Human resistin gene polymorphism: association with serum resistin level and insulin resistance in type 2 diabetes mellitus

Resistin is an adipocyte - secreted cytokine associated with insulin resistance in rodents. In humans, it remains controversial whether circulating resistin levels are associated with insulin resistance, type 2 diabetes, or obesity. The role of resistin gene, referred to RETN, in human type 2 diabetes or obesity is largely unclear in studies of its association with SNPs or serum resistin. Major genetic factors of type 2 diabetes, a probable polygenic disease, remain to be identified. Therefore the aim of our work was to study circulating level of resistin and to correlate this level with resistin gene 3'UTR+62G-A polymorphism and factors related to insulin resistance in type 2 diabetic patients. 40 male patients with type 2 diabetes [group I] and 10 age-matched healthy controls [group II] were included. All patients and controls were subjected to full history taking, clinical examination stressing on waist circumference, BMI and blood pressure. Laboratory investigations included lipid panel [TG, total cholesterol, HDL-C and LDL-C], glycemic parameters [FBS, Hb A1c, fasting insulin, HOMA, IR], serum uric acid, highly sensitive CRP, serum resistin and molecular detection of resistin gene 3'UTR+62G-A polymorphism using PCR-RFLP. Serum resistin levels, highly sensitive CRP, anthropometric measures and metabolic parameters were significantly higher in type 2 diabetic patients [group I] than in healthy controls [group II] [P<0.05]. In type 2 diabetic patients the serum resistin was negatively correlated with HDL-C and positively correlated with BMI, HOMA-IR and highly sensitive CRP [P < 0.05]. In diabetic subjects the genotype distributions of resistin gene 3'UTR polymorphism were as follows: 3 [7.5%] subjects were heterozygous [GA], 1 [2.5%] was homozygous [AA] for the mutant allele and 36 [90%] were homozygous [GG] for the wild allele. Type 2 diabetic subjects had a significantly lower frequency of resistin gene 3'UTR + 62A variant [GG: GA/AA, 90%:10%] than control subjects [GG: GA/AA, 60%:40%; odds ratio, 6.0; 95% confidence interval, 1.17 to 30.7; P = 0.041]. G allele was linked to greater insulin resistance as indicated by higher HOMA-IR index [P = 0.004]. Also diabetic subjects harboring the G allele showed significant higher levels of serum resistin, BMI, highly sensitive CRP as well as a significant decrease in HDL-cholesterol [P = 0.042, 0.007, 0.008, 0.003 respectively]. These findings suggest that resistin gene 3'UTR + 62G-A is associated with serum resistin level and may play a role in the pathogenesis of type 2 diabetes and insulin resistance. The strong correlation of resistin with highly sensitive CRP suggests that resistin may be considered as inflammatory marker associated with type 2 diabetes

Transferrinuria in type 2 diabetes mellitus: An early marker of diabetic nephropathy

