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.


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.
Department of Pathology and Molecular Medicine, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
Hiroki
H
Mizukami
Department of Pathology and Molecular Medicine, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
Kazunori
K
Takahashi
Department of Pathology and Molecular Medicine, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
Wataru
W
Inaba
Department of Pathology and Molecular Medicine, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
Kentaro
K
Tsuboi
Department of Pathology and Molecular Medicine, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
Sho
S
Osonoi
Department of Pathology and Molecular Medicine, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
Taro
T
Yoshida
Department of Pathology and Molecular Medicine, Hirosaki University Graduate School of Medicine, Hirosaki, Japan yagihasi@cc.hirosaki-u.ac.jp.
Soroku
S
Yagihashi
D000368:Aged; D044466:Asian People; D001343:Autophagy / Q000502:physiology; D001344:Autopsy; D004249:DNA Damage / Q000502:physiology*; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology*; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D005260:Female; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism; D007564:Japan; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress / Q000502:physiology*; D010179:Pancreas / Q000473:pathology