TY - JOUR
T1 - A 48-hour exposure of pancreatic islets to calpain inhibitors impairs mitochondrial fuel metabolism and the exocytosis of insulin
AU - Zhou, Yun Ping
AU - Sreenan, Seamus
AU - Pan, Chien Yuan
AU - Currie, Kevin P M
AU - Bindokas, Vytautas P.
AU - Horikawa, Yukio
AU - Lee, Jean Pyo
AU - Ostrega, Diane
AU - Ahmed, Noreen
AU - Baldwin, Aaron C.
AU - Cox, Nancy J.
AU - Fox, Aaron P.
AU - Miller, Richard J.
AU - Bell, Graeme I.
AU - Polonsky, Kenneth S.
PY - 2003/5/1
Y1 - 2003/5/1
N2 - Genetic variation in the gene for a cytosolic cysteine protease, calpain-10, increases the susceptibility to type 2 diabetes apparently by altering levels of gene expression. In view of the importance of altered β-cell function in the pathophysiology of type 2 diabetes, the present study was undertaken to define the effects on insulin secretion of exposing pancreatic islets to calpain inhibitors for 48 hours. Exposure of mouse islets to calpain inhibitors (ALLN, ALLM, E-64-d, MDL 18270, and PD147631) f different structure and mechanism of action for 48 hours reversibly suppresses glucose-induced insulin secretion by 40% to 80%. Exposure of islets to inhibitors of other proteases, ie, cathepsin B and proteasome, did not affect insulin secretion. The 48-hour incubation with calpain inhibitors also attenuates insulin secretory responses to the mitochondrial fuel α-ketoisocaproate (KIC). The same incubation also suppresses glucose metabolism and intracellular calcium ([Ca2-]i) responses to glucose or KIC in islets. In summary, long-term inhibition of islet calpain activity attenuates insulin secretion possibly by limiting the rate of glucose metabolism. A reduction of calpain activity in islet could contribute to the development of β-cell failure in type 2 diabetes thereby providing a link between genetic susceptibility to diabetes and the pathophysiologic manifestations of the disease.
AB - Genetic variation in the gene for a cytosolic cysteine protease, calpain-10, increases the susceptibility to type 2 diabetes apparently by altering levels of gene expression. In view of the importance of altered β-cell function in the pathophysiology of type 2 diabetes, the present study was undertaken to define the effects on insulin secretion of exposing pancreatic islets to calpain inhibitors for 48 hours. Exposure of mouse islets to calpain inhibitors (ALLN, ALLM, E-64-d, MDL 18270, and PD147631) f different structure and mechanism of action for 48 hours reversibly suppresses glucose-induced insulin secretion by 40% to 80%. Exposure of islets to inhibitors of other proteases, ie, cathepsin B and proteasome, did not affect insulin secretion. The 48-hour incubation with calpain inhibitors also attenuates insulin secretory responses to the mitochondrial fuel α-ketoisocaproate (KIC). The same incubation also suppresses glucose metabolism and intracellular calcium ([Ca2-]i) responses to glucose or KIC in islets. In summary, long-term inhibition of islet calpain activity attenuates insulin secretion possibly by limiting the rate of glucose metabolism. A reduction of calpain activity in islet could contribute to the development of β-cell failure in type 2 diabetes thereby providing a link between genetic susceptibility to diabetes and the pathophysiologic manifestations of the disease.
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U2 - 10.1053/meta.2003.50091
DO - 10.1053/meta.2003.50091
M3 - Article
C2 - 12759879
AN - SCOPUS:0038748363
SN - 0026-0495
VL - 52
SP - 528
EP - 534
JO - Metabolism: Clinical and Experimental
JF - Metabolism: Clinical and Experimental
IS - 5
ER -