Influence of genetic variability at the ACE locus in intron 16 on Diabetic Nephropathy in T1DM patients.

Background: Diallelic [insertion/deletion (I/D)] polymorphism in the angiotensin-converting enzyme (ACE) gene has been reported inconsistently as being associated with risk of diabetic nephropathy (DN). Objective: To examine the three ACE poly-morphic variants in intron 16 for a possible role in modulating DN in T1DM patients from Kutch region, Gujarat. Design and setting: I/D polymorphism in intron 16 of the ACE gene was examined in a case-control group (280 participants with T1DM, case participants n=138; control participants n=142) for association with nephropathy. All recruited individuals were carefully phenotyped and genotyping was performed using polymerase chain reaction and gel electrophoresis methods. Suitable descriptive statistics was used for different variables. Results: No departure from Hardy-Weinberg equilibrium was observed in cases or controls. Genetic polymorphism at the ACE locus in intron 16 were significantly associated with nephropathy when analyzed either by genotype or allele frequencies and D/D variant were significantly (p=0.0002) associated with nephropathy at the 5% level. In multivariate analysis, D/D variant had an independent and strongest influence on the micro-albumin excretion (p=0.002, OR=2.11, 95% CI=1.26– 4.48). However, it did not independently change the odds of having macroalbuminuria versus microalbuminuria. Conclusion: Genotype-associated differences in ACE in intron 16, have functional consequences in genetic susceptibility to diabetic nephropathy in a population with T1DM, and thus represent a potential DN genetic susceptibility locus worthy of replication.

High risk factors for elevated excretion of albumin in diabetic subjects.

Background: Microalbuminuria refers to the excretion of albumin in the urine at a rate that exceeds normal limits but is less than the detection level for traditional dipstick methods and is considered as a marker of diabetic nephropathy. Aims: To establish the prevalence of elevated urinary albumin levels (microalbuminuria) in a sequential sample of diabetic patients and to determine its relationship with known and putative risk factors, to ascertain relationship of serum angiotensin converting enzyme (ACE) activity with diabetic incipient nephropathy. Study design: This cross-sectional analytical study included 100 control and 325 diabetic patients (180 type 2 and 145 type 1 diabetic patients) subjects attending outpatient department of the hospital. Patients having clinical albuminuria and with other causes of proteinuria were excluded. Result: Microalbuminuria was observed in 34.48% in patients with type 1 and 28.33% in patients with type 2 diabetes mellitus respectively. Having the condition was significantly associated with advanced age, poor glycaemic control, dyslipidemia (with respect to total cholesterol, triglycerides and LDL-C), smoking, body mass index and coexisting hypertension. The duration of diabetes was a significant correlate in type 1 DM subjects only. No significant association with gender, HDL-C levels, age at onset of DM, mode of treatment, socio-economic status and other lifestyle variations was found. All clinical and biochemical parameters in patient with microalbuminuria was more adversely affected than patients with normoalbuminuria. Serum angiotensin converting enzyme (ACE) levels were significantly elevated (P<0.001) in both of the diabetic groups, moreover, its levels were higher in subjects with microalbuminuria than in those without this complication (P<0.05). Conclusions: Microalbuminuria in diabetes, which represents an earlier phase in the development of clinical nephropathy, is associated with many potentially modifiable risk factors. In estimating diabetic nephropathy risk, AER is most important and should be done frequently but there are gains to be made in predictive precision by considering family history, smoking habits, glycemia, B.P.,BMI lipid levels and ACE activity. Early screening for incipient diabetic nephropathy and aggressive management of these risk factors is important in optimising the renal outcome of patients with diabetes mellitus.

Glucose tolerance & insulin response in patients with hypertension.

Background: Insulin resistance leads to impaired glucose tolerance, dyslipidemia, and other adverse cardiovascular effects. Euglycemic insulin clamp have shown that essential hypertension per se is a state of insulin resistance and has been associated with an increased incidence of diabetes Aims: To ascertain the prevalence of several degrees of glucose abnormalities in patients with hypertension and to examine the insulin secretory response to oral glucose load. Study design, Material and Method: This cross-sectional analytical study included 325 hypertensive patients (with or without diabetes)and 100 control subjects. An oral glucose tolerance test (OGTT) following WHO guidelines was performed in all subjects, with measurement of insulin at baseline and every 30 minutes after the glucose load. Results: Abnormal glucose metabolism was observed in 70.77% of patients (95% confidence interval [CI], 65.87% - 74.21%). Of the 325 patients, 29.23% patients showed normal glucose metabolism. Impaired glucose tolerance (IGT) and Impaired fasting glycemia (IFG) were diagnosed in 30.46% and 16.61% patients respectively .Total diabetic population in the hypertensive patients were 23.69% (silent previously undiagnosed diabetes mellitus was diagnosed in 9.53% of patients while 14.15%reported a previous diagnosis of diabetes mellitus).Decreasing glucose tolerance was associated with insulin resistance. From normal glucose tolerance condition through IGT, IFG to diabetic, the HOMA IR progressively increased. Results of standard OGTT and corresponding insulin response after 0, 30, 60 and 120 minutes were significantly higher in patients compared with control subjects. LVMI and severity of glucose intolerance were significantly related. Male gender, higher levels of insulin (fasting insulin/HOMA IR) and greater adiposity (BMI) were all strongly associated with the severity of glucose abnormalities. Prevalence of metabolic syndrome increased progressively with severity of glucose abnormality. Conclusions: More than two-third of the hypertensive patients exhibited different glucose abnormalities and exaggerated insulin response to glucose load (hyperinsulinemia) along with cluster of other cardiovascular risk factors, whose prevalence increases with severity of glucose intolerance.