Basal Receptor Activation by Locally Produced Glucagon-Like Peptide-1 Contributes to Maintaining β-Cell Function

Type 2 diabetes mellitus is associated with progressive decreases in pancreatic β-cell function. Most patients thus require increasingly intensive treatment, including oral combination therapies followed by insulin. Fear of hypoglycemia is a potential barrier to treatment adherence and glycemic control, while weight gain can exacerbate hyperglycemia or insulin resistance. Administration of insulin can roughly mimic physiologic insulin secretion but does not address underlying pathophysiology. Glucagon-like peptide 1 (GLP-1) is an incretin hormone released by the gut in response to meal intake that helps to maintain glucose homeostasis through coordinated effects on islet α- and β-cells, inhibiting glucagon output, and stimulating insulin secretion in a glucose-dependent manner. Biological effects of GLP-1 include slowing gastric emptying and decreasing appetite. Incretin mimetics (GLP-1 receptor agonists with more suitable pharmacokinetic properties versus GLP-1) significantly lower hemoglobin A1c, body weight, and postprandial glucose excursions in humans and significantly improve β-cell function in vivo (animal data). These novel incretin-based therapies offer the potential to reduce body weight or prevent weight gain, although the durability of these effects and their potential long-term benefits need to be studied further. This article reviews recent clinical trials comparing therapy with the incretin mimetic exenatide to insulin in patients with oral treatment failure, identifies factors consistent with the use of each treatment, and delineates areas for future research.

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Exaggerated Glucagon-Like Peptide 1 Response Is Important for Improved β-Cell Function and Glucose Tolerance After Roux-en-Y Gastric Bypass in Patients With Type 2 Diabetes

Diabetes ◽

10.2337/db13-0022 ◽

2013 ◽

Vol 62 (9) ◽

pp. 3044-3052 ◽

Cited By ~ 195

Author(s):

Nils B. Jørgensen ◽

Carsten Dirksen ◽

Kirstine N. Bojsen-Møller ◽

Siv H. Jacobsen ◽

Dorte Worm ◽

...

Keyword(s):

Type 2 Diabetes ◽

Gastric Bypass ◽

Glucose Tolerance ◽

Cell Function ◽

Β Cell ◽

Β Cell Function ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

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Determinants of glucose metabolism and the role of NPY in the progression of insulin resistance in chronic migraine

Cephalalgia ◽

10.1177/0333102417748928 ◽

2017 ◽

Vol 38 (11) ◽

pp. 1773-1781 ◽

Cited By ~ 9

Author(s):

Zeynep Oşar Siva ◽

Derya Uluduz ◽

Fatma Ela Keskin ◽

Feyza Erenler ◽

Huriye Balcı ◽

...

Keyword(s):

Insulin Resistance ◽

Neuropeptide Y ◽

Chronic Migraine ◽

Cell Function ◽

Episodic Migraine ◽

Oral Glucose ◽

Β Cell ◽

Β Cell Function ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

Background Chronic migraine has a well-documented association with increased insulin resistance and metabolic syndrome. The hypothalamus may play a role in the progression of insulin resistance in chronic migraine through the regulation of orexigenic peptides such as neuropeptide Y. Insulin resistance may lead to increased risk of future type 2 diabetes mellitus in patients with chronic migraine, which is more likely to occur if other pathogenetic defects of type 2 diabetes mellitus, such as impaired pancreatic β-cell functions and defects in intestinal glucagon-like peptide-1 secretion after meals. We studied the relationship of fasting neuropeptide Y with insulin resistance, β-cell function, and glucagon-like peptide-1 secretion in non-obese female chronic migraine patients. We also aimed to investigate glucose-stimulated insulin and glucagon-like peptide-1 secretions as early pathogenetic mechanisms responsible for the development of carbohydrate intolerance. Methods In this cross-sectional controlled study, 83 non-obese female migraine patients of reproductive age categorized as having episodic migraine or chronic migraine were included. The control group consisted of 36 healthy females. We studied glucose-stimulated insulin and glucagon-like peptide-1 secretion during a 75 g oral glucose tolerance test. We investigated the relationship of neuropeptide Y levels with insulin resistance and β-cell insulin secretion functions. Results Fasting glucose levels were significantly higher in migraine patients. Plasma glucose and insulin levels during the oral glucose tolerance test were otherwise similar in chronic migraine, episodic migraine and controls. Patients with chronic migraine were more insulin resistant than episodic migraine or controls ( p = 0.048). Glucagon-like peptide-1 levels both at fasting and two hours after glucose intake were similar in chronic migraine, episodic migraine, and controls. Neuropeptide Y levels were higher in migraineurs. In chronic migraine, neuropeptide Y was positively correlated with fasting glucagon-like peptide-1 levels (r = 0.57, p = 0.04), but there was no correlation with insulin resistance (r = 0.49, p = 0.09) or β-cell function (r = 0.50, p = 0.07). Discussion Non-obese premenopausal female patients with chronic migraine have higher insulin resistance, but normal β-cell function is to compensate for the increased insulin demand during fasting and after glucose intake. Increased fasting neuropeptide Y levels in migraine may be a factor leading to increased insulin resistance by specific alterations in energy intake and activation of the sympathoadrenal system.

