then reviewed the drug discovery strategies for the development of peptide and non-peptide GLP-1 receptor agonists (GLP-1 RAs). Furthermore, the drug design strategies for DPP-4 inhibitors and GLP-1R agonists were detailed accurately. This review might provide an efficient evidence for the highly potent and selective DPP-4 inhibitors and the GLP-1 RAs, as novel medicines for patients suffering from T2DM.
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16
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Graham GV, McCloskey A, Abdel-Wahab YH, Conlon JM, Flatt PR. A long-acting, dual-agonist analogue of lamprey GLP-1 shows potent insulinotropic, β-cell protective, and anorexic activities and improves glucose homeostasis in high fat-fed mice. Mol Cell Endocrinol 2020; 499:110584. [PMID: 31539596 DOI: 10.1016/j.mce.2019.110584] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2019] [Revised: 08/05/2019] [Accepted: 09/16/2019] [Indexed: 12/12/2022]
Abstract
Peptidase-resistant analogues of GLP-1 peptides from sea lamprey and paddlefish ([D-Ala2]palmitoyl-lamprey GLP-1 and [D-Ala2]palmitoyl-paddlefish GLP-1) produced significant (P ≤ 0.05) and concentration-dependent increases in insulin release from BRIN-BD11 clonal β-cells and from isolated mouse islets. Both analogues retained the ability of the native peptides to activate both the GLP-1 receptor (GLP1R) and the glucagon receptor (GCGR). [D-Ala2]palmitoyl-lamprey GLP-1 significantly (P < 0.001) stimulated proliferation of BRIN-BD11 cells and protected against cytokine-induced apoptosis. Administration of the lamprey analogue (25 nmol/kg body weight) to lean mice up to 4 h before a glucose load improved glucose tolerance and increased plasma insulin concentrations. Twice daily administration of the lamprey GLP-1 analogue to high fat-fed mice for 21 days decreased body weight, food intake, and circulating glucose and insulin concentrations. The analogue significantly improved glucose tolerance and insulin sensitivity with beneficial effects on islet β-cell area and insulin secretory responsiveness. Islet gene expression of Glp1r, Gcgr and Gipr significantly increased. The lamprey GLP-1 analogue shows therapeutic promise for treatment of patients with obesity-related Type 2 diabetes.
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Affiliation(s)
- Galyna V Graham
- SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland BT52 1SA, UK
| | - Andrew McCloskey
- SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland BT52 1SA, UK
| | - Yasser H Abdel-Wahab
- SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland BT52 1SA, UK
| | - J Michael Conlon
- SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland BT52 1SA, UK.
| | - Peter R Flatt
- SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland BT52 1SA, UK
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17
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Gilbert MP, Pratley RE. GLP-1 Analogs and DPP-4 Inhibitors in Type 2 Diabetes Therapy: Review of Head-to-Head Clinical Trials. Front Endocrinol (Lausanne) 2020; 11:178. [PMID: 32308645 PMCID: PMC7145895 DOI: 10.3389/fendo.2020.00178] [Citation(s) in RCA: 205] [Impact Index Per Article: 41.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Accepted: 03/12/2020] [Indexed: 12/15/2022] Open
Abstract
The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are released from enteroendocrine cells in response to the presence of nutrients in the small intestines. These homones facilitate glucose regulation by stimulating insulin secretion in a glucose dependent manner while suppressing glucagon secretion. In patients with type 2 diabetes (T2DM), an impaired insulin response to GLP-1 and GIP contributes to hyperglycemia. Dipeptidyl peptidase-4 (DPP-4) inhibitors block the breakdown of GLP-1 and GIP to increase levels of the active hormones. In clinical trials, DPP-4 inhibitors have a modest impact on glycemic control. They are generally well-tolerated, weight neutral and do not increase the risk of hypoglycemia. GLP-1 receptor agonists (GLP-1 RA) are peptide derivatives of either exendin-4 or human GLP-1 designed to resist the activity of DPP-4 and therefore, have a prolonged half-life. In clinical trials, they have demonstrated superior efficacy to many oral antihyperglycemic drugs, improved weight loss and a low risk of hypoglycemia. However, GI adverse events, particularly nausea, vomiting, and diarrhea are seen. Both DPP-4 inhibitors and GLP-1 RAs have demonstrated safety in robust cardiovascular outcome trials, while several GLP-1 RAs have been shown to significantly reduce the risk of major adverse cardiovascular events in persons with T2DM with pre-existing cardiovascular disease (CVD). Several clinical trials have directly compared the efficacy and safety of DPP-4 inhibitors and GLP-1 RAs. These studies have generally demonstrated that the GLP-1 RA provided superior glycemic control and weight loss relative to the DPP-4 inhibitor. Both treatments were associated with a low and comparable incidence of hypoglycemia, but treatment with GLP-1 RAs were invariably associated with a higher incidence of GI adverse events. A few studies have evaluated switching patients from DPP-4 inhibitors to a GLP-1RA and, as expected, improved glycemic control and weight loss are seen following the switch. According to current clinical guidelines, GLP-1RA and DPP-4 inhibitors are both indicated for the glycemic management of patients with T2DM across the spectrum of disease. GLP-1RA may be preferred over DPP- 4 inhibitors for many patients because of the greater reductions in hemoglobin A1c and weight loss observed in the clinical trials. Among patients with preexisting CVD, GLP-1 receptor agonists with a proven cardiovascular benefit are indicated as add-on to metformin therapy.
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Affiliation(s)
- Matthew P. Gilbert
- Division of Endocrinology and Diabetes, Department of Medicine, Larner College of Medicine at the University of Vermont, Burlington, VT, United States
- *Correspondence: Matthew P. Gilbert
| | - Richard E. Pratley
- AdventHealth Diabetes Institute, Translational Research Institute for Metabolism and Diabetes, Orlando, FL, United States
- Richard E. Pratley
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18
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Müller TD, Finan B, Bloom SR, D'Alessio D, Drucker DJ, Flatt PR, Fritsche A, Gribble F, Grill HJ, Habener JF, Holst JJ, Langhans W, Meier JJ, Nauck MA, Perez-Tilve D, Pocai A, Reimann F, Sandoval DA, Schwartz TW, Seeley RJ, Stemmer K, Tang-Christensen M, Woods SC, DiMarchi RD, Tschöp MH. Glucagon-like peptide 1 (GLP-1). Mol Metab 2019; 30:72-130. [PMID: 31767182 PMCID: PMC6812410 DOI: 10.1016/j.molmet.2019.09.010] [Citation(s) in RCA: 1109] [Impact Index Per Article: 184.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Revised: 09/10/2019] [Accepted: 09/22/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The glucagon-like peptide-1 (GLP-1) is a multifaceted hormone with broad pharmacological potential. Among the numerous metabolic effects of GLP-1 are the glucose-dependent stimulation of insulin secretion, decrease of gastric emptying, inhibition of food intake, increase of natriuresis and diuresis, and modulation of rodent β-cell proliferation. GLP-1 also has cardio- and neuroprotective effects, decreases inflammation and apoptosis, and has implications for learning and memory, reward behavior, and palatability. Biochemically modified for enhanced potency and sustained action, GLP-1 receptor agonists are successfully in clinical use for the treatment of type-2 diabetes, and several GLP-1-based pharmacotherapies are in clinical evaluation for the treatment of obesity. SCOPE OF REVIEW In this review, we provide a detailed overview on the multifaceted nature of GLP-1 and its pharmacology and discuss its therapeutic implications on various diseases. MAJOR CONCLUSIONS Since its discovery, GLP-1 has emerged as a pleiotropic hormone with a myriad of metabolic functions that go well beyond its classical identification as an incretin hormone. The numerous beneficial effects of GLP-1 render this hormone an interesting candidate for the development of pharmacotherapies to treat obesity, diabetes, and neurodegenerative disorders.
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Affiliation(s)
- T D Müller
- Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany; Department of Pharmacology and Experimental Therapy, Institute of Experimental and Clinical Pharmacology and Toxicology, Eberhard Karls University Hospitals and Clinics, Tübingen, Germany.
