OBJECTIVEDeficits of b-cells characterize the islet pathology in type 2 diabetes. It is yet to be clear how the b-cell loss develops in type 2 diabetes. We explored the implication of oxidative stress, endoplasmic reticulum (ER)-induced stress, and autophagy deficit in the b-cell decline in Japanese type 2 diabetic patients. RESEARCH DESIGN AND METHODSPancreases 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), b-cell (Vb), and a-cell (Va) were measured. To evaluate cell damage of endocrine cells, immunohistochemical expressions of oxidative stress-related DNA damage as expressed by gH2AX, ER stress-related cell damage as CCAAT/enhancer 1 binding protein-b (C/EBP-b), and autophagy deficit as P62 were semiquantified, and their correlations to islet changes were sought. RESULTSCompared with nondiabetic subjects, Vb was reduced in diabetic subjects. Contrariwise, there was an increase in Va. There was a significant link between reduced Vb and increased HbA 1c levels (P < 0.01) and a trend of inverse correlation between Vb and duration of diabetes (P = 0.06). Expressions of gH2AX, P62, and C/EBP-b were all enhanced in diabetic islets, and reduced Vb correlated with the intensity of gH2AX expression but not with C/EBP-b or P62 expressions. Combined expressions of gH2AX, P62, and C/EBP-b were associated with severe reduction of Vb. CONCLUSIONSb-Cell deficit in type 2 diabetes was associated with increased oxidative stress and may further be augmented by autophagic deficits and ER stress.

AimsIslet amyloid is a hallmark in type 2 diabetic subjects, but its implication in clinical features and development of islet pathology is still unclear.MethodsFrom 118 autopsy cases with type 2 diabetes, 26 cases with islet amyloid deposition (DA+) were selected. Twenty diabetic subjects without obvious amyloid deposition (DA−) matched for the age and diabetes duration and 20 non-diabetic subjects (ND) served for comparison. We examined the severity of amyloid deposition and its relationships with population of endocrine cells, expression of cell damage markers or macrophage infiltration. Correlation of clinical profile with islet pathology was also sought on the subset of the investigated patients.Resultsβ-Cell volume density was nearly 40% less in DA+ and 20% less in DA− when compared to ND. Severity of amyloid deposition correlated with reduced volume densities of β-cell and α-cell, and increased body mass index (BMI), but not with duration of diabetes, age or HbA1c. Amyloid-rich islets contained an increased number of macrophages mixed with β-cells with oxidative stress-related DNA damage, characterized by γH2AX expression, and suppressed (pro)insulin mRNA expression.ConclusionsIn Japanese type 2 diabetic patients, islet amyloid was more common with severe β-cell loss and high BMI, associated with macrophage infiltration.

eT2DM is distinct from mT2DM and characterized by pancreas atrophy, ductal lesions, and amyloid deposition.

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