|
1
|
Lewandowski SL, El K, Campbell JE. Evaluating glucose-dependent insulinotropic polypeptide and glucagon as key regulators of insulin secretion in the pancreatic islet. Am J Physiol Endocrinol Metab 2024; 327:E103-E110. [PMID: 38775725 PMCID: PMC11390117 DOI: 10.1152/ajpendo.00360.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 02/27/2024] [Accepted: 05/09/2024] [Indexed: 06/04/2024]
Abstract
The incretin axis is an essential component of postprandial insulin secretion and glucose homeostasis. There are two incretin hormones, glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which exert multiple actions throughout the body. A key cellular target for the incretins are pancreatic β-cells, where they potentiate nutrient-stimulated insulin secretion. This feature of incretins has made this system an attractive target for therapeutic interventions aimed at controlling glycemia. Here, we discuss the role of GIP in both β-cells and α-cells within the islet, to stimulate insulin and glucagon secretion, respectively. Moreover, we discuss how glucagon secretion from α-cells has important insulinotropic actions in β-cells through an axis termed α- to β-cell communication. These recent advances have elevated the potential of GIP and glucagon as a therapeutic targets, coinciding with emerging compounds that pharmacologically leverage the actions of these two peptides in the context of diabetes and obesity.
Collapse
Affiliation(s)
- Sophie L Lewandowski
- Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, United States
| | - Kimberley El
- Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, United States
| | - Jonathan E Campbell
- Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, United States
- Division of Endocrinology, Department of Medicine, Duke University, Durham, North Carolina, United States
- Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina, United States
| |
Collapse
|
|
2
|
Brubaker PL. The Molecular Determinants of Glucagon-like Peptide Secretion by the Intestinal L cell. Endocrinology 2022; 163:6717959. [PMID: 36156130 DOI: 10.1210/endocr/bqac159] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Indexed: 11/19/2022]
Abstract
The intestinal L cell secretes a diversity of biologically active hormones, most notably the glucagon-like peptides, GLP-1 and GLP-2. The highly successful introduction of GLP-1-based drugs into the clinic for the treatment of patients with type 2 diabetes and obesity, and of a GLP-2 analog for patients with short bowel syndrome, has led to the suggestion that stimulation of the endogenous secretion of these peptides may serve as a novel therapeutic approach in these conditions. Situated in the intestinal epithelium, the L cell demonstrates complex relationships with not only circulating, paracrine, and neural regulators, but also ingested nutrients and other factors in the lumen, most notably the microbiota. The integrated input from these numerous secretagogues results in a variety of temporal patterns in L cell secretion, ranging from minutes to 24 hours. This review combines the findings of traditional, physiological studies with those using newer molecular approaches to describe what is known and what remains to be elucidated after 5 decades of research on the intestinal L cell and its secreted peptides, GLP-1 and GLP-2.
Collapse
Affiliation(s)
- Patricia L Brubaker
- Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada
- Department of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada
| |
Collapse
|
|
3
|
Gasbjerg LS, Bari EJ, Christensen M, Knop FK. Exendin(9-39)NH 2 : Recommendations for clinical use based on a systematic literature review. Diabetes Obes Metab 2021; 23:2419-2436. [PMID: 34351033 DOI: 10.1111/dom.14507] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 07/23/2021] [Accepted: 07/28/2021] [Indexed: 12/25/2022]
Abstract
AIM To present an overview of exendin(9-39)NH2 usage as a scientific tool in humans and provide recommendations for dosage and infusion regimes. METHODS We systematically searched the literature on exendin(9-39)NH2 and included for review 44 clinical studies reporting use of exendin(9-39)NH2 in humans. RESULTS Exendin(9-39)NH2 binds to the orthosteric binding site of the glucagon-like peptide-1 (GLP-1) receptor with high affinity. The plasma elimination half-life of exendin(9-39)NH2 after intravenous administration is ~30 minutes, requiring ~2.5 hours of constant infusion before steady-state plasma concentrations can be expected. Studies utilizing infusions with exendin(9-39)NH2 in humans have applied varying regimens (priming with a bolus or constant infusion) and dosages (continuous infusion rate range 30-900 pmol/kg/min) with subsequent differences in effects. Administration of exendin(9-39)NH2 in healthy individuals, patients with diabetes, obese patients, and patients who have undergone bariatric surgery significantly increases fasting and postprandial levels of glucose and glucagon, but has inconsistent effects on circulating concentrations of insulin and C-peptide, gastric emptying, appetite sensations, and food intake. Importantly, exendin(9-39)NH2 induces secretion of all L cell products (ie, in addition to GLP-1, also peptide YY, glucagon-like peptide-2, oxyntomodulin, and glicentin) complicating use of exendin(9-39)NH2 as a tool to study the isolated effect of GLP-1. CONCLUSIONS Exendin(9-39)NH2 is selective for the GLP-1 receptor, with numerous and complex whole-body effects. To obtain GLP-1 receptor blockade in humans, we recommend an initial high-dose infusion, followed by a continuous infusion rate aiming at a ratio of exendin(9-39)NH2 to GLP-1 of 2000:1. Highlights Exendin(9-39)NH2 is a competitive antagonist of the human GLP-1 receptor. Exendin(9-39)NH2 has been used as a tool to delineate human GLP-1 physiology since 1998. Exendin(9-39)NH2 induces secretion of GLP-1 and other L cell products. Reported effects of exendin(9-39)NH2 on insulin levels and food intake are inconsistent. Here, we provide recommendations for the use of exendin(9-39)NH2 in clinical studies.
Collapse
Affiliation(s)
- Laerke Smidt Gasbjerg
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Emilie Johanning Bari
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Mikkel Christensen
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Department of Clinical Pharmacology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark
- Copenhagen Center for Translational Research, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Filip Krag Knop
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Foundation Centre for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Steno Diabetes Centre Copenhagen, Gentofte, Denmark
| |
Collapse
|
|
4
|
Nauck MA, Quast DR, Wefers J, Pfeiffer AFH. The evolving story of incretins (GIP and GLP-1) in metabolic and cardiovascular disease: A pathophysiological update. Diabetes Obes Metab 2021; 23 Suppl 3:5-29. [PMID: 34310013 DOI: 10.1111/dom.14496] [Citation(s) in RCA: 171] [Impact Index Per Article: 42.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 07/13/2021] [Accepted: 07/13/2021] [Indexed: 11/27/2022]
Abstract
The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) have their main physiological role in augmenting insulin secretion after their nutrient-induced secretion from the gut. A functioning entero-insular (gut-endocrine pancreas) axis is essential for the maintenance of a normal glucose tolerance. This is exemplified by the incretin effect (greater insulin secretory response to oral as compared to "isoglycaemic" intravenous glucose administration due to the secretion and action of incretin hormones). GIP and GLP-1 have additive effects on insulin secretion. Local production of GIP and/or GLP-1 in islet α-cells (instead of enteroendocrine K and L cells) has been observed, and its significance is still unclear. GLP-1 suppresses, and GIP increases glucagon secretion, both in a glucose-dependent manner. GIP plays a greater physiological role as an incretin. In type 2-diabetic patients, the incretin effect is reduced despite more or less normal secretion of GIP and GLP-1. While insulinotropic effects of GLP-1 are only slightly impaired in type 2 diabetes, GIP has lost much of its acute insulinotropic activity in type 2 diabetes, for largely unknown reasons. Besides their role in glucose homoeostasis, the incretin hormones GIP and GLP-1 have additional biological functions: GLP-1 at pharmacological concentrations reduces appetite, food intake, and-in the long run-body weight, and a similar role is evolving for GIP, at least in animal studies. Human studies, however, do not confirm these findings. GIP, but not GLP-1 increases triglyceride storage in white adipose tissue not only through stimulating insulin secretion, but also by interacting with regional blood vessels and GIP receptors. GIP, and to a lesser degree GLP-1, play a role in bone remodelling. GLP-1, but not GIP slows gastric emptying, which reduces post-meal glycaemic increments. For both GIP and GLP-1, beneficial effects on cardiovascular complications and neurodegenerative central nervous system (CNS) disorders have been observed, pointing to therapeutic potential over and above improving diabetes complications. The recent finding that GIP/GLP-1 receptor co-agonists like tirzepatide have superior efficacy compared to selective GLP-1 receptor agonists with respect to glycaemic control as well as body weight has renewed interest in GIP, which previously was thought to be without any therapeutic potential. One focus of this research is into the long-term interaction of GIP and GLP-1 receptor signalling. A GLP-1 receptor antagonist (exendin [9-39]) and, more recently, a GIP receptor agonist (GIP [3-30] NH2 ) and, hopefully, longer-acting GIP receptor agonists for human use will be helpful tools to shed light on the open questions. A detailed knowledge of incretin physiology and pathophysiology will be a prerequisite for designing more effective incretin-based diabetes drugs.
Collapse
Affiliation(s)
- Michael A Nauck
- Diabetes Division, Katholisches Klinikum Bochum, St. Josef Hospital, Ruhr University Bochum, Bochum, Germany
| | - Daniel R Quast
- Diabetes Division, Katholisches Klinikum Bochum, St. Josef Hospital, Ruhr University Bochum, Bochum, Germany
| | - Jakob Wefers
- Diabetes Division, Katholisches Klinikum Bochum, St. Josef Hospital, Ruhr University Bochum, Bochum, Germany
| | - Andreas F H Pfeiffer
- Charité - Universitätsmedizin Berlin, Klinik für Endokrinologie, Stoffwechsel- und Ernährungsmedizin, Berlin, Germany
| |
Collapse
|
|
5
|
Cordiner RLM, Mari A, Tura A, Pearson ER. The Impact of Low-dose Gliclazide on the Incretin Effect and Indices of Beta-cell Function. J Clin Endocrinol Metab 2021; 106:2036-2046. [PMID: 33693776 PMCID: PMC8692237 DOI: 10.1210/clinem/dgab151] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Indexed: 12/02/2022]
Abstract
AIMS/HYPOTHESIS Studies in permanent neonatal diabetes suggest that sulphonylureas lower blood glucose without causing hypoglycemia, in part by augmenting the incretin effect. This mechanism has not previously been attributed to sulphonylureas in patients with type 2 diabetes (T2DM). We therefore aimed to evaluate the impact of low-dose gliclazide on beta-cell function and incretin action in patients with T2DM. METHODS Paired oral glucose tolerance tests and isoglycemic infusions were performed to evaluate the difference in the classical incretin effect in the presence and absence of low-dose gliclazide in 16 subjects with T2DM (hemoglobin A1c < 64 mmol/mol, 8.0%) treated with diet or metformin monotherapy. Beta-cell function modeling was undertaken to describe the relationship between insulin secretion and glucose concentration. RESULTS A single dose of 20 mg gliclazide reduced mean glucose during the oral glucose tolerance test from 12.01 ± 0.56 to 10.82 ± 0.5mmol/l [P = 0.0006; mean ± standard error of the mean (SEM)]. The classical incretin effect was augmented by 20 mg gliclazide, from 35.5% (lower quartile 27.3, upper quartile 61.2) to 54.99% (34.8, 72.8; P = 0.049). Gliclazide increased beta-cell glucose sensitivity by 46% [control 22.61 ± 3.94, gliclazide 33.11 ± 7.83 (P = 0.01)] as well as late-phase incretin potentiation [control 0.92 ± 0.05, gliclazide 1.285 ± 0.14 (P = 0.038)]. CONCLUSIONS/INTERPRETATION Low-dose gliclazide reduces plasma glucose in response to oral glucose load, with concomitant augmentation of the classical incretin effect. Beta-cell modeling shows that low plasma concentrations of gliclazide potentiate late-phase insulin secretion and increase glucose sensitivity by 50%. Further studies are merited to explore whether low-dose gliclazide, by enhancing incretin action, could effectively lower blood glucose without risk of hypoglycemia.
