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.

Diabetes is defined as a disease of hyperglycemic metabolic disorder caused by impaired insulin action or low insulin secretion, resulting in the occurrence of vascular complications. Based on this definition, diabetes therapy has long been oriented to correct hyperglycemia against the specific complications of diabetes. This definition has posed some difficulties, however, in understanding of the pathophysiology of this complicated disease and as such in the establishment of an effective treatment. With continuing efforts to explore the structural basis for diabetes onset and methodological development of immunohistochemistry, progressive decline of β‐cells is now established as a salient feature of type 2 diabetes. Accordingly, diabetes therapy has now turned out to protect β‐cells concurrently with the correction of hyperglycemia. Together with this effort, exploration of the means to regenerate β‐cells or to supply new β‐cells by, for example, induced pluripotential stem cells, are vigorously made with the search for the mechanism of β‐cell decline in diabetes. In the present review, we describe the advances in the islet pathology in type 2 diabetes with special reference to the dynamic alterations of islet endocrine cells in the milieu of maturation, obesity, aging and ethnic differences. The effect of amyloid deposition is also discussed. We hope it will help with understanding the pathophysiology of diabetes, and suggest the future direction of diabetes treatment.

BackgroundSystemic inflammatory response syndrome is a fatal disease because of multiple organ failure. Acute kidney injury is a serious complication of systemic inflammatory response syndrome and its genesis is still unclear posing a difficulty for an effective treatment. Aldose reductase (AR) inhibitor is recently found to suppress lipopolysaccharide (LPS)-induced cardiac failure and its lethality. We studied the effects of AR inhibitor on LPS-induced acute kidney injury and its mechanism.MethodsMice were injected with LPS and the effects of AR inhibitor (Fidarestat 32 mg/kg) before or after LPS injection were examined for the mortality, severity of renal failure and kidney pathology. Serum concentrations of cytokines (interleukin-1β, interleukin-6, monocyte chemotactic protein-1 and tumor necrosis factor-α) and their mRNA expressions in the lung, liver, spleen and kidney were measured. We also evaluated polyol metabolites in the kidney.ResultsMortality rate within 72 hours was significantly less in LPS-injected mice treated with AR inhibitor both before (29%) and after LPS injection (40%) than untreated mice (90%). LPS-injected mice showed marked increases in blood urea nitrogen, creatinine and cytokines, and AR inhibitor treatment suppressed the changes. LPS-induced acute kidney injury was associated with vacuolar degeneration and apoptosis of renal tubular cells as well as infiltration of neutrophils and macrophages. With improvement of such pathological findings, AR inhibitor treatment suppressed the elevation of cytokine mRNA levels in multiple organs and renal sorbitol accumulation.ConclusionAR inhibitor treatment ameliorated LPS-induced acute kidney injury, resulting in the lowered mortality.