title: A 48-hour exposure of pancreatic islets to calpain inhibitors impairs mitochondrial fuel metabolism and the exocytosis of insulin.
abstract: 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 beta-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) of 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 alpha-ketoisocaproate (KIC). The same incubation also suppresses glucose metabolism and intracellular calcium ([Ca(2+)](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 beta-cell failure in type 2 diabetes thereby providing a link between genetic susceptibility to diabetes and the pathophysiologic manifestations of the disease.
authors.affiliation: Departments of Medicine, Neurobiology, Pharmacology and Physiology, Biochemistry and Molecular Biology, Human Genetics, and the Howard Hughes Medical Institute, University of Chicago, Chicago, IL, USA.
authors.forename: Yun-Ping
authors.initials: YP
authors.lastname: Zhou
authors.forename: Seamus
authors.initials: S
authors.lastname: Sreenan
authors.forename: Chien-Yuan
authors.initials: CY
authors.lastname: Pan
authors.forename: Kevin P M
authors.initials: KP
authors.lastname: Currie
authors.forename: Vytautas P
authors.initials: VP
authors.lastname: Bindokas
authors.forename: Yukio
authors.initials: Y
authors.lastname: Horikawa
authors.forename: Jean-Pyo
authors.initials: JP
authors.lastname: Lee
authors.forename: Diane
authors.initials: D
authors.lastname: Ostrega
authors.forename: Noreen
authors.initials: N
authors.lastname: Ahmed
authors.forename: Aaron C
authors.initials: AC
authors.lastname: Baldwin
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Cox
authors.forename: Aaron P
authors.initials: AP
authors.lastname: Fox
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Miller
authors.forename: Graeme I
authors.initials: GI
authors.lastname: Bell
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Polonsky
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002154:Calpain / Q000037:antagonists & inhibitors*; D002469:Cell Separation; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D004151:Dipeptides / Q000494:pharmacology; D004734:Energy Metabolism / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D007930:Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009249:NADP / Q000378:metabolism; D010084:Oxidation-Reduction
chemical_list: D015853:Cysteine Proteinase Inhibitors; D004151:Dipeptides; D007328:Insulin; D009249:NADP; D002154:Calpain; D007930:Leucine; D005947:Glucose; C108192:aloxistatin; D002118:Calcium; C058076:calpain inhibitor III