The SNP rs9677 of VPAC1 gene is associated with glycolipid control and heart function in female patients with type 2 diabetes: A follow-up study.

BACKGROUND AND AIMS: In a previous study, the single-nucleotide polymorphism (SNP) rs9677, mapped in the 3'-UTR of vasoactive intestinal peptide receptor 1 (VPAC1) gene, was found to be associated with type 2 diabetes (T2D) in Caucasian women. Moreover, the CC genotype correlated with a worse glycolipid profile. The objectives of this study were to confirm this correlation and assess the prevalence of coronary artery disease (CAD) in the previously investigated diabetic women after a follow-up of 4.6 years. METHODS AND RESULTS: A total of 143 women with T2D, with 53 carrying the CC genotype (age: 71.7 ± 7.4 years, diabetes duration: 17.2 ± 9.9 years) and 90 carrying the CT + TT genotypes (age: 69.4 ± 8.8 years, diabetes duration: 14.3 ± 8.2 years), were followed up for 4.6 ± 1.8 years. At follow-up, the clinical and haematochemical parameters were analysed. Twelve-lead electrocardiography, Doppler echocardiography and the percentage of patients with acute myocardial infarction (AMI) or of those subjected to coronary angioplasty and coronary artery bypass surgery were evaluated. At follow-up, there was no significant difference in terms of the clinical and haematochemical parameters between the two groups. However, despite a significantly increased use of statin therapy, no significant improvement in the LDL cholesterol levels was observed in CC female patients unlike those with CT + TT (P = 0.02). Moreover, the CC female patients presented a significantly higher percentage of echocardiographic abnormalities (P = 0.035), especially left ventricular (LV) diastolic dysfunction (P = 0.04). CONCLUSIONS: The rs9677 CC genotype could be correlated with a reduced response to statin therapy and seems to be involved in diabetes cardiomyopathy in female patients with T2D.

Metabolic syndrome and erectile dysfunction among obese non-diabetic subjects.

OBJECTIVE: To investigate whether MS is associated with erectile dysfunction (ED) among obese non diabetic individuals. METHODS: A cross-sectional study was carried out to examine the association between the cluster of abnormalities related to the MS and ED as evaluated by the International Index of Erectile Function (IIEF). Fifty consecutive obese [i.e. body mass index (BMI) > or =30 kg/m2], nondiabetic whites (age 42.1+/-11.3 yr, BMI 43.3+/-8.7 kg/m2) were recruited. RESULTS: The prevalence of MS as well as that of any MS component were not different between subjects with or without ED. Neither the prevalence of ED (34.3% vs 33.4%, p=0.6), nor IIEF score (21.5+/-3.9 vs 21.7+/-3.7, p=0.8), were different between patients with or without MS. IIEF was similar across subgroups of individuals stratified according to the number of MS components and was not related to HOMAIR index. Hypogonadism was observed in 30.8% and 28.1% individuals with and without MS (p=0.58). Testosterone and BMI levels were inversely related (r=-0.3, p=0.04). CONCLUSION: Among obese non-diabetic individuals the risk of developing ED is independent of the presence of MS factors. Testosterone levels progressively decrease with increasing body weight.

Search for genetic variants of the SYNTAXIN 1A (STX1A) gene: the -352 A>T variant in the STX1A promoter associates with impaired glucose metabolism in an Italian obese population.

OBJECTIVE: To test if sequence variations of the SYNTAXIN 1A (STX1A) gene contribute to the susceptibility to type 2 diabetes in a cohort of overweight/obese subjects. METHODS: A total of 717 overweight/obese individuals underwent oral glucose tolerance test and were stratified in four groups according to fasting and 2 h glucose levels (NGT, IGT, CGI, T2DM), representing the natural history of diabetes from normal glucose tolerance to overt disease. These subjects were analysed by a two-step genetic study. Functional analysis was performed by electrophoretic mobility shift assay (EMSA) and by supershift with CCAAT/enhancer-binding protein (C/EBP)beta antibody. RESULTS: Among the several sequence variations detected in the STX1A gene, the T allele of the -352 A>T single nucleotide polymorphism in the promoter was found in a lower frequency in the subset of individuals with greater impairment of insulin secretion (CGI). To confirm that a lower frequency of the T allele was associated with this condition, we genotyped a second group of 202 overweight/obese individuals with type 2 diabetes, and the frequency of the T allele was reduced in this group also (P<0.01). Logistic regression confirmed a protective odds ratio (0.49, P<0.01) for the T allele. The EMSA showed that the PRM -352 A allele binds transcription factors with lower affinity compared to the T allele, and incubation with C/EBPbeta antibody 'supershifted' the complex, indicating that C/EBPbeta had a different binding with the PRM -352T allele. CONCLUSION: A lower frequency of the PRM -352T allele of the STX1A gene was observed in overweight/obese subjects with impaired glucose regulation, particularly among individuals with combined glucose intolerance and overt diabetes. Both these groups have a greater defect in beta-cell function compared to normal and glucose intolerant subjects, and this association together with the functional study suggests a possible role of the PRM -352 A>T variant in insulin secretion.