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GLP-1 signaling suppresses menin’s transcriptional block by phosphorylation in β cells

The Journal of Cell Biology ◽

10.1083/jcb.201805049 ◽

2019 ◽

Vol 218 (3) ◽

pp. 855-870 ◽

Cited By ~ 1

Author(s):

Bowen Xing ◽

Jian Ma ◽

Zongzhe Jiang ◽

Zijie Feng ◽

Sunbin Ling ◽

...

Keyword(s):

Cell Proliferation ◽

Gene Transcription ◽

Histone Deacetylases ◽

Cell Function ◽

Β Cells ◽

Β Cell ◽

Histone Modifiers ◽

Β Cell Function ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

Both menin and glucagon-like peptide 1 (GLP-1) pathways play central yet opposing role in regulating β cell function, with menin suppressing, and GLP-1 promoting, β cell function. However, little is known as to whether or how GLP-1 pathway represses menin function. Here, we show that GLP-1 signaling–activated protein kinase A (PKA) directly phosphorylates menin at the serine 487 residue, relieving menin-mediated suppression of insulin expression and cell proliferation. Mechanistically, Ser487-phosphorylated menin gains increased binding affinity to nuclear actin/myosin IIa proteins and gets sequestrated from the Ins1 promoter. This event leads to reduced binding of repressive epigenetic histone modifiers suppressor variegation 3–9 homologue protein 1 (SUV39H1) and histone deacetylases 1 (HDAC1) at the locus and subsequently increased Ins1 gene transcription. Ser487 phosphorylation of menin also increases expression of proproliferative cyclin D2 and β cell proliferation. Our results have uncovered a previously unappreciated physiological link in which GLP-1 signaling suppresses menin function through phosphorylation-triggered and actin/myosin cytoskeletal protein–mediated derepression of gene transcription.

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Glucagon-like-peptide-1 (GLP-1) is important for the improved β-cell function in type 2 diabetic subjects after Roux-en-Y gastric bypass (RYGB)

Regulatory Peptides ◽

10.1016/j.regpep.2012.05.042 ◽

2012 ◽

Vol 177 ◽

pp. S23

Author(s):

N.B. Jørgensen ◽

C. Dirksen ◽

S.H. Jacobsen ◽

K.N. Bojsen-Møller ◽

D. Worm ◽

...

Keyword(s):

Gastric Bypass ◽

Cell Function ◽

Β Cell ◽

Β Cell Function ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Type 2 Diabetic

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Liraglutide – A Once-daily Human Glucagon-like Peptide-1 Analogue Treatment for Type 2 Diabetes

European Endocrinology ◽

10.17925/ee.2009.05.00.38 ◽

2009 ◽

Vol 05 (0) ◽

pp. 38

Author(s):

Chantal Mathieu ◽

Keyword(s):

Type 2 Diabetes ◽

Cell Function ◽

Patient Acceptance ◽

Β Cell ◽

Dipeptidyl Peptidase 4 ◽

Receptor Agonists ◽

Β Cell Function ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

Type 2 diabetes is a progressive disease characterised by deteriorating β-cell function and glycaemic control. To counter this, affected individuals require regular intensification of their antidiabetes treatments to provide appropriate metabolic control. However, current treatment options – such as sulphonylureas, thiazolidinediones and insulins – induce weight gain, which can reduce patient acceptance and/or compliance with treatment and may have significant health implications. In addition, many of the antidiabetic therapies raise the risk of hypoglycaemic episodes. Therefore, patients, physicians and healthcare providers are looking for new therapeutic options to address this large and growing burden of diabetes. Incretin-based therapies – including glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors – are becoming a popular treatment option for patients with type 2 diabetes because they offer many benefits compared with other antidiabetic therapies. First, incretin-based therapies are associated with significant reductions in glycated haemoglobin (HbA1c) with a low inherent risk of hypoglycaemic events. In addition, GLP-1 receptor agonists are associated with reductions in bodyweight and systolic blood pressure. Incretin-based therapies such as liraglutide also offer the potential to improve β-cell function, an important underlying mechanism of type 2 diabetes.

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