scholarly journals miR-7 Regulates GLP-1-Mediated Insulin Release by Targeting β-Arrestin 1

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1621 ◽  
Author(s):  
Alessandro Matarese ◽  
Jessica Gambardella ◽  
Angela Lombardi ◽  
Xujun Wang ◽  
Gaetano Santulli
Keyword(s):  
Insulin Release ◽  
Cell Function ◽  
Specific Interaction ◽  
Β Cells ◽  
Β Cell Function ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Glucose Stimulated Insulin Secretion ◽  
First Time

Glucagon-like peptide-1 (GLP-1) has been shown to potentiate glucose-stimulated insulin secretion binding GLP-1 receptor on pancreatic β cells. β-arrestin 1 (βARR1) is known to regulate the desensitization of GLP-1 receptor. Mounting evidence indicates that microRNAs (miRNAs, miRs) are fundamental in the regulation of β cell function and insulin release. However, the regulation of GLP-1/βARR1 pathways by miRs has never been explored. Our hypothesis is that specific miRs can modulate the GLP-1/βARR1 axis in β cells. To test this hypothesis, we applied a bioinformatic approach to detect miRs that could target βARR1; we identified hsa-miR-7-5p (miR-7) and we validated the specific interaction of this miR with βARR1. Then, we verified that GLP-1 was indeed able to regulate the transcription of miR-7 and βARR1, and that miR-7 significantly regulated GLP-1-induced insulin release and cyclic AMP (cAMP) production in β cells. Taken together, our findings indicate, for the first time, that miR-7 plays a functional role in the regulation of GLP-1-mediated insulin release by targeting βARR1. These results have a decisive clinical impact given the importance of drugs modulating GLP-1 signaling in the treatment of patients with type 2 diabetes mellitus.

GLP-1 response to sequential mixed meals: influence of insulin resistance

2017 ◽  
Vol 131 (24) ◽  
pp. 2901-2910 ◽  
Author(s):  
Eleni Rebelos ◽  
Brenno Astiarraga ◽  
Roberto Bizzotto ◽  
Andrea Mari ◽  
Maria Laura Manca ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Release ◽  
Cell Function ◽  
Fasting Glucose ◽  
Insulin Resistant ◽  
Esterified Fatty Acids ◽  
Β Cell Function ◽  
Glucose Sensitivity ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Previous work has shown that potentiation of insulin release is impaired in non-diabetic insulin resistance; we tested the hypothesis that this defect may be related to altered glucagon-like peptide-1 (GLP-1) release. On consecutive days, 82 non-diabetic individuals, classified as insulin sensitive (IS, n=41) or insulin resistant (IR, n=41) by the euglycaemic clamp, were given two sequential mixed meals with standard (75 g, LCD) or double (150 g, HCD) carbohydrate content. Plasma glucose, insulin, C-peptide, non-esterified fatty acids (NEFA) and GLP-1 concentrations were measured; β-cell function (glucose sensitivity and potentiation) was resolved by mathematical modelling. Fasting GLP-1 levels were higher in IR than IS (by 15%, P=0.006), and reciprocally related to insulin sensitivity after adjustment for sex, age, fat mass, fasting glucose or insulin concentrations. Mean postprandial GLP-1 responses were tightly correlated with fasting GLP-1, were higher for the second than the first meal, and higher in IR than IS subjects but only with LCD. In contrast, incremental GLP-1 responses were higher during (i) the second than the first meal, (ii) on HCD than LCD, and (iii) significantly smaller in IR than IS independently of meal and load. Potentiation of insulin release was markedly reduced in IR vs IS across meal and carbohydrate loading. In the whole dataset, incremental GLP-1 was directly related to potentiation, and both were inversely related to mean NEFA concentrations. We conclude that (a) raised GLP-1 tone may be inherently linked with a reduced GLP-1 response and (b) defective post-meal GLP-1 response may be one mechanism for impaired potentiation of insulin release in insulin resistance.

scholarly journals Emerging role of testosterone in pancreatic β cell function and insulin secretion

2019 ◽  
Vol 240 (3) ◽  
pp. R97-R105 ◽  
Author(s):  
Weiwei Xu ◽  
Jamie Morford ◽  
Franck Mauvais-Jarvis
Keyword(s):  
Insulin Secretion ◽  
Metabolic Regulation ◽  
Cell Function ◽  
Visceral Obesity ◽  
Β Cells ◽  
Β Cell ◽  
Β Cell Function ◽  
Glucagon Like Peptide 1 ◽  
Glucose Stimulated Insulin Secretion

One of the most sexually dimorphic aspects of metabolic regulation is the bidirectional modulation of glucose homeostasis by testosterone in male and females. Severe testosterone deficiency predisposes men to type 2 diabetes (T2D), while in contrast, androgen excess predisposes women to hyperglycemia. The role of androgen deficiency and excess in promoting visceral obesity and insulin resistance in men and women respectively is well established. However, although it is established that hyperglycemia requires β cell dysfunction to develop, the role of testosterone in β cell function is less understood. This review discusses recent evidence that the androgen receptor (AR) is present in male and female β cells. In males, testosterone action on AR in β cells enhances glucose-stimulated insulin secretion by potentiating the insulinotropic action of glucagon-like peptide-1. In females, excess testosterone action via AR in β cells promotes insulin hypersecretion leading to oxidative injury, which in turn predisposes to T2D.

scholarly journals Exploiting the antidiabetic properties of incretins to treat type 2 diabetes mellitus: glucagon-like peptide 1 receptor agonists or insulin for patients with inadequate glycemic control?

2008 ◽  
Vol 158 (6) ◽  
pp. 773-784 ◽  
Author(s):  
Luc F Van Gaal ◽  
Stephen W Gutkin ◽  
Michael A Nauck
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Body Weight ◽  
Cell Function ◽  
Β Cell ◽  
Β Cell Function ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

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.

scholarly journals 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 ◽  
2013 ◽  
Vol 62 (9) ◽  
pp. 3044-3052 ◽  
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

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

2019 ◽  
Vol 218 (3) ◽  
pp. 855-870 ◽  
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.

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

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.

Novel Approaches to the Treatment of Type 2 Diabetes

2009 ◽  
Vol 22 (3) ◽  
pp. 320-332 ◽  
Author(s):  
Erin L. St. Onge ◽  
Shannon A. Miller ◽  
James R. Taylor
Keyword(s):  
Type 2 Diabetes ◽  
Cell Function ◽  
Glucagon Secretion ◽  
Current Evidence ◽  
Β Cell Function ◽  
Dipeptidyl Peptidase Iv Inhibitors ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Third Line

The emergence of the glucoregulatory hormone, glucagon-like peptide-1, has expanded our understanding of glucose homeostasis. The glucoregulatory actions of glucagon-like peptide-1 include enhancement of glucose-dependent insulin secretion, suppression of inappropriately elevated glucagon secretion, slowing of gastric emptying, and reduction of food intake. Two approaches have been developed to potentiate the effects of glucagon-like peptide-1 in those with type 2 diabetes. The glucagon-like peptide-1 analogs, such as exenatide, and dipeptidyl peptidase-IV inhibitors, such as sitagliptin, are currently available whereas others are in the final stages of development. These agents effectively reduce hemoglobin A1c while providing the other benefits associated with increased glucagon-like peptide-1. They also offer the potential to preserve the β-cell function. The effects on cardiovascular disease, if any, are unknown. Based on the current evidence, these agents represent viable second-and third-line options in the management of type 2 diabetes.

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