Involvement of Oxidative Stress-induced DNA Damage, Endoplasmic Reticulum Stress, and Autophagy Deficits in the Decline of β-cell Mass in Japanese Type 2 Diabetic Patients

Objective: Deficits of β-cells characterize the islet pathology in type 2 diabetes. It is yet to be clear how the β-cell loss develops in type 2 diabetes. We explored the implication of oxidative stress, endoplasmic reticulum (ER)-induced stress, and autophagy deficit in the β-cell decline in Japanese type 2 diabetic patients.

Research Design And Methods: Pancreases from recent autopsy cases of 47 type 2 diabetic and 30 nondiabetic subjects were investigated on the islet structure with morphometric analysis. Volume densities of islet (Vi), β-cell (Vβ), and α-cell (Vα) were measured. To evaluate cell damage of endocrine cells, immunohistochemical expressions of oxidative stress-related DNA damage as expressed by γH2AX, ER stress-related cell damage as CCAAT/enhancer 1 binding protein-β (C/EBP-β), and autophagy deficit as P62 were semiquantified, and their correlations to islet changes were sought.

Results: Compared with nondiabetic subjects, Vβ was reduced in diabetic subjects. Contrariwise, there was an increase in Vα. There was a significant link between reduced Vβ and increased HbA1c levels (P < 0.01) and a trend of inverse correlation between Vβ and duration of diabetes (P = 0.06). Expressions of γH2AX, P62, and C/EBP-β were all enhanced in diabetic islets, and reduced Vβ correlated with the intensity of γH2AX expression but not with C/EBP-β or P62 expressions. Combined expressions of γH2AX, P62, and C/EBP-β were associated with severe reduction of Vβ.

Conclusions: β-Cell deficit in type 2 diabetes was associated with increased oxidative stress and may further be augmented by autophagic deficits and ER stress.