The Multiple Actions of GLP-1 on the Process of Glucose-Stimulated Insulin Secretion

MacDonald, Patrick E.; El-kholy, Wasim; Riedel, Michael; Salapatek, Anne Marie; Light, Peter E.; Wheeler, Michael B.

doi:10.2337/diabetes.51.2007.s434

Cited by 499 publications

(363 citation statements)

References 125 publications

(102 reference statements)

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“…In general, the b-cells adapt insulin secretion to prevailing blood glucose levels through glucose metabolism. 23 The closure of ATP-sensitive K C channels (K ATP channels) and the subsequent generation of action potentials via activation of voltage-dependent L-type Ca 2C -channels are the key events linking elevated glucose metabolism to alterations of electrical activity and eventually the release of insulin granules. Insulin secretion terminates when the b-cell is repolarized by the opening of potassium channels including members of the voltage-and calcium-activated potassium channel families.…”

Section: Discussionmentioning

confidence: 99%

Chromanol 293B, an inhibitor of KCNQ1 channels, enhances glucose-stimulated insulin secretion and increases glucagon-like peptide-1 level in mice

Liu

Wang

et al. 2014

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Glucose-stimulated insulin secretion (GSIS) is a highly regulated process involving complex interaction of multiple factors. Potassium voltage-gated channel subfamily KQT member 1 (KCNQ1) is a susceptibility gene for type 2 diabetes (T2D) and the risk alleles of the KCNQ1 gene appear to be associated with impaired insulin secretion. The role of KCNQ1 channel in insulin secretion has been explored by previous work in clonal pancreatic b-cells but has yet to be investigated in the context of primary islets as well as intact animals. Genetic studies suggest that altered incretin glucagon-like peptide-1 (GLP-1) secretion might be a potential link between KCNQ1 variants and impaired insulin secretion, but this hypothesis has not been verified so far. In the current study, we examined KCNQ1 expression in pancreas and intestine from normal mice and then investigated the effects of chromanol 293B, a KCNQ1 channel inhibitor, on insulin secretion in vitro and in vivo. By double-immunofluorescence staining, KCNQ1 was detected in insulin-positive b-cells and GLP-1-positive L-cells. Administration of chromanol 293B enhanced GSIS in cultured islets and intact animals. Along with the potentiated insulin secretion during oral glucose tolerance tests (OGTT), plasma GLP-1 level after gastric glucose load was increased in 293B treated mice. These data not only provided new evidence for the participation of KCNQ1 in GSIS at the level of pancreatic islet and intact animal but also indicated the potential linking role of GLP-1 between KCNQ1 and insulin secretion.

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Section: Discussionmentioning

confidence: 99%

Chromanol 293B, an inhibitor of KCNQ1 channels, enhances glucose-stimulated insulin secretion and increases glucagon-like peptide-1 level in mice

Liu

Wang

et al. 2014

Islets

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“…However, since GLP-1 still retains a significant insulinreleasing effect after 18-h culture with PMA, the effects on K ATP channel-independent insulin secretion appear to involve PKC-independent components. Signalling via cAMP, which is elevated by GLP-1, is thought to have PKA-dependent and -independent components (MacDonald et al 2002, Gromada et al 2004. It also seems that the SUR1 is involved in mediating the PKA-independent effects of GLP-1 upon K ATP channel-independent insulin secretion, since islets isolated from SUR1 K/K mice lack the PKA-independent component of exocytosis (Nakazaki et al 2002, Eliasson et al 2003.…”

Section: Glp-1 Augments K Atp Channel-dependent and -Independent Insumentioning

confidence: 99%

“…The effects of GLP-1 on insulin release are mediated by binding to a specific G-protein-coupled receptor on the b-cell plasma membrane, resulting in the activation of adenylate cyclase. This causes an increase in b-cell cAMP production, which in turn leads to activation of protein kinase A (PKA) and insulin secretion (MacDonald et al 2002, Gromada et al 2004. GLP-1 also enhances insulin secretion by interacting with multiple cellular processes, including regulation of ionchannel activity, intracellular calcium handling and insulin exocytosis (MacDonald et al 2002, Gromada et al 2004.…”

Section: Introductionmentioning

confidence: 99%

Actions of glucagon-like peptide-1 on KATP channel-dependent and -independent effects of glucose, sulphonylureas and nateglinide