| | - B Finan
- Novo Nordisk Research Center Indianapolis, Indianapolis, IN, USA
| | - S R Bloom
- Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London, UK
| | - D D'Alessio
- Division of Endocrinology, Duke University Medical Center, Durham, NC, USA
| | - D J Drucker
- The Department of Medicine, Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, University of Toronto, Ontario, M5G1X5, Canada
| | - P R Flatt
- SAAD Centre for Pharmacy & Diabetes, Ulster University, Coleraine, Northern Ireland, UK
| | - A Fritsche
- German Center for Diabetes Research (DZD), Neuherberg, Germany; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany; Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, Department of Internal Medicine, University of Tübingen, Tübingen, Germany
| | - F Gribble
- Metabolic Research Laboratories and Medical Research Council Metabolic Diseases Unit, Wellcome Trust-Medical Research Council, Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, CB2 0QQ, UK
| | - H J Grill
- Institute of Diabetes, Obesity and Metabolism, Department of Psychology, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - J F Habener
- Laboratory of Molecular Endocrinology, Massachusetts General Hospital, Harvard University, Boston, MA, USA
| | - J J Holst
- Novo Nordisk Foundation Center for Basic Metabolic Research, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - W Langhans
- Physiology and Behavior Laboratory, ETH Zurich, Schwerzenbach, Switzerland
| | - J J Meier
- Diabetes Division, St Josef Hospital, Ruhr-University Bochum, Bochum, Germany
| | - M A Nauck
- Diabetes Center Bochum-Hattingen, St Josef Hospital (Ruhr-Universität Bochum), Bochum, Germany
| | - D Perez-Tilve
- Department of Internal Medicine, University of Cincinnati-College of Medicine, Cincinnati, OH, USA
| | - A Pocai
- Cardiovascular & ImmunoMetabolism, Janssen Research & Development, Welsh and McKean Roads, Spring House, PA, 19477, USA
| | - F Reimann
- Metabolic Research Laboratories and Medical Research Council Metabolic Diseases Unit, Wellcome Trust-Medical Research Council, Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, CB2 0QQ, UK
| | - D A Sandoval
- Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA
| | - T W Schwartz
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, DL-2200, Copenhagen, Denmark; Department of Biomedical Sciences, University of Copenhagen, DK-2200, Copenhagen, Denmark
| | - R J Seeley
- Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA
| | - K Stemmer
- Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - M Tang-Christensen
- Obesity Research, Global Drug Discovery, Novo Nordisk A/S, Måløv, Denmark
| | - S C Woods
- Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, OH, USA
| | - R D DiMarchi
- Novo Nordisk Research Center Indianapolis, Indianapolis, IN, USA; Department of Chemistry, Indiana University, Bloomington, IN, USA
| | - M H Tschöp
- German Center for Diabetes Research (DZD), Neuherberg, Germany; Division of Metabolic Diseases, Department of Medicine, Technische Universität München, Munich, Germany; Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
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19
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Guan B, Wang L, Ma L, Liu X, Liu L. EFFECTS OF EXENDIN-4 ON ENDOPLASMIC RETICULUM STRESS-MEDIATED INSULIN RESISTANCE IN 3T3-L1 ADIPOCYTES. ACTA ENDOCRINOLOGICA-BUCHAREST 2019; 15:158-164. [PMID: 31508171 DOI: 10.4183/aeb.2019.158] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Objective Endoplasmic reticulum stress (ERS) is suspected as an important factor in the initiation of insulin resistance. Aim To explore the effects of exendin-4 (Ex-4) on the endoplasmic reticulum stress (ERS)-mediated insulin resistance in 3T3-L1 adipocytes. In our study, 3T3-L1 adipocytes were pre-treated with ERS inhibitors tauroursodeoxycholic acid (TUDCA), Ex-4 and an ERS inducer tunicamycin (TM) then induced insulin resistance. Glucose consumption of the adipocytes was measured. Western blots determined the protein levels of ERS markers and insulin signaling pathway. Results TM treatment reduced insulin-stimulated glucose consumption by 19.7% in 3T3-L1 adipocytes. This repression was blunted by 24h pre-treatment with TUDCA or Ex-4. Ex-4 augmented insulin-stimulated glucose consumption in adipocytes by 14.9%. Western blotting showed that TM treatment significantly increased the ER stress markers including p-IRE, p-JNK, p-PERK, p-eIF2a and ATF6 expression, whereas 24h pre-treatment of adipocytes with TUDCA or Ex-4 alleviated the ER stress. Ex-4 alleviates ERS-induced insulin resistance by upregulating the expression of phosphorylated Akt. Conclusion ERs mediates insulin resistance in 3T3-L1 adipocytes, and exendin-4 significantly improves this insulin resistance.
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Affiliation(s)
- B Guan
- Dept. of Endocrinology, Union Hospital, Fujian Medical University, Fuzhou, Fujian, China
| | - L Wang
- Dept. of Endocrinology, Union Hospital, Fujian Medical University, Fuzhou, Fujian, China
| | - L Ma
- Dept. of Endocrinology, Union Hospital, Fujian Medical University, Fuzhou, Fujian, China
| | - X Liu
- Dept. of Endocrinology, Union Hospital, Fujian Medical University, Fuzhou, Fujian, China
| | - L Liu
- Dept. of Endocrinology, Union Hospital, Fujian Medical University, Fuzhou, Fujian, China
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20
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Nolen-Doerr E, Stockman MC, Rizo I. Mechanism of Glucagon-Like Peptide 1 Improvements in Type 2 Diabetes Mellitus and Obesity. Curr Obes Rep 2019; 8:284-291. [PMID: 31124035 DOI: 10.1007/s13679-019-00350-4] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
PURPOSE OF REVIEW The purpose of this review is to emphasize the pivotal role of glucagon-like peptide 1 (GLP-1) in tackling the parallel epidemics of obesity and type 2 diabetes (T2DM). RECENT FINDINGS GLP-1-based therapies and in particular GLP-1 receptor agonists (GLP-1 RA) have proven to be effective in lowering blood glucose and decreasing weight. GLP-1 RA not only mitigate these significant medical burdens but also result in weight loss and weight loss independent factors that decrease cardiovascular disease (CVD) and microvascular complications of T2DM, such as diabetic nephropathy. GLP-1-based therapies are critical for a patient-centered approach in choosing appropriate pharmacotherapy for T2DM and obesity while also taking into consideration comorbidities, such as cardiovascular and chronic kidney diseases.
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Affiliation(s)
- Eric Nolen-Doerr
- Section of Endocrinology, Diabetes, Nutrition, and Weight Management, Boston University School of Medicine and Boston Medical Center, 720 Harrison Avenue, Doctor's Office Building, Suite 8100, Boston, MA, 02118, USA.
| | - Mary-Catherine Stockman
- Section of Endocrinology, Diabetes, Nutrition, and Weight Management, Boston University School of Medicine and Boston Medical Center, 720 Harrison Avenue, Doctor's Office Building, Suite 8100, Boston, MA, 02118, USA.
| | - Ivania Rizo
- Section of Endocrinology, Diabetes, Nutrition, and Weight Management, Boston University School of Medicine and Boston Medical Center, 720 Harrison Avenue, Doctor's Office Building, Suite 8100, Boston, MA, 02118, USA.
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21
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Zhu W, Huang W, Xu Z, Cao M, Hu Q, Pan C, Guo M, Wei JF, Yuan H. Analysis of Patents Issued in China for Antihyperglycemic Therapies for Type 2 Diabetes Mellitus. Front Pharmacol 2019; 10:586. [PMID: 31214029 PMCID: PMC6556973 DOI: 10.3389/fphar.2019.00586] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2018] [Accepted: 05/07/2019] [Indexed: 01/11/2023] Open
Abstract
Type 2 diabetes mellitus (T2DM) is prevalent, with a dramatic increase in recent years. Moreover, its microvascular and macrovascular complications cause significant societal issues. The demand for new and effective antidiabetic therapies grows with each passing day and motivates organizations and individuals to pay more attention to such products. In this article, we focused on oral antihyperglycemic drugs patented in China and introduced them according to their antihyperglycemic mechanisms. By searching the website of State Intellectual Property Office of the People's Republic of China (http://www.sipo.gov.cn), 2,500 antihyperglycemic patents for T2DM were identified and analyzed. These consisted of 4 patents for derivatives of herbal extracts (0.2%), 162 patents for herbal extracts (6.5%), 61 compositions for traditional Chinese medicine (TCM) (2.4%), 2,263 patents for synthetic compounds (90.5%), and 10 (0.4%) patents of the combination of synthetic compounds and TCM. As the most common drugs for diabetes mellitus, synthetic compounds can also be classified into several categories according to their working mechanisms, such as insulin secretion promotor agents, insulin sensitizer agents, α-glucosidase inhibitors, and so forth. This article discussed the chemical structure, potential antihyperglycemic mechanism of these antihyperglycemic drugs in patents in China. Expert opinion: Insulin sensitivity and β-cell function could be improved by weight loss to prevent prediabetes into T2DM. However, 40-50% patients with impaired glucose tolerance (IGT) still progress to T2DM, even after successful long-term weight loss. Antihyperglycemic remedies provide a treatment option to improve insulin sensitivity and maintain β-cell function. Combination therapy is the best treatment for diabetes. Combination therapy can reduce the dosage of each single drug option, and avoid the side effects. Drugs with different mechanisms are complementary, and are better adapted to patients with changing conditions. Classical combination therapies include combinations such as sulfonylureas plus biguanides or glucosidase inhibitors, biguanide plus glucosidase inhibitors or insulin sensitizers, insulin treatment plus biguanides or glucosidase inhibitors. The general principle of combination therapy is that two drugs with different mechanisms are selected jointly, and the combination of three types of hypoglycemic drugs is not recommended. After reading a large amount of literature, we have rarely found a case of three oral hypoglycemic agents, which may mean that the combination of three oral hypoglycemic agents is unnecessary and has unpredictable risks. There is no objection to the idea of multi-drug therapy. But multiple drugs can only be used when it shows a significant benefit to the patients. Combined use of multiple antidiabetic drugs poses a risk to patients due to drug interactions and overtreatment.
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Affiliation(s)
- Wei Zhu
- Research Division of Clinical Pharmacology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Wen Huang
- Department of GCP Office, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Zhiqiang Xu
- Research Division of Clinical Pharmacology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Mengda Cao
- Research Division of Clinical Pharmacology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Qiaoli Hu
- Research Division of Clinical Pharmacology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Chen Pan
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Miao Guo
- Research Division of Clinical Pharmacology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Ji-Fu Wei
- Research Division of Clinical Pharmacology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Hongyu Yuan
- Research Division of Clinical Pharmacology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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22
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Ho HJ, Shirakawa H, Hirahara K, Sone H, Kamiyama S, Komai M. Menaquinone-4 Amplified Glucose-Stimulated Insulin Secretion in Isolated Mouse Pancreatic Islets and INS-1 Rat Insulinoma Cells. Int J Mol Sci 2019; 20:ijms20081995. [PMID: 31018587 PMCID: PMC6515216 DOI: 10.3390/ijms20081995] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2019] [Revised: 04/15/2019] [Accepted: 04/22/2019] [Indexed: 12/21/2022] Open
Abstract
Vitamin K2 is indispensable for blood coagulation and bone metabolism. Menaquinone-4 (MK-4) is the predominant homolog of vitamin K2, which is present in large amounts in the pancreas, although its function is unclear. Meanwhile, β-cell dysfunction following insulin secretion has been found to decrease in patients with type 2 diabetes mellitus. To elucidate the physiological function of MK-4 in pancreatic β-cells, we studied the effects of MK-4 treatment on isolated mouse pancreatic islets and rat INS-1 cells. Glucose-stimulated insulin secretion significantly increased in isolated islets and INS-1 cells treated with MK-4. It was further clarified that MK-4 enhanced cAMP levels, accompanied by the regulation of the exchange protein directly activated by the cAMP 2 (Epac2)-dependent pathway but not the protein kinase A (PKA)-dependent pathway. A novel function of MK-4 on glucose-stimulated insulin secretion was found, suggesting that MK-4 might act as a potent amplifier of the incretin effect. This study therefore presents a novel potential therapeutic approach for impaired insulinotropic effects.
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Affiliation(s)
- Hsin-Jung Ho
- Laboratory of Nutrition, Graduate School of Agricultural Science, Tohoku University, Sendai 980-8572, Japan.
| | - Hitoshi Shirakawa
- Laboratory of Nutrition, Graduate School of Agricultural Science, Tohoku University, Sendai 980-8572, Japan.
