Calcium-activated calpain-2 is a mediator of beta cell dysfunction and apoptosis in type 2 diabetes.
The islet in type 2 diabetes (T2DM) and the brain in neurodegenerative diseases share progressive cell dysfunction, increased apoptosis, and accumulation of locally expressed amyloidogenic proteins (islet amyloid polypeptide (IAPP) in T2DM). Excessive activation of the Ca(2+)-sensitive protease calpain-2 has been implicated as a mediator of oligomer-induced cell death and dysfunction in neurodegenerative diseases. To establish if human IAPP toxicity is mediated by a comparable mechanism, we overexpressed human IAPP in rat insulinoma cells and freshly isolated human islets. Pancreas was also obtained at autopsy from humans with T2DM and nondiabetic controls. We report that overexpression of human IAPP leads to the formation of toxic oligomers and increases beta cell apoptosis mediated by increased cytosolic Ca(2+) and hyperactivation of calpain-2. Cleavage of alpha-spectrin, a marker of calpain hyperactivation, is increased in beta cells in T2DM. We conclude that overactivation of Ca(2+)-calpain pathways contributes to beta cell dysfunction and apoptosis in T2DM.
Larry Hillblom Islet Research Center, David Geffen School of Medicine, California Nano Systems Institute, UCLA, Los Angeles, California 90024-2852, USA.
Chang-jiang
CJ
Huang
Tatyana
T
Gurlo
Leena
L
Haataja
Safia
S
Costes
Marie
M
Daval
Sergey
S
Ryazantsev
Xiuji
X
Wu
Alexandra E
AE
Butler
Peter C
PC
Butler
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000682:Amyloid / Q000633:toxicity; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D002154:Calpain / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology*; D004151:Dipeptides / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology* / Q000648:ultrastructure; D058228:Islet Amyloid Polypeptide; D008297:Male; D008875:Middle Aged; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013049:Spectrin / Q000378:metabolism
D000682:Amyloid; D004151:Dipeptides; D058228:Islet Amyloid Polypeptide; D011993:Recombinant Fusion Proteins; D013049:Spectrin; C071482:calpeptin; D002154:Calpain; C569870:CAPN2 protein, human; D002118:Calcium