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High Expression Rates of Human Islet Amyloid Polypeptide Induce Endoplasmic Reticulum Stress–Mediated ß-Cell Apoptosis, a Characteristic of Humans With Type 2 but Not Type 1 Diabetes

¹ Larry Hillblom Islet Research Center, University of California, Los Angeles, Los Angeles, California
² Endocrine Research Unit, Mayo Medical College, Rochester, Minnesota

Address correspondence and reprint requests to Peter C. Butler, Larry Hillblom Islet Research Center, UCLA, Los Angeles, CA 90024-2852. E-mail: pbutler{at}mednet.ucla.edu

Abbreviations: Ad-hIAPP, adenovirus-expressing human islet amyloid polypeptide precursor protein; Ad-rIAPP, adenovirus-expressing rat islet amyloid polypeptide precursor protein; CHOP, CEBP homologous protein; EGFP, enhanced green fluorescent protein; ER, endoplasmic reticulum; GFP, green fluorescent protein; HBSS, Hanks’ balanced salt solution; IAPP, islet amyloid polypeptide; IHC, immunohistochemistry; MOI, multiplicity of infection; preproIAPP, IAPP precursor protein; siCHOP, small interfering CHOP; siRNA, small interfering RNA; TBS, Tris-buffered solution; TUNEL, transferase-mediated dUTP nick-end labeling; UPR, unfolded protein response

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 ß-cell apoptosis. We questioned the following: 1) whether IAPP-induced ß-cell apoptosis is mediated by ER stress and 2) whether ß-cells in type 2 diabetes are characterized by ER stress.

RESEARCH DESIGN AND 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 ß-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 ß-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 ß-cell apoptosis and is characteristic of ß-cells in humans with type 2 diabetes but not type 1 diabetes. These findings are consistent with a role of protein misfolding in ß-cell apoptosis in type 2 diabetes.

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