- International Education and Research Center for Food Agricultural Immunology, Graduate School of Agricultural Science, Tohoku University, Sendai 980-8572, Japan.
| | - Keisukei Hirahara
- Laboratory of Nutrition, Graduate School of Agricultural Science, Tohoku University, Sendai 980-8572, Japan.
| | - Hideyuki Sone
- Department of Health and Nutrition, Faculty of Human Life Studies, University of Niigata Prefecture, Niigata 950-8680, Japan.
| | - Shin Kamiyama
- Department of Health and Nutrition, Faculty of Human Life Studies, University of Niigata Prefecture, Niigata 950-8680, Japan.
| | - Michio Komai
- Laboratory of Nutrition, Graduate School of Agricultural Science, Tohoku University, Sendai 980-8572, Japan.
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Current Progress in Pharmacogenetics of Second-Line Antidiabetic Medications: Towards Precision Medicine for Type 2 Diabetes. J Clin Med 2019; 8:jcm8030393. [PMID: 30901912 PMCID: PMC6463061 DOI: 10.3390/jcm8030393] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Revised: 03/15/2019] [Accepted: 03/18/2019] [Indexed: 12/17/2022] Open
Abstract
Precision medicine is a scientific and medical practice for personalized therapy based on patients’ individual genetic, environmental, and lifestyle characteristics. Pharmacogenetics and pharmacogenomics are also rapidly developing and expanding as a key element of precision medicine, in which the association between individual genetic variabilities and drug disposition and therapeutic responses are investigated. Type 2 diabetes (T2D) is a chronic metabolic disorder characterized by hyperglycemia mainly associated with insulin resistance, with the risk of clinically important cardiovascular, neurological, and renal complications. The latest consensus report from the American Diabetes Association and European Association for the Study of Diabetes (ADA-EASD) on the management of T2D recommends preferential use of glucagon-like peptide-1 (GLP-1) receptor agonists, sodium-glucose cotransporter-2 (SGLT2) inhibitors, and some dipeptidyl peptidase-4 (DPP-4) inhibitors after initial metformin monotherapy for diabetic patients with established atherosclerotic cardiovascular or chronic kidney disease, and with risk of hypoglycemia or body weight-related problems. In this review article, we summarized current progress on pharmacogenetics of newer second-line antidiabetic medications in clinical practices and discussed their therapeutic implications for precision medicine in T2D management. Several biomarkers associated with drug responses have been identified from extensive clinical pharmacogenetic studies, and functional variations in these genes have been shown to significantly affect drug-related glycemic control, adverse reactions, and risk of diabetic complications. More comprehensive pharmacogenetic research in various clinical settings will clarify the therapeutic implications of these genes, which may be useful tools for precision medicine in the treatment and prevention of T2D and its complications.
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24
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Hasib A, Ng MT, Tanday N, Craig SL, Gault VA, Flatt PR, Irwin N. Exendin-4(Lys 27 PAL)/gastrin/xenin-8-Gln: A novel acylated GLP-1/gastrin/xenin hybrid peptide that improves metabolic status in obese-diabetic (ob/ob) mice. Diabetes Metab Res Rev 2019; 35:e3106. [PMID: 30499633 DOI: 10.1002/dmrr.3106] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Revised: 11/19/2018] [Accepted: 11/27/2018] [Indexed: 12/27/2022]
Abstract
BACKGROUND Therapeutic benefits of peptide-based drugs is limited by rapid renal elimination. METHODS Therefore, to prolong the biological action profile of the recently characterized triple-acting hybrid peptide, exendin-4/gastrin/xenin-8-Gln, a fatty acid (C-16) has been covalently attached, creating exendin-4(Lys27 PAL)/gastrin/xenin-8-Gln. Exendin-4/gastrin and liraglutide/gastrin/xenin-8-Gln were also synthesized as direct comparator peptides. RESULTS All hybrid peptides evoked significant concentration-dependent increases of insulin secretion from isolated murine islets and BRIN-BD11 cells. Following administration of peptides with glucose to mice, all hybrids significantly reduced the overall glycaemic excursion and increased insulin concentrations. In contrast to other treatments, exendin-4(Lys27 PAL)/gastrin/xenin-8-Gln displayed impressive antihyperglycaemic actions even 12 hours after administration, highlighting protracted duration of effects. Exendin-4/gastrin/xenin-8-Gln, exendin-4/gastrin, and exendin-4(Lys27 PAL)/gastrin/xenin-8-Gln were then progressed to a 31-day twice-daily treatment regimen in obese-diabetic ob/ob mice. All treatments decreased nonfasting glucose and HbA1c concentrations, as well as enhancing circulating and pancreatic insulin levels. Exendin-4/gastrin and exendin-4/gastrin/xenin-8-Gln also decreased food intake. Glucose tolerance was improved by all treatments, but only exendin-4(Lys27 PAL)/gastrin/xenin-8-Gln augmented glucose-induced insulin secretion. Interestingly, treatment regimens that included a xenin component induced clear advantages on the metabolic response to glucose-dependent insulinotropic polypeptide (GIP) and the glucose-lowering actions of insulin. CONCLUSION This study emphasizes the therapeutic promise of long-acting, multi-targeting hybrid gut peptides for type 2 diabetes.
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Affiliation(s)
- Annie Hasib
- Centre for Pharmacy and Diabetes, Ulster University, Coleraine, UK
| | - Ming T Ng
- Centre for Pharmacy and Diabetes, Ulster University, Coleraine, UK
| | - Neil Tanday
- Centre for Pharmacy and Diabetes, Ulster University, Coleraine, UK
| | - Sarah L Craig
- Centre for Pharmacy and Diabetes, Ulster University, Coleraine, UK
| | - Victor A Gault
- Centre for Pharmacy and Diabetes, Ulster University, Coleraine, UK
| | - Peter R Flatt
- Centre for Pharmacy and Diabetes, Ulster University, Coleraine, UK
| | - Nigel Irwin
- Centre for Pharmacy and Diabetes, Ulster University, Coleraine, UK
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25
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Liu Y, Harashima S, Wang Y, Suzuki K, Tokumoto S, Usui R, Tatsuoka H, Tanaka D, Yabe D, Harada N, Hayashi Y, Inagaki N. Sphingosine kinase 1–interacting protein is a dual regulator of insulin and incretin secretion. FASEB J 2019; 33:6239-6253. [DOI: 10.1096/fj.201801783rr] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Affiliation(s)
- Yanyan Liu
- Department of DiabetesEndocrinology and NutritionGraduate School of MedicineKyoto University Kyoto Japan
| | - Shin‐Ichi Harashima
- Department of DiabetesEndocrinology and NutritionGraduate School of MedicineKyoto University Kyoto Japan
| | - Yu Wang
- Department of DiabetesEndocrinology and NutritionGraduate School of MedicineKyoto University Kyoto Japan
| | - Kazuyo Suzuki
- Department of DiabetesEndocrinology and NutritionGraduate School of MedicineKyoto University Kyoto Japan
| | - Shinsuke Tokumoto
- Department of DiabetesEndocrinology and NutritionGraduate School of MedicineKyoto University Kyoto Japan
| | - Ryota Usui
- Department of DiabetesEndocrinology and NutritionGraduate School of MedicineKyoto University Kyoto Japan
| | - Hisato Tatsuoka
- Department of DiabetesEndocrinology and NutritionGraduate School of MedicineKyoto University Kyoto Japan
| | - Daisuke Tanaka
- Department of DiabetesEndocrinology and NutritionGraduate School of MedicineKyoto University Kyoto Japan
| | - Daisuke Yabe
- Department of DiabetesEndocrinology and NutritionGraduate School of MedicineKyoto University Kyoto Japan
| | - Norio Harada
- Department of DiabetesEndocrinology and NutritionGraduate School of MedicineKyoto University Kyoto Japan
| | - Yoshitaka Hayashi
- Division of Stress Adaptation and ProtectionDepartment of GeneticsResearch Institute of Environmental MedicineNagoya University Nagoya Japan
| | - Nobuya Inagaki
- Department of DiabetesEndocrinology and NutritionGraduate School of MedicineKyoto University Kyoto Japan
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26
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Mahanta N, Szantai-Kis DM, Petersson EJ, Mitchell DA. Biosynthesis and Chemical Applications of Thioamides. ACS Chem Biol 2019; 14:142-163. [PMID: 30698414 PMCID: PMC6404778 DOI: 10.1021/acschembio.8b01022] [Citation(s) in RCA: 111] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Thioamidation as a posttranslational modification is exceptionally rare, with only a few reported natural products and exactly one known protein example (methyl-coenzyme M reductase from methane-metabolizing archaea). Recently, there has been significant progress in elucidating the biosynthesis and function of several thioamide-containing natural compounds. Separate developments in the chemical installation of thioamides into peptides and proteins have enabled cell biology and biophysical studies to advance the current understanding of natural thioamides. This review highlights the various strategies used by Nature to install thioamides in peptidic scaffolds and the potential functions of this rare but important modification. We also discuss synthetic methods used for the site-selective incorporation of thioamides into polypeptides with a brief discussion of the physicochemical implications. This account will serve as a foundation for the further study of thioamides in natural products and their various applications.