Collapse
Affiliation(s)
- Ruth L M Cordiner
- Division of Population Health and Genomics, School of Medicine, University of Dundee, UK
| | - Andrea Mari
- Institute of Neuroscience, National Research Council, Padua, Italy
| | - Andrea Tura
- Institute of Neuroscience, National Research Council, Padua, Italy
| | - Ewan R Pearson
- Division of Population Health and Genomics, School of Medicine, University of Dundee, UK
- Correspondence: Professor Ewan Pearson, Head of Division, Population Health & Genomics, School of Medicine, University of Dundee, DD1 9SY, UK.
| |
Collapse
|
|
6
|
Aulinger BA, Perabo M, Seeley RJ, Parhofer KG, D'Alessio DA. Rapid hepatic metabolism blunts the endocrine action of portally infused GLP-1 in male rats. Am J Physiol Endocrinol Metab 2020; 318:E189-E197. [PMID: 31743041 PMCID: PMC7052580 DOI: 10.1152/ajpendo.00298.2019] [Citation(s) in RCA: 5] [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] [Indexed: 01/11/2023]
Abstract
Glucagon-like peptide-1 (GLP-1) is an enteral peptide that contributes to the incretin effect. GLP-1 action is typically described as endocrine, but this mechanism has been questioned because rapid inactivation in the circulation by dipeptidylpeptidase 4 (DPP4) results in a short half-life, limiting the amount of the hormone that can reach the pancreatic islet. An alternative mechanism for GLP-1 to regulate insulin secretion through neuroendocrine signaling originating from sensors in the portal vein has been proposed. We hypothesized that portal infusion of GLP-1 would cause greater glucose-stimulated insulin secretion than equimolar administration into the jugular vein. To test this, hyperglycemic clamps with superimposed graded infusions of GLP-1 into the jugular or portal veins of male rats were performed. These experiments were repeated with pharmacologic DPP4 inhibition to determine the effect of GLP-1 metabolism in the jugular and portal venous beds. Contrary to our hypothesis, we found a higher insulinotropic effect with jugular compared with portal GLP-1, which was associated with higher plasma concentrations of intact GLP-1. The greater insulinotropic effect of jugular venous GLP-1 persisted even with pharmacological DPP4 inhibition. These findings do not support an important role of portal vein GLP-1 signaling for the incretin effect but highlight the hepatoportal bed as a major site of GLP-1 degradation that persists even with pharmacological inhibition. Together, these results support rapid inactivation of enterally released GLP-1 in the liver as limiting endocrine actions on the β-cell and raise questions about the conventional endocrine model of pharmacologic effects of DPP4 inhibitors.
Collapse
Affiliation(s)
- Benedikt A Aulinger
- Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio
- Department of Medicine II, University Hospital, LMU Munich, Germany
| | - Marta Perabo
- Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Randy J Seeley
- Department of Surgery, University of Michigan, Ann Arbor, Michigan
| | - Klaus G Parhofer
- Department of Medicine IV, University Hospital, LMU Munich, Germany
| | - David A D'Alessio
- Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio
- Department of Medicine, Duke University Medical Center, Durham, North Carolina
| |
Collapse
|
|
7
|
Mussa BM, Sood S, Verberne AJM. Implication of neurohormonal-coupled mechanisms of gastric emptying and pancreatic secretory function in diabetic gastroparesis. World J Gastroenterol 2018; 24:3821-3833. [PMID: 30228777 PMCID: PMC6141338 DOI: 10.3748/wjg.v24.i34.3821] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Revised: 06/22/2018] [Accepted: 06/27/2018] [Indexed: 02/06/2023] Open
Abstract
Recently, diabetic gastroparesis (DGP) has received much attention as its prevalence is increasing in a dramatic fashion and management of patients with DGP represents a challenge in the clinical practice due to the limited therapeutic options. DGP highlights an interrelationship between the gastric emptying and pancreatic secretory function that regulate a wide range of digestive and metabolic functions, respectively. It well documented that both gastric emptying and pancreatic secretion are under delicate control by multiple neurohormonal mechanisms including extrinsic parasympathetic pathways and gastrointestinal (GI) hormones. Interestingly, the latter released in response to various determinants that related to the rate and quality of gastric emptying. Others and we have provided strong evidence that the central autonomic nuclei send a dual output (excitatory and inhibitory) to the stomach and the pancreas in response to a variety of hormonal signals from the abdominal viscera. Most of these hormones released upon gastric emptying to provide feedback, and control this process and simultaneously regulate pancreatic secretion and postprandial glycemia. These findings emphasize an important link between gastric emptying and pancreatic secretion and its role in maintaining homeostatic processes within the GI tract. The present review deals with the neurohormonal-coupled mechanisms of gastric emptying and pancreatic secretory function that implicated in DGP and this provides new insights in our understanding of the pathophysiology of DGP. This also enhances the process of identifying potential therapeutic targets to treat DGP and limit the complications of current management practices.
Collapse
Affiliation(s)
- Bashair M Mussa
- Department of Basic Medical Science, College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Sanjay Sood
- Department of Basic Medical Science, College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Anthony JM Verberne
- Department of Medicine, Austin Health, University of Melbourne, Melbourne 3084, Australia
| |
Collapse
|
|
8
|
Lixisenatide ameliorates cerebral ischemia-reperfusion injury via GLP-1 receptor dependent/independent pathways. Eur J Pharmacol 2018; 833:145-154. [DOI: 10.1016/j.ejphar.2018.05.045] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2018] [Revised: 05/25/2018] [Accepted: 05/29/2018] [Indexed: 02/06/2023]
|
|
9
|
The endocrine disrupting potential of monosodium glutamate (MSG) on secretion of the glucagon-like peptide-1 (GLP-1) gut hormone and GLP-1 receptor interaction. Toxicol Lett 2017; 265:97-105. [DOI: 10.1016/j.toxlet.2016.11.015] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2016] [Revised: 11/04/2016] [Accepted: 11/23/2016] [Indexed: 12/19/2022]
|
|
10
|
Jodal A, Schibli R, Béhé M. Targets and probes for non-invasive imaging of β-cells. Eur J Nucl Med Mol Imaging 2016; 44:712-727. [PMID: 28025655 PMCID: PMC5323463 DOI: 10.1007/s00259-016-3592-1] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2015] [Accepted: 12/01/2016] [Indexed: 12/16/2022]
Abstract
β-cells, located in the islets of the pancreas, are responsible for production and secretion of insulin and play a crucial role in blood sugar regulation. Pathologic β-cells often cause serious medical conditions affecting blood glucose level, which severely impact life quality and are life-threatening if untreated. With 347 million patients, diabetes is one of the most prevalent diseases, and will continue to be one of the largest socioeconomic challenges in the future. The diagnosis still relies mainly on indirect methods like blood sugar measurements. A non-invasive diagnostic imaging modality would allow direct evaluation of β-cell mass and would be a huge step towards personalized medicine. Hyperinsulinism is another serious condition caused by β-cells that excessively secrete insulin, like for instance β-cell hyperplasia and insulinomas. Treatment options with drugs are normally not curative, whereas curative procedures usually consist of the resection of affected regions for which, however, an exact localization of the foci is necessary. In this review, we describe potential tracers under development for targeting β-cells with focus on radiotracers for PET and SPECT imaging, which allow the non-invasive visualization of β-cells. We discuss either the advantages or limitations for the various tracers and modalities. This article concludes with an outlook on future developments and discuss the potential of new imaging probes including dual probes that utilize functionalities for both a radioactive and optical moiety as well as for theranostic applications.
Collapse
Affiliation(s)
- Andreas Jodal
- Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institut, 5232, Villigen, Switzerland
| | - Roger Schibli
- Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institut, 5232, Villigen, Switzerland.,Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, Switzerland
| | - Martin Béhé
- Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institut, 5232, Villigen, Switzerland.
| |
Collapse
|
|
11
|
Campbell RK. Diabetes: Rationale for Dipeptidyl Peptidase 4 Inhibitors: A New Class of Oral Agents for the Treatment of Type 2 Diabetes Mellitus. Ann Pharmacother 2016; 41:51-60. [PMID: 17190843 DOI: 10.1345/aph.1h459] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Objective: To review advances in understanding the pathophysiologic basis of type 2 diabetes mellitus and the pharmacology and mechanism of action of dipeptidyl peptidase 4 (DPP-4) inhibition in correcting the underlying defects in glycemic control. Data Sources: Articles were identified through MEDLINE for the period 1966 through November 2006. Abstracts and presentations from the American Diabetes Association Scientific Sessions and the European Association for the Study of Diabetes (2002–2006) were also searched for scientific reports on DPP-4 inhibitors. Study Selection And Data Extraction: Abstracts, original clinical and preclinical research reports, and review articles published in the English language were identified for review. Literature discussing glucose regulation, incretin hormones, type 2 diabetes pathophysiology, and DPP-4 inhibition were evaluated and selected based on consideration of their support for the proof of concept, mechanistic and in vivo findings, and timeliness. Data Synthesis: The search for new and effective therapies for type 2 diabetes has led to the identification of a novel therapeutic target, the incretin hormones, which play a role in mediating glucose homeostasis via effects on glucagon and insulin secretion from pancreatic islet α- and β-cells, respectively. The incretins' glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide are rapidly inactivated by the enzyme DPP-4. DPP-4 inhibitor agents act by blocking the active site of DPP-4, thereby preventing inactivation of and prolonging the duration of action of incretins, which in turn helps to correct the defective insulin and glucagon secretion that marks type 2 diabetes. Clinical studies to date indicate that DPP-4 inhibitors effectively stimulate insulin secretion, suppress glucagon release, and improve glucose control in patients with type 2 diabetes. These agents are well tolerated and have a low incidence of adverse effects. Conclusions: The DPP-4 inhibitors are novel agents for the treatment of type 2 diabetes. Compounds under development in this new class of oral antidiabetic drugs may be free of the limitations of current therapies.
Collapse
Affiliation(s)
- R Keith Campbell
- College of Pharmacy, Wegner Hall #147, PO Box 646510, Washington State University, Pullman, WA 99164, USA.
| |
Collapse
|
|
12
|
Selective beneficial cardiometabolic effects of vertical sleeve gastrectomy are predominantly mediated through glucagon-like peptide (GLP-1) in Zucker diabetic fatty rats. Ann Med Surg (Lond) 2016; 12:65-74. [PMID: 27900077 PMCID: PMC5123065 DOI: 10.1016/j.amsu.2016.11.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2016] [Revised: 11/15/2016] [Accepted: 11/16/2016] [Indexed: 12/12/2022] Open
Abstract
Background Glucagon-like peptide-1 (GLP-1) level was significantly increased post Vertical Sleeve Gastrectomy (VSG), an effect believed to contribute to its beneficial cardiometabolic effects. Objective To validate the beneficial GLP-1 mediated cardiometabolic effects post VSG using GLP-1 antagonist (exendin 9-39) in Zucker diabetic fatty rats. Methods Animals were divided into three (n = 5) groups: (i) sham, (ii) VSG, and (iii) VSG received exendin 9–39 (GLP-1 receptor antagonist). The study was performed over 12 weeks and parameters were measured 12 weeks post-surgery. Results and discussion As expected, fasting blood glucose and insulin levels were improved post VSG due to enhanced GLP-1 secretion. However, both fasting glucose and insulin levels were impaired in the presence of GLP-1 antagonist. Baseline total cholesterol level pre-surgery was 100±1 mg/dl which remained unchanged in the VSG group but significantly increased to 140±8 mg/dl in the presence of antagonist. Interestingly, post-surgery there was a nearly 70% reduction in triglyceride level in the VSG group compared to sham which was overcome in the presence of antagonist. Myographic studies using aortic rings showed no significant change between groups. Additionally, blood pressure and heart rate also remained unchanged in all groups. Serum bile acid and L-PGDS levels increased post VSG but significantly decreased in the presence of antagonist, suggesting a strong association with GLP-1 and a novel mechanism of action. Conclusion Enhanced GLP-1 secretion post VSG imparted beneficial cardiometabolic effects on blood glucose, insulin, total cholesterol, triglyceride, bile acids and L-PGDS levels which were abated in the presence of GLP-1 antagonist.
GLP-1 increases post-VSG 30 min after glucose load. Post-VSG GLP-1 secretion is associatged with lower cholesterol and triglycerides. Bile acids and L-PGDS increase post-VSG and are inhibited in the presence of GLP-1 antagonist. Heart rate, blood pressure and myograph profile remain unchanged.
