Prevention of type 2 diabetes mellitus due to antihypertensive treatment affecting renin-angiotensin system

Hypertension is often associated with an impairment of glucose tolerance and is a risk factor for the development of type 2 diabetes mellitus. The occurrence of diabetes may be also influenced by the selection of the type of antihypertensive treatment. While it has been shown that the use of older type antihypertensives - diuretics and beta-blockers - may precipitate diabetes, newer drugs which inhibit the renin-angiotensin system have a positive effect on glucose tolerance. Several recent clinical trials of ACE-inhibitors and AT1-blockers have demonstrated a decreased risk of the occurrence of diabetes in comparison with placebo or conventional antihypertensive drugs. The mechanisms responsible for the antidiabetic effect of these newer antihypertensive agents remain largely speculative. Insulin resistance may be improved in several ways, e.g. by changes in microcirculation or direct effects on insulin response and glucose transport in target organ cells. However, as shown in experimental studies, improved islet function and insulin secretion may also have role due to an inhibitory effect on the local renin-angiotensin system in the pancreas. Ongoing prospective clinical trials having the occurrence of diabetes as a primary specified endpoint should confirm the preventive potential of the inhibitors of the renin-angiotensin system. Since direct comparisons are lacking, current data are inconclusive as to the superiority of one of the two classes of these inhibitors or of any single drug. Nevertheless, inhibitors of the renin-angiotensin system should definitely represent first choice antihypertensive agents for persons with additional risk factors such as family history of diabetes, obesity or impaired glucose tolerance.     

Genetic etiology of type 2 diabetes mellitus: a review

Type 2 diabetes mellitus (T2DM) is the most common form of diabetes characterized by elevated levels of plasma glucose caused by impairment in both insulin secretion and action. It is becoming an epidemic leading to various complications and its prevalence and incidence are increasing at an alarming rate in developing countries like India, raising a major public health concern. Both the genetic and environmental factors play a strong role in the manifestation of this complex genetic disorder. In the recent years, there has been a spate of molecular genetic investigations, including whole genome scans, to test the association of genetic variants with T2DM in different patho-physiological pathways. A large number of candidate genes have been identified to be associated with T2DM, albeit only a couple of them show consistency in association in different populations/ethnic groups. Given relatively high risk for T2DM in India and immense genetic heterogeneity and substructure of the constituent populations, the number of studies is too small to be able to characterize the genetic basis of the disease in India. The recent dramatic increase in number of affected people indicates that lifestyle factors related to urbanization and sedentary occupations may be particularly important in triggering the genetic elements that cause this type of diabetes. Therefore, it is imperative to precisely establish the underlying genetic and environmental factors behind this complex genetic disorder so that preventive measures can be initiated. We have attempted to review the molecular genetic studies conducted, till date, globally on T2DM along with the epidemiological, environmental and ethnic factors implicated in the manifestation of T2DM.     

Genetic variation and activity of the renin-angiotensin system and severe hypoglycemia in type 1 diabetes

Background

The deletion-allele of the angiotensin-converting enzyme (ACE) gene and elevated ACE activity are associated with increased risk of severe hypoglycemia in type 1 diabetes. We explored whether genetic and phenotypic variations in other components of the renin-angiotensin system are similarly associated.

Methods

Episodes of severe hypoglycemia were recorded in 171 consecutive type 1 diabetic outpatients during a 1-year follow-up. Participants were characterized at baseline by gene polymorphisms in angiotensinogen, ACE, angiotensin-II receptor types 1 (AT1R) and 2 (AT2R), and by plasma angiotensinogen concentration and serum ACE activity.

Results

Three risk factors for severe hypoglycemia were identified: plasma angiotensinogen concentration in the upper quartile (relative rate [RR] vs. lower quartile 3.1, 95% confidence interval [CI,] 1.4-6.8), serum ACE activity in the upper quartile (RR vs. lower quartile 2.9, 95% CI, 1.3-6.2), and homo- or hemizygosity for the A-allele of the X chromosome-located AT2R 1675G/A polymorphism (RR vs. noncarriers 2.5, 95% CI, 1.4-5.0). The three risk factors contributed independently to prediction of severe hypoglycemia. A backward multiple regression analysis identified a high number of renin-angiotensin system-related risk factors and reduced ability to perceive hypoglycemic warning symptoms (impaired hypoglycemia awareness) as predictors of severe hypoglycemia.

Conclusions

High renin-angiotensin system activity and the A-allele of the AT2R 1675G/A polymorphism associate with high risk of severe hypoglycemia in type 1 diabetes. A potential preventive effect of renin-angiotensin system blocking drugs in patients with recurrent severe hypoglycemia merits further investigation.     