McClenaghan

Flatt

Ball

2006

Journal of Endocrinology

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This study examined the effects of glucagon-like peptide-1 (GLP-1) on insulin secretion alone and in combination with sulphonylureas or nateglinide, with particular attention to K ATP channel-independent insulin secretion. In depolarised cells, GLP-1 significantly augmented glucose-induced K ATP channel-independent insulin secretion in a glucose concentration-dependent manner. GLP-1 similarly augmented the K ATP channel-independent insulin-releasing effects of tolbutamide, glibenclamide or nateglinide. Downregulation of protein kinase A (PKA)-or protein kinase C (PKC)-signalling pathways in culture revealed that the K ATP channel-independent effects of sulphonylureas or nateglinide were critically dependent upon intact PKA and PKC signalling. In contrast, GLP-1 exhibited a reduced but still significant insulin-releasing effect following PKA and PKC downregulation, indicating that GLP-1 can modulate K ATP channel-independent insulin secretion by protein kinase-dependent and -independent mechanisms. The synergistic insulin-releasing effects of combinatorial GLP-1 and sulphonylurea/nateglinide were lost following PKA-or PKCdesensitisation, despite GLP-1 retaining an insulin-releasing effect, demonstrating that GLP-1 can induce insulin release under conditions where sulphonylureas and nateglinide are no longer effective. Our results provide new insights into the mechanisms of action of GLP-1, and further highlight the promise of GLP-1 or similarly acting analogues alone or in combination with sulphonylureas or meglitinide drugs in type 2 diabetes therapy.

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“…1 GLP-1 promotes the maintenance of beta-cell mass through stimulation of cell proliferation and neogenesis while inhibiting apoptosis, [2][3][4] and has been shown to be effective in reducing diabetes incidence in models of type-1 diabetes. 5 In addition to its effects on beta-cell survival and growth, GLP-1 acutely stimulates glucose-dependent insulin secretion and can increase insulin gene expression through several mechanisms including upregulation of the transcription factor pancreatic duodenal homeobox-1 (Pdx-1).…”

Section: Introductionmentioning

confidence: 99%

DsAAV8-mediated expression of glucagon-like peptide-1 in pancreatic beta-cells ameliorates streptozotocin-induced diabetes

et al. 2009

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Glucagon-like peptide-1 (GLP-1) is an incretin hormone that performs a wide array of well-characterized antidiabetic actions, including stimulation of glucose-dependent insulin secretion, upregulation of insulin gene expression and improvements in beta-cell survival. GLP-1-receptor agonists have been developed for treatment of diabetes; however, the short biological half-lives of these peptide-based therapeutics requires that frequent injections be administered to maintain sufficient circulating levels. Thus, novel methods of delivering GLP-1 remain an important avenue of active research. It has recently been demonstrated that self-complimentary, double-stranded, adeno-associated virus serotype-8 (DsAAV8) can efficiently transduce pancreatic beta-cells in vivo, resulting in long-term transgene expression. In this study, we engineered a DsAAV8 vector containing a GLP-1 transgene driven by the mouse insulin-II promoter (MIP). Biological activity of the GLP-1 produced from this transgene was assessed using a luciferase-based bioassay. DsAAV8-MIP-GLP-1 was delivered via intraperitoneal injection and beta-cell damage induced by multiple low dose streptozotocin (STZ) administration. Glucose tolerance was assessed following intraperitoneal glucose injections and beta-cell proliferation measured by PCNA expression. Expression of GLP-1 in Min6 beta-cells resulted in glucose-dependent secretion of biologically active GLP-1. Intraperitoneal delivery of DsAAV8-MIP-GLP-1 to mice led to localized GLP-1 expression in beta-cells and protection against development of diabetes induced by multiple low-dose STZ administration. This protection was associated with significant increase in beta-cell proliferation. Results from this study indicate that expression and secretion of GLP-1 from beta-cells in vivo via DsAAV8 represents a novel therapeutic strategy for treatment of diabetes.

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The Multiple Actions of GLP-1 on the Process of Glucose-Stimulated Insulin Secretion

Cited by 499 publications

References 125 publications

Chromanol 293B, an inhibitor of KCNQ1 channels, enhances glucose-stimulated insulin secretion and increases glucagon-like peptide-1 level in mice

Chromanol 293B, an inhibitor of KCNQ1 channels, enhances glucose-stimulated insulin secretion and increases glucagon-like peptide-1 level in mice

Actions of glucagon-like peptide-1 on KATP channel-dependent and -independent effects of glucose, sulphonylureas and nateglinide

DsAAV8-mediated expression of glucagon-like peptide-1 in pancreatic beta-cells ameliorates streptozotocin-induced diabetes

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