Collapse
|
|
13
|
Zhang L, Thurber GM. Quantitative Impact of Plasma Clearance and Down-regulation on GLP-1 Receptor Molecular Imaging. Mol Imaging Biol 2016; 18:79-89. [PMID: 26194012 DOI: 10.1007/s11307-015-0880-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
PURPOSE Quantitative molecular imaging of beta cell mass (BCM) would enable early detection and treatment monitoring of type 1 diabetes. The glucagon-like peptide-1 (GLP-1) receptor is an attractive target due to its beta cell specificity and cell surface location. We quantitatively investigated the impact of plasma clearance and receptor internalization on targeting efficiency in healthy B6 mice. PROCEDURES Four exenatide-based probes were synthesized that varied in molecular weight, binding affinity, and plasma clearance. The GLP-1 receptor internalization rate and in vivo receptor expression were quantified. RESULTS Receptor internalization (54,000 receptors/cell in vivo) decreased significantly within minutes, reducing the benefit of a slower-clearing agent. The multimers and albumin binding probes had higher kidney and liver uptake, respectively. CONCLUSIONS Slow plasma clearance is beneficial for GLP-1 receptor peptide therapeutics. However, for exendin-based imaging of islets, down-regulation of the GLP-1 receptor and non-specific background uptake result in a higher target-to-background ratio for fast-clearing agents.
Collapse
Affiliation(s)
- Liang Zhang
- Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Greg M Thurber
- Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, 48109, USA. .,Department of Biomedical Engineering, University of Michigan, 2800 Plymouth Rd., Ann Arbor, MI, 48109, USA.
| |
Collapse
|
|
14
|
Natochin YV, Marina AS, Kutina AV, Balbotkina EV, Karavashkina TA. The mechanism of glucagon-like peptide-1 participation in the osmotic homeostasis. DOKLADY BIOLOGICAL SCIENCES : PROCEEDINGS OF THE ACADEMY OF SCIENCES OF THE USSR, BIOLOGICAL SCIENCES SECTIONS 2016; 469:156-8. [PMID: 27595820 DOI: 10.1134/s0012496616040086] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/22/2016] [Indexed: 11/22/2022]
Abstract
We have found the physiological mechanism of intensification of the excessive fluid removal from the body under the action of glucagon-like peptide-1 and its analog exenatide. Under the water load in rats, exenatide significantly increased the clearance of lithium, reduced fluid reabsorption in the proximal tubule of the nephron and intensified reabsorption of sodium ions in the distal parts, which contributed to the formation of sodium-free water and faster recovery of osmotic homeostasis. Blocking this pathway with a selective antagonist of glucagon-like peptide-1 receptors slowed down the elimination of excessive water from the body.
Collapse
Affiliation(s)
- Yu V Natochin
- Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg, Russia.
| | - A S Marina
- Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg, Russia
| | - A V Kutina
- Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg, Russia
| | - E V Balbotkina
- Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg, Russia
| | - T A Karavashkina
- Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg, Russia
| |
Collapse
|
|
15
|
Smits MM, van Raalte DH, Tonneijck L, Muskiet MHA, Kramer MHH, Cahen DL. GLP-1 based therapies: clinical implications for gastroenterologists. Gut 2016; 65:702-11. [PMID: 26786687 DOI: 10.1136/gutjnl-2015-310572] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2015] [Accepted: 12/23/2015] [Indexed: 12/13/2022]
Abstract
The gut-derived incretin hormone, glucagon-like peptide 1 (GLP-1) lowers postprandial blood glucose levels by stimulating insulin and inhibiting glucagon secretion. Two novel antihyperglycaemic drug classes augment these effects; GLP-1 receptor agonists and inhibitors of the GLP-1 degrading enzyme dipeptidyl peptidase 4. These so called GLP-1 based or incretin based drugs are increasingly used to treat type 2 diabetes, because of a low risk of hypoglycaemia and favourable effect on body weight, blood pressure and lipid profiles. Besides glucose control, GLP-1 functions as an enterogastrone, causing a wide range of GI responses. Studies have shown that endogenous GLP-1 and its derived therapies slow down digestion by affecting the stomach, intestines, exocrine pancreas, gallbladder and liver. Understanding the GI actions of GLP-1 based therapies is clinically relevant; because GI side effects are common and need to be recognised, and because these drugs may be used to treat GI disease.
Collapse
Affiliation(s)
- Mark M Smits
- Department of Internal Medicine, Diabetes Center, VU University Medical Center, Amsterdam, The Netherlands
| | - Daniel H van Raalte
- Department of Internal Medicine, Diabetes Center, VU University Medical Center, Amsterdam, The Netherlands
| | - Lennart Tonneijck
- Department of Internal Medicine, Diabetes Center, VU University Medical Center, Amsterdam, The Netherlands
| | - Marcel H A Muskiet
- Department of Internal Medicine, Diabetes Center, VU University Medical Center, Amsterdam, The Netherlands
| | - Mark H H Kramer
- Department of Internal Medicine, Diabetes Center, VU University Medical Center, Amsterdam, The Netherlands
| | - Djuna L Cahen
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands
| |
Collapse
|
|
16
|
Wang F, Yang Q, Huesman S, Xu M, Li X, Lou D, Woods SC, Marziano C, Tso P. The role of apolipoprotein A-IV in regulating glucagon-like peptide-1 secretion. Am J Physiol Gastrointest Liver Physiol 2015; 309:G680-7. [PMID: 26294669 PMCID: PMC4609932 DOI: 10.1152/ajpgi.00075.2015] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2015] [Accepted: 08/14/2015] [Indexed: 01/31/2023]
Abstract
Both glucagon-like peptide-1 (GLP-1) and apolipoprotein A-IV (apoA-IV) are produced from the gut and enhance postprandial insulin secretion. This study investigated whether apoA-IV regulates nutrient-induced GLP-1 secretion and whether apoA-IV knockout causes compensatory GLP-1 release. Using lymph-fistula-mice, we first determined lymphatic GLP-1 secretion by administering apoA-IV before an intraduodenal Ensure infusion. apoA-IV changed neither basal nor Ensure-induced GLP-1 secretion relative to saline administration. We then assessed GLP-1 in apoA-IV-/- and wild-type (WT) mice administered intraduodenal Ensure. apoA-IV-/- mice had comparable lymph flow, lymphatic triglyceride, glucose, and protein outputs as WT mice. Intriguingly, apoA-IV-/- mice had higher lymphatic GLP-1 concentration and output than WT mice 30 min after Ensure administration. Increased GLP-1 was also observed in plasma of apoA-IV-/- mice at 30 min. apoA-IV-/- mice had comparable total gut GLP-1 content relative to WT mice under fasting, but a lower GLP-1 content 30 min after Ensure administration, suggesting that more GLP-1 was secreted. Moreover, an injection of apoA-IV protein did not reverse the increased GLP-1 secretion in apoA-IV-/- mice. Finally, we assessed gene expression of GLUT-2 and the lipid receptors, including G protein-coupled receptor (GPR) 40, GPR119, and GPR120 in intestinal segments. GLUT-2, GPR40 and GPR120 mRNAs were unaltered by apoA-IV knockout. However, ileal GPR119 mRNA was significantly increased in apoA-IV-/- mice. GPR119 colocalizes with GLP-1 in ileum and stimulates GLP-1 secretion by sensing OEA, lysophosphatidylcholine, and 2-monoacylglycerols. We suggest that increased ileal GPR119 is a potential mechanism by which GLP-1 secretion is enhanced in apoA-IV-/- mice.
Collapse
Affiliation(s)
- Fei Wang
- 1Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, Ohio; and
| | - Qing Yang
- 1Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, Ohio; and
| | - Sarah Huesman
- 1Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, Ohio; and
| | - Min Xu
- 1Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, Ohio; and
| | - Xiaoming Li
- 1Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, Ohio; and
| | - Danwen Lou
- 1Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, Ohio; and
| | - Stephen C. Woods
- 2Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, Ohio
| | - Corina Marziano
- 1Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, Ohio; and
| | - Patrick Tso
- Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, Ohio; and
| |
Collapse
|
|
17
|
Duca FA, Bauer PV, Hamr SC, Lam TKT. Glucoregulatory Relevance of Small Intestinal Nutrient Sensing in Physiology, Bariatric Surgery, and Pharmacology. Cell Metab 2015. [PMID: 26212718 DOI: 10.1016/j.cmet.2015.07.003] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Emerging evidence suggests the gastrointestinal tract plays an important glucoregulatory role. In this perspective, we first review how the intestine senses ingested nutrients, initiating crucial negative feedback mechanisms through a gut-brain neuronal axis to regulate glycemia, mainly via reduction in hepatic glucose production. We then highlight how intestinal energy sensory mechanisms are responsible for the glucose-lowering effects of bariatric surgery, specifically duodenal-jejunal bypass, and the antidiabetic agents metformin and resveratrol. A better understanding of these pathways lays the groundwork for intestinally targeted drug therapy for the treatment of diabetes.
Collapse
Affiliation(s)
- Frank A Duca
- Toronto General Research Institute and Department of Medicine, UHN, Toronto, ON M5G 1L7, Canada
| | - Paige V Bauer
- Toronto General Research Institute and Department of Medicine, UHN, Toronto, ON M5G 1L7, Canada; Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Sophie C Hamr
- Toronto General Research Institute and Department of Medicine, UHN, Toronto, ON M5G 1L7, Canada; Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Tony K T Lam
- Toronto General Research Institute and Department of Medicine, UHN, Toronto, ON M5G 1L7, Canada; Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada; Banting and Best Diabetes Centre, University of Toronto, Toronto, ON M5G 2C4, Canada.
| |
Collapse
|
|
18
|
Tudurí E, Beiroa D, Porteiro B, López M, Diéguez C, Nogueiras R. Acute but not chronic activation of brain glucagon-like peptide-1 receptors enhances glucose-stimulated insulin secretion in mice. Diabetes Obes Metab 2015; 17:789-99. [PMID: 25962313 DOI: 10.1111/dom.12488] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2015] [Revised: 04/24/2015] [Accepted: 05/03/2015] [Indexed: 01/15/2023]
Abstract
AIM To investigate the role of brain glucagon-like peptide-1 (GLP-1) in pancreatic β-cell function. METHODS To determine the role of brain GLP-1 receptor (GLP-1R) on β-cell function, we administered intracerebroventricular (i.c.v.) infusions of GLP-1 or the specific GLP-1 antagonist exendin-9 (Ex-9), in both an acute and a chronic setting. RESULTS We observed that acute i.c.v. GLP-1 infusion potentiates glucose-stimulated insulin secretion (GSIS) and improves glucose tolerance, whereas central GLP-1R blockade with Ex-9 impaired glucose excursion after a glucose load. Sustained activation of central nervous system GLP-1R, however, did not produce any effect on either GSIS or glucose tolerance. Similarly, ex vivo GSIS performed in islets from mice chronically infused with i.c.v. GLP-1 resulted in no differences compared with controls. In addition, in mice fed a high-fat diet we observed that acute i.c.v. GLP-1 infusion improved glucose tolerance without changes in GSIS, while chronic GLP-1R activation had no effect on glucose homeostasis. CONCLUSIONS Our results indicate that, under non-clamped conditions, brain GLP-1 plays a functional neuroendocrine role in the acute regulation of glucose homeostasis in both lean and obese rodents.