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Affiliation(s)
| | - D Miklos Szantai-Kis
- Department of Biochemistry and Molecular Biophysics, Perelman School of Medicine , University of Pennsylvania , 3700 Hamilton Walk , Philadelphia , Pennsylvania 19104 , United States
| | - E James Petersson
- Department of Biochemistry and Molecular Biophysics, Perelman School of Medicine , University of Pennsylvania , 3700 Hamilton Walk , Philadelphia , Pennsylvania 19104 , United States
- Department of Chemistry , University of Pennsylvania , 231 South 34th Street , Philadelphia , Pennsylvania 19104 , United States
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27
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Brandt SJ, Müller TD, DiMarchi RD, Tschöp MH, Stemmer K. Peptide-based multi-agonists: a new paradigm in metabolic pharmacology. J Intern Med 2018; 284:581-602. [PMID: 30230640 DOI: 10.1111/joim.12837] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Obesity and its comorbidities, such as type 2 diabetes, are pressing worldwide health concerns. Available anti-obesity treatments include weight loss pharmacotherapies and bariatric surgery. Whilst surgical interventions typically result in significant and sustained weight loss, available pharmacotherapies are far less effective, typically decreasing body weight by no more than 5-10%. An emerging class of multi-agonist drugs may eventually bridge this gap. This new class of specially tailored drugs hybridizes the amino acid sequences of key metabolic hormones into one single entity with enhanced potency and sustained action. Successful examples of this strategy include multi-agonist drugs targeting the receptors for glucagon-like peptide-1 (GLP-1), glucagon and the glucose-dependent insulinotropic polypeptide (GIP). Due to the simultaneous activity at several metabolically relevant receptors, these multi-agonists offer improved body weight loss and glucose tolerance relative to their constituent monotherapies. Further advancing this concept, chimeras were generated that covalently link nuclear acting hormones such as oestrogen, thyroid hormone (T3 ) or dexamethasone to peptide hormones such as GLP-1 or glucagon. The benefit of this strategy is to restrict the nuclear hormone action exclusively to cells expressing the peptide hormone receptor, thereby maximizing combinatorial metabolic efficacy of both drug constituents in the target cells whilst preventing the nuclear hormone cargo from entering and acting on cells devoid of the peptide hormone receptor, in which the nuclear hormone might have unwanted effects. Many of these multi-agonists are in preclinical and clinical development and may represent new and effective tools in the fight against obesity and its comorbidities.
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Affiliation(s)
- S J Brandt
- Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany.,German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - T D Müller
- Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany.,German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - R D DiMarchi
- Department of Chemistry, Indiana University, Bloomington, IN, USA
| | - M H Tschöp
- Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany.,German Center for Diabetes Research (DZD), Neuherberg, Germany.,Division of Metabolic Diseases, Technische Universität München, Munich, Germany
| | - K Stemmer
- Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany.,German Center for Diabetes Research (DZD), Neuherberg, Germany
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28
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Cardoso JCR, Félix RC, Costa C, Palma PFS, Canário AVM, Power DM. Evolution of the glucagon-like system across fish. Gen Comp Endocrinol 2018; 264:113-130. [PMID: 29056448 DOI: 10.1016/j.ygcen.2017.10.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2017] [Revised: 10/04/2017] [Accepted: 10/10/2017] [Indexed: 12/25/2022]
Abstract
In fishes, including the jawless lampreys, the most ancient lineage of extant vertebrates, plasma glucose levels are highly variable and regulation is more relaxed than in mammals. The regulation of glucose and lipid in fishes in common with mammals involves members of the glucagon (GCG)-like family of gastrointestinal peptides. In mammals, four peptides GCG, glucagon-like peptide 1 and 2 (GLP1 and GLP2) and glucose-dependent insulinotropic peptide (GIP) that activate four specific receptors exist. However, in lamprey and other fishes the glucagon-like family evolved differently and they retained additional gene family members (glucagon-related peptide, gcrp and its receptor, gcrpr) that are absent from mammals. In the present study, we analysed the evolution of the glucagon-like system in fish and characterized gene expression of the family members in the European sea bass (Dicentrarchus labrax) a teleost fish. Phylogenetic analysis revealed that multiple receptors and peptides of the glucagon-like family emerged early during the vertebrate radiation and evolved via lineage specific events. Synteny analysis suggested that family member gene loss is likely to be the result of a single gene deletion event. Lamprey was the only fish where a putative glp1r persisted and the presence of the receptor gene in the genomes of the elephant shark and coelacanth remains unresolved. In the coelacanth and elephant shark, unique proglucagon genes were acquired which in the former only encoded Gcg and Glp2 and in the latter, shared a similar structure to the teleost proglucagon gene but possessed an extra exon coding for Glp-like peptide that was most similar to Glp2. The variable tissue distribution of the gene transcripts encoding the ligands and receptors of the glucagon-like system in an advanced teleost, the European sea bass, suggested that, as occurs in mammals, they have acquired distinct functions. Statistically significant (p < .05) down-regulation of teleost proglucagon a in sea bass with modified plasma glucose levels confirmed the link between these peptides and metabolism. The tissue distribution of members of the glucagon-like system in sea bass and human suggests that evolution of the brain-gut-peptide regulatory loop diverged between teleosts and mammals despite the overall conservation and similarity of glucagon-like family members.
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Affiliation(s)
- João C R Cardoso
- Comparative Endocrinology and Integrative Biology, Centre of Marine Sciences, Universidade do Algarve, Campus de Gambelas, 8005-139 Faro, Portugal.
| | - Rute C Félix
- Comparative Endocrinology and Integrative Biology, Centre of Marine Sciences, Universidade do Algarve, Campus de Gambelas, 8005-139 Faro, Portugal.
| | - Carina Costa
- Comparative Endocrinology and Integrative Biology, Centre of Marine Sciences, Universidade do Algarve, Campus de Gambelas, 8005-139 Faro, Portugal
| | - Pedro F S Palma
- Comparative Endocrinology and Integrative Biology, Centre of Marine Sciences, Universidade do Algarve, Campus de Gambelas, 8005-139 Faro, Portugal.
| | - Adelino V M Canário
- Comparative Endocrinology and Integrative Biology, Centre of Marine Sciences, Universidade do Algarve, Campus de Gambelas, 8005-139 Faro, Portugal.
| | - Deborah M Power
- Comparative Endocrinology and Integrative Biology, Centre of Marine Sciences, Universidade do Algarve, Campus de Gambelas, 8005-139 Faro, Portugal.
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29
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Lang Lehrskov L, Lyngbaek MP, Soederlund L, Legaard GE, Ehses JA, Heywood SE, Wewer Albrechtsen NJ, Holst JJ, Karstoft K, Pedersen BK, Ellingsgaard H. Interleukin-6 Delays Gastric Emptying in Humans with Direct Effects on Glycemic Control. Cell Metab 2018; 27:1201-1211.e3. [PMID: 29731416 DOI: 10.1016/j.cmet.2018.04.008] [Citation(s) in RCA: 77] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2017] [Revised: 02/09/2018] [Accepted: 04/06/2018] [Indexed: 02/07/2023]
Abstract
Gastric emptying is a critical regulator of postprandial glucose and delayed gastric emptying is an important mechanism of improved glycemic control achieved by short-acting glucagon-like peptide-1 (GLP-1) analogs in clinical practice. Here we report on a novel regulatory mechanism of gastric emptying in humans. We show that increasing interleukin (IL)-6 concentrations delays gastric emptying leading to reduced postprandial glycemia. IL-6 furthermore reduces insulin secretion in a GLP-1-dependent manner while effects on gastric emptying are GLP-1 independent. Inhibitory effects of IL-6 on gastric emptying were confirmed following exercise-induced increases in IL-6. Importantly, gastric- and insulin-reducing effects were maintained in individuals with type 2 diabetes. These data have clinical implications with respect to the use of IL-6 inhibition in autoimmune/inflammatory disease, and identify a novel target that could be exploited pharmacologically to delay gastric emptying and spare insulin, which may be beneficial for the beta cell in type 2 diabetes.
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Affiliation(s)
- Louise Lang Lehrskov
- The Centre of Inflammation and Metabolism and the Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, Copenhagen 2100, Denmark
| | - Mark Preben Lyngbaek
- The Centre of Inflammation and Metabolism and the Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, Copenhagen 2100, Denmark
| | - Line Soederlund
- The Centre of Inflammation and Metabolism and the Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, Copenhagen 2100, Denmark
| | - Grit Elster Legaard
- The Centre of Inflammation and Metabolism and the Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, Copenhagen 2100, Denmark
| | - Jan Adam Ehses
- Department of Surgery, Child and Family Research Institute, University of British Columbia, Vancouver, V5Z 4H4, Canada
| | - Sarah Elizabeth Heywood
- The Centre of Inflammation and Metabolism and the Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, Copenhagen 2100, Denmark
| | - Nicolai Jacob Wewer Albrechtsen
- Department of Biomedical Sciences and the NNF Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark
| | - Jens Juul Holst
- Department of Biomedical Sciences and the NNF Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark
| | - Kristian Karstoft
- The Centre of Inflammation and Metabolism and the Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, Copenhagen 2100, Denmark
| | - Bente Klarlund Pedersen
- The Centre of Inflammation and Metabolism and the Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, Copenhagen 2100, Denmark
| | - Helga Ellingsgaard
- The Centre of Inflammation and Metabolism and the Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, Copenhagen 2100, Denmark.
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30
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Hasib A, Ng MT, Khan D, Gault VA, Flatt PR, Irwin N. A novel GLP-1/xenin hybrid peptide improves glucose homeostasis, circulating lipids and restores GIP sensitivity in high fat fed mice. Peptides 2018; 100:202-211. [PMID: 29412820 DOI: 10.1016/j.peptides.2017.10.015] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2017] [Revised: 10/24/2017] [Accepted: 10/24/2017] [Indexed: 02/08/2023]
Abstract
Combined modulation of peptide hormone receptors including, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and xenin, have established benefits for the treatment of diabetes. The present study has assessed the biological actions and therapeutic efficacy of a novel exendin-4/xenin-8-Gln hybrid peptide, both alone and in combination with the GIP receptor agonist (DAla2)GIP. Exendin-4/xenin-8-Gln was enzymatically stable and exhibited enhanced insulin secretory actions when compared to its parent peptides. Exendin-4/xenin-8-Gln also possessed ability to potentiate the in vitro actions of GIP. Acute administration of exendin-4/xenin-8-Gln in mice induced appetite suppressive effects, as well as significant and protracted glucose-lowering and insulin secretory actions. Twice daily administration of exendin-4/xenin-8-Gln, alone or in combination with (DAla2)GIP, for 21-days significantly reduced non-fasting glucose and increased circulating insulin levels in high fat fed mice. In addition, all exendin-4/xenin-8-Gln treated mice displayed improved glucose tolerance, insulin sensitivity and metabolic responses to GIP. Combination therapy with (DAla2)GIP did not result in any obvious further benefits. Metabolic improvements in all treatment groups were accompanied by reduced pancreatic beta-cell area and insulin content, suggesting reduced insulin demand. Interestingly, body weight, food intake, circulating glucagon, metabolic rate and amylase activity were unaltered by the treatment regimens. However, all treatment groups, barring (DAla2)GIP alone, exhibited marked reductions in total- and LDL-cholesterol. Furthermore, exendin-4 therapy also reduced circulating triacylglycerol. This study highlights the positive antidiabetic effects of exendin-4/xenin-8-Gln, and suggests that combined modulation of GLP-1 and xenin related signalling pathways represents an exciting treatment option for type 2 diabetes.
