Michiyo Ishii

Interleukin-6 polymorphism (-634C/G) in the promotor region and the progression of diabetic nephropathy in type 2 diabetes.

Aims Interleukin‐6 (IL‐6) is a multifunctional cytokine produced by many different cell types, including glomerular mesangial cells. Recently, a novel C/G polymorphism at position −634 in the promotor region of the IL‐6 gene has been reported. The aim of this study was to investigate whether the −634C/G polymorphism is associated with an increased risk for progression to diabetic nephropathy as well as elevated levels of IL‐6 secretion by peripheral blood mononuclear cells.

In vivo functioning and transplantable mature pancreatic islet-like cell clusters differentiated from embryonic stem cells.

Introduction Although the differentiation of embryonic stem (ES) cells to islet like clusters using differentiation method without employing gene transfer technique has been recently reported, neither endocrine granules in the cytoplasm nor in vivo function of differentiated islet like clusters has been demonstrated. Aims To investigate whether ES cells could be differentiated to mature islet like clusters which show in vivo function after transplantation as well as retain endocrine granules in the cytoplasm by electron microscopic observation. Methodology In this experiment, using mouse embryonic stem (mES) cells as a model system for lineage specific differentiation, we tried to differentiate mES cells to pancreatic islet-like cell clusters (PICCs) through a series of treatments (4-step procedure). Differentiated PICCs were analyzed and characterized by various techniques, such as RT-PCR, immunohistochemistry, electron microscopic observation, in vitro static incubation test, and in vivo transplantation to diabetic animals. Results Differentiated islet-like cell clusters from ES cells using our newly developed method (four-step procedure) showed strong expression of essential specific genes to the endocrine pancreas and also specific genes to the exocrine pancreas demonstrating that these islet-like clusters were mature from the developmental biologic point of view. These differentiated cells clearly revealed many mature insulin secretory granules of pleomorphic shape in the cytoplasm as well as well-developed rough endoplasmic reticulum. In vitro study indicated that differentiated cells retain a potent insulin secretory responsiveness to glucose stimulation. Furthermore, the islet-like cell clusters significantly decreased high blood glucose levels almost to normal levels when grafted to streptozotocin-induced diabetic mice without induction of any teratoma formation after transplantation. Conclusion Our results provide evidence that ES cells could differentiate to functioning and transplantable mature pancreatic islet-like cell clusters using our newly developed differentiation method without employing gene transfer technique. This study may lead to a basis for production of indefinite sources of islets that could be applicable for future clinical trial.

Short-term exposure of high glucose concentration induces generation of reactive oxygen species in endothelial cells: implication for the oxidative stress associated with postprandial hyperglycemia

Abstract Recent studies demonstrating a close relationship between postprandial hyperglycemia and the incidence of atherosclerotic cardiovascular disease prompted us to investigate the generation and source of reactive oxygen species (ROS) in endothelial cells stimulated by short-term exposure to a high glucose concentration. In addition, we investigated the effect of insulin on ROS production induced by high glucose concentration. Cultured bovine aortic endothelial cells demonstrated a significant increase in intracellular ROS generation after a 3-h exposure to 25 mM glucose (131.4% versus 5 mM glucose). This increased generation of ROS was suppressed by an inhibitor of NAD(P)H oxidase. Intracellular ROS production in cells exposed to 3 h of high glucose concentration was increased significantly by the presence of a physiological concentration of insulin. However, after a 1-h exposure to high glucose levels, ROS generation in cells incubated with insulin was only about 80% of that measured in cells incubated without insulin. The generation of intracellular nitric oxide (NO) resulting from an acute insulin effect may account for this difference. In conclusion, acute hyperglycemia itself may possibly cause endothelial oxidative stress in patients with postprandial hyperglycemia. Endothelial oxidative stress may be determined by the interaction between NO and superoxide generation.

Intercellular adhesion molecule-1 (ICAM-1) polymorphism is associated with diabetic retinopathy in Type 2 diabetes mellitus.

Aims Leucocyte adhesion to the diabetic retinal vasculature has been implicated in the pathogenesis of diabetic retinopathy. We evaluated the relationship between genetic polymorphisms in leucocyte and endothelial cell adhesion molecules and diabetic retinopathy in Type 2 diabetes mellitus.

Leukocyte-endothelial cell adhesion molecule 1 (LECAM-1) polymorphism is associated with diabetic nephropathy in type 2 diabetes mellitus

BACKGROUND/AIMS Glomerular infiltration with monocytes/macrophages has been implicated in the pathogenesis of diabetic nephropathy. In this study, we evaluated the relationship between the genetic polymorphism in leukocyte-endothelial adhesion molecule-1 (LECAM-1) and diabetic nephropathy in patients with type 2 diabetes mellitus. METHODS We determined the frequency of the LECAM-1 P213S genotype in 102 diabetic patients with diabetic nephropathy, 90 diabetic patients with no evidence of diabetic nephropathy, and 200 healthy control individuals. RESULTS The frequency of the LECAM-1 213PP genotype and P allele in patients with diabetic nephropathy was significantly higher than that in patients without nephropathy (genotype 68% vs. 53%, chi(2)=6.78, P=.034; allele 83% vs. 72%, chi(2)=6.26, P=.012). The LECAM-1 P213 genotype was associated with a 1.86-fold increased risk for nephropathy independently of other risk factors. CONCLUSION The data suggest that the LECAM-1 213PP genotype is a genetic risk factor for the development of nephropathy in type 2 diabetes mellitus.

Relationship between limited joint mobility of the hand and diabetic foot risk in patients with type 2 diabetes.

Foot ulceration is a serious problem for patients with type 2 diabetes (T2D), and the early detection of risks for this condition is important to prevent complications. The present cross‐sectional study in T2D patients determined the relationship between limited joint mobility (LJM) of the hand and diabetic foot risk classified using the criteria of the International Working Group on the Diabetic Foot (IWGDF).

Replacement of neutral protamine Hagedorn insulin with the long-acting insulin analogue, detemir, improves glycemic control without weight gain in basal-bolus insulin therapy in Japanese patients with type 1 diabetes.

Aims/Introduction:  The aim of the present study was to evaluate the efficacy of replacing neutral protamine Hagedorn insulin (NPH) with the long‐acting insulin analogue, detemir, in clinical practice.