Collapse
Affiliation(s)
- E Tudurí
- Instituto de Investigaciones Sanitarias, CIMUS, University of Santiago de Compostela, Santiago de Compostela, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición, Santiago de Compostela, Spain
| | - D Beiroa
- Instituto de Investigaciones Sanitarias, CIMUS, University of Santiago de Compostela, Santiago de Compostela, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición, Santiago de Compostela, Spain
- Department of Physiology, CIMUS, University of Santiago de Compostela, Santiago de Compostela, Spain
| | - B Porteiro
- Instituto de Investigaciones Sanitarias, CIMUS, University of Santiago de Compostela, Santiago de Compostela, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición, Santiago de Compostela, Spain
- Department of Physiology, CIMUS, University of Santiago de Compostela, Santiago de Compostela, Spain
| | - M López
- Instituto de Investigaciones Sanitarias, CIMUS, University of Santiago de Compostela, Santiago de Compostela, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición, Santiago de Compostela, Spain
- Department of Physiology, CIMUS, University of Santiago de Compostela, Santiago de Compostela, Spain
| | - C Diéguez
- Instituto de Investigaciones Sanitarias, CIMUS, University of Santiago de Compostela, Santiago de Compostela, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición, Santiago de Compostela, Spain
- Department of Physiology, CIMUS, University of Santiago de Compostela, Santiago de Compostela, Spain
| | - R Nogueiras
- Instituto de Investigaciones Sanitarias, CIMUS, University of Santiago de Compostela, Santiago de Compostela, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición, Santiago de Compostela, Spain
- Department of Physiology, CIMUS, University of Santiago de Compostela, Santiago de Compostela, Spain
| |
Collapse
|
|
19
|
Camilleri M. Peripheral mechanisms in appetite regulation. Gastroenterology 2015; 148:1219-33. [PMID: 25241326 PMCID: PMC4369188 DOI: 10.1053/j.gastro.2014.09.016] [Citation(s) in RCA: 152] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2014] [Revised: 09/09/2014] [Accepted: 09/15/2014] [Indexed: 12/13/2022]
Abstract
Peripheral mechanisms in appetite regulation include the motor functions of the stomach, such as the rate of emptying and accommodation, which convey symptoms of satiation to the brain. The rich repertoire of peripherally released peptides and hormones provides feedback from the arrival of nutrients in different regions of the gut from where they are released to exert effects on satiation, or regulate metabolism through their incretin effects. Ultimately, these peripheral factors provide input to the highly organized hypothalamic circuitry and vagal complex of nuclei to determine cessation of energy intake during meal ingestion, and the return of appetite and hunger after fasting. Understanding these mechanisms is key to the physiological control of feeding and the derangements that occur in obesity and their restoration with treatment (as shown by the effects of bariatric surgery).
Collapse
Affiliation(s)
- Michael Camilleri
- Clinical Enteric Neuroscience Translational and Epidemiological Research, Mayo Clinic College of Medicine, Rochester, Minnesota.
| |
Collapse
|
|
20
|
Reidelberger R, Haver A, Anders K, Apenteng B. Role of capsaicin-sensitive peripheral sensory neurons in anorexic responses to intravenous infusions of cholecystokinin, peptide YY-(3-36), and glucagon-like peptide-1 in rats. Am J Physiol Endocrinol Metab 2014; 307:E619-29. [PMID: 25117406 PMCID: PMC4200310 DOI: 10.1152/ajpendo.00024.2014] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Cholecystokinin (CCK)-induced suppression of feeding is mediated by vagal sensory neurons that are destroyed by the neurotoxin capsaicin (CAP). Here we determined whether CAP-sensitive neurons mediate anorexic responses to intravenous infusions of gut hormones peptide YY-(3-36) [PYY-(3-36)] and glucagon-like peptide-1 (GLP-1). Rats received three intraperitoneal injections of CAP or vehicle (VEH) in 24 h. After recovery, non-food-deprived rats received at dark onset a 3-h intravenous infusion of CCK-8 (5, 17 pmol·kg⁻¹·min⁻¹), PYY-(3-36) (5, 17, 50 pmol·kg⁻¹·min⁻¹), or GLP-1 (17, 50 pmol·kg⁻¹·min⁻¹). CCK-8 was much less effective in reducing food intake in CAP vs. VEH rats. CCK-8 at 5 and 17 pmol·kg⁻¹·min⁻¹ reduced food intake during the 3-h infusion period by 39 and 71% in VEH rats and 7 and 18% in CAP rats. In contrast, PYY-(3-36) and GLP-1 were similarly effective in reducing food intake in VEH and CAP rats. PYY-(3-36) at 5, 17, and 50 pmol·kg⁻¹·min⁻¹ reduced food intake during the 3-h infusion period by 15, 33, and 70% in VEH rats and 13, 30, and 33% in CAP rats. GLP-1 at 17 and 50 pmol·kg⁻¹·min⁻¹ reduced food intake during the 3-h infusion period by 48 and 60% in VEH rats and 30 and 52% in CAP rats. These results suggest that anorexic responses to PYY-(3-36) and GLP-1 are not primarily mediated by the CAP-sensitive peripheral sensory neurons (presumably vagal) that mediate CCK-8-induced anorexia.
Collapse
MESH Headings
- Animals
- Anorexia/metabolism
- Anorexia/physiopathology
- Anorexia/prevention & control
- Behavior, Animal/drug effects
- Capsaicin/administration & dosage
- Capsaicin/toxicity
- Cholecystokinin/administration & dosage
- Cholecystokinin/metabolism
- Disease Models, Animal
- Energy Intake/drug effects
- Feeding Behavior/drug effects
- Glucagon-Like Peptide 1/administration & dosage
- Glucagon-Like Peptide 1/metabolism
- Infusions, Intravenous
- Injections, Intraperitoneal
- Intestinal Mucosa/drug effects
- Intestinal Mucosa/innervation
- Intestinal Mucosa/metabolism
- Intestinal Mucosa/physiopathology
- Intestine, Small/drug effects
- Intestine, Small/innervation
- Intestine, Small/metabolism
- Intestine, Small/physiopathology
- Male
- Neuritis/chemically induced
- Neuritis/metabolism
- Neuritis/physiopathology
- Neurons, Afferent/drug effects
- Neurons, Afferent/metabolism
- Peptide Fragments/administration & dosage
- Peptide Fragments/metabolism
- Peptide YY/administration & dosage
- Peptide YY/metabolism
- Rats
- Vagus Nerve/drug effects
- Vagus Nerve/metabolism
- Vagus Nerve/physiopathology
- Vagus Nerve Diseases/chemically induced
- Vagus Nerve Diseases/metabolism
- Vagus Nerve Diseases/physiopathology
Collapse
Affiliation(s)
- Roger Reidelberger
- Veterans Affairs Research Service, Veterans Affairs Nebraska Western Iowa Health Care System, Omaha, Nebraska; and Department of Biomedical Sciences, Creighton University, Omaha, Nebraska
| | - Alvin Haver
- Veterans Affairs Research Service, Veterans Affairs Nebraska Western Iowa Health Care System, Omaha, Nebraska; and Department of Biomedical Sciences, Creighton University, Omaha, Nebraska
| | - Krista Anders
- Department of Biomedical Sciences, Creighton University, Omaha, Nebraska
| | - Bettye Apenteng
- Department of Biomedical Sciences, Creighton University, Omaha, Nebraska
| |
Collapse
|
|
21
|
Tasyurek HM, Altunbas HA, Balci MK, Sanlioglu S. Incretins: their physiology and application in the treatment of diabetes mellitus. Diabetes Metab Res Rev 2014; 30:354-71. [PMID: 24989141 DOI: 10.1002/dmrr.2501] [Citation(s) in RCA: 78] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2013] [Revised: 11/06/2013] [Accepted: 11/12/2013] [Indexed: 12/18/2022]
Abstract
Therapies targeting the action of incretin hormones have been under close scrutiny in recent years. The incretin effect has been defined as postprandial enhancement of insulin secretion by gut-derived factors. Likewise, incretin mimetics and incretin effect amplifiers are the two different incretin-based treatment strategies developed for the treatment of diabetes. Although, incretin mimetics produce effects very similar to those of natural incretin hormones, incretin effect amplifiers act by inhibiting dipeptidyl peptidase-4 (DPP-4) enzyme to increase plasma concentration of incretins and their biologic effects. Because glucagon-like peptide-1 (GLP-1) is an incretin hormone with various anti-diabetic actions including stimulation of glucose-induced insulin secretion, inhibition of glucagon secretion, hepatic glucose production and gastric emptying, it has been evaluated as a novel therapeutic agent for the treatment of type 2 diabetes mellitus (T2DM). GLP-1 also manifests trophic effects on pancreas such as pancreatic beta cell growth and differentiation. Because DPP-4 is the enzyme responsible for the inactivation of GLP-1, DPP-4 inhibition represents another potential strategy to increase plasma concentration of GLP-1 to enhance the incretin effect. Thus, anti-diabetic properties of these two classes of drugs have stimulated substantial clinical interest in the potential of incretin-based therapeutic agents as a means to control glucose homeostasis in T2DM patients. Despite this fact, clinical use of GLP-1 mimetics and DPP-4 inhibitors have raised substantial concerns owing to possible side effects of the treatments involving increased risk for pancreatitis, and C-cell adenoma/carcinoma. Thus, controversial issues in incretin-based therapies under development are reviewed and discussed in this manuscript.
Collapse
|
|
22
|
Aulinger BA, Bedorf A, Kutscherauer G, de Heer J, Holst JJ, Göke B, Schirra J. Defining the role of GLP-1 in the enteroinsulinar axis in type 2 diabetes using DPP-4 inhibition and GLP-1 receptor blockade. Diabetes 2014; 63:1079-92. [PMID: 24296715 DOI: 10.2337/db13-1455] [Citation(s) in RCA: 75] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Understanding the incretin pathway has led to significant advancements in the treatment of type 2 diabetes (T2D). Still, the exact mechanisms are not fully understood. In a randomized, placebo-controlled, four-period, crossover study in 24 patients with T2D, dipeptidyl peptidase-4 (DPP-4) inhibition and its glucose-lowering actions were tested after an oral glucose tolerance test (OGTT). The contribution of GLP-1 was examined by infusion of the GLP-1 receptor (GLP-1r) antagonist exendin-9. DPP-4 inhibition reduced glycemia and enhanced insulin levels and the incretin effect (IE). Glucagon was suppressed, and gastric emptying (GE) was decelerated. Exendin-9 increased glucose levels and glucagon secretion, attenuated insulinemia and the IE, and accelerated GE. With the GLP-1r antagonist, the glucose-lowering effects of DPP-4 inhibition were reduced by ∼ 50%. However, a significant effect on insulin secretion remained during GLP-1r blockade, whereas the inhibitory effects of DPP-4 inhibition on glucagon and GE were abolished. Thus, in this cohort of T2D patients with a substantial IE, GLP-1 contributed ∼ 50% to the insulin excursion after an OGTT with and without DPP-4 inhibition. Thus, a significant DPP-4-sensitive glucose-lowering mechanism contributes to glycemic control in T2D patients that may be not mediated by circulating GLP-1.
Collapse
Affiliation(s)
- Benedikt A Aulinger
- Department of Internal Medicine II, Clinical Research Unit, Clinical Center of the Ludwig-Maximilians University, Campus Grosshadern, Munich, Germany
| | | | | | | | | | | | | |
Collapse
|
|
23
|
Lee YS, Jun HS. Anti-diabetic actions of glucagon-like peptide-1 on pancreatic beta-cells. Metabolism 2014; 63:9-19. [PMID: 24140094 DOI: 10.1016/j.metabol.2013.09.010] [Citation(s) in RCA: 212] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2013] [Revised: 09/05/2013] [Accepted: 09/14/2013] [Indexed: 12/11/2022]
Abstract
Glucagon-like peptide-1 (GLP-1), an incretin hormone, is released from intestinal L-cells in response to nutrients. GLP-1 lowers blood glucose levels by stimulating insulin secretion from pancreatic beta-cells in a glucose-dependent manner. In addition, GLP-1 slows gastric emptying, suppresses appetite, reduces plasma glucagon, and stimulates glucose disposal, which are beneficial for glucose homeostasis. Therefore, incretin-based therapies such as GLP-1 receptor agonists and inhibitors of dipeptidyl peptidase IV, an enzyme which inactivates GLP-1, have been developed for treatment of diabetes. This review outlines our knowledge of the actions of GLP-1 on insulin secretion and biosynthesis, beta-cell proliferation and regeneration, and protection against beta-cell damage, as well as the involvement of recently discovered signaling pathways of GLP-1 action, mainly focusing on pancreatic beta-cells.