The vitamin D receptor gene variant is associated with the prevalence of type 2 diabetes mellitus and coronary artery disease.

AIMS: Vitamin D can influence lipolysis and insulin secretion. A common genetic polymorphism of the vitamin D receptor, which has been found to be associated with bone mineral density, has also been reported to be associated with insulin-dependent diabetes mellitus. To test the influence of the vitamin D receptor polymorphism on the prevalence of Type 2 diabetes mellitus and coronary artery disease we studied a population of high-risk patients, who were referred to our clinic for diagnostic coronary angiography. METHODS: A total of 293 patients considered at high risk for coronary artery disease because of angina pectoris and known hypercholesterolaemia underwent diagnostic coronary angiography. The BsmI vitamin D receptor polymorphism was analysed by polymerase chain reaction. RESULTS: Prevalence of Type 2 diabetes mellitus and coronary artery disease was gradually dependent on the number of B alleles (BB 28%, Bb 13%, bb 8% for Type 2 diabetes mellitus, P = 0.002; BB 88% Bb 72%, bb 66% coronary artery disease, P = 0.01). Patients with the BB genotype had an odds ratio of 3.64 (95% confidence interval 1.53-8.55, P = 0.002) to have Type 2 diabetes mellitus compared with patients with the bb genotype. CONCLUSIONS: The genotype of the vitamin D receptor polymorphism determines the prevalence of Type 2 diabetes mellitus and coronary artery disease in a high-risk cohort population.     

High prevalence of type 2 diabetes mellitus in affluent urban Indians

The highest prevalence of type 2 diabetes mellitus in developing countries occurs in the upper socio-economic group, but this has not been well documented in Indians. The age and sex standardized prevalence of diabetes in 1112 affluent adult Indian subjects was 21.1%. This is the highest prevalence of diabetes reported from India.     

Sleep duration is a significant predictor of cardiac autonomic neuropathy in type 2 diabetes mellitus

AimTo investigate the association between sleep quality outcomes and measures of cardiac autonomic function and to assess the predictive ability of sleep quality outcomes for cardiac autonomic neuropathy (CAN) in type 2 diabetes mellitus (T2DM).MethodsFifty patients with T2DM (age, 51.3 ± 7.01 years; glycemic control, 8.4 ± 1.65%) completed the study. Patients were diagnosed for CAN using the standard clinical autonomic test battery and were also assessed for heart rate variability (HRV) under resting conditions. Sleep quality was examined using the Pittsburg Sleep Quality Index (PSQI).ResultsSleep duration, sleep onset latency, sleep efficiency, daytime dysfunction and global PSQI score showed significant correlations with measures of cardiac autonomic control (p < 0.05). At an optimal cut-off of ≤ 5.83 h (area under the curve: 0.76, p = 0.0003; sensitivity: 50%; specificity: 94.4%), sleep duration predicted occurrence of CAN (odds ratio, confidence interval: 0.18, 0.04–0.70; p = 0.01) in T2DM after adjusting for various clinical confounders.ConclusionFindings of the present study suggest that subjective sleep outcomes such as sleep duration, sleep onset latency, sleep efficiency, daytime dysfunction and overall sleep quality are associated with the indices of cardiac autonomic function in T2DM. Moreover, short sleep duration may be considered a predictor in the occurrence of CAN in these patients. Considering the role of sleep in the pathophysiology of CAN, sleep should be routinely examined in patients with T2DM and appropriate therapeutic interventions should be implemented particularly in case of reduced sleep duration.     

Genetic susceptibility to macrovascular complications of type 2 diabetes mellitus

Patients with type 2 diabetes mellitus have a threefold increased risk of developing macrovascular disease such that 75% of such patients will die of cardiovascular complications. This increased risk is, however, not completely explained by traditional risk factors such as smoking, hypercholesterolaemia, hypertension and glycaemic control. Moreover, the fact that not all patients with type 2 diabetes develop these complications, together with evidence of family clustering (a heritability of 50%), suggests that a proportion of the susceptibility to ischaemic heart disease in type 2 diabetes may be genetic. Unravelling the polygenic susceptibility factors for the complications of a disease that itself has multifactorial inheritance has proved difficult and has focused largely on the candidate gene approach. A review of some of the studies testing candidate genes specifically in patients with both type 2 diabetes and ischaemic heart disease is presented. These studies focus largely on four main areas: lipoprotein metabolism, glycation