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OBJECTIVE -We examined the endothelial nitric oxide (eNOS) gene polymorphisms to assess its possible association with diabetic retinopathy and macular edema.RESEARCH DESIGN AND METHODS -A total of 226 patients with type 2 diabetes and 186 healthy subjects were studied. Type 2 diabetic patients consisted of 110 patients without retinopathy, 46 patients with nonproliferative diabetic retinopathy, and 71 patients with proliferative diabetic retinopathy. Diabetic macular edema was present in 48 patients. Three polymorphisms of the eNOS gene were determined: T-786C in the promoter region, 27-bp repeat in intron 4, and Glu298Asp in exon 7.RESULTS -Close linkage disequilibrium was observed between the T-786C polymorphism and the 27-bp repeat, as has been previously reported, but Glu298Asp was not in linkage disequilibrium with the other two polymorphisms. The eNOS gene polymorphisms were not significantly associated with the presence of retinopathy or with retinopathy severity or type 2 diabetes itself. However, by both association study and multiple logistic regression analysis, the T-786C and 27-bp repeat polymorphisms were significantly associated with a risk of developing macular edema with the Ϫ786C allele and the "a" allele increasing the risk.CONCLUSIONS -The present study suggests that the eNOS gene is a novel genetic risk factor for diabetic macular edema. The eNOS gene polymorphisms may contribute to the development of macular edema by impairing basal eNOS expression and resulting in the breakdown of the blood-retina barrier. Diabetes Care 27:2184 -2190, 2004D iabetic retinopathy (DR) remains the major cause of blindness among adults (1). In addition, diabetic maculopathy or macular edema (ME), which may occur at any stage of DR, is an important cause of visual impairment (1-3). Among the pathophysiological steps involved in the development of ME, the most important mechanism is breakdown of the blood-retina barrier (BRB) (2,3). Both the inner BRB formed by the retinal capillary endothelial cell tight junctions and the outer BRB formed by the retinal pigment epithelial cell tight junctions can be affected during the development of ME.Nitric oxide (NO) is a multifunctional molecule that plays a key role in physiological processes such as the regulation of vascular tone and the antiproliferative effects on vascular smooth muscle cells (4,5). NO is produced by three different isoforms of NO synthase (NOS): endothelial NOS (eNOS), neural NOS, and inducible NOS (iNOS). Although NO produced in large amounts by iNOS is regarded as a toxic, damaging agent, it is suggested that a low concentration of NO produced by constitutively expressed eNOS is necessary to maintain good endothelial function (5). Thus, eNOS appears to present an attractive candidate susceptibility gene for diabetic microvascular complications as well as cardiovascular diseases.Several polymorphisms have been identified in the eNOS gene (NOS3) (6,7). In particular, T-786C in the promoter region, 27-bp repeat in intron 4, and Glu298Asp in exon 7 have...

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Japanese type 2 diabetic patients were treated with sitagliptin to evaluate the efficacy of this agent, and also to investigate the clinical characteristics of those who responded to sitagliptin. In total, 1001 diabetic patients, inadequately controlled (HbA1c ≥ 6.5%) with oral hypoglycemic agents (OHA) other than DPP-4 inhibitors or with diet and exercise only, were enrolled. We added 50mg of sitagliptin to the therapeutic regimens of 410 patients including 68 OHA naïve patients, while the other 591 patients were switched from a single OHA to 50 mg of sitagliptin. After 6 months, glycemic control was significantly improved due to both reduced insulin resistance, as demonstrated by a significant HOMA-R reduction, and recovery of pancreatic β cell function, as assessed by HOMA-β and the proinsulin/insulin (PI/I) ratio. In the bivariable analysis, a good response, defined as an HbA1c reduction during the 6 months of at least 0.9%, was associated with high HbA1c and PI/I at baseline and combination treatments with sulfonylurea, biguanide and α-glucosidase inhibitors, but not with obesity. On the other hand, in the multivariable regression analysis, only high baseline HbA1c and combination treatment with an α-glucosidase inhibitor were significantly associated with a good response to sitagliptin. In patients with type 2 diabetes, the addition of sitagliptin or switching from another OHA to this agent achieved an HbA1c reduction without overloading β cells. In particular, we suggest that a good response to sitagliptin can be expected when this agent is combined with an α-glucosidase inhibitor (UMIN No. #000014157).

Type 2 diabeTes is a common metabolic disease, and the worldwide prevalence is rising rapidly. Management of type 2 diabetes usually requires multiple oral hypoglycemic agents (OHA) to maintain glycemic control. In obese diabetic patients, metformin and/or thiazolidinediones (TZD) are frequently used as initial therapy [1,2]. However, when diabetic patients show marked insulin resistance, as with severe obesity, even the maximum doses of OHA including insulin secretagogues are often inadequate to achieve recommended treatment goals. These patients must thus be treated with insulin. However, insulin treatment can lead to marked weight gain and more hypoglycemic episodes, resulting in an increased risk of macrovascular events, ≥ 25). The subjects were randomized to either treatment with colestimide 4g/day (T group, n=23) or continuation of their current therapy (C group, n=20). In the T group patients, mean hemoglobin A1c (HbA1c) and fasting glucose improved markedly (from 7.71 ± 0.32% to 6.97 ± 0.20%; from 147.4 ± 7.3mg/dL to 127.0 ± 5.0mg/dL, respectively), while obesityrelated parameters, i.e. body weight, waist circumference, and visceral fat and subcutaneous fat as determined by umbilical slice abdominal CT, showed no significant changes. Fractionation analyses of serum bile acids revealed significantly increased cholic acids (CA) and decreased chenodeoxycholic acids (CDCA) in the T group patients. However, no correlation was observed between these changes and ΔHbA1c. According to logistic regression analysis, baseline HbA1c was the only variable predicting the decrease of HbA1c (>0.5%) among sex, age, BMI, total cholesterol, ΔCA and ΔCDCA. The index of insulin resistance, i.e. homeostasis model assessment of insulin resistance (HOMA-R), did not improve, and the index of β cell function, i.e. homeostasis model assessment of β-cell function (HOMA-β), actually increased significantly. These results suggests that, in obese patients with type 2 diabetes, the mechanism underlying improved glycemic control with colestimide treatment involves enhanced β cell activity rather than improved insulin resistance.