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.

Aims/Introduction: Impaired growth and premature death of b-cells are implicated in the progression of islet pathology in type 2 diabetes. It remains unclear, however, how aging affects islet cells, or whether the islet change in diabetes is an augmented process of aging. We studied age-related changes of the islet structure in Japanese non-diabetic subjects and explored the underlying mechanism of the changes. Materials and Methods: A total of 115 non-diabetic autopsy cases were subjected to morphometric analysis for volume densities of islets, b-and non-b-cells, as well as their masses. Proliferation activity identified by Ki67, and expressions of pancreatic and duodenal homeobox (PDX)-1, cell cycle inhibitor P16, and oxidative stress marker cH2AX were also examined.Results: There was a gradual and marginal decline of volume densities of islets, b-and non-b-cells with aging, while masses of these components were increased during maturation and slowly decreased after the 40s. Islet density was high in the young, but reduced after maturation. There was only a minimal influence of increased body mass index (BMI) on the increase in b-cell mass, but not on the other variables. Ki67 positivity and PDX-1 expressions were high in the young, but low after maturation, whereas expressions of P16 and cH2AX were elevated in the aged. Conclusions: Age-associated decline of b-cell mass is marginal after maturation, and the reduction of b-cell mass could be a specific process in diabetes. The impact of BMI on the islet structure is limited in Japanese with normal glucose tolerance.

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Incretin-related therapy was found to be beneficial for experimental diabetic neuropathy, but its mechanism is obscure. The purpose of this study is to explore the mechanism through which dipeptidyl peptidase IV inhibitor, vildagliptin (VG), influences neuropathy in diabetic rodents. To this end, nonobese type 2 diabetic Goto-Kakizaki rats (GK) and streptozotocin (STZ)-induced diabetic mice were treated with VG orally. Neuropathy was evaluated by nerve conduction velocity (NCV) in both GK and STZ-diabetic mice, whereas calcitonin-gene-related peptide expressions, neuronal cell size of dorsal root ganglion (DRG) and intraepidermal nerve fiber density were examined in GK. DRG from GK and STZ-diabetic mice served for the analyses of GLP-1 and insulin signaling. As results, VG treatment improved glucose intolerance and increased serum insulin and GLP-1 in GK accompanied by the amelioration of delayed NCV and neuronal atrophy, reduced calcitonin-gene-related peptide expressions and intraepidermal nerve fiber density. Diet restriction alone did not significantly influence these measures. Impaired GLP-1 signals such as cAMP response element binding protein, protein kinase B/ Akt (PKB/Akt) and S6RP in DRG of GK were restored in VGtreated group, but the effect was equivocal in diet-treated GK. Concurrently, decreased phosphorylation of insulin receptor substrate 2 in GK was corrected by VG treatment. Consistent with the effect on GK, VG treatment improved NCV in diabetic mice without influence on hyperglycemia. DRG of VG-treated diabetic mice were characterized by correction of GLP-1 signals and insulin receptor substrate 2 phosphorylation without effects on insulin receptor b expression. The results suggest close association of neuropathy development with impaired signaling of insulin and GLP-1 in diabetic rodents.