Collapse
Affiliation(s)
- Young-Sun Lee
- Lee Gil Ya Cancer and Diabetes Institute, Gachon University, 7-45 Songdo-dong, Yeonsu-ku, Incheon 406-840, South Korea
| | | |
Collapse
|
|
24
|
Nielsen ST, Lehrskov-Schmidt L, Krogh-Madsen R, Solomon TPJ, Lehrskov-Schmidt L, Holst JJ, Møller K. Tumour necrosis factor-alpha infusion produced insulin resistance but no change in the incretin effect in healthy volunteers. Diabetes Metab Res Rev 2013; 29:655-63. [PMID: 23904405 DOI: 10.1002/dmrr.2441] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2013] [Accepted: 06/10/2013] [Indexed: 01/04/2023]
Abstract
BACKGROUND Type 2 diabetes mellitus (T2DM) is associated with peripheral insulin resistance, impaired incretin effect, and increased plasma levels of tumour necrosis factor-alpha (TNF-α). Although TNF-α infusion at a dose that induces systemic inflammation in healthy volunteers has been demonstrated to induce peripheral insulin resistance, the influence of this cytokine on the incretin effect is unknown. METHODS We investigated whether systemic inflammation induced by TNF-α infusion in healthy volunteers alters the incretin hormone response to oral and intravenous glucose loads in a crossover study design with ten healthy male volunteers (mean age 24 years, mean body mass index 23.7 kg/m(2) ). The study consisted of four study days: days 1 and 2, 6-h infusion of saline; days 3 and 4, 6-h infusion of TNF-α; days 1 and 3, 4-h oral glucose tolerance test; and days 2 and 4, 4-h corresponding intravenous isoglycaemic glucose tolerance test. Glucose tolerance tests were initiated after 2 h of saline/TNF-α infusion. Plasma concentrations of TNF-α, interleukin 6, glucose, incretin hormones, and cortisol, and serum concentrations of C-peptide and insulin were measured throughout the study days. Insulin sensitivity was estimated by the Matsuda index and homeostasis model assessment of insulin resistance (HOMA-IR). Prehepatic insulin secretion rates were calculated. RESULTS TNF-α infusion induced symptoms of systemic inflammation; increased plasma levels of cortisol, TNF-α, and interleukin 6; and increased the HOMA-IR. The secretion of incretin hormones as well as the incretin effect remained unchanged. CONCLUSION In healthy young male volunteers, acute systemic inflammation induced by infusion of TNF-α is associated with insulin resistance with no change in the incretin effect.
Collapse
Affiliation(s)
- Signe Tellerup Nielsen
- Centre of Inflammation and Metabolism and CMRC, Section 7641 Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
| | | | | | | | | | | | | |
Collapse
|
|
25
|
Liraglutide, a long-acting GLP-1 mimetic, and its metabolite attenuate inflammation after intracerebral hemorrhage. J Cereb Blood Flow Metab 2012; 32:2201-10. [PMID: 22968320 PMCID: PMC3519414 DOI: 10.1038/jcbfm.2012.133] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
The inflammatory response plays a pivotal role in propagating injury of intracerebral hemorrhage (ICH). Glucagon-like-peptide-1 (GLP-1) is a hormone with antidiabetic effect and may also have antiinflammatory properties. Despite consensus that the glucoregulatory action is mediated by the GLP-1 receptor (GLP-1R), mechanisms in the brain remain unclear. We investigated the effect of a long-acting GLP-1 analog, liraglutide, and its truncated metabolite, GLP-1(9-36)a from dipeptidyl peptidase-4 (DPP-4) cleavage in ICH-induced brain injury. Primary outcomes were cerebral edema formation, neurobehavior, and inflammatory parameters. GLP-1(9-36)a, GLP-1R inhibitor, adenosine monophosphate-activated protein kinase (AMPK) phosphorylation inhibitor and DPP-4 inhibitor were administered to examine the mechanisms of action. Liraglutide suppressed neuroinflammation, prevented brain edema and neurologic deficit following ICH, which were partially reversed by GLP-1R inhibitor and AMPK phosphorylation inhibitor. Liraglutide-mediated AMPK phosphorylation was unaffected by GLP-1R inhibitor, and was found to be induced by GLP-1(9-36)a. GLP-1(9-36)a showed salutary effects on primary outcomes that were reversed by AMPK phosphorylation inhibitor but not by GLP-1R inhibitor. Liraglutide and DPP-4 inhibitor co-administration reversed liraglutide-mediated AMPK phosphorylation and antiinflammatory effects. Liraglutide exerted duals actions and the antiinflammatory effects are partially mediated by its metabolite in a phosphorylated AMPK-dependent manner. Therapies that inhibit GLP-1 degradation may weaken the metabolite-mediated effects.
Collapse
|
|
26
|
Donnelly D. The structure and function of the glucagon-like peptide-1 receptor and its ligands. Br J Pharmacol 2012; 166:27-41. [PMID: 21950636 DOI: 10.1111/j.1476-5381.2011.01687.x] [Citation(s) in RCA: 186] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Glucagon-like peptide-1(7-36)amide (GLP-1) is a 30-residue peptide hormone released from intestinal L cells following nutrient consumption. It potentiates the glucose-induced secretion of insulin from pancreatic beta cells, increases insulin expression, inhibits beta-cell apoptosis, promotes beta-cell neogenesis, reduces glucagon secretion, delays gastric emptying, promotes satiety and increases peripheral glucose disposal. These multiple effects have generated a great deal of interest in the discovery of long-lasting agonists of the GLP-1 receptor (GLP-1R) in order to treat type 2 diabetes. This review article summarizes the literature regarding the discovery of GLP-1 and its physiological functions. The structure, function and sequence-activity relationships of the hormone and its natural analogue exendin-4 (Ex4) are reviewed in detail. The current knowledge of the structure of GLP-1R, a Family B GPCR, is summarized and discussed, before its known interactions with the principle peptide ligands are described and summarized. Finally, progress in discovering non-peptide ligands of GLP-1R is reviewed. GLP-1 is clearly an important hormone linking nutrient consumption with blood sugar control, and therefore knowledge of its structure, function and mechanism of action is of great importance.
Collapse
Affiliation(s)
- Dan Donnelly
- Faculty of Biological Sciences, University of Leeds, Leeds, UK.
| |
Collapse
|
|
27
|
Grigoryan M, Kedees MH, Charron MJ, Guz Y, Teitelman G. Regulation of mouse intestinal L cell progenitors proliferation by the glucagon family of peptides. Endocrinology 2012; 153:3076-88. [PMID: 22569789 PMCID: PMC3380309 DOI: 10.1210/en.2012-1120] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Glucagon like peptide-1 (GLP-1) and GLP-2 are hormones secreted by intestinal L cells that stimulate glucose-dependent insulin secretion and regulate intestinal growth, respectively. Mice with deletion of the glucagon receptor (Gcgr) have high levels of circulating GLP-1 and GLP-2. We sought to determine whether the increased level of the glucagon-like peptides is due to L cell hyperplasia. We found, first, that high levels of the glucagon-like peptides increase L cell number but does not affect the number of other intestinal epithelial cell types. Second, a large proportion of ileal L cells of Gcgr(-/-) mice coexpressed glucose-dependent insulinotropic peptide (GIP). Cells coexpressing GIP and GLP-1 are termed LK cells. Third, the augmentation in L cell number was due to a higher rate of proliferation of L cell progenitors rather than to the entrance of mature L cells into the cell cycle. Fourth, a high concentration of the glucagon-like peptides in the circulation augmented the mRNA levels of transcription factors expressed by late but not early enteroendocrine progenitors. Fifth, the administration of exendin 9-39, a GLP-1 receptor antagonist, resulted in a decrease in the rate of L cell precursor proliferation. Finally, we determined that L cells do not express the GLP-1 receptor, suggesting that the effect of GLP-1 is mediated by paracrine and/or neuronal signals. Our results suggest that GLP-1 plays an important role in the regulation of L cell number.
Collapse
Affiliation(s)
- Marine Grigoryan
- Department of Cell Biology, State University of New York-Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, New York 11203, USA
| | | | | | | | | |
Collapse
|
|
28
|
Baraboi ED, St-Pierre DH, Shooner J, Timofeeva E, Richard D. Brain activation following peripheral administration of the GLP-1 receptor agonist exendin-4. Am J Physiol Regul Integr Comp Physiol 2011; 301:R1011-24. [DOI: 10.1152/ajpregu.00424.2010] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The aim of our study was to investigate the anorectic and brain stimulatory effects of various doses of exendin-4 (Ex-4) and to investigate the role of the vagus nerve in Ex-4-induced brain activation. A dose-related increase in c- fos mRNA expression was observed following Ex-4 administration (0.155–15.5 μg/kg). Doses of Ex-4 that caused anorexia without aversive effects (0.155, 0.775 μg/kg) induced c- fos expression in the hypothalamic arcuate and paraventricular (PVH; parvocellular) nuclei as well as in the limbic and brainstem structures. Doses of Ex-4 that caused aversion (1.55, 15.5 μg/kg) stimulated the same regions (in a more intense way) and additionally activated the magnocellular hypothalamic structures (supraoptic nucleus and PVH magnocellular). The brain c- fos pattern induced by Ex-4 showed both similarities and differences with that induced by refeeding. Subdiaphragmatic vagotomy significantly blunted the stimulation of c- fos mRNA expression induced by Ex-4 in the nodose ganglion, the medial part of nucleus of the solitary tract, and the parvocellular division of the PVH. Pretreatment with Ex-9-39 (330 μg/kg ip) impaired the neuronal activation evoked by Ex-4 in all brain regions and in the nodose ganglion. Effects of Ex-4 on hypothalamic-pituitary-adrenal axis activity were not altered by vagotomy. Results of this study demonstrate and relate the anorectic and brain stimulatory effects of aversive and nonaversive doses of Ex-4 and indicate that the activation of specific central regions induced by the peripheral administration of Ex-4 is, at least in part, dependent on the integrity of the vagus nerve.
Collapse
Affiliation(s)
- Elena-Dana Baraboi
- Merck-Frosst/Canadian Institutes of Health Research Chair in Obesity and Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, Canada
| | - David H. St-Pierre
- Merck-Frosst/Canadian Institutes of Health Research Chair in Obesity and Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, Canada
| | - Julie Shooner
- Merck-Frosst/Canadian Institutes of Health Research Chair in Obesity and Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, Canada
| | - Elena Timofeeva
- Merck-Frosst/Canadian Institutes of Health Research Chair in Obesity and Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, Canada
| | - Denis Richard
- Merck-Frosst/Canadian Institutes of Health Research Chair in Obesity and Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, Canada
| |
Collapse
|
|
29
|
Patterson JT, Ottaway N, Gelfanov VM, Smiley DL, Perez-Tilve D, Pfluger PT, Tschöp MH, DiMarchi RD. A novel human-based receptor antagonist of sustained action reveals body weight control by endogenous GLP-1. ACS Chem Biol 2011; 6:135-45. [PMID: 20939591 DOI: 10.1021/cb1002015] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Ex-4 (9-39)a is a well characterized GLP-1 receptor antagonist that suffers from two notable limitations, its nonhuman amino acid sequence and its relatively short in vivo duration of action. Comparable N-terminal shortening of human GLP-1 lessens agonism but does not provide a high potency antagonist. Through a series of GLP-1/Ex-4 hybrid peptides, the minimal structural changes required to generate a pure GLP-1-based antagonist were identified as Glu16, Val19, and Arg20, yielding an antagonist of approximately 3-fold greater in vitro potency compared with Ex-4 (9-39)a. The structural basis of antagonism appears to result from stabilization of the α helix combined with enhanced electrostatic and hydrophobic interactions with the extracellular domain of the receptor. Site-specific acylation of the human-based antagonist yielded a peptide of increased potency as a GLP-1 receptor antagonist and 10-fold greater selectivity relative to the GIP receptor. The acylated antagonist demonstrated sufficient duration of action to maintain inhibitory activity when administered as a daily subcutaneous injection. The sustained pharmacokinetics and enhanced human sequence combine to form an antagonist optimized for clinical study. Daily administration of this antagonist by subcutaneous injection to diet-induced obese mice for 1 week caused a significant increase in food intake, body weight, and glucose intolerance, demonstrating endogenous GLP-1 as a relevant hormone in mammalian energy balance in the obese state.
