ATP-sensitive K+ channel mediates the zinc switch-off signal for glucagon response during glucose deprivation.
OBJECTIVE
The intraislet insulin hypothesis proposes that glucagon secretion during hypoglycemia is triggered by a decrease in intraislet insulin secretion. A more recent hypothesis based on in vivo data from hypoglycemic rats is that it is the decrease in zinc cosecreted with insulin from beta-cells, rather than the decrease in insulin itself, that signals glucagon secretion from alpha-cells during hypoglycemia. These studies were designed to determine whether closure of the alpha-cell ATP-sensitive K(+) channel (K(ATP) channel) is the mechanism through which the zinc switch-off signal triggers glucagon secretion during glucose deprivation.


METHODS
All studies were performed using perifused isolated islets.


RESULTS
In control experiments, the expected glucagon response to an endogenous insulin switch-off signal during glucose deprivation was observed in wild-type mouse islets. In experiments with streptozotocin-treated wild-type islets, a glucagon response to an exogenous zinc switch-off signal was observed during glucose deprivation. However, this glucagon response to the zinc switch-off signal during glucose deprivation was not seen in the presence of nifedipine, diazoxide, or tolbutamide or if K(ATP) channel knockout mouse islets were used. All islets had intact glucagon responses to epinephrine.


CONCLUSIONS
These data demonstrate that closure of K(ATP) channels and consequent opening of calcium channels is the mechanism through which the zinc switch-off signal triggers glucagon secretion during glucose deprivation.
Slucca
Michela
M
Pacific Northwest Diabetes Research Institute and the Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine and Department of Pharmacology, University of Washington, Seattle, Washington, USA.
Harmon
Jamie S
JS
Oseid
Elizabeth A
EA
Bryan
Joseph
J
Robertson
R Paul
RP
D000818:Animals; D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D005260:Female; D005934:Glucagon / Q000378:metabolism / Q000502:physiology*; D050416:Glucagon-Secreting Cells / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007003:Hypoglycemia / Q000139:chemically induced / Q000453:epidemiology; D007328:Insulin / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D000078790:Insulin Secretion; D054086:KATP Channels / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009543:Nifedipine / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction / Q000502:physiology; D015032:Zinc / Q000502:physiology*
D015220:Calcium Channels; D007328:Insulin; D054086:KATP Channels; D005934:Glucagon; D009543:Nifedipine; D015032:Zinc