Glucagon-like peptide I stimulates insulin gene expression and increases cyclic AMP levels in a rat islet cell line.

Drucker, Daniel J.; Philippe, Jacques; Mojsov, Svetlana; Chick, William L.; Habener, Joel F.

doi:10.1073/pnas.84.10.3434

Cited by 783 publications

(567 citation statements)

References 32 publications

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“…In addition, the increased early response of insulin secretion during the GTT in liraglutide-treated mice is in line with the working mechanism of GLP-1 [25,26]. This was associated with a major reduction in beta cell mass in both control and HFD-fed mice.…”

Section: Discussionsupporting

confidence: 67%

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: Discussionsupporting

confidence: 67%

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

et al. 2013

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“…function, such as Pdx-1, Glut2, glucokinase, and insulin (12)(13)(14)(15)(16), and by providing protection against apoptosis (17). Recently we have also demonstrated that an important site of GLP-1 action is on the hepatoportal glucose sensor.…”

Section: Gluco-incretins Control Insulin Secretion At Multiple Levelsmentioning

confidence: 99%

Gluco-incretins control insulin secretion at multiple levels as revealed in mice lacking GLP-1 and GIP receptors

Preitner¹,

Ibberson²,

Franklin³

et al. 2004

J. Clin. Invest.

116

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The role of the gluco-incretin hormones GIP and GLP-1 in the control of β cell function was studied by analyzing mice with inactivation of each of these hormone receptor genes, or both. Our results demonstrate that glucose intolerance was additively increased during oral glucose absorption when both receptors were inactivated. After intraperitoneal injections, glucose intolerance was more severe in double-as compared to single-receptor KO mice, and euglycemic clamps revealed normal insulin sensitivity, suggesting a defect in insulin secretion. When assessed in vivo or in perfused pancreas, insulin secretion showed a lack of first phase in Glp-1R -/-but not in Gipr -/-mice. In perifusion experiments, however, first-phase insulin secretion was present in both types of islets. In double-KO islets, kinetics of insulin secretion was normal, but its amplitude was reduced by about 50% because of a defect distal to plasma membrane depolarization. Thus, gluco-incretin hormones control insulin secretion (a) by an acute insulinotropic effect on β cells after oral glucose absorption (b) through the regulation, by GLP-1, of in vivo first-phase insulin secretion, probably by an action on extra-islet glucose sensors, and (c) by preserving the function of the secretory pathway, as evidenced by a β cell autonomous secretion defect when both receptors are inactivated.

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“…GLP-1 exerts its multiple biological effects through binding of its specific G-protein-coupled receptor, GLP1R. GLP1R is mainly expressed by pancreatic β-cells, and activation of this receptor in response to ligand stimulation increases the intracellular cAMP level, leading to stimulation of insulin secretion by two different pathways, PKA-dependent and PKA-independent exchange protein directly activated by cAMP (EPAC) pathways (Drucker et al, 1987;Fehmann et al, 1995). Subsequently, PKA and EPAC increase protein phosphorylation and intracellular Ca 2+ concentration (Kieffer et al, 1999), causing increased synthesis and secretion of insulin by β-cells.…”

Section: Introductionmentioning

confidence: 99%

Insulin Contributes to Fine-Tuning of the Pancreatic Beta-Cell Response to Glucagon-Like Peptide-1

Moon

Kim

Park

et al. 2011

Molecules and Cells

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Glucagon-like peptide-1 (GLP-1) stimulates insulin secretion from pancreatic β-cells in a glucose-dependent manner. However, factors other than glucose that regulate the β-cell response to GLP-1 remain poorly understood. In this study, we examined the possible involvement of insulin and receptor tyrosine kinase signaling in regulation of the GLP-1 responsiveness of β-cells. Pretreatment of β-cells with HNMPA, an insulin receptor inhibitor, and AG1478, an epidermal growth factor receptor inhibitor, further increased the cAMP level and Erk phosphorylation in the presence of exendin-4 (exe-4), a GLP-1 agonist. When β-cells were exposed to a high concentration of glucose (25 mM), which stimulates insulin secretion, exe-4-induced cAMP formation declined gradually as exposure time was increased. This decreased cAMP formation was not observed in the presence of HNMPA. HNMPA was able to further increase the exe-4-induced insulin secretion when β-cells were exposed to high glucose for 18 h. Treatment of β-cells with insulin significantly decreased exe-4-induced cAMP formation in a dose-dependent manner. Lowering the phospho-Akt level by HNMPA or LY294002, a PI3K inhibitor, further augmented exe-4-induced cAMP formation and Erk phosphorylation. These results suggest that insulin contributes to fine-tuning of the β-cell response to GLP-1.

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Glucagon-like peptide I stimulates insulin gene expression and increases cyclic AMP levels in a rat islet cell line.

Cited by 783 publications

References 32 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

Gluco-incretins control insulin secretion at multiple levels as revealed in mice lacking GLP-1 and GIP receptors

Insulin Contributes to Fine-Tuning of the Pancreatic Beta-Cell Response to Glucagon-Like Peptide-1

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