<scp>GLP</scp>‐1 receptor activated insulin secretion from pancreatic β‐cells: mechanism and glucose dependence

Meloni, Alison R.; DeYoung, Mary Beth; Lowe, Catherine; Parkes, David G.

doi:10.1111/j.1463-1326.2012.01663.x

Cited by 280 publications

(215 citation statements)

References 103 publications

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“…Interestingly, we also show that alpha cell mass was reduced to such an extent that the ratio of alpha to beta cells remained unchanged. Acute GLP-1R stimulation of beta cells is known to increase insulin secretion in a glucose-dependent manner [17][18][19]. We show that sustained GLP-1RA treatment during normoglycaemic conditions is associated with increased insulin secretion from isolated islets even in the absence of direct GLP-1RA stimulation in vitro.…”

Section: Discussionmentioning

confidence: 73%

“…The effect of GLP-1-based therapy on insulin secretion from beta cells has been reported to be glucose dependent [17][18][19], but its effect on beta cell mass under different glycaemic conditions is less clear. While GLP-1RA treatment increases beta cell mass in animal models of diabetes, we now show a reduction in beta cell mass in normoglycaemic mice.…”

Section: Discussionmentioning

confidence: 99%

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Glucagon-like peptide-1 receptor agonist treatment reduces beta cell mass in normoglycaemic mice

et al. 2013

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Aims/hypothesis Incretin-based therapies improve glycaemic control in patients with type 2 diabetes. In animal models of diabetes, glucagon-like peptide-1 receptor agonists (GLP-1RAs) increase beta cell mass. GLP-1RAs are also evaluated in nondiabetic individuals with obesity and cardiovascular disease. However, their effect on beta cell mass in normoglycaemic conditions is not clear. Here, we investigate the effects of the GLP-1RA liraglutide on beta cell mass and function in normoglycaemic mice. Methods C57BL/6J mice were treated with the GLP-1RA liraglutide or PBS and fed a control or high-fat diet (HFD) for 1 or 6 weeks. Glucose and insulin tolerance tests were performed after 6 weeks. BrdU was given to label proliferating cells 1 week before the animals were killed. The pancreas was taken for either histology or islet isolation followed by a glucose-induced insulin-secretion test. Results Treatment with liraglutide for 6 weeks led to increased insulin sensitivity and attenuation of HFD-induced insulin resistance. A reduction in beta cell mass was observed in liraglutide-treated control and HFD-fed mice at 6 weeks, and was associated with a lower beta cell proliferation rate after 1 week of treatment. A similar reduction in alpha cell mass occurred, resulting in an unchanged alpha to beta cell ratio. In contrast, acinar cell proliferation was increased. Finally, islets isolated from liraglutide-treated control mice had enhanced glucose-induced insulin secretion. Conclusions/interpretation Our data show that GLP-1RA treatment in normoglycaemic mice leads to increases in insulin sensitivity and beta cell function that are associated with reduced beta cell mass to maintain normoglycaemia.

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Section: Discussionmentioning

confidence: 73%

Section: Discussionmentioning

confidence: 99%

Glucagon-like peptide-1 receptor agonist treatment reduces beta cell mass in normoglycaemic mice

et al. 2013

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“…Once‐weekly exenatide has been shown to improve glycaemic control in a glucose‐dependent manner, with a low risk of hypoglycaemia, in people with type 2 diabetes 10. The extended‐release delivery method, glucose‐dependent effects on insulin and glucagon,11 and improved postprandial glucose (PPG) control observed with once‐weekly exenatide12 are proposed to lead to less glycaemic variability, although studies specifically designed to evaluate glycaemic variability with once‐weekly exenatide treatment have been limited.…”

Section: Introductionmentioning

confidence: 99%

Exenatide once weekly improved 24‐hour glucose control and reduced glycaemic variability in metformin‐treated participants with type 2 diabetes: a randomized, placebo‐controlled trial