Collapse
Affiliation(s)
- James T. Patterson
- Department of Chemistry, Indiana University, Bloomington, Indiana 47405, United States
| | - Nickki Ottaway
- Metabolic Disease Institute, Division of Endocrinology, Department of Medicine, University of Cincinnati, Ohio 45237, United States
| | - Vasily M. Gelfanov
- Department of Chemistry, Indiana University, Bloomington, Indiana 47405, United States
| | - David L. Smiley
- Department of Chemistry, Indiana University, Bloomington, Indiana 47405, United States
| | - Diego Perez-Tilve
- Metabolic Disease Institute, Division of Endocrinology, Department of Medicine, University of Cincinnati, Ohio 45237, United States
| | - Paul T. Pfluger
- Metabolic Disease Institute, Division of Endocrinology, Department of Medicine, University of Cincinnati, Ohio 45237, United States
| | - Matthias H. Tschöp
- Metabolic Disease Institute, Division of Endocrinology, Department of Medicine, University of Cincinnati, Ohio 45237, United States
| | - Richard D. DiMarchi
- Department of Chemistry, Indiana University, Bloomington, Indiana 47405, United States
| |
Collapse
|
|
30
|
Fujita Y, Wideman RD, Asadi A, Yang GK, Baker R, Webber T, Zhang T, Wang R, Ao Z, Warnock GL, Kwok YN, Kieffer TJ. Glucose-dependent insulinotropic polypeptide is expressed in pancreatic islet alpha-cells and promotes insulin secretion. Gastroenterology 2010; 138:1966-75. [PMID: 20138041 DOI: 10.1053/j.gastro.2010.01.049] [Citation(s) in RCA: 119] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2008] [Revised: 01/19/2010] [Accepted: 01/27/2010] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS Glucose-dependent insulinotropic polypeptide (GIP) and the proglucagon product glucagon-like peptide-1 (GLP-1) are gastrointestinal hormones that are released in response to nutrient intake and promote insulin secretion. Interestingly, a subset of enteroendocrine cells express both GIP and GLP-1. We sought to determine whether GIP also might be co-expressed with proglucagon in pancreatic alpha-cells. METHODS We assessed GIP expression via reverse-transcription polymerase chain reaction, in situ hybridization, and immunohistochemistry. We developed a novel bioassay to measure GIP release from isolated islets, compared the biological activities of full-length and truncated GIP, and assessed the impact of immunoneutralization of islet GIP on glucose-stimulated insulin secretion in isolated islets. RESULTS GIP messenger RNA was present in mouse islets; GIP protein localized to islet alpha-cells of mouse, human, and snake pancreas, based on immunohistochemical analyses. However, using a C-terminal GIP antibody, immunoreactivity was detected in islets from prohormone convertase (PC) 2 knockout but not wild-type mice. Bioactive GIP was secreted from mouse and human islets after arginine stimulation. In the perfused mouse pancreas, GIP(1-42) and amidated GIP(1-30) had equipotent insulinotropic actions. Finally, immunoneutralization of GIP secreted by isolated islets decreased glucose-stimulated insulin secretion. CONCLUSIONS GIP is expressed in and secreted from pancreatic islets; in alpha-cells, PC2 processes proGIP to yield a truncated but bioactive form of GIP that differs from the PC1/3-derived form from K-cells. Islet-derived GIP promotes islet glucose competence and also could support islet development and/or survival.
Collapse
Affiliation(s)
- Yukihiro Fujita
- Laboratory of Molecular and Cellular Medicine, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
31
|
Abstract
Incretin hormones are secreted in response to food ingestion and help manage glycemic control by regulating insulin and glucagon release, slowing gastric emptying, and reducing caloric intake. Glucagonlike peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide, secreted from the L-cells of the lower gut and K-cells of the intestines, respectively, are responsible for these incretin effects, which are reduced in patients with type 2 diabetes mellitus. Initially, the rapid degradation of either incretin by dipeptidyl peptidase-4 (DPP-4) complicated the development of viable therapeutics based on either hormone. However, the US Food and Drug Administration (FDA) has approved 2 incretin-based therapies in which their mechanisms of action augment or amplify the effects of naturally occurring GLP-1. Exenatide, a first-in-class GLP-1 receptor agonist, exhibits the same mechanisms of action as native GLP-1. Sitagliptin inhibits the DPP-4 enzyme, thus increasing the half-life of endogenous GLP-1. This review examines data from recent GLP-1 receptor agonist and DPP-4 inhibitor studies in patients with type 2 diabetes, as well as data on other incretin-based therapies in clinical development.
Collapse
|
|
32
|
Barrera JG, D'Alessio DA, Drucker DJ, Woods SC, Seeley RJ. Differences in the central anorectic effects of glucagon-like peptide-1 and exendin-4 in rats. Diabetes 2009; 58:2820-7. [PMID: 19741167 PMCID: PMC2780868 DOI: 10.2337/db09-0281] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
OBJECTIVE Glucagon-like peptide (GLP)-1 is a regulatory peptide synthesized in the gut and the brain that plays an important role in the regulation of food intake. Both GLP-1 and exendin (Ex)-4, a long-acting GLP-1 receptor (GLP-1r) agonist, reduce food intake when administered intracerebroventricularly, whereas Ex4 is much more potent at suppressing food intake when given peripherally. It has generally been hypothesized that this difference is due to the relative pharmacokinetic profiles of GLP-1 and Ex4, but it is possible that the two peptides control feeding via distinct mechanisms. RESEARCH DESIGN AND METHODS In this study, the anorectic effects of intracerebroventricular GLP-1 and Ex4, and the sensitivity of these effects to GLP-1r antagonism, were compared in rats. In addition, the GLP-1r dependence of the anorectic effect of intracerebroventricular Ex4 was assessed in GLP-1r(-/-) mice. RESULTS Intracerebroventricular Ex4 was 100-fold more potent than GLP-1 at reducing food intake, and this effect was insensitive to GLP-1r antagonism. However, GLP-1r antagonists completely blocked the anorectic effect of intraperitoneal Ex4. Despite the insensitivity of intracerebroventricular Ex4 to GLP-1r antagonism, intracerebroventricular Ex4 failed to reduce food intake in GLP-1r(-/-) mice. CONCLUSIONS These data suggest that although GLP-1rs are required for the actions of Ex4, there appear to be key differences in how GLP-1 and Ex4 interact with central nervous system GLP-1r and in how Ex4 interacts with GLP-1r in the brain versus the periphery. A better understanding of these unique differences may lead to expansion and/or improvement of GLP-1-based therapies for type 2 diabetes and obesity.
Collapse
Affiliation(s)
- Jason G Barrera
- Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio, USA.
| | | | | | | | | |
Collapse
|
|
33
|
Duodenal-jejunal exclusion improves glucose tolerance in the diabetic, Goto-Kakizaki rat by a GLP-1 receptor-mediated mechanism. J Gastrointest Surg 2009; 13:1762-72. [PMID: 19488823 DOI: 10.1007/s11605-009-0912-9] [Citation(s) in RCA: 99] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2009] [Accepted: 04/15/2009] [Indexed: 01/31/2023]
Abstract
BACKGROUND Gastric bypass results in the rapid resolution of type 2 diabetes. No causal evidence exists to link specific gut hormone changes with improvements in glucose homeostasis post-operatively. We hypothesized that surgical augmentation of the glucoregulatory factor GLP-1 would improve glucose tolerance in diabetic GK rats. We compared two procedures that increase distal small bowel stimulation, ileal interposition (IT), and duodenal-jejunal exclusion (DJE). METHODS DJE, IT, DJE Sham, or IT Sham were performed in GK rats. Glucose tolerance was tested at 4 and 6 weeks, the latter with and without Exendin-[9-39], a GLP-1 receptor antagonist. Small bowel segments were harvested for GLP-1 protein content 2 weeks after DJE or Sham surgery. RESULTS Despite similar weight profiles, a significant improvement in the OGTT was noted at 4 weeks after DJE and IT. Plasma GLP-1 levels were significantly elevated after DJE and IT. Intestinal GLP-1 was increased in the mid-jejunum and ileum after DJE. Exendin-[9-39] abolished the improvement in glucose tolerance after DJE. CONCLUSIONS DJE increased GLP-1 secretion and improved glucose tolerance, an effect that was reversed by GLP-1 receptor antagonism. This study provides direct evidence that improvement of glucose tolerance following a gastric bypass-like surgery is mediated by enhanced GLP-1 action.
Collapse
|
|
34
|
Ørskov JJHC. Incretin hormones - an update. Scandinavian Journal of Clinical and Laboratory Investigation 2009. [DOI: 10.1080/clb.61.234.75.85] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
|
|
35
|
Abstract
Incretins are gut hormones that are secreted from enteroendocrine cells into the blood within minutes after eating. One of their many physiological roles is to regulate the amount of insulin that is secreted after eating. In this manner, as well as others to be described in this review, their final common raison d'être is to aid in disposal of the products of digestion. There are two incretins, known as glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1), that share many common actions in the pancreas but have distinct actions outside of the pancreas. Both incretins are rapidly deactivated by an enzyme called dipeptidyl peptidase 4 (DPP4). A lack of secretion of incretins or an increase in their clearance are not pathogenic factors in diabetes. However, in type 2 diabetes (T2DM), GIP no longer modulates glucose-dependent insulin secretion, even at supraphysiological (pharmacological) plasma levels, and therefore GIP incompetence is detrimental to beta-cell function, especially after eating. GLP-1, on the other hand, is still insulinotropic in T2DM, and this has led to the development of compounds that activate the GLP-1 receptor with a view to improving insulin secretion. Since 2005, two new classes of drugs based on incretin action have been approved for lowering blood glucose levels in T2DM: an incretin mimetic (exenatide, which is a potent long-acting agonist of the GLP-1 receptor) and an incretin enhancer (sitagliptin, which is a DPP4 inhibitor). Exenatide is injected subcutaneously twice daily and its use leads to lower blood glucose and higher insulin levels, especially in the fed state. There is glucose-dependency to its insulin secretory capacity, making it unlikely to cause low blood sugars (hypoglycemia). DPP4 inhibitors are orally active and they increase endogenous blood levels of active incretins, thus leading to prolonged incretin action. The elevated levels of GLP-1 are thought to be the mechanism underlying their blood glucose-lowering effects.
Collapse
Affiliation(s)
- Wook Kim
- National Institute on Aging, National Institutes of Health, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA
| | | |
Collapse
|
|
36
|
Singh SK, Bartoo AC, Krishnan S, Boylan MO, Schwartz JH, Michael Wolfe M. Glucose-dependent insulinotropic polypeptide (GIP) stimulates transepithelial glucose transport. Obesity (Silver Spring) 2008; 16:2412-6. [PMID: 18719661 DOI: 10.1038/oby.2008.393] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The purpose of this study was to characterize the effects of glucose-dependent insulinotropic peptide (GIP) on small intestinal glucose transport in vitro. Stripped proximal jejunum from fasted mice was mounted in Ussing chambers. The serosal side was bathed in Regular Ringer solution containing 5 mmol/l glucose, and the mucosal side, with solution containing 10 mmol/l 3-O-methyl glucose (3OMG). Intercellular cyclic adenosine monophosphate (cAMP), mucosa-to-serosa fluxes of 3OMG (J(ms)(3OMG)), and short-circuit current (I(SC)) were measured in the presence and absence of GIP. GIP increased cAMP by 2.5-fold in isolated enterocytes, consistent with a direct effect of GIP on these epithelial cells. GIP also increased I(SC) and J(ms)(3OMG) by 68 and 53%, respectively, indicating that the increase in J(ms)(3OMG) was primarily electrogenic, with a small electroneutral component. The stimulatory effect of GIP on J(ms)(3OMG) was concentration dependent. In addition, 1,000 nmol/l and 10 nmol/l GIP increased J(ms)(3OMG) by 70 and 30% over control, respectively, consistent with receptor activation. Phlorizin (20 mumol/l), an inhibitor of Na(+)-glucose cotransporter (SGLT-1), abolished the increase in I(SC) and decreased J(ms)(3OMG) by approximately 65%. These results indicate that stimulation of SGLT-1 activity by GIP partially accounts for the increase in J(ms)(30MG). These studies are the first to demonstrate direct stimulation of intestinal glucose transport by GIP independent of its insulinotropic properties. GIP stimulates cellular accumulation of cAMP and thereby upregulates glucose transport. The GIP-induced increase in glucose transport appears to be mediated, at least in part, by SGLT-1.
