The β-Cell K ATP Channel

Ashcroft, S. J. H.

doi:10.1007/s002320001095

Cited by 44 publications

(33 citation statements)

References 4 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A high ATP/ADP ratio subsequently closes K ATP channels in pancreatic b-cells, leading to membrane depolarization. 28 Resultant opening of voltage-dependent calcium channels injects more calcium into cytosolic milieu. This eventually leads to exocytosis of insulin granules.…”

Section: Discussionmentioning

confidence: 99%

“…With a holding potential of À60 mM and in the absence of Ca 2 þ from the bath solution, neither voltage-dependent K þ channel nor calcium-activated K þ channels would have been activated. 26,27 H 2 S at 100 mM significantly increased K ATP channel currents that were subsequently inhibited by gliclazide (1 mM), a classical K ATP channel blocker, 28,29 in b-cells from both ZL (Figure 7a) and ZDF rats (Figure 7b). The amplitude of K ATP channel cur- rents at resting condition appeared to be lower in ZDF b-cells than ZL b-cells (Figure 7c).…”

Section: Insulin Tolerance and Pancreatic Insulin Releasementioning

confidence: 99%

See 1 more Smart Citation

Pancreatic islet overproduction of H2S and suppressed insulin release in Zucker diabetic rats

Yang

Jia

et al. 2009

Laboratory Investigation

197

156

View full text Add to dashboard Cite

Hydrogen sulfide (H 2 S) has been traditionally known for its toxic effects on living organisms. The role of H 2 S in the homeostatic regulation of pancreatic insulin metabolism has been unclear. The present study is aimed at elucidating the effect of endogenously produced H 2 S on pancreatic insulin release and its role in diabetes development. Diabetes development in Zucker diabetic fatty (ZDF) rats was evaluated in comparison with Zucker fatty (ZF) and Zucker lean (ZL) rats. Pancreatic H 2 S production and insulin release were also assayed. It was found that H 2 S was generated in rat pancreas islets, catalyzed predominantly by cystathionine g-lyase (CSE). Pancreatic CSE expression and H 2 S production were greater in ZDF rats than in ZF or ZL rats. ZDF rats exhibited reduced serum insulin level, hyperglycemia, and insulin resistance. Inhibition of pancreatic H 2 S production in ZDF rats by intraperitoneal injection of DL-propargylglycine (PPG) for 4 weeks increased serum insulin level, lowered hyperglycemia, and reduced hemoglobin A1c level (Po0.05). Although in ZF rats it also reduced pancreatic H 2 S production and serum H 2 S level, PPG treatment did not alter serum insulin and glucose level. Finally, H 2 S significantly increased K ATP channel activity in freshly isolated rat pancreatic b-cells. It appears that insulin release is impaired in ZDF because of abnormally high pancreatic production of H 2 S. New therapeutic approach for diabetes management can be devised based on our observation by inhibiting endogenous H 2 S production from pancreas. KEYWORDS: diabetes; hydrogen sulfide; insulin release; K ATP channel; pancreas; type 2 diabetes mellitus Known as a swamp gas or 'rotten egg' gas, hydrogen sulfide (H 2 S) has yielded a public image of air pollutant for centuries. Physiological importance of H 2 S as a gasotransmitter has been realized for less than a decade. Endogenous production of H 2 S from L-cysteine is catalyzed by cystathionine b-synthase (CBS) and/or cystathionine g-lyase (CSE) with ammonium and pyruvate as co-products. 1 This process occurs in different organs and tissues, such as neuronal, vascular, and intestinal tissues. 2 Physiological concentrations of circulating H 2 S have been reported in the range of 45-300 mM. 1 At this physiological range, exogenous H 2 S has been shown to relax different vascular tissues, including isolated rat aortae and perfused mesenteric artery bed. 3-5 Altered cell proliferation or apoptosis induced by H 2 S has also been widely reported. [6][7][8][9][10] Endogenous production and physiological function of H 2 S in pancreas have been studied with identification of both CBS and CSE in rat pancreatic tissues or cloned rat pancreatic b-cell line. 11,12 In recent years, pathophysiological implications of the CSE/H 2 S system in diabetes have been reported. 12 CSE mRNA expression and H 2 S formation in rat pancreas was significantly increased after diabetes induction by streptozotocin injection. 12 CBS expression was reported in pancreatic acinar cells. 13 Y...

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Insulin Tolerance and Pancreatic Insulin Releasementioning

confidence: 99%

Pancreatic islet overproduction of H2S and suppressed insulin release in Zucker diabetic rats

Yang

Jia

et al. 2009

Laboratory Investigation

197

156

View full text Add to dashboard Cite

show abstract

“…4.3.1 K ATP channels-Pharmacological deactivators of K ATP channels have been in clinical use for many years, consequently they have been extensively characterized in terms of their structure, electrophysiology, and their mechanism of action and we refer the reader to these recent reviews (Ashcroft, 2000;Gribble and Reimann, 2003;Matsuo et al, 2005;Nichols, 2006). Briefly, as illustrated in Fig.…”

Section: Potassium Channelsmentioning

confidence: 99%

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

Doyle

Egan

2007

Pharmacology & Therapeutics

576

465

View full text Add to dashboard Cite

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

show abstract

“…Closure (inactivation) of K ATP channels in response to glucose or other insulin secretagogues depolarizes ␤-cells, resulting in the activation of voltage-dependent Ca 2ϩ channels, a rise in cytosolic calcium concentration, and a rise in insulin secretion (50). Glucose-induced insulin secretion is further potentiated by hormone-mediated elevation of the intracellular second messengers cAMP/protein kinase A and phospholipase C/protein kinase C. Electrophysiological characterization of the effects of leptin on pancreatic ␤-cells revealed that leptin hyperpolarized the cell membrane, which led to inhibition of insulin secretion (22,27).…”

Section: Multiple Molecular Effects Of Leptin In Pancreatic ␤-Cellsmentioning

confidence: 99%