Calpains play a role in insulin secretion and action.
Studies of the genetic basis of type 2 diabetes suggest that variation in the calpain-10 gene affects susceptibility to this common disorder, raising the possibility that calpain-sensitive pathways may play a role in regulating insulin secretion and/or action. Calpains are ubiquitously expressed cysteine proteases that are thought to regulate a variety of normal cellular functions. Here, we report that short-term (4-h) exposure to the cell-permeable calpain inhibitors calpain inhibitor II and E-64-d increases the insulin secretory response to glucose in mouse pancreatic islets. This dose-dependent effect is observed at glucose concentrations above 8 mmol/l. This effect was also seen with other calpain inhibitors with different mechanisms of action but not with cathepsin inhibitors or other protease inhibitors. Enhancement of insulin secretion with short-term exposure to calpain inhibitors is not mediated by increased responses in intracellular Ca2+ or increased glucose metabolism in islets but by accelerated exocytosis of insulin granules. In muscle strips and adipocytes, exposure to both calpain inhibitor II and E-64-d reduced insulin-mediated glucose transport. Incorporation of glucose into glycogen in muscle also was reduced. These results are consistent with a role for calpains in the regulation of insulin secretion and insulin action.
Sreenan
S K
SK
Deppartment of Medicine, the University of Chicago, Chicago, Illinois, USA.
Zhou
Y P
YP
Otani
K
K
Hansen
P A
PA
Currie
K P
KP
Pan
C Y
CY
Lee
J P
JP
Ostrega
D M
DM
Pugh
W
W
Horikawa
Y
Y
Cox
N J
NJ
Hanis
C L
CL
Burant
C F
CF
Fox
A P
AP
Bell
G I
GI
Polonsky
K S
KS
D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000502:physiology; D002154:Calpain / Q000037:antagonists & inhibitors / Q000502:physiology*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D003847:Deoxyglucose / Q000493:pharmacokinetics; D004553:Electric Conductivity; D005947:Glucose / Q000378:metabolism; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D000078790:Insulin Secretion; D007425:Intracellular Membranes / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D007930:Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D009994:Osmolar Concentration; D013997:Time Factors
D015853:Cysteine Proteinase Inhibitors; D007328:Insulin; D009842:Oligopeptides; C069861:calpain inhibitor 2; D009249:NADP; D003847:Deoxyglucose; D002154:Calpain; D007930:Leucine; D005947:Glucose; C108192:aloxistatin; D002118:Calcium