Collapse
Affiliation(s)
- Satish K Singh
- Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA.
| | | | | | | | | | | |
Collapse
|
|
37
|
De León DD, Li C, Delson MI, Matschinsky FM, Stanley CA, Stoffers DA. Exendin-(9-39) corrects fasting hypoglycemia in SUR-1-/- mice by lowering cAMP in pancreatic beta-cells and inhibiting insulin secretion. J Biol Chem 2008; 283:25786-93. [PMID: 18635551 DOI: 10.1074/jbc.m804372200] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
Congenital hyperinsulinism is a disorder of pancreatic beta-cell function characterized by failure to suppress insulin secretion in the setting of hypoglycemia, resulting in brain damage or death if untreated. Loss-of-function mutations in the K(ATP) channel (composed of two subunits: Kir6.2 and SUR-1) are responsible for the most common and severe form of congenital hyperinsulinism. Most patients are unresponsive to available medical therapy and require palliative pancreatectomy. Similar to the human condition, the SUR-1(-/-) mouse is hypoglycemic when fasted and hyperglycemic when glucose-loaded. We have previously reported that the glucagon-like peptide-1 receptor antagonist exendin-(9-39) raises fasting blood glucose in normal mice. Here we examine the effect of exendin-(9-39) on fasting blood glucose in SUR-1(-/-) mice. Mice were randomized to receive exendin-(9-39) or vehicle. Fasting blood glucose levels in SUR-1(-/-) mice treated with exendin-(9-39) were significantly higher than in vehicle-treated mice and not different from wild-type littermates. Exendin-(9-39) did not further worsen glucose tolerance and had no effect on body weight and insulin sensitivity. Isolated islet perifusion studies demonstrated that exendin-(9-39) blocked amino acid-stimulated insulin secretion, which is abnormally increased in SUR-1(-/-) islets. Furthermore, cAMP content in SUR-1(-/-) islets was reduced by exendin-(9-39) both basally and when stimulated by amino acids, whereas cytosolic calcium levels were not affected. These findings suggest that cAMP plays a key role in K(ATP)-independent insulin secretion and that the GLP-1 receptor is constitutively active in SUR-1(-/-) beta-cells. Our findings indicate that exendin-(9-39) normalizes fasting hypoglycemia in SUR-1(-/-) mice via a direct effect on insulin secretion, thereby raising exendin-(9-39) as a potential therapeutic agent for K(ATP) hyperinsulinism.
Collapse
Affiliation(s)
- Diva D De León
- Division of Endocrinology, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
| | | | | | | | | | | |
Collapse
|
|
38
|
Sandoval D. CNS GLP-1 regulation of peripheral glucose homeostasis. Physiol Behav 2008; 94:670-4. [PMID: 18508100 DOI: 10.1016/j.physbeh.2008.04.018] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2008] [Accepted: 04/02/2008] [Indexed: 02/08/2023]
Abstract
Current models hold that peripheral and CNS GLP-1 signaling operate as distinct systems whereby CNS GLP-1 regulates food intake and circulating GLP-1 regulates glucose homeostasis. There is accumulating evidence that the arcuate nucleus, an area of the CNS that regulates energy homeostasis, responds to hormones and nutrients to regulate glucose homeostasis as well. Recent data suggest that GLP-1 may be another signal acting on the arcuate to regulate glucose homeostasis challenging the conventional model of GLP-1 physiology. This review discusses the peripheral and central GLP-1 systems and presents a model whereby these systems are integrated in regulation of glucose homeostasis.
Collapse
Affiliation(s)
- Darleen Sandoval
- Department of Psychiatry, Genome Research Institute, University of Cincinnati, Cincinnati, Ohio 45237, USA.
| |
Collapse
|
|
39
|
Chu ZL, Carroll C, Alfonso J, Gutierrez V, He H, Lucman A, Pedraza M, Mondala H, Gao H, Bagnol D, Chen R, Jones RM, Behan DP, Leonard J. A role for intestinal endocrine cell-expressed g protein-coupled receptor 119 in glycemic control by enhancing glucagon-like Peptide-1 and glucose-dependent insulinotropic Peptide release. Endocrinology 2008; 149:2038-47. [PMID: 18202141 DOI: 10.1210/en.2007-0966] [Citation(s) in RCA: 308] [Impact Index Per Article: 18.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
We recently showed that activation of G protein-coupled receptor 119 (GPR119) (also termed glucose dependent insulinotropic receptor) improves glucose homeostasis via direct cAMP-mediated enhancement of glucose-dependent insulin release in pancreatic beta-cells. Here we show that GPR119 also stimulates incretin hormone release and thus may regulate glucose homeostasis by this additional mechanism. GPR119 mRNA was found to be expressed at significant levels in intestinal subregions that produce glucose-dependent insulinotropic peptide and glucagon-like peptide (GLP)-1. Furthermore, in situ hybridization studies indicated that most GLP-1-producing cells coexpress GPR119 mRNA. In GLUTag cells, a well-established model of intestinal L-cell function, the potent GPR119 agonist AR231453 stimulated cAMP accumulation and GLP-1 release. When administered in mice, AR231453 increased active GLP-1 levels within 2 min after oral glucose delivery and substantially enhanced total glucose-dependent insulinotropic peptide levels. Blockade of GLP-1 receptor signaling with exendin(9-39) reduced the ability of AR231453 to improve glucose tolerance in mice. Conversely, combined administration of AR231453 and the DPP-4 inhibitor sitagliptin to wild-type mice significantly amplified both plasma GLP-1 levels and oral glucose tolerance, relative to either agent alone. In mice lacking GPR119, no such enhancement was seen. Thus, GPR119 regulates glucose tolerance by acting on intestinal endocrine cells as well as pancreatic beta-cells. These data also suggest that combined stimulation of incretin hormone release and protection against incretin hormone degradation may be an effective antidiabetic strategy.
Collapse
Affiliation(s)
- Zhi-Liang Chu
- Arena Pharmaceuticals, 6166 Nancy Ridge Drive, San Diego, California 92121, USA
| | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
40
|
D'Alessio D, Lu W, Sun W, Zheng S, Yang Q, Seeley R, Woods SC, Tso P. Fasting and postprandial concentrations of GLP-1 in intestinal lymph and portal plasma: evidence for selective release of GLP-1 in the lymph system. Am J Physiol Regul Integr Comp Physiol 2007; 293:R2163-9. [PMID: 17898126 DOI: 10.1152/ajpregu.00911.2006] [Citation(s) in RCA: 69] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Glucagon like peptide 1 (GLP-1) is an intestinal hormone that plays an important role in glucose metabolism. GLP-1 is released from mucosal L cells following nutrient ingestion and contributes to the incretin effect, with the enhancement of insulin secretion occurring with enteral compared with intravenous glucose administration. The mechanisms linking nutrient absorption and GLP-1 secretion are unknown, and studies addressing this topic, particularly in small animal models, have been hampered by the relatively low concentrations of GLP-1 in the circulation. We hypothesized that GLP-1 levels would be higher in samples of intestinal lymph compared with plasma and could provide a novel system in which to study meal-induced hormone secretion. We addressed this hypothesis in conscious rats with indwelling catheters in the portal vein and distal intestinal lymph duct. These animals had plasma and lymph sampled before and for 240 min after instillation of a liquid meal in the gastrointestinal tract. Lymph contained detectable concentrations of glucose, insulin, and GLP-1 that were reliably measured using our assays. Before and after the Ensure feeding, plasma insulin levels were approximately two times as high in portal plasma as intestinal lymph. In marked contrast, GLP-1 levels were five to six times higher in lymph relative to portal plasma following nutrient administration. This relative difference in GLP-1 levels was even greater when lymph was compared with peripheral plasma and dramatically exceeded the ratio of lymph to plasma peptide tyrosine-tyrosine concentrations. This is the first observation of a gastrointestinal hormone being disproportionately transported in lymph. The remarkable levels of GLP-1 in intestinal lymph demonstrate the potential for lymphatic sampling as a more sensitive means of studying the secretory physiology of this hormone in vivo. In addition, these data raise the possibility that intestinal lymph may serve as a specialized signaling conduit for regulatory peptides secreted by gastrointestinal endocrine cells.
Collapse
Affiliation(s)
- David D'Alessio
- Department of Medicine, University of Cincinnati, Cincinnati, Ohio 45267, USA.
| | | | | | | | | | | | | | | |
Collapse
|
|
41
|
Abstract
Glucagon-like peptide 1 (GLP-1) is a 30-amino acid peptide hormone produced in the intestinal epithelial endocrine L-cells by differential processing of proglucagon, the gene which is expressed in these cells. The current knowledge regarding regulation of proglucagon gene expression in the gut and in the brain and mechanisms responsible for the posttranslational processing are reviewed. GLP-1 is released in response to meal intake, and the stimuli and molecular mechanisms involved are discussed. GLP-1 is extremely rapidly metabolized and inactivated by the enzyme dipeptidyl peptidase IV even before the hormone has left the gut, raising the possibility that the actions of GLP-1 are transmitted via sensory neurons in the intestine and the liver expressing the GLP-1 receptor. Because of this, it is important to distinguish between measurements of the intact hormone (responsible for endocrine actions) or the sum of the intact hormone and its metabolites, reflecting the total L-cell secretion and therefore also the possible neural actions. The main actions of GLP-1 are to stimulate insulin secretion (i.e., to act as an incretin hormone) and to inhibit glucagon secretion, thereby contributing to limit postprandial glucose excursions. It also inhibits gastrointestinal motility and secretion and thus acts as an enterogastrone and part of the "ileal brake" mechanism. GLP-1 also appears to be a physiological regulator of appetite and food intake. Because of these actions, GLP-1 or GLP-1 receptor agonists are currently being evaluated for the therapy of type 2 diabetes. Decreased secretion of GLP-1 may contribute to the development of obesity, and exaggerated secretion may be responsible for postprandial reactive hypoglycemia.
Collapse
Affiliation(s)
- Jens Juul Holst
- Department of Medical Physiology, The Panum Institute, University of Copenhagen, Copenhagen, Denmark.
| |
Collapse
|
|
42
|
Vahl TP, Tauchi M, Durler TS, Elfers EE, Fernandes TM, Bitner RD, Ellis KS, Woods SC, Seeley RJ, Herman JP, D'Alessio DA. Glucagon-like peptide-1 (GLP-1) receptors expressed on nerve terminals in the portal vein mediate the effects of endogenous GLP-1 on glucose tolerance in rats. Endocrinology 2007; 148:4965-73. [PMID: 17584962 DOI: 10.1210/en.2006-0153] [Citation(s) in RCA: 264] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Glucagon-like peptide-1 (GLP-1) is an intestinal hormone that is secreted during meal absorption and is essential for normal glucose homeostasis. However, the relatively low plasma levels and rapid metabolism of GLP-1 raise questions as to whether direct endocrine action on target organs, such as islet cells, account for all of its effects on glucose tolerance. Recently, an alternative neural pathway initiated by sensors in the hepatic portal region has been proposed to mediate GLP-1 activity. We hypothesized that visceral afferent neurons in the portal bed express the GLP-1 receptor (GLP-1r) and regulate glucose tolerance. Consistent with this hypothesis, GLP-1r mRNA was present in the nodose ganglia, and nerve terminals innervating the portal vein contained the GLP-1r. Rats given an intraportal infusion of the GLP-1r antagonist, [des-His(1),Glu(9)] exendin-4, in a low dose, had glucose intolerance, with a 53% higher glucose excursion compared with a vehicle-infused control group. Infusion of [des-His(1),Glu(9)] exendin-4 at an identical rate into the jugular vein had no effect on glucose tolerance, demonstrating that this dose of GLP-1r antagonist did not affect blood glucose due to spillover into the systemic circulation. These studies demonstrate that GLP-1r are present on nerve terminals in the hepatic portal bed and that GLP-1 antagonism localized to this region impairs glucose tolerance. These data are consistent with an important component of neural mediation of GLP-1 action.