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Affiliation(s)
- Annie Hasib
- From the SAAD Centre for Pharmacy and Diabetes, University of Ulster, Coleraine, Northern Ireland, UK
| | - Ming T Ng
- From the SAAD Centre for Pharmacy and Diabetes, University of Ulster, Coleraine, Northern Ireland, UK
| | - Dawood Khan
- From the SAAD Centre for Pharmacy and Diabetes, University of Ulster, Coleraine, Northern Ireland, UK
| | - Victor A Gault
- From the SAAD Centre for Pharmacy and Diabetes, University of Ulster, Coleraine, Northern Ireland, UK
| | - Peter R Flatt
- From the SAAD Centre for Pharmacy and Diabetes, University of Ulster, Coleraine, Northern Ireland, UK
| | - Nigel Irwin
- From the SAAD Centre for Pharmacy and Diabetes, University of Ulster, Coleraine, Northern Ireland, UK.
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31
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Robinson SD, Safavi-Hemami H. Venom peptides as pharmacological tools and therapeutics for diabetes. Neuropharmacology 2017; 127:79-86. [PMID: 28689026 DOI: 10.1016/j.neuropharm.2017.07.001] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2017] [Revised: 06/24/2017] [Accepted: 07/04/2017] [Indexed: 12/31/2022]
Abstract
Diabetes mellitus is a chronic disease caused by a deficiency in production of insulin by the beta cells of the pancreas (type 1 diabetes, T1D), or by partial deficiency of insulin production and the ineffectiveness of the insulin produced (type 2 diabetes, T2D). Animal venoms are a unique source of compounds targeting ion channels and receptors in the nervous and cardiovascular systems. In recent years, several venom peptides have also emerged as pharmacological tools and therapeutics for T1D and T2D. Some of these peptides act directly as mimics of endogenous metabolic hormones while others act on ion channels expressed in pancreatic beta cells. Here, we provide an overview of the discovery of these venom peptides, their mechanisms of action in the context of diabetes, and their therapeutic potential for the treatment of this disease. This article is part of the Special Issue entitled 'Venom-derived Peptides as Pharmacological Tools.'
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Affiliation(s)
- Samuel D Robinson
- Department of Biology, University of Utah, Salt Lake City, UT 84112, USA
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Liraglutide suppression of caloric intake competes with the intake-promoting effects of a palatable cafeteria diet, but does not impact food or macronutrient selection. Physiol Behav 2017; 177:4-12. [PMID: 28366815 DOI: 10.1016/j.physbeh.2017.03.045] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2016] [Revised: 03/15/2017] [Accepted: 03/29/2017] [Indexed: 12/22/2022]
Abstract
Liraglutide, a Glucagon-Like Peptide-1 (GLP-1) receptor agonist, is used as a treatment for Type 2 diabetes mellitus and obesity because it improves glycemia and decreases food intake. Here, we tested whether chronic activation of the GLP-1 receptor system with liraglutide would induce decreases in intake accompanied by changes in proportional food or macronutrient intake similar to those seen following RYGB in rats when a variety of palatable food options are available. A "cafeteria diet" was used that included: laboratory rodent chow, refried beans (low-fat/low-sugar), low-fat yogurt (low-fat/high-sugar), peanut butter (high-fat/low-sugar) and sugar-fat whip (high-fat/high-sugar). Liraglutide (1mg/kg daily, sc, n=6) induced significant reductions in body weight and total caloric intake compared to saline-injected control rats (n=6). Although access to a cafeteria diet induced increases in caloric intake in both groups relative to chow alone, liraglutide still effectively decreased intake compared with saline-injected rats suggesting that chronic GLP-1 activation competes with the energy density and palatability of available food options in modulating ingestive behavior. Even with the substantial effects on overall intake, liraglutide did not change food choice or relative macronutrient intake when compared to pre-treatment baseline. When drug treatment was discontinued, the liraglutide group increased caloric intake and rapidly gained body weight to match that of the saline group. These results demonstrate that, while liraglutide effectively decreases caloric intake and body weight in rats, it does not cause adjustments in relative macronutrient consumption. Our data also show that drug-induced decreases in intake and body weight are not maintained following termination of treatment.
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Sim YB, Park SH, Kim SS, Lee JR, Jung JS, Sharma N, Suh HW. The modulatory roles of oxyntomodulin and glucagon-like peptide 1 administered spinally in the regulation of the blood glucose level. NEUROCHEM J+ 2017. [DOI: 10.1134/s1819712416040115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Wei W, Buysman E, Grabner M, Xie L, Brekke L, Ke X, Chu JW, Levin PA. A real-world study of treatment patterns and outcomes in US managed-care patients with type 2 Diabetes initiating injectable therapies. Diabetes Obes Metab 2017; 19:375-386. [PMID: 27860158 PMCID: PMC5347924 DOI: 10.1111/dom.12828] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2016] [Revised: 11/04/2016] [Accepted: 11/12/2016] [Indexed: 12/28/2022]
Abstract
AIMS Examine real-world outcomes in patients with type 2 diabetes mellitus (T2DM) initiating injectable therapy as part of the Initiation of New Injectable Treatment Introduced after Antidiabetic Therapy with Oral-only Regimens (INITIATOR) study. MATERIALS AND METHODS Linked insurance claims and medical record data were collected from 2 large US health insurers (April 1, 2010 to March 31, 2012) of T2DM adults initiating treatment with glargine (GLA) or liraglutide (LIRA). Baseline characteristics were examined and changes in 12-month follow-up outcomes were described for both treatment groups: HbA1c, weight change, hypoglycaemia, persistence, healthcare utilisation and costs. RESULTS A total of 4490 patients were included (GLA, 2116; LIRA, 2374). At baseline, GLA patients had significantly higher HbA1c vs LIRA patients (9.72% vs 8.19%; P < .001), lower likelihood of having HbA1c < 7% (7.1% vs 23.8%; P < .001), lower bodyweight (100.9 kg vs 110.9 kg, P < .001), higher Charlson Comorbidity Index score (0.88 vs 0.63; P < .001), and higher diabetes-related costs ($3492 vs $2089; P < .001), respectively. During 12-months of follow-up, treatment persistence was 64%, mean HbA1c reduction was -1.24% and weight change was + 1.17 among GLA patients, and was 49%, -0.51% and -2.74 kg, respectively, among LIRA patients. Diabetes-related costs increased significantly from baseline to follow-up for LIRA patients ($2089 vs $3258, P < .001) but not for GLA patients ($3492 vs $3550, P = .890). CONCLUSIONS There were clinically relevant baseline differences in both groups, suggesting that GLA and LIRA are prescribed for different patient groups, and highlighting that efficacy results from clinical trials do not always translate into real-world practice. Significant increases in healthcare costs were observed in the LIRA group, warranting further cost-effectiveness analysis.
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Affiliation(s)
| | | | | | - Lin Xie
- STATinMED ResearchAnn ArborMichigan
| | | | | | - James W. Chu
- Monterey Endocrine & Diabetes InstituteMontereyCalifornia
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Osté MCJ, Corpeleijn E, Navis GJ, Keyzer CA, Soedamah-Muthu SS, van den Berg E, Postmus D, de Borst MH, Kromhout D, Bakker SJL. Mediterranean style diet is associated with low risk of new-onset diabetes after renal transplantation. BMJ Open Diabetes Res Care 2017; 5:e000283. [PMID: 28123752 PMCID: PMC5253439 DOI: 10.1136/bmjdrc-2016-000283] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2016] [Revised: 10/18/2016] [Accepted: 10/29/2016] [Indexed: 12/15/2022] Open
Abstract
OBJECTIVE The incidence of new-onset diabetes after transplantation (NODAT) and premature mortality is high in renal transplant recipients (RTR). We hypothesized that a Mediterranean Style diet protects against NODAT and premature mortality in RTR. RESEARCH DESIGN AND METHODS A prospective cohort study of adult RTR with a functioning graft for >1 year. Dietary intake was assessed with a 177-item validated food frequency questionnaire. Patients were divided based on a 9-point Mediterranean Style Diet Score (MDS): low MDS (0-4 points) versus high MDS (5-9 points). A total of 468 RTR were eligible for analyses. Logistic multivariable regression analyses were used to study the association of MDS with NODAT and Cox multivariable regression models for the association with all-cause mortality. RESULTS Mean±SD age was 51.3±13.2 years and 56.6% were men. About 50% of the patients had a high MDS. During median follow-up of 4.0 (IQR, 0.4-5.4) years, 22 (5%) RTR developed NODAT and 50 (11%) died. High MDS was significantly associated with both a lower risk of NODAT (HR=0.23; 95% CI 0.09 to 0.64; p=0.004) and all-cause mortality (HR=0.51; 95% CI 0.29 to 0.89, p=0.02) compared to low MDS, independent of age and sex. Adjustment for other potential confounders, including total energy intake, physical activity and smoking status, did not materially change the results of the analyses. CONCLUSIONS Dietary habits leading to high MDS were associated with lower risk of NODAT. These results suggest that healthy dietary habits are of paramount importance for RTR.