Frías

Nakhle²,

Ruggles

et al. 2016

Diabetes Obesity Metabolism

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AimTo assess the effects of once‐weekly exenatide on 24‐hour glucose control and variability.Materials and methodsThis double‐blind, placebo‐controlled trial randomized metformin‐treated adults with type 2 diabetes to once‐weekly exenatide 2.0 mg or placebo. Continuous glucose monitoring (CGM) was performed at baseline and weeks 4 and 10. The primary outcome was change in CGM‐measured 24‐hour mean glucose level.ResultsIn the once‐weekly exenatide (n = 60) and placebo (n = 56) groups (modified intention‐to‐treat population), the baseline glycated haemoglobin (HbA1c) concentrations were 8.2% and 8.0%, respectively, and the fasting plasma glucose (FPG) concentration was 9.86 and 9.32 mmol/L, respectively. Once‐weekly exenatide significantly (p < 0.001) reduced 24‐hour mean glucose level versus placebo (week 4, −1.44 vs −0.29 mmol/L; week 10, −1.71 vs −0.17 mmol/L), with consistent control throughout the week. Once‐weekly exenatide significantly reduced FPG and 2‐hour postprandial glucose (PPG) levels versus placebo at week 4 (FPG, −1.65 vs −0.11 mmol/L; PPG, −1.79 vs −0.11 mmol/L) and week 10 (FPG, −2.32 vs −0.28 mmol/L; PPG, −2.46 vs −0.33 mmol/L). At week 10, once‐weekly exenatide reduced the mean amplitude of glucose excursions (MAGE; −0.84 vs 0.16 mmol/L) and standard deviation (s.d.) of mean glucose (−0.35 vs 0.04 mmol/L). By week 10, once‐weekly exenatide‐treated participants spent more time in euglycaemia (once‐weekly exenatide, 77% vs placebo, 58%), less time in hyperglycaemia (22% vs 42%), and a similar time in hypoglycaemia (0.7% vs 0.3%). Common adverse events were injection‐site nodule (once‐weekly exenatide, 10.0% vs placebo, 0.0%), urinary tract infection (6.7% vs 8.9%) and nausea (6.7% vs 0.0%).ConclusionsIn metformin‐treated participants with type 2 diabetes, once‐weekly exenatide significantly improved daily glucose control and reduced glycaemic variability at weeks 4 and 10, as shown by reductions in 24‐hour glucose, FPG and PPG levels, MAGE and s.d., and increased time spent in euglycaemia.

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“…2e, secreted insulin levels were similar in control and CUGBP1 OE islets in the presence of 3.3 mmol/l glucose; however, upon 16.7 mmol/l glucose stimulation insulin levels in CUGBP1 OE islets were significantly lower than in control islets (p < 0.05). GLP-1 is known to stimulate insulin secretion through binding to and activating the GLP-1 receptor, and thereby inducing cAMP production [39]. We therefore tested whether CUGBP1 has a role in GLP-1-induced insulin secretion.…”

Section: Cugbp1 Is Overexpressed In the Islets Of Diabetic Micementioning

confidence: 99%

RNA-binding protein CUGBP1 regulates insulin secretion via activation of phosphodiesterase 3B in mice

Zhai

Yang

et al. 2016

Diabetologia

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Aims/hypothesis CUG-binding protein 1 (CUGBP1) is a multifunctional RNA-binding protein that regulates RNA processing at several stages including translation, deadenylation and alternative splicing, as well as RNA stability. Recent studies indicate that CUGBP1 may play a role in metabolic disorders. Our objective was to examine its role in endocrine pancreas function through gain-and loss-of-function experiments and to further decipher the underlying molecular mechanisms. Methods A mouse model in which type 2 diabetes was induced by a high-fat diet (HFD; 60% energy from fat) and mice on a standard chow diet (10% energy from fat) were compared. Pancreas-specific CUGBP1 overexpression and knockdown mice were generated. Different lengths of the phosphodiesterase subtype 3B (PDE3B) 3′ untranslated region (UTR) were cloned for luciferase reporter analysis. Purified CUGBP1 protein was used for gel shift experiments.Results CUGBP1 is present in rodent islets and in beta cell lines; it is overexpressed in the islets of diabetic mice. Compared with control mice, the plasma insulin level after a glucose load was significantly lower and glucose clearance was greatly delayed in mice with pancreas-specific CUGBP1 overexpression; the opposite results were obtained upon pancreas-specific CUGBP1 knockdown. Glucose-and glucagon-like peptide1 (GLP-1)-stimulated insulin secretion was significantly attenuated in mouse islets upon CUGBP1 overexpression. This was associated with a strong decrease in intracellular cAMP levels, pointing to a potential role for cAMP PDEs. CUGBP1 overexpression had no effect on the mRNA levels of PDE1A, 1C, 2A, 3A, 4A, 4B, 4D, 7A and 8B subtypes, but resulted in increased PDE3B expression. CUGBP1 was found to directly bind to a specific ATTTGTT sequence residing in the 3′ UTR of PDE3B and stabilised PDE3B mRNA. In the presence of the PDE3 inhibitor cilostamide, glucose-and GLP-1-stimulated insulin secretion was no longer reduced by CUGBP1 overexpression. Similar to CUGBP1, PDE3B was overexpressed in the islets of diabetic mice. Conclusions/interpretation We conclude that CUGBP1 is a critical regulator of insulin secretion via activating PDE3B. Repressing this protein might provide a potential strategy for treating type 2 diabetes.

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GLP‐1 receptor activated insulin secretion from pancreatic β‐cells: mechanism and glucose dependence

Cited by 280 publications

References 103 publications

Glucagon-like peptide-1 receptor agonist treatment reduces beta cell mass in normoglycaemic mice

Glucagon-like peptide-1 receptor agonist treatment reduces beta cell mass in normoglycaemic mice

Exenatide once weekly improved 24‐hour glucose control and reduced glycaemic variability in metformin‐treated participants with type 2 diabetes: a randomized, placebo‐controlled trial

RNA-binding protein CUGBP1 regulates insulin secretion via activation of phosphodiesterase 3B in mice

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