Hypoglycemic effects of colestimide on type 2 diabetic patients with obesity.

Recent studies have shown colestimide, a bile acid-binding resin, to also exert a glucose-lowering effect via amelioration of insulin resistance. To evaluate the effects of colestimide on glucose metabolism and to elucidate the underlying mechanism, we conducted a 6-month, open-label pilot study on 43 type 2 diabetic patients with obesity (BMI ≥ 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 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 obesity-related 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. HOMA-R, did not improve, and the index of ß cell function, i.e. HOMA-ß, 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 ß cell activity rather than improved insulin resistance.

Promoter polymorphisms of the pigment epithelium-derived factor gene are associated with diabetic retinopathy.

Pigment epithelium-derived factor (PEDF or SERPINF1), a neuroprotective and anti-angiogenic factor, may play an important role in the pathogenesis of diabetic retinopathy (DR). In 416 patients with type 2 diabetes, four polymorphisms in the PEDF SNPs were identified, rs12150053 and rs12948385 in the promoter region, rs9913583 in the 5'-untranslated region, and rs1136287 (Met72Thr) in exon 3. Based on case-control studies, rs12150053 and rs12948385, but not rs9913583 and rs1136287, were significantly associated with DR. A logistic regression analysis revealed that the TC or CC genotype of rs12150053 was a significant risk factor for DR (odds ratio 2.40, p=0.0004). The GA or AA genotype of rs12948385 was also a significant risk factor for DR. In addition, a significant interaction between the vascular endothelial growth factor (VEGF) and PEDF SNPs in the susceptibility to DR was found. These results demonstrate that the PEDF gene, in cooperation with the VEGF gene, may contribute to the development of DR.

Functional VEGF C-634G polymorphism is associated with development of diabetic macular edema and correlated with macular retinal thickness in type 2 diabetes.

Since vascular endothelial growth factor (VEGF) has a strong effect on induction of vascular permeability, VEGF is an attractive candidate gene for development of diabetic macular edema (ME). Among the 378 patients with type 2 diabetes studied, 203 patients had no retinopathy, 93 had non-proliferative diabetic retinopathy (NPDR), and 82 had proliferative diabetic retinopathy (PDR). ME was present in 16 patients with NPDR and 47 patients with PDR. We genotyped three VEGF polymorphisms: C-2,578A, G-1,154A, and C-634G. Genotype and allele distribution of C-634G, but not C-2,578A or G-1,154A, were significantly different between patients with and without diabetic retinopathy. Logistic regression analysis revealed that the C-634G genotype was a risk factor for DR (p = 0.002), and furthermore for ME (p = 0.047), independently from severity of DR, with the -634C allele increasing the risk. Macular thickness measured by optical coherence tomography was correlated with the C-634G genotype, with the trend increasing with the presence of more -634C alleles (p = 0.006). Stepwise regression analysis showed that duration of diabetes and presence of the C-634G genotype were independent predictors of macular thickness. In addition, basic transcriptional activity levels associated with the -634C allele were greater compared to those seen with the -634G allele in human glioma and lymphoblastic T-lymphocyte cells. These results demonstrate that the VEGF C-634G polymorphism is a genetic risk factor for ME as well as DR.

Endothelial nitric oxide synthase gene is associated with diabetic macular edema in type 2 diabetes.

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 -786C 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.