Glucagon-like peptide 1 stimulates insulin gene promoter activity by protein kinase A-independent activation of the rat insulin I gene cAMP response element.

Skoglund, Gunnar; Hussain, Mehboob A.; Holz, George G.

doi:10.2337/diabetes.49.7.1156

Cited by 120 publications

(99 citation statements)

References 63 publications

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“…The single RIP (RIP1) CRE site is not palindromic (TGACGTCC) and differs from the canonical CRE site by one C/A nucleotide substitution (Oetjen et al, 1994). In separate studies, the Habener (Kemp and Habener, 2001) and Holz laboratories Skoglund et al, 2000), using luciferase reporter gene assays in INS-1 cells, found that GLP-1 (10 nM or 100 nM) and Ex-4 (10 nM) induction of rat insulin I gene was not inhibited by H89 (10 μM). In both instances the results obtained are quite clear with no statistical difference between reporter assay results in the presence and absence of H89.…”

Section: Glp-1 Regulation Of Insulin Transcriptionmentioning

confidence: 98%

“…Thus it became apparent that the beneficial effects of GLP-1 on insulin secretion arose from the stimulation of transcription in the β cell as well as enhancement of acute insulin secretory responses to glucose. The ability of GLP-1 to induce transcription of the insulin gene was later demonstrated using a luciferase reporter gene assay for the rat insulin I gene in INS-1 cells (Skoglund et al, 2000) where a maximum 2-fold increase in luciferase activity was noted. More recently similar results were also obtained when the luciferase-linked human insulin promoter was transfected into INS-1 cells ).…”

Section: Chronic Effects Of Glp-1 On Insulin Synthesis and Secretionmentioning

confidence: 99%

“…However co-transfection with a dominant negative isoform of Epac2 had no effect on Ex-4-mediated activation of RIP1 . Furthermore co-transfection with a dominant negative G αs did not alter the response of the RIP1 luciferase reporter gene (Kemp and Habener, 2001;Skoglund et al, 2000). In a further dissection of the regulation of the RIP1 by GLP-1 the Holz research team showed that the serine/threonine inhibitor Ro 31-8220 that targets PKC, S6K1, and mitogen-and stress activated protein kinase family of CREB binding proteins blocked the action of Ex-4 on RIP1 .…”

Section: Glp-1 Regulation Of Insulin Transcriptionmentioning

confidence: 99%

“…Secondly, regulation of the rat and human insulin promoters is very different as illustrated by the following example. Co-transfection with dominant negative CREB (A-CREB), a genetically engineered form of CREB that binds to bZIP transcription factors, abolished the effect of GLP-1 (Skoglund et al, 2000) and Ex-4 (Chepurny et al, 2002) at the RIP1. However, co-transfection with a dominant negative form of a related bZIP protein activating transcription factor 2 (ATF-2) did not have an effect on RIP1.…”

Section: Glp-1 Regulation Of Insulin Transcriptionmentioning

confidence: 99%

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Mechanisms of action of glucagon-like peptide 1 in the pancreas

Doyle

Egan

2007

Pharmacology & Therapeutics

574

465

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Glucagon-like peptide-1 is a hormone that is encoded in the proglucagon gene. It is mainly produced in enteroendocrine L cells of the gut and is secreted into the blood stream when food containing fat, protein hydrolysate and/or glucose enters the duodenum. Its particular effects on insulin and glucagon secretion have generated a flurry of research activity over the past twenty years culminating in a naturally occurring GLP-1 receptor agonist, exendin-4, now being used to treat type 2 diabetes. GLP-1 engages a specific G-protein coupled receptor that is present in tissues other than the pancreas (brain, kidney, lung, heart, major blood vessels). The most widely studied cell activated by GLP-1 is the insulin-secreting beta cell where its defining action is augmentation of glucose-induced insulin secretion. Upon GLP-1 receptor activation, adenylyl cyclase is activated and cAMP generated, leading, in turn, to cAMP-dependent activation of second messenger pathways, such as the PKA and Epac pathways. As well as short-term effects of enhancing glucose-induced insulin secretion, continuous GLP-1 receptor activation also increases insulin synthesis, and beta cell proliferation and neogenesis. Although these latter effects cannot be currently monitored in humans, there are substantial improvements in glucose tolerance and increases in both first phase and plateau phase insulin secretory responses in type 2 diabetic patients treated with exendin-4. This review we will focus on the effects resulting from GLP-1 receptor activation in islets of Langerhans

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Section: Glp-1 Regulation Of Insulin Transcriptionmentioning

confidence: 98%

Section: Chronic Effects Of Glp-1 On Insulin Synthesis and Secretionmentioning

confidence: 99%

Section: Glp-1 Regulation Of Insulin Transcriptionmentioning

confidence: 99%

Section: Glp-1 Regulation Of Insulin Transcriptionmentioning

confidence: 99%

See 2 more Smart Citations

Mechanisms of action of glucagon-like peptide 1 in the pancreas

Doyle

Egan

2007

Pharmacology & Therapeutics

574

465

View full text Add to dashboard Cite

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“…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). [6][7][8] GLP-1 also reduces blood glucose levels by inhibiting glucagon secretion from alpha-cells, an effect likely mediated through increased somatostatin release from delta-cells. 9 Delayed gastric emptying and increased satiety result in inhibition of food intake following activation of GLP-1 receptors in the stomach and CNS, respectively.…”

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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Islet Amyloid Polypeptide/GLP‐1/Exendin

Baggio

Drucker

2003

International Textbook of Diabetes Mellitus

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Gastrointestinal peptides exert important physiological roles in the control of feeding behavior, gut motility, nutrient absorption, and energy assimilation. Islet amyloid polypeptide is secreted from islet β‐cells, and exerts inhibitory actions on appetite, gastric motility, and glucagon secretion. Glucagon‐like peptide 1 (GLP‐1) is released from enteroendocrine cells and regulates food intake, gastric emptying, insulin and glucagon secretion, and β‐cell proliferation and apoptosis. Exendin‐4, a lizard‐derived peptide, is a potent and stable GLP‐1R agonist that exerts GLP‐1‐like actions in vivo . The overlapping glucose‐lowering properties of these peptides have fostered considerable interest in their development as new therapeutic agents for the treatment of diabetes mellitus.

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Glucagon-like peptide 1 stimulates insulin gene promoter activity by protein kinase A-independent activation of the rat insulin I gene cAMP response element.

Cited by 120 publications

References 63 publications

Mechanisms of action of glucagon-like peptide 1 in the pancreas

Mechanisms of action of glucagon-like peptide 1 in the pancreas

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

Islet Amyloid Polypeptide/GLP‐1/Exendin

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