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Affiliation(s)
- Maryse C J Osté
- Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Eva Corpeleijn
- Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Gerjan J Navis
- Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Charlotte A Keyzer
- Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | | | - Else van den Berg
- Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Douwe Postmus
- Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Martin H de Borst
- Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Daan Kromhout
- Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- Department of Human Nutrition,University of Wageningen, Wageningen, The Netherlands
| | - Stephan J L Bakker
- Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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Farkas I, Vastagh C, Farkas E, Bálint F, Skrapits K, Hrabovszky E, Fekete C, Liposits Z. Glucagon-Like Peptide-1 Excites Firing and Increases GABAergic Miniature Postsynaptic Currents (mPSCs) in Gonadotropin-Releasing Hormone (GnRH) Neurons of the Male Mice via Activation of Nitric Oxide (NO) and Suppression of Endocannabinoid Signaling Pathways. Front Cell Neurosci 2016; 10:214. [PMID: 27672360 PMCID: PMC5018486 DOI: 10.3389/fncel.2016.00214] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2016] [Accepted: 08/26/2016] [Indexed: 12/25/2022] Open
Abstract
Glucagon-like peptide-1 (GLP-1), a metabolic signal molecule, regulates reproduction, although, the involved molecular mechanisms have not been elucidated, yet. Therefore, responsiveness of gonadotropin-releasing hormone (GnRH) neurons to the GLP-1 analog Exendin-4 and elucidation of molecular pathways acting downstream to the GLP-1 receptor (GLP-1R) have been challenged. Loose patch-clamp recordings revealed that Exendin-4 (100 nM-5 μM) elevated firing rate in hypothalamic GnRH-GFP neurons of male mice via activation of GLP-1R. Whole-cell patch-clamp measurements demonstrated increased excitatory GABAergic miniature postsynaptic currents (mPSCs) frequency after Exendin-4 administration, which was eliminated by the GLP-1R antagonist Exendin-3(9-39) (1 μM). Intracellular application of the G-protein inhibitor GDP-β-S (2 mM) impeded action of Exendin-4 on mPSCs, suggesting direct excitatory action of GLP-1 on GnRH neurons. Blockade of nitric-oxide (NO) synthesis by Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME; 100 μM) or N(5)-[Imino(propylamino)methyl]-L-ornithine hydrochloride (NPLA; 1 μM) or intracellular scavenging of NO by 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (CPTIO; 1 mM) partially attenuated the excitatory effect of Exendin-4. Similar partial inhibition was achieved by hindering endocannabinoid pathway using cannabinoid receptor type-1 (CB1) inverse-agonist 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-(1-piperidyl) pyrazole-3-carboxamide (AM251; 1 μM). Simultaneous blockade of NO and endocannabinoid signaling mechanisms eliminated action of Exendin-4 suggesting involvement of both retrograde machineries. Intracellular application of the transient receptor potential vanilloid 1 (TRPV1)-antagonist 2E-N-(2, 3-Dihydro-1,4-benzodioxin-6-yl)-3-[4-(1, 1-dimethylethyl)phenyl]-2-Propenamide (AMG9810; 10 μM) or the fatty acid amide hydrolase (FAAH)-inhibitor PF3845 (5 μM) impeded the GLP-1-triggered endocannabinoid pathway indicating an anandamide-TRPV1-sensitive control of 2-arachidonoylglycerol (2-AG) production. Furthermore, GLP-1 immunoreactive (IR) axons innervated GnRH neurons in the hypothalamus suggesting that GLP-1 of both peripheral and neuronal sources can modulate GnRH neurons. RT-qPCR study confirmed the expression of GLP-1R and neuronal NO synthase (nNOS) mRNAs in GnRH-GFP neurons. Immuno-electron microscopic analysis revealed the presence of nNOS protein in GnRH neurons. These results indicate that GLP-1 exerts direct facilitatory actions via GLP-1R on GnRH neurons and modulates NO and 2-AG retrograde signaling mechanisms that control the presynaptic excitatory GABAergic inputs to GnRH neurons.
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Affiliation(s)
- Imre Farkas
- Laboratory of Endocrine Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences Budapest, Hungary
| | - Csaba Vastagh
- Laboratory of Endocrine Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences Budapest, Hungary
| | - Erzsébet Farkas
- Laboratory of Integrative Neuroendocrinology, Institute of Experimental Medicine, Hungarian Academy of SciencesBudapest, Hungary; Roska Tamás Doctoral School of Sciences and Technology, Faculty of Information Technology and Bionics, Pázmány Péter Catholic UniversityBudapest, Hungary
| | - Flóra Bálint
- Laboratory of Endocrine Neurobiology, Institute of Experimental Medicine, Hungarian Academy of SciencesBudapest, Hungary; Roska Tamás Doctoral School of Sciences and Technology, Faculty of Information Technology and Bionics, Pázmány Péter Catholic UniversityBudapest, Hungary
| | - Katalin Skrapits
- Laboratory of Endocrine Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences Budapest, Hungary
| | - Erik Hrabovszky
- Laboratory of Endocrine Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences Budapest, Hungary
| | - Csaba Fekete
- Laboratory of Integrative Neuroendocrinology, Institute of Experimental Medicine, Hungarian Academy of SciencesBudapest, Hungary; Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Tupper Research Institute, Tufts Medical CenterBoston, MA, USA
| | - Zsolt Liposits
- Laboratory of Endocrine Neurobiology, Institute of Experimental Medicine, Hungarian Academy of SciencesBudapest, Hungary; Department of Neuroscience, Faculty of Information Technology and Bionics, Pázmány Péter Catholic UniversityBudapest, Hungary
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Guo XH. The value of short- and long-acting glucagon-like peptide-1 agonists in the management of type 2 diabetes mellitus: experience with exenatide. Curr Med Res Opin 2016; 32:61-76. [PMID: 26439329 DOI: 10.1185/03007995.2015.1103214] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
BACKGROUND Only about half of patients with type 2 diabetes treated with antihyperglycemic drugs achieve glycemic control (HbA1c <7%), most commonly due to poor treatment adherence. Glucagon-like peptide-1 (GLP-1) receptor agonists act on multiple targets involved in glucose homeostasis and have a low risk of causing hypoglycemia. While GLP-1 receptor (GLP-1R) agonists share the same mechanism of action, clinical profiles of individual agents differ, particularly between short- and long-acting agents. In this article, recent findings regarding the pharmacology of GLP-1 agonists are reviewed, and the clinical effects of short- versus long-acting agents are compared. DATA SOURCES Relevant articles were identified through a search of PubMed using the keywords glucagon-like peptide-1, GLP-1, glucagon-like peptide-1 receptor agonist, GLP-1R agonist, and exenatide for publications up to 22 May 2015. Supporting data were obtained from additional searches for albiglutide, dulaglutide, liraglutide and lixisenatide as well as from the bibliographies of key articles. FINDINGS Short-acting GLP-1R agonists produce greater reductions in postprandial glucose levels by slowing gastric emptying, whereas long-acting GLP-1R agonists produce greater reductions in fasting blood glucose by stimulating insulin secretion from the pancreas. These characteristics can be exploited to provide individualized treatment to patients. A large body of evidence supports the benefits of short- and long-acting exenatide as add-on therapy in patients with inadequate glycemic control despite maximum tolerated doses of metformin and/or sulfonylurea. Exenatide is generally well tolerated and no new safety concerns were identified during long-term follow-up of up to 5 years. A limitation of this review of short-and long-acting GLP-1 receptor agonists is that it focuses on exenatide rather than all the drugs in this class. However, the focus on a single molecule helps to avoid any confusion that may be introduced as a result of differences in molecular structure and size. CONCLUSIONS Short-acting GLP-1R agonists including exenatide are well suited to patients with type 2 diabetes with exaggerated postprandial glucose excursions and for co-administration with basal insulin therapy. Long-acting GLP-1R agonists including once weekly exenatide offer greater convenience and are well suited to patients who require specific control of fasting hyperglycemia.
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Affiliation(s)
- Xiao-Hui Guo
- a Endocrinology Department , Peking University First Hospital , Beijing , China
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38
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Heppner KM, Perez-Tilve D. GLP-1 based therapeutics: simultaneously combating T2DM and obesity. Front Neurosci 2015; 9:92. [PMID: 25852463 PMCID: PMC4367528 DOI: 10.3389/fnins.2015.00092] [Citation(s) in RCA: 89] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2015] [Accepted: 03/05/2015] [Indexed: 12/13/2022] Open
Abstract
Glucagon-like peptide-1 (GLP-1) enhances meal-related insulin secretion, which lowers blood glucose excursions. In addition to its incretin action, GLP-1 acts on the GLP-1 receptor (GLP-1R) in the brain to suppress feeding. These combined actions of GLP-1R signaling cause improvements in glycemic control as well as weight loss in type II diabetes (T2DM) patients treated with GLP-1R agonists. This is a superior advantage of GLP-1R pharmaceuticals as many other drugs used to treat T2DM are weight neutral or actual cause weight gain. This review summarizes GLP-1R action on energy and glucose metabolism, the effectiveness of current GLP-1R agonists on weight loss in T2DM patients, as well as GLP-1R combination therapies.
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Affiliation(s)
- Kristy M Heppner
- Division of Diabetes, Obesity and Metabolism, Oregon National Primate Research Center, Oregon Health and Science University Beaverton, OR, USA
| | - Diego Perez-Tilve
- Department of Medicine, Metabolic Diseases Institute, University of Cincinnati Cincinnati, OH, USA
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Toth PP. Linagliptin: A New DPP-4 Inhibitor for the Treatment of Type 2 Diabetes Mellitus. Postgrad Med 2015; 123:46-53. [DOI: 10.3810/pgm.2011.07.2303] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Marić G, Gazibara T, Zaletel I, Labudović Borović M, Tomanović N, Ćirić M, Puškaš N. The role of gut hormones in appetite regulation (review). ACTA ACUST UNITED AC 2015; 101:395-407. [PMID: 25532952 DOI: 10.1556/aphysiol.101.2014.4.1] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Eating process is an aggregate of complex and different forms of behavior. Its regulation is based on energy homeostasis and appetite control which includes two components: the homeostatic and the hedonistic control. Important signals in appetite regulation are gut-derived hormones. They are produced by enteroendocrine cells in response to nutrient and energy intake, and achieve their effects by influencing brain structures involved in food intake regulation. The key brain structure involved in this process is the hypothalamus. Gut hormones reach the hypothalamus from the circulation or by the vagal nerve via the nucleus of the solitary tract. Among gut peptides, ghrelin is the only orexigenic hormone, leading to an increase in food intake and body weight. All others, such as cholecystokinin, glucagon like peptide-1, oxyntomodulin, peptide tyrosine tyrosine or pancreatic polypeptide, are anorexigenic, leading to decrease in food intake. Also, gut-derived endocannabinoids exert orexigenic effect on appetite. Keeping in mind the growing problem of obesity, the crucial issue when considering gut derived peptides is to understand their mechanisms of acting because of potential role in clinical therapy, and discovering long-lasting gut peptides or their analogues, with no or minimal side effects.
