Regulation of glucose-dependent insulin secretion by insulin: possible role of AMP-activated protein kinase.
OBJECTIVE
Extracellular insulin affects insulin secretion from pancreatic beta-cells in an autocrine fashion, but the role of glucose in this signaling pathway remains unclear. This study was conducted to evaluate the glucose dependency of extracellular insulin-mediated regulation of insulin secretion and the potential underlying mechanism.


METHODS
Pancreatic beta-cells from male Sprague-Dawley rats and INS-1, a rat insulinoma cell line, were used. The mechanism of extracellular insulin-mediated, glucose-dependent insulin secretion was explored by analyzing the activity of ATP-sensitive K(+) (K(ATP)) channels, changes in cell membrane potential, and cytosolic free Ca2+ concentration ([Ca2+](c)), as well as phosphorylation of the insulin signaling pathway and the metabolic sensor AMP-activated protein kinase (AMPK).


RESULTS
Treatment of native beta-cells with 100 nM insulin under basal glucose conditions (< or =5 mM) reduced subsequent high glucose-induced insulin secretory responses, demonstrating less inhibition of K(ATP) channels and decreased elevation of [Ca2+](c). In contrast, insulin treatment under high glucose conditions potentiated the insulin secretory responses of beta-cells. While insulin treatment attenuated phosphorylation on the Thr172 of AMPK and the Ser789 of insulin receptor substrate (IRS)-1, which was increased by lowering glucose concentration, it enhanced phosphorylation of AMPK and IRS-1, which was decreased by elevating glucose concentration. This glucose-dependent regulation of insulin even occurred in the presence of LY294002, a phosphoinositide-3 kinase inhibitor.


CONCLUSIONS
Considering that the phosphorylated AMPK could inhibit K(ATP) currents in beta-cells, which triggers glucose-stimulated insulin secretion, extracellular insulin may regulate the phosphorylation status of AMPK through IRS-1 to modulate insulin secretion in a glucose-dependent way.
Park
Sung-Hee
SH
Department of Physiology, Keimyung University School of Medicine & Chronic Disease Research Center, 194, Dongsan-Dong, Jung-Gu, Daegu 700-712, South Korea.
Kim
So-Yeon
SY
Baek
Won-Ki
WK
Lim
Bora
B
Park
Jae-Hyung
JH
Sung
Hye-Young
HY
Kim
Yu-Kyung
YK
Bae
Ki-Cheor
KC
Bae
Jae-Hoon
JH
Song
Dae-Kyu
DK
D055372:AMP-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D025461:Feedback, Physiological; D005947:Glucose / Q000378:metabolism* / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D054086:KATP Channels / Q000378:metabolism; D008297:Male; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley
D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; D054086:KATP Channels; D055372:AMP-Activated Protein Kinases; D005947:Glucose; D002118:Calcium