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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.

¹Larry Hillblom Islet Research Center, UCLA, Los Angeles, CA, United States, 90095
²Endocrine Research Unit, Mayo Medical College, Rochester, MN, United States, 55905

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 (T2DM) is characterized by islet amyloid derived from Islet Amyloid Polypeptide (IAPP) and increased beta-cell apoptosis. We questioned (1) is IAPP induced beta cell apoptosis mediated by ER stress, (2) Are beta cells in T2DM characterized by ER stress?

Materials 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 beta cell CHOP expression in 7 lean non-diabetic (LND), 12 obese non-diabetic (OND) and 14 obese type 2 diabetic (OD) human pancreases obtained at autopsy. To assure specificity for T2DM we also examined pancreas from 8 cases of T1DM.

Results.: IAPP induces beta cell apoptosis by ER stress in INS-1 cells and HIP rats. Perinuclear CHOP was rare in LND (2.6±2.0%), more frequent in OND (14.6±3.0%) and OD (18.5±3.6%). Nuclear CHOP was not detected in LND, rare in OND (0.08±0.04%) but 6-times higher (p<0.010) in OD (0.49±0.17%). In T1DM perinuclear CHOP was rare (2.5±2.3%) and nuclear CHOP was not detected.

Conclusions/Interpretation.: 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.

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