Collapse
Affiliation(s)
- Torsten P Vahl
- Department of Internal Medicine, Division of Endocrinology and Metabolism, University of Cincinnati, 2170 East Galbraith Road, Cincinnati, Ohio 45267, USA
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
43
|
Pratley RE, Salsali A. Inhibition of DPP-4: a new therapeutic approach for the treatment of type 2 diabetes. Curr Med Res Opin 2007; 23:919-31. [DOI: 10.1185/030079906x162746] [Citation(s) in RCA: 143] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Affiliation(s)
| | - Afshin Salsali
- University of Vermont College of Medicine, Burlington, VT, USA
| |
Collapse
|
|
44
|
Abstract
The glucoincretins, glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP), are intestinal peptides secreted in response to glucose or lipid intake. Data on isolated intestinal tissues, dietary treatments and knockout mice strongly suggest that GIP and GLP-1 secretion requires glucose and lipid metabolism by intestinal cells. However, incretin secretion can also be induced by non-digestible carbohydrates and involves the autonomic nervous system and endocrine factors such as GIP itself and cholecystokinin. The classical pharmacological approach and the recent use of knockout mice for the incretin receptors have shown that a remarkable feature of incretins is the ability to stimulate insulin secretion in the presence of hyperglycaemia only, hence avoiding any hypoglycaemic episode. This important role is the basis of ongoing clinical trials using GLP-1 analogues. Since most of the data concern GLP-1, we will focus on this incretin. In addition, GLP-1 is involved in glucose sensing by the autonomic nervous system of the hepato-portal vein controlling muscle glucose utilization and indirectly insulin secretion. GLP-1 has been shown to decrease glucagon secretion, food intake and gastric emptying, preventing excessive hyperglycaemia and overfeeding. Another remarkable feature of GLP-1 is its secretion by the brain. Recently, elegant data showed that cerebral GLP-1 is involved in cognition and memory. Experiments using knockout mice suggest that the lack of the GIP receptor prevents diet-induced obesity. Consequently, macronutrients controlling intestinal glucose and lipid metabolism would control incretin secretion and would consequently be beneficial for health. The control of incretin secretion represents a major goal for new therapeutic as well as nutrition strategies for treating and/or reducing the risk of hyperglycaemic syndromes, excessive body weight and thus improvement of well-being.
Collapse
Affiliation(s)
- Rémy Burcelin
- UMR 5018 CNRS-UPS and IFR 31, Rangueil Hospital, Toulouse, France.
| |
Collapse
|
|
45
|
Abstract
Glucagon-like peptide-1 (7-36) amide (GLP-1) is a gut hormone, released postprandially,which stimulates insulin secretion and insulin gene expression as well as pancreatic B-cell growth. Together with glucose-dependent insulinotropic polypeptide (GIP), it is responsible for the incretin effect which is the augmentation of insulin secretion following oral administration of glucose. Patients with Type 2 diabetes have greatly impaired or absent incretin-mediated insulin secretion which is mainly as a result of decreased secretion of GLP-1. However,the insulinotropic action of GLP-1 is preserved in patients with Type 2 diabetes,and this has encouraged attempts to treat Type 2 diabetic patients with GLP-1.GLP-1 also possesses a number of potential advantages over existing agents for the treatment of Type 2 diabetes. In addition to stimulating insulin secretion and promoting pancreatic B-cell mass, GLP-1 suppresses glucagon secretion,delays gastric emptying and inhibits food intake. Continuous intravenous and subcutaneous administration significantly improves glycaemic control and causes reductions in both HbA1c and body weight. However, GLP-1 is metabolized extremely rapidly in the circulation by the enzyme dipeptidyl peptidase IV(DPP-IV). This is the probable explanation for the short-lived effect of single doses of native GLP-1, making it an unlikely glucose-lowering agent. The DPP-IV resistant analogue, exenatide, has Food and Drug Administration (FDA) approval for the treatment of Type 2 diabetes and selective DPP-IV inhibitors are underdevelopment. Both approaches have demonstrated remarkable efficacy in animal models and human clinical studies. Both are well tolerated and appear to have advantages over current therapies for Type 2 diabetes, particularly in terms of the effects on pancreatic B-cell restoration and potential weight loss.
Collapse
Affiliation(s)
- J F Todd
- Department of Metabolic Medicine, Imperial College London, Hammersmith Hospital, London, UK
| | | |
Collapse
|
|
46
|
Abstract
Gut peptides, exemplified by glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are secreted in a nutrient-dependent manner and stimulate glucose-dependent insulin secretion. Both GIP and GLP-1 also promote beta cell proliferation and inhibit apoptosis, leading to expansion of beta cell mass. GLP-1, but not GIP, controls glycemia via additional actions on glucose sensors, inhibition of gastric emptying, food intake and glucagon secretion. Furthermore, GLP-1, unlike GIP, potently stimulates insulin secretion and reduces blood glucose in human subjects with type 2 diabetes. This article summarizes current concepts of incretin action and highlights the potential therapeutic utility of GLP-1 receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors for the treatment of type 2 diabetes.
Collapse
Affiliation(s)
- Daniel J Drucker
- Department of Medicine, The Banting and Best Diabetes Centre, Toronto General Hospital, University of Toronto, Ontario M5G 2C4, Canada.
| |
Collapse
|
|
47
|
D'Alessio DA, Sandoval DA, Seeley RJ. New ways in which GLP-1 can regulate glucose homeostasis. J Clin Invest 2006; 115:3406-8. [PMID: 16322789 PMCID: PMC1297270 DOI: 10.1172/jci27207] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Glucagon-like peptide-1 (GLP-1) has a diverse set of peripheral actions which all serve to promote enhanced glucose tolerance, and for this reason it has become the basis for new treatments for type 2 diabetes. In this issue of the JCI, Knauf et al. provide clear evidence that GLP-1 signaling in the CNS is also linked to the control of peripheral glucose homeostasis by inhibiting non-insulin-mediated glucose uptake by muscle and increasing insulin secretion from the pancreas. The authors' work points to an important need to integrate diverse GLP-1 signaling actions and peripheral GLP-1 function in order to better understand both normal and abnormal glucose homeostasis.
Collapse
Affiliation(s)
- David A D'Alessio
- Department of Medicine, Genome Research Institute, University of Cincinnati, Cincinnati, Ohio 45267, USA
| | | | | |
Collapse
|
|
48
|
D'Alessio DA, Vahl TP. Utilizing the GLP-1 signaling system to treat diabetes: sorting through the pharmacologic approaches. Curr Diab Rep 2005; 5:346-52. [PMID: 16188169 DOI: 10.1007/s11892-005-0092-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
Glucagon-like peptide-1 (GLP-1) is an intestinal hormone that promotes glucose homeostasis through the regulation of insulin and glucagon secretion, gastric emptying, and food intake. This spectrum of effects makes GLP-1 an attractive candidate for drug development. However, because GLP-1 is a small peptide with rapid metabolism in the circulation, its usefulness to treat patients is limited. However, GLP-1 mimetics that are resistant to degradation have been developed and are effective in lowering blood glucose in diabetic patients. A second strategy for harnessing GLP-1 therapeutically is to inhibit the metabolism of endogenous GLP-1; several orally available compounds are in clinical trials. These two new classes of drugs both enhance GLP-1 signaling but differ in several key characteristics that may lead to distinct roles in the treatment of diabetic patients.
Collapse
Affiliation(s)
- David A D'Alessio
- University of Cincinnati, Division of Endocrinology/Metabolism, ML 0547, Vontz Center, 3125 Eden Avenue, Cincinnati, OH 45220-0547, USA.
| | | |
Collapse
|
|
49
|
Hansotia T, Drucker DJ. GIP and GLP-1 as incretin hormones: lessons from single and double incretin receptor knockout mice. ACTA ACUST UNITED AC 2005; 128:125-34. [PMID: 15780432 DOI: 10.1016/j.regpep.2004.07.019] [Citation(s) in RCA: 128] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2004] [Revised: 07/08/2004] [Accepted: 07/15/2004] [Indexed: 11/18/2022]
Abstract
Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are gut-derived incretins secreted in response to nutrient ingestion. Both incretins potentiate glucose-dependent insulin secretion and enhance beta-cell mass through regulation of beta-cell proliferation, neogenesis and apoptosis. In contrast, GLP-1, but not GIP, inhibits gastric emptying, glucagon secretion, and food intake. Furthermore, human subjects with Type 2 diabetes exhibit relative resistance to the actions of GIP, but not GLP-1R agonists. The physiological importance of both incretins has been investigated through generation and analysis of incretin receptor knockout mice. Elimination of incretin receptor action in GIPR-/- or GLP-1R-/- mice produces only modest impairment in glucose homeostasis. Similarly, double incretin receptor knockout (DIRKO) mice exhibit normal body weight and normal levels of plasma glucagon and hypoglycemic responses to exogenous insulin. However, glucose-stimulated insulin secretion is significantly decreased following oral but not intraperitoneal glucose challenge in DIRKO mice and the glucose lowering actions of dipeptidyl peptidase-IV (DPP-IV) inhibitors are extinguished in DIRKO mice. Hence, incretin receptor signaling exerts physiologically relevant actions critical for glucose homeostasis, and represents a pharmacologically attractive target for development of agents for the treatment of Type 2 diabetes.
Collapse
Affiliation(s)
- Tanya Hansotia
- Department of Medicine, Banting and Best Diabetes Centre, Toronto General Hospital, and the University of Toronto, 200 Elizabeth Street MBRW4R-402, Toronto, Ontario, Canada M5G 2C4
| | | |
Collapse
|
|
50
|
Baggio LL, Drucker DJ. Harnessing the therapeutic potential of glucagon-like peptide-1: a critical review. ACTA ACUST UNITED AC 2005; 1:117-25. [PMID: 15765627 DOI: 10.2165/00024677-200201020-00005] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Glucagon-like peptide-1 (GLP-1) is synthesized from proglucagon in enteroendocrine cells and regulates glucose homeostasis via multiple complementary actions on appetite, gastrointestinal motility and islet hormone secretion. GLP-1 is secreted from the distal gut in response to food ingestion, and levels of circulating GLP-1 may be diminished in patients with type 2 diabetes mellitus. GLP-1 administration stimulates glucose-dependent insulin secretion, inhibits glucagon secretion, and lowers blood glucose in normal and diabetic rodents and in humans. GLP-1 exerts additional glucose-lowering actions in patients with diabetes mellitus already treated with metformin or sulfonylurea therapy. GLP-1 inhibits gastric emptying in healthy individuals and those with diabetes mellitus, and excess GLP-1 administration may cause nausea or vomiting in susceptible individuals. Chronic GLP-1 treatment of normal or diabetic rodents is associated with bodyweight loss and GLP-1 agonists transiently inhibit food intake and may prevent bodyweight gain in humans. The potential for GLP-1 therapy to prevent deterioration of beta-cell function is exemplified by studies demonstrating that GLP-1 analogs stimulate proliferation and neogenesis of beta-cells, leading to expansion of beta-cell mass in diabetic rodents. The rapid N-terminal inactivation of bioactive GLP-1 by dipeptidyl peptidase-IV (DPP-IV) limits the utility of the native peptide for the treatment of patients with diabetes mellitus, and has fostered the development of more potent and stable protease-resistant GLP-1 analogs which exhibit longer durations of action. The importance of DPP-IV for glucose control is illustrated by the phenotype of rodents with genetic inactivation of DPP-IV which exhibit reduced glycemic excursion and increased levels of circulating GLP-1 in vivo. Inhibitors of DPP-IV potentiate incretin action by preventing degradation of GLP-1 and glucose-dependent insulinotropic peptide, and lower blood glucose in normal rodents and in experimental models of diabetes mellitus. Hence, orally available DPP-IV inhibitors also represent a new class of therapeutic agents that enhance incretin action for the treatment of patients with type 2 diabetes mellitus.
Collapse
Affiliation(s)
- Laurie L Baggio
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | | |
Collapse
|