Waist circumference reduction after insulin detemir therapy in type 2 diabetes patients previously treated with NPH.

We studied the weight-sparing effect and treatment satisfaction when switching from NPH to insulin detemir in type 2 diabetes. Mean HbA(1c) (P<0.05) and waist circumference (P<0.05) were reduced while treatment satisfaction improved (P<0.03). No weight gain was observed. Detemir improves glycemic control, treatment satisfaction, and may provide additional weight-sparing benefits.

Angiotensin blockade and matrix synthesis by glomerular epithelial cells in high glucose: a further experimental insight into the pathophysiology of diabetic nephropathy.

AIMS: Angiotensin converting enzyme inhibitors (ACEIs) and angiotensin II receptor-1 (AT-1) antagonists are used in the treatment of proteinuria of diabetic nephropathy. One of the major pathogenic events in this condition is represented by the alteration of the extracellular matrix protein synthesis by glomerular epithelial cells. MATERIALS AND METHODS: We evaluated the effects of the angiotensin converting enzyme inhibitor, Enalaprilat, and the AT-1 receptor antagonist, Losartan, on mRNA fibronectin and laminin synthesis by glomerular epithelial cells, in conditions mimicking hyperglycemia. RESULTS: In high glucose conditions, Enalaprilat reduced significantly the mRNA expression of fibronectin (p 0.03), but not significantly that of laminin. Losartan addition to high glucose incubated cells reduced (-30%) mRNA expression of fibronectin, and significantly (p 0.05) the mRNA expression of laminin. CONCLUSIONS: In addition to the known hemodynamic effects, the improvement of renal function in diabetic patients treated with these compounds may also be due to a modulator effect on extracellular matrix content and composition.

The G972R variant of the insulin receptor substrate-1 (IRS-1) gene is associated with insulin resistance in "uncomplicated" obese subjects evaluated by hyperinsulinemic-euglycemic clamp.

Several association studies have indicated the insulin receptor substrate-1 (IRS-1) gene G972R variant as a genetic risk factor for insulin resistance, particularly in presence of obesity. A few studies have also suggested a possible effect of the G972R variant on insulin secretion. The aim of this study was to evaluate the role of the IRS-1 gene G972R variant in 61 subjects with "uncomplicated" obesity [i.e. without diabetes, hypertension, dyslipidemia, coronary artery disease (CAD)], studied by hyperinsulinemic-euglycemic clamp. The presence of the G972R variant, detected in real-time with LightCycler hybridisation probes, was related to the indexes of insulin sensitivity. Furthermore, the possible role of this variant on insulin secretion was studied by means of insulin release indexes derived from oral tolerance test (OGTT). Twenty-four point five percent (24.5%) (no.=15) of the obese subjects proved to be carriers of the G972R variant. M index (p<0.05), non-oxidative glucose (p<0.01), insulin clearance (p<0.03) and insulin sensitivity index (ISI) (p<0.005) were all significantly reduced in G972R carriers compared to non-carriers, indicating a significant reduction in insulin sensitivity in carriers of the variant. A logistic regression analysis confirmed the independent association between the G972R variant and reduced insulin sensitivity (p<0.03). The interaction between obesity and the G972R variant was also independently associated with a reduced insulin sensitivity (p<0.005), suggesting that obesity and G972R variant were more than additive in predicting insulin resistance. The analysis of insulin release indexes did not show any significant differences. Our results demonstrate the association of the G972R variant of the IRS-1 gene with reduced insulin sensitivity in obese subjects, and indicate a possible interaction between the IRS-1 variant and obesity in worsening of insulin sensitivity.