Diabetic nephropathy is the commonest cause of end-stage renal failure in the Western world. The incidence of DN rises rapidly over the first 15 to 20 years of diabetes to decline sharply afterwards. The stages of DN progress from normoalbuminuria to microalbuminuria to clinical proteinuria and finally to end-stage renal failure. Several studies proved the applicability of urinary albumin quantification in the early diagnosis of diabetic nephropathy. Several studies of different urinary proteins demonstrated the increased excretion of other high and low molecular mass proteins in different stages of diabetic nephropathy: macromolecular, e.g. transferrin and micromolecular proteins like alpha 1-microalbumin. Elevated urinary transferrin excretion rates have been reported in patients with type 2 diabetes and its complications. Therefore, the aim of the present study was to evaluate the role of transferrin as an early marker for the detection of nephropathy in Egyptian type 2 diabetic patients. Sixty Egyptian type 2 diabetic patients grouped according to the presence or absence of albumin in urine into three groups: group I consisted of 20 normoalbuminuric Egyptian type 2 diabetic patients, group II included 20 microalbuminuric Egyptian type 2 diabetic patients, and group Ill comprised 20 macroalbuminuric Egyptian type 2 diabetic patients. Twenty healthy subjects of matched age and sex were included as a control group. Laboratory investigations included FBG and 2 hours PPBG, HbA[1C] serum albumin, ALT, AST, prothrombin activity, blood urea, serum creatinine and creatinine clearance, and complete urine analysis. Determination of microalbuminuria in fresh urine samples was done using immunoturbidimetry. Estimation of urinary transferrin was done by immuno-nephelometry. Results: Type 2 diabetic patients who had frank proteinuria had a significantly longer duration of diabetes mellitus as compared to micro and norrnoalbuminuric patients. Type 2 diabetic patients with frank proteinuria had significantly higher FBG, PPBG and HbA[1C] levels as compared to normoalbuminuric type 2 diabetic patients and controls. Type 2 diabetic patients with frank proteinuria had significantly higher blood urea and serum creatinine and a significantly lower creatinine clearance as compared to norrnoalbuminuric type 2 diabetic patients and controls. Type 2 diabetic patients with frank proteinuria showed significantly higher urinary albumin and transferrin excretion as compared to normo-and microalbuminuric type 2 diabetic patients and controls. Also, microalbuminuric type 2 diabetic patients had significantly higher urinary albumin and transferrin excretion as compared to normoalbuminuric type 2 diabetic patients and controls. In normoalbuminuric type 2 diabetic patients, a negative correlation was observed between creatinine clearance and transferrinuria. In microalbuminuric type 2 diabetic patients, a strong positive correlation was found between albuminuria and transferrinuria. In type 2 diabetic patients with frank proteinuria, strong positive correlations were obtained between blood urea and serum creatinine and transferrinuria, while a strong negative correlation was observed between creatinine clearance and transferrinuria. However, no significant correlations were found in any of the type 2 diabetic groups between duration of the disease, blood pressure, FBG, PPBG, or HbA[1C] and transferrinuria. Urinary transferrin is a convenient diagnostic parameter of renal impairment in Egyptian type 2 diabetic patients. Transferrinuria could be considered as an early marker of diabetic nephropathy as compared to microalbuminuria

Association of polymorphism in both tryptophan 64 arginine of the beta 3-adrenergic receptor gene and TNF-alpha gene with features of the metabolic syndrome in Egyptians

Several candidate genes have been tested for their association with the metabolic syndrome. Among these genes, the Beta 3-Adrenergic receptor gene [ADRB3] and the TNF-alpha gene locus has been the object of many studies. Therefore the aim of this work was to investigate the possible association of the beta 3-Adrenergic Receptor Trp64Arg polymorphism and the -308G/A polymorphism in the promoter region of TNF-alpha, in a group of male Egyptians with features of the metabolic syndrome.30 male patients with features of metabolic syndrome [group I], fifteen age matched healthy males were included as controls [group II]. Patients and controls were subjected to full history taking, clinical examination stressing on blood pressure, waist circumference, and waist/ hip [W/H] ratio; laboratory investigations included lipid profile [TG, total cholesterol, HDL-C, LDL-C], FBS, fasting insulin and HOMA-IR index, and molecular detection of Trp64Arg variant of the beta 3- adrenergic receptor as well as the TNF alpha gene promoter polymoprhism using RFLP-PCR in blood. The studied clinical parameters, lipid profile, fasting blood sugar, fasting insulin and HOMA-IR index were significantly higher in group I than that observed in group II. There was no statistically significant difference between the beta 3- adrenergic receptor wild and mutant subjects among group I as regards the studied clinical parameters, lipid profile, fasting blood glucose, fasting serum insulin and HOMA-IR index. While subjects harboring the A allele of the TNF alpha gene promoter showed significant higher levels of fasting insulin [p=0.002] fasting blood glucose, [p=0.014] and HOMA index [p < 0.001] as well as a significant decrease in HDL cholesterol levels [p=0.041]. In contrast, no association was found with total cholesterol, LDL cholesterol, triglycerides levels between the different genotypes. The correlation between HOMA-IR index and other studied parameters was not statistically significant among group I. The beta-3-adrenergic receptor locus does not play an important role in the metabolic syndrome susceptibility or in the insulin resistance. While, the -308 G/A TNF-alpha gene variant might confer an increased risk for the development of insulin resistance