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Affiliation(s)
- G Marić
- University of Belgrade Institute of Epidemiology, Faculty of Medicine Belgrade Serbia
| | - T Gazibara
- University of Belgrade Institute of Epidemiology, Faculty of Medicine Belgrade Serbia
| | - I Zaletel
- University of Belgrade Institute of Histology and Embryology, Faculty of Medicine Višegradska 26 11000 Belgrade Serbia
| | - M Labudović Borović
- University of Belgrade Institute of Histology and Embryology, Faculty of Medicine Višegradska 26 11000 Belgrade Serbia
| | - N Tomanović
- University of Belgrade Institute of Pathology, Faculty of Medicine Belgrade Serbia
| | - M Ćirić
- University of Nis Institute of Physiology, Faculty of Medicine Nis Serbia
| | - Nela Puškaš
- University of Belgrade Institute of Histology and Embryology, Faculty of Medicine Višegradska 26 11000 Belgrade Serbia
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Triggle CR, Ding H. Cardiovascular impact of drugs used in the treatment of diabetes. Ther Adv Chronic Dis 2014; 5:245-68. [PMID: 25364492 PMCID: PMC4205571 DOI: 10.1177/2040622314546125] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
The International Diabetes Federation predicts that by 2035 10% of the population of the world will have been diagnosed with diabetes, raising serious concerns over the resulting elevated morbidity and mortality as well as the impact on health care budgets. It is also well recognized that cardiovascular disease is the primary cause of the high morbidity and mortality associated with diabetes, raising the concern that appropriate drug therapy should not only correct metabolic dysfunction, but also protect the cardiovascular system from the effects of, in particular, the epigenetic changes that result from hyperglycaemia. A number of new classes of drugs for the treatment of diabetes have been introduced in the past decade, providing the opportunity to optimize treatment; however, comparative information of the cardiovascular benefits, or risks, of the newer drugs versus older therapies such as metformin is variable. This review, in addition to summarizing the cellular basis for the therapeutic action of these drugs, addresses the evidence for their cardiovascular benefits and risks. A particular focus is provided on metformin as it is the first choice drug for most patients with type 2 diabetes.
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Affiliation(s)
- Chris R Triggle
- Departments of Pharmacology and Medical Education, Weill Cornell Medical College in Qatar, PO Box 24144, Education City, Doha, Qatar
| | - Hong Ding
- Departments of Pharmacology and Medical Education, Weill Cornell Medical College in Qatar, Education City, Doha, Qatar
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Bolli GB, Owens DR. Lixisenatide, a novel GLP-1 receptor agonist: efficacy, safety and clinical implications for type 2 diabetes mellitus. Diabetes Obes Metab 2014; 16:588-601. [PMID: 24373190 DOI: 10.1111/dom.12253] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2013] [Revised: 04/15/2013] [Accepted: 10/24/2013] [Indexed: 01/13/2023]
Abstract
Recent advances in therapies for the treatment of type 2 diabetes mellitus (T2DM) have led to the development of glucagon-like peptide-1 receptor agonists (GLP-1 RAs), which, unlike insulin and sulphonylurea, are effective, with a low risk of hypoglycaemia. Lixisenatide is recommended as a once-daily GLP-1 RA for the treatment of T2DM. In persons with T2DM, lixisenatide 20 µg once-daily given by bolus subcutaneous injection improves insulin secretion and suppresses glucagon secretion in a glucose-dependent manner. Compared with the longer-acting GLP-1 RA liraglutide, lixisenatide achieved a significantly greater reduction in postprandial plasma glucose (PPG) during a standardized test breakfast in persons with T2DM otherwise insufficiently controlled on metformin alone. This is primarily due to the greater inhibition of gastric motility by lixisenatide compared with liraglutide. The efficacy and safety of lixisenatide was evaluated across a spectrum of T2DM in a series of phase III, randomized, placebo-controlled trials known as the GetGoal programme. Lixisenatide monotherapy or as add-on to oral antidiabetic agents or basal insulin achieved significant reductions in glycated haemoglobin, PPG and fasting plasma glucose, with either weight loss or no weight gain. The most frequent adverse events were gastrointestinal and transient in nature. Lixisenatide provides an easy, once-daily, single-dose, add-on treatment to oral antidiabetic agents or basal insulin for the management of T2DM, with little or no increased risk of hypoglycaemia and a potential beneficial effect on body weight.
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Affiliation(s)
- G B Bolli
- Department of Medicine, University of Perugia, Hospital S.M. della Misericordia, Perugia, Italy
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Liu XH, Wang YP, Wang LX, Chen Z, Liu XY, Liu LB. Exendin-4 protects murine MIN6 pancreatic β-cells from interleukin-1β-induced apoptosis via the NF-κB pathway. J Endocrinol Invest 2013; 36:803-11. [PMID: 23609920 DOI: 10.3275/8938] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
BACKGROUND Glucagon-like peptide-1 (GLP-1) and its potent analog, exendin-4, are well known to inhibit β- cell apoptosis and promote β-cell proliferation. Meanwhile, cytokines, such as interleukin-1β (IL-1β), stimulate inducible nitric oxide synthase (iNOS) expression and nitric oxide overproduction leading to β-cell damage. However, the protective mechanisms of GLP-1 in β-cells exposed to cytokines have not been fully elucidated. AIMS In this study, the protective effects of exendin-4 on IL-1β-induced apoptosis were investigated in murine MIN6 pancreatic β-cells. The role of nuclear factor-κB (NF-κB) signaling in this process was also explored. METHODS The effects of exendin-4 pre-treatment on IL-1β-induced apoptosis were investigated by Hoechst/PI and Annexin V/PI staining. Levels of iNOS and NF-κB proteins were investigated by Western blotting and cytoplasmic nitrite levels were determined using Griess reagent. RESULTS IL-1β treatment (range, 5-40 ng/ml) for 24 h was positively correlated with nitrite production (R2=0.9668, p<0.01), a significant increase in the percentage of apoptotic cells (p<0.01) and a concomitant dose-dependent increase in cytoplasmic levels of iNOS and NF-κB p65 activation. N-acetyl- L-cysteine (NAC), NG-nitro-L-arginine methyl ester (L-NAME) and pyrrolidine dithiocarbamate (PDTC), partially rescued apoptotic β-cells, suggesting involvement of NF-κB-iNOS-nitrite in this process. Exendin-4 (100 nM) treatment significantly decreased IL-1β-induced apoptosis (p<0.01), downregulated NF-κB activation and subsequently decreased iNOS and nitrite levels in IL-1β-induced β-cells (p<0.001), in a similar manner to L-NAME, PDTC and NAC. CONCLUSIONS These results suggest that exendin-4 protects against IL-1β- induced apoptosis in β-cells via downregulation of the NF- κB-iNOS-nitrite pathway.
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Affiliation(s)
- X H Liu
- Department of Endocrinology, Fujian Institute of Endocrinology, Union Hospital of Fujian Medical University, 29 Xinquan Road, Fuzhou, Fujian 350001, People's Republic of China
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Rosenstock J, Raccah D, Korányi L, Maffei L, Boka G, Miossec P, Gerich JE. Efficacy and safety of lixisenatide once daily versus exenatide twice daily in type 2 diabetes inadequately controlled on metformin: a 24-week, randomized, open-label, active-controlled study (GetGoal-X). Diabetes Care 2013; 36:2945-51. [PMID: 23698396 PMCID: PMC3781502 DOI: 10.2337/dc12-2709] [Citation(s) in RCA: 185] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVE To compare efficacy and safety of lixisenatide once daily versus exenatide twice daily in type 2 diabetes inadequately controlled with metformin. RESEARCH DESIGN AND METHODS Adults with diabetes inadequately controlled (HbA1c 7-10%) with metformin were randomized to lixisenatide 20 μg once daily (n=318) or exenatide 10 μg twice daily (n=316) in a 24-week (main period), open-label, parallel-group, multicenter study. The primary objective was a noninferiority assessment of lixisenatide versus exenatide in HbA1c change from baseline to week 24. RESULTS Lixisenatide once daily demonstrated noninferiority in HbA1c reduction versus exenatide twice daily. The least squares mean change was -0.79% (mean decrease 7.97 to 7.17%) for lixisenatide versus -0.96% (mean decrease 7.96 to 7.01%) for exenatide, and treatment difference was 0.17% (95% CI, 0.033-0.297), meeting a predefined noninferiority upper CI margin of 0.4%. Responder rate (HbA1c<7.0%) and improvements in fasting plasma glucose were comparable. Both agents induced weight loss (from 94.5 to 91.7 kg and from 96.7 to 92.9 kg with lixisenatide and exenatide, respectively). Incidence of adverse events (AEs) was similar for lixisenatide and exenatide, as was incidence of serious AEs (2.8 and 2.2%, respectively). Discontinuations attributable to AEs occurred in 33 lixisenatide (10.4%) and 41 exenatide (13.0%) patients. In the lixisenatide group, fewer participants experienced symptomatic hypoglycemia (2.5 vs. 7.9%; P<0.05), with fewer gastrointestinal events (especially nausea; 24.5 vs. 35.1%; P<0.05). CONCLUSIONS Add-on lixisenatide once daily in type 2 diabetes inadequately controlled with metformin demonstrated noninferior improvements in HbA1c, with slightly lower mean weight loss, lower incidence of hypoglycemia, and better gastrointestinal tolerability compared with exenatide twice daily.
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Schwasinger-Schmidt T, Robbins DC, Williams SJ, Novikova L, Stehno-Bittel L. Long-term liraglutide treatment is associated with increased insulin content and secretion in β-cells, and a loss of α-cells in ZDF rats. Pharmacol Res 2013; 76:58-66. [PMID: 23891763 DOI: 10.1016/j.phrs.2013.07.005] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2013] [Revised: 07/15/2013] [Accepted: 07/16/2013] [Indexed: 11/17/2022]
Abstract
The ultimate treatment goal of diabetes is to preserve and restore islet cell function. Treatment of certain diabetic animal models with incretins has been reported to preserve and possibly enhance islet function and promote islet cell growth. The studies reported here detail islet cell anatomy in animals chronically treated with the incretin analog, liraglutide. Our aim was to quantitatively and qualitatively analyze islet cells from diabetic animals treated with vehicle (control) or liraglutide to determine whether normal islet cell anatomy is maintained or enhanced with pharmaceutical treatment. We harvested pancreata from liraglutide and vehicle-treated Zucker Diabetic Fatty (ZDF) rats to examine islet structure and function and obtain isolated islets. Twelve-week-old male rats were assigned to 3 groups: (1) liraglutide-treated diabetic, (2) vehicle-treated diabetic, and (3) lean non-diabetic. Liraglutide was given SC twice daily for 9 weeks. As expected, liraglutide treatment reduced body weight by 15% compared to the vehicle-treated animals, eventually to levels that were not different from lean controls. At the termination of the study, blood glucose was significantly less in the liraglutide-treated rats compared to vehicle treated controls (485.8±22.5 and 547.2±33.1mg/dl, respectively). Insulin content/islet (measured by immunohistochemistry) was 34.2±0.7 pixel units in vehicle-treated rats, and 54.9±0.6 in the liraglutide-treated animals. Glucose-stimulated insulin secretion from isolated islets (measured as the stimulation index) was maintained in the liraglutide-treated rats, but not in the vehicle-treated. However, liraglutide did not preserve normal islet architecture. There was a decrease in the glucagon-positive area/islet and in the α-cell numbers/area with liraglutide treatment (6.5 cells/field), compared to vehicle (17.9 cells/field). There was an increase in β-cell numbers, the β- to α-cell ratio that was statistically higher in the liraglutide-treated rats (24.3±4.4) compared to vehicle (9.1±2.8). Disrupted mitochondria were more commonly observed in the α-cells (51.9±10.3% of cells) than in the β-cells (27.2±4.4%) in the liraglutide-treated group. While liraglutide enhanced or maintained growth and function of certain islet cells, the overall ratio of α- to β-cells was decreased and there was an absolute reduction in islet α-cell content. There was selective disruption of intracellular α-cell organelles, representing an uncoupling of the bihormonal islet signaling that is required for normal metabolic regulation. The relevance of the findings to long-term liraglutide treatment in people with diabetes is unknown and should be investigated in appropriately designed clinical studies.
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Feng XH, Zhou LH, Wang D, Yuan X. GLP-1 expression in von Ebner's gland of diabetic rats. Peptides 2012; 38:137-41. [PMID: 22986021 DOI: 10.1016/j.peptides.2012.09.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2011] [Revised: 09/01/2012] [Accepted: 09/02/2012] [Indexed: 12/25/2022]
Abstract
GLP-1, a peptidergic endocrine hormone, which associate with appetite control, glucose homeostasis and satiety. It might play an important role in the gustatory system. We tried to investigate the expression of GLP-1 in von Ebner's gland of diabetic and control rats, and the ultrastructure changes on von Ebner's gland of diabetes rats. GLP-1 expression in von Ebner's gland was evaluated by immunohistochemistry. The number of GLP-1 positive cells in diabetic rat von Ebner's gland was significantly higher than that in normal controls. Electron micrographs showed that a series of pathologic changes in von Ebner's gland of diabetes rats. The results suggest that GLP-1 have some effects within the gustatory systems, and elevated von Ebner's gland GLP-1 expression may be one cause of diabetic taste impairment.
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Affiliation(s)
- Xiao-hong Feng
- Department of Endocrinology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310006, China.
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Furuta S, Smart C, Hackett A, Benning R, Warrington S. Pharmacokinetics and metabolism of [14C]anagliptin, a novel dipeptidyl peptidase-4 inhibitor, in humans. Xenobiotica 2012; 43:432-42. [PMID: 23075005 DOI: 10.3109/00498254.2012.731618] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
1. The disposition of anagliptin, an orally active, highly selective dipeptidyl peptidase-4 inhibitor, was investigated after a single oral dose of 100 mg/1.92 MBq [(14)C]anagliptin to six healthy men. Almost all the dose (98.2%) was recovered within 168 h: 73.2% in urine and 25.0% in faeces. 2. Anagliptin was rapidly absorbed, with peak plasma concentrations of unchanged drug attained at a mean time of 1.8-h postdose. Mean fraction of the dose absorbed was >73%. Unchanged drug and a carboxylate metabolite (M1) were the major components in plasma, accounting for 66.0 and 23.4% of total plasma radioactivity area under the curve, respectively. 3. Anagliptin was incompletely metabolized, with about 50% dose eliminated as unchanged drug (46.6% in urine and 4.1% in faeces). Metabolism to M1 accounted for 29.2% of the dose. No other metabolite accounted for >1% dose in excreta or yielded measurable systemic exposure. Terminal half-life of anagliptin and M1 was 4.37 and 9.88 h, respectively. Renal clearance of unbound anagliptin and unbound M1 far exceeded glomerular filtration rate, indicating active renal elimination: that might reflect the fact that anagliptin may be a substrate of OAT1, OAT3, MDR1 and MRP2, and M1 a substrate of OAT3, BCRP, MRP2 and MRP4.
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Affiliation(s)
- Shinji Furuta
- Pharmaceutical Research Laboratories, Sanwa Kagaku Kenkyusho, Co. Ltd, Mie, Japan.
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Stefater MA, Wilson-Pérez HE, Chambers AP, Sandoval DA, Seeley RJ. All bariatric surgeries are not created equal: insights from mechanistic comparisons. Endocr Rev 2012; 33:595-622. [PMID: 22550271 PMCID: PMC3410227 DOI: 10.1210/er.2011-1044] [Citation(s) in RCA: 230] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Despite considerable scientific progress on the biological systems that regulate energy balance, we have made precious little headway in providing new treatments to curb the obesity epidemic. Diet and exercise are the most popular treatment options for obesity, but rarely are they sufficient to produce long-term weight loss. Bariatric surgery, on the other hand, results in dramatic, sustained weight loss and for this reason has gained increasing popularity as a treatment modality for obesity. At least some surgical approaches also reduce obesity-related comorbidities including type 2 diabetes and hyperlipidemia. This success puts a premium on understanding how these surgeries exert their effects. This review focuses on the growing human and animal model literature addressing the underlying mechanisms. We compare three common procedures: Roux-en-Y Gastric Bypass (RYGB), vertical sleeve gastrectomy (VSG), and adjustable gastric banding (AGB). Although many would group together VSG and AGB as restrictive procedures of the stomach, VSG is more like RYGB than AGB in its effects on a host of endpoints including intake, food choice, glucose regulation, lipids and gut hormone secretion. Our strong belief is that to advance our understanding of these procedures, it is necessary to group bariatric procedures not on the basis of surgical similarity but rather on how they affect key physiological variables. This will allow for greater mechanistic insight into how bariatric surgery works, making it possible to help patients better choose the best possible procedure and to develop new therapeutic strategies that can help a larger portion of the obese population.
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Affiliation(s)
- Margaret A Stefater
- Metabolic Diseases Institute, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA
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Chiang YTA, Ip W, Jin T. The role of the Wnt signaling pathway in incretin hormone production and function. Front Physiol 2012; 3:273. [PMID: 22934027 PMCID: PMC3429047 DOI: 10.3389/fphys.2012.00273] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2012] [Accepted: 06/26/2012] [Indexed: 12/23/2022] Open
Abstract
Glucose metabolism is tightly controlled by multiple hormones and neurotransmitters in response to nutritional, environmental, and emotional changes. In addition to insulin and glucagon produced by pancreatic islets, two incretin hormones, namely glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP, also known as glucose-dependent insulinotropic peptide), also play important roles in blood glucose homeostasis. The incretin hormones mainly exert their regulatory effects via their corresponding receptors, which are expressed in pancreatic islets as well as many other extra-pancreatic organs. Recent studies have shown that the genes which encode these two incretin hormones can be regulated by the effectors of the Wnt signaling pathway, including TCF7L2, a transcription factor identified recently by extensive genome wide association studies as an important type 2 diabetes risk gene. Interestingly, TCF7L2 and β-catenin (β-cat), another effector of Wnt signaling pathway, may also mediate the function of the incretin hormones as well as the expression of their receptors in pancreatic β-cells. In this review, we have introduced the incretin hormones and the Wnt signaling pathway, summarized recent findings in the field, and provided our perspectives.
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Affiliation(s)
- Yu-Ting A Chiang
- Department of Physiology, University of Toronto Toronto, ON, Canada
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Burmeister MA, Ferre T, Ayala JE, King EM, Holt RM, Ayala JE. Acute activation of central GLP-1 receptors enhances hepatic insulin action and insulin secretion in high-fat-fed, insulin resistant mice. Am J Physiol Endocrinol Metab 2012; 302:E334-43. [PMID: 22094469 DOI: 10.1152/ajpendo.00409.2011] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Glucagon-like peptide-1 (GLP-1) receptor knockout (Glp1r(-/-)) mice exhibit impaired hepatic insulin action. High fat (HF)-fed Glp1r(-/-) mice exhibit improved, rather than the expected impaired, hepatic insulin action. This is due to decreased lipogenic gene expression and triglyceride accumulation. The present studies overcome these secondary adaptations by acutely modulating GLP-1R action in HF-fed wild-type mice. The central GLP-1R was targeted given its role as a regulator of hepatic insulin action. We hypothesized that acute inhibition of the central GLP-1R impairs hepatic insulin action beyond the effects of HF feeding. We further hypothesized that activation of the central GLP-1R improves hepatic insulin action in HF-fed mice. Insulin action was assessed in conscious, unrestrained mice using the hyperinsulinemic euglycemic clamp. Mice received intracerebroventricular (icv) infusions of artificial cerebrospinal fluid, GLP-1, or the GLP-1R antagonist exendin-9 (Ex-9) during the clamp. Intracerebroventricular Ex-9 impaired the suppression of hepatic glucose production by insulin, whereas icv GLP-1 improved it. Neither treatment affected tissue glucose uptake. Intracerebroventricular GLP-1 enhanced activation of hepatic Akt and suppressed hypothalamic AMP-activated protein kinase. Central GLP-1R activation resulted in lower hepatic triglyceride levels but did not affect muscle, white adipose tissue, or plasma triglyceride levels during hyperinsulinemia. In response to oral but not intravenous glucose challenges, activation of the central GLP-1R improved glucose tolerance. This was associated with higher insulin levels. Inhibition of the central GLP-1R had no effect on oral or intravenous glucose tolerance. These results show that inhibition of the central GLP-1R deteriorates hepatic insulin action in HF-fed mice but does not affect whole body glucose homeostasis. Contrasting this, activation of the central GLP-1R improves glucose homeostasis in HF-fed mice by increasing insulin levels and enhancing hepatic insulin action.
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Affiliation(s)
- Melissa A Burmeister
- Metabolic Signaling and Disease Program, Diabetes and Obesity Research Center, Orlando, Florida, USA
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