Pharmacological Agents That Directly Modulate Insulin Secretion

Doyle, Maı̀re E.; Egan, Josephine M.

doi:10.1124/pr.55.1.7

Cited by 224 publications

(141 citation statements)

References 298 publications

(274 reference statements)

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“…5b). Similarly, a combination of 22.2 mmol/l glucose and IBMX, an inhibitor of cAMP phosphodiesterase that causes elevated intracellular cAMP levels that lead to increased exocytosis of insulin [37], had no significant effect on Akt phosphorylation. Therefore, in our hands, glucose was unable to induce Akt phosphorylation in human islets immediately following isolation.…”

Section: Regular Medium Replacement Decreases Akt Phosphorylationmentioning

confidence: 97%

Autocrine insulin action activates Akt and increases survival of isolated human islets

et al. 2006

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Aims/hypothesis The phosphatidylinositol 3-kinase (PI3K)/ Akt pathway plays a critical role in promoting the survival of pancreatic beta cells. Akt becomes activated in isolated human islets following overnight culture despite significant levels of cell death. The aim of the current study was to identify the cause of the observed increase in Akt phosphorylation in isolated islets. We hypothesised that a factor secreted by the islets in culture was acting in an autocrine manner to activate Akt. Methods In order to identify the stimulus of the PI3K/Akt pathway in culture, we examined the effects of different culture conditions on Akt phosphorylation and islet survival during the immediate post-isolation period. Results We demonstrated that islet-conditioned medium induced Akt phosphorylation in freshly isolated human islets, whereas frequent medium replacement decreased Akt phosphorylation. Following overnight culture, islet-conditioned medium contained significantly elevated levels of insulin, indicating that insulin may be responsible for the observed increase in Akt phosphorylation. Indeed, treatment with an anti-insulin antibody or with inhibitors of insulin receptor/IGF receptor 1 kinase activity suppressed Akt phosphorylation, leading to decreased islet survival. In addition, dispersion of islets into single cells also suppressed Akt phosphorylation and induced islet cell death, indicating that islet integrity is also required for maximal Akt phosphorylation. Conclusions/interpretation Our findings demonstrate that insulin acts in an autocrine manner to activate Akt and mediate the survival of isolated human islets. These findings provide new information on how culturing islets prior to transplantation may be beneficial to their survival by allowing for autocrine activation of the pro-survival Akt pathway.

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Section: Regular Medium Replacement Decreases Akt Phosphorylationmentioning

confidence: 97%

Autocrine insulin action activates Akt and increases survival of isolated human islets

et al. 2006

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“…NFAT is expressed in the rat pancreatic β cell (Lawrence et al, 2002) and the dephosphorylated NFAT complex is maintained in the nucleus as long as Ca 2+ concentrations are elevated, thus maintaining calcineurin in the activated state (Timmerman et al, 1996). The participation of PP2-B and NFAT in multiple aspects of insulin secretion has been highlighted by the use of the PP2-B inhibitor FK506 (also known as tacrolimus) and cyclosporin A (reviewed in Doyle and Egan, 2003).…”

Section: Glp-1 Regulation Of Insulin Transcriptionmentioning

confidence: 99%

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

Doyle

Egan

2007

Pharmacology & Therapeutics

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583

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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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“…Activated PKA may close K ATP channels, and activate Ca 2+ channels and exocytosis of insulin containing granules [3]. GLP-1 also increases insulin secretion in a calcium-and PKA-independent manner by mobilizing secretory vesicles to enter the readily releasable pool [6]. R. radix, Ginseng radix and S. radix may enhance glucose-stimulated insulin secretion through cAMP/PKA-dependent and/or -independent pathways.…”

Section: Glucose-stimulated Insulin Secretion In Isletsmentioning

confidence: 99%

Extracts of Rehmanniae radix, Ginseng radix and Scutellariae radix improve glucose-stimulated insulin secretion and β-cell proliferation through IRS2 induction

et al. 2007

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Recent studies have revealed that b-cell dysfunction is an important factor in developing type 2 diabetes. b-cell dysfunction is related to impairment of the insulin/ IGF-1 signaling cascade through insulin receptor substrate-2 (IRS2). The induction of IRS2 in b-cells plays an important role in potentiating b-cell function and mass. In this study, we investigated whether herbs used for treating diabetes in Chinese medicine-Galla rhois, Rehmanniae radix, Machilus bark, Ginseng radix, Polygonatum radix, and Scutellariae radix-improved IRS2 induction in rat islets, glucose-stimulated insulin secretion and b-cell survival. R. radix, Ginseng radix and S. radix significantly enhanced glucose-stimulated insulin secretion compared to the control, i.e., by 49, 67 and 58%, respectively. These herbs induced the expression of IRS2, pancreas duodenum homeobox-1 (PDX-1), and glucokinase. The increased level of glucokinase could explain the enhancement of glucosestimulated insulin secretion with these extracts. Increased PDX-1 expression was associated with b-cell proliferation, which was consistent with the cell viability assay. In conclusion, R. radix, Ginseng radix and S. radix had an insulinotropic action similar to that of exendin-4.

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Pharmacological Agents That Directly Modulate Insulin Secretion

Cited by 224 publications

References 298 publications

Autocrine insulin action activates Akt and increases survival of isolated human islets

Autocrine insulin action activates Akt and increases survival of isolated human islets

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

Extracts of Rehmanniae radix, Ginseng radix and Scutellariae radix improve glucose-stimulated insulin secretion and β-cell proliferation through IRS2 induction

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