High expression rates of human islet amyloid polypeptide induce endoplasmic reticulum stress mediated beta-cell apoptosis, a characteristic of humans with type 2 but not type 1 diabetes.
OBJECTIVE
Endoplasmic reticulum (ER) stress-induced apoptosis may be a common cause of cell attrition in diseases characterized by misfolding and oligomerisation of amyloidogenic proteins. The islet in type 2 diabetes is characterized by islet amyloid derived from islet amyloid polypeptide (IAPP) and increased beta-cell apoptosis. We questioned the following: 1) whether IAPP-induced beta-cell apoptosis is mediated by ER stress and 2) whether beta-cells in type 2 diabetes are characterized by ER stress.


METHODS
The mechanism of IAPP-induced apoptosis was investigated in INS-1 cells and human IAPP (HIP) transgenic rats. ER stress in humans was investigated by beta-cell C/EBP homologous protein (CHOP) expression in 7 lean nondiabetic, 12 obese nondiabetic, and 14 obese type 2 diabetic human pancreata obtained at autopsy. To assure specificity for type 2 diabetes, we also examined pancreata from eight cases of type 1 diabetes.


RESULTS
IAPP induces beta-cell apoptosis by ER stress in INS-1 cells and HIP rats. Perinuclear CHOP was rare in lean nondiabetic (2.6 +/- 2.0%) and more frequent in obese nondiabetic (14.6 +/- 3.0%) and obese diabetic (18.5 +/- 3.6%) pancreata. Nuclear CHOP was not detected in lean nondiabetic and rare in obese nondiabetic (0.08 +/- 0.04%) but six times higher (P < 0.01) in obese diabetic (0.49 +/- 0.17%) pancreata. In type 1 diabetic pancreata, perinuclear CHOP was rare (2.5 +/- 2.3%) and nuclear CHOP not detected.


CONCLUSIONS
ER stress is a mechanism by which IAPP induces beta-cell apoptosis and is characteristic of beta-cells in humans with type 2 diabetes but not type 1 diabetes. These findings are consistent with a role of protein misfolding in beta-cell apoptosis in type 2 diabetes.
Huang
Chang-jiang
CJ
Larry Hillblom Islet Research Center, University of California, Los Angeles, Los Angeles, CA 90024-2852., USA.
Lin
Chia-yu
CY
Haataja
Leena
L
Gurlo
Tatyana
T
Butler
Alexandra E
AE
Rizza
Robert A
RA
Butler
Peter C
PC
D000369:Aged, 80 and over; D000682:Amyloid / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis; D015415:Biomarkers / Q000378:metabolism; D053454:Caspase 12 / Q000378:metabolism; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000378:metabolism*; D058228:Islet Amyloid Polypeptide; D008297:Male; D051381:Rats; D051742:Transcription Factor CHOP / Q000378:metabolism
D000682:Amyloid; D015415:Biomarkers; D007328:Insulin; D058228:Islet Amyloid Polypeptide; D051742:Transcription Factor CHOP; D053454:Caspase 12