Role of KATP Channels in Glucose-Regulated Glucagon Secretion and Impaired Counterregulation in Type 2 Diabetes

Quan Zhang,Reshma Ramracheya,Frank Reimann,Patrik Rorsman,Carolina Lahmann,Albert Salehi,Martin Bengtsson,Matthias Braun,Juris Galvanovskis,Orit Braha,Melissa F Brereton ,Mary E Travers ,Nils J.g Rorsman ,Frances M Ashcroft ,Lukas N Groschner ,Anna L Gloyn ,Andrei I Tarasov ,Fiona M Gribble ,Alejandro González ,Paul Johnson ,Stephan C Collins ,Jonathan N Walker

doi:10.1016/j.cmet.2013.10.014

Quan Zhang, Reshma Ramracheya + Show 20 more

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https://doi.org/10.1016/j.cmet.2013.10.014

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SummaryGlucagon, secreted by pancreatic islet α cells, is the principal hyperglycemic hormone. In diabetes, glucagon secretion is not suppressed at high glucose, exacerbating the consequences of insufficient insulin secretion, and is inadequate at low glucose, potentially leading to fatal hypoglycemia. The causal mechanisms remain unknown. Here we show that α cell KATP-channel activity is very low under hypoglycemic conditions and that hyperglycemia, via elevated intracellular ATP/ADP, leads to complete inhibition. This produces membrane depolarization and voltage-dependent inactivation of the Na+ channels involved in action potential firing that, via reduced action potential height and Ca2+ entry, suppresses glucagon secretion. Maneuvers that increase KATP channel activity, such as metabolic inhibition, mimic the glucagon secretory defects associated with diabetes. Low concentrations of the KATP channel blocker tolbutamide partially restore glucose-regulated glucagon secretion in islets from type 2 diabetic organ donors. These data suggest that impaired metabolic control of the KATP channels underlies the defective glucose regulation of glucagon secretion in type 2 diabetes.

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Glucagon and insulin are the body’s principal plasma glucoseregulating hormones
Glucagon secretion is not suppressed at high glucose, exacerbating the consequences of insufficient insulin secretion, and is inadequate at low glucose, potentially leading to fatal hypoglycemia
We show that a cell KATP-channel activity is very low under hypoglycemic conditions and that hyperglycemia, via elevated intracellular ATP/ADP, leads to complete inhibition. This produces membrane depolarization and voltage-dependent inactivation of the Na+ channels involved in action potential firing that, via reduced action potential height and Ca2+ entry, suppresses glucagon secretion

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Glucagon and insulin are the body’s principal plasma glucoseregulating hormones. They are secreted from the a and b cells of the pancreatic islets, respectively. Glucagon secretion responds normally to hypoglycemia after denervation of the pancreas (Sherck et al, 2001) These considerations suggest that a cells, in addition to being under paracrine control, possess an intrinsic glucose-sensing mechanism. This remains poorly defined, but studies on KATP-channel knockout mice indicate that KATP-channels are somehow involved (Cheng-Xue et al, 2013; Gromada et al, 2004; Munoz et al, 2005; Shiota et al, 2005) and the inhibitory effect of high glucose can be reversed by low concentrations of the KATP-channel activator diazoxide (Gopel et al, 2000b; MacDonald et al, 2007). Closure of these channels by metabolically generated ATP leads to membrane depolarization, electrical activity, and insulin secretion It is not immediately evident, how regulation of the same channels by glucose in a cells could suppress glucagon secretion.

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