Regulation of glucagon secretion at low glucose concentrations: Evidence for adenosine triphosphate-sensitive potassium channel involvement

Alvaro Munõz, Min Hu, Khalid Hussain, Joseph Bryan, Lydia Aguilar-Bryan, Arun S. Rajan

Research output: Contribution to journalArticlepeer-review

42 Scopus citations

Abstract

Glucagon is a potent counterregulatory hormone that opposes the action of insulin in controlling glycemia. The cellular mechanisms by which pancreatic α-cell glucagon secretion occurs in response to hypoglycemia are poorly known. SUR1/KIR6.2-type ATP-sensitive K+ (KATP) channels have been implicated in the glucagon counterregulatory response at central and peripheral levels, but their role is not well understood. In this study, we examined hypoglycemia-induced glucagon secretion in vitro in isolated islets and in vivo using Sur1KO mice lacking neuroendocrine-type KATP channels and paired wild-type (WT) controls. Sur1KO mice fed ad libitum have normal glucagon levels and mobilize hepatic glycogen in response to exogenous glucagon but exhibit a blunted glucagon response to insulin-induced hypoglycemia. Glucagon release from Sur1KO and WT islets is increased at 2.8 mmol/liter glucose and suppressed by increasing glucose concentrations. WT islets increase glucagon secretion approximately 20-fold when challenged with 0.1 mmol/liter glucose vs. approximately 2.7-fold for Sur1KO islets. Glucagon release requires Ca2+ and is inhibited by nifedipine. Consistent with a regulatory interaction between KATP channels and intraislet zinc-insulin, WT islets exhibit an inverse correlation between β-cell secretion and glucagon release. Glibenclamide stimulated insulin secretion and reduced glucagon release in WT islets but was without effect on secretion from Sur1KO islets. The results indicate that loss of β-cell KATP channels uncouples glucagon release from inhibition by β-cells and reveals a role for KATP channels in the regulation of glucagon release by low glucose.

Original languageEnglish (US)
Pages (from-to)5514-5521
Number of pages8
JournalEndocrinology
Volume146
Issue number12
DOIs
StatePublished - Dec 2005

ASJC Scopus subject areas

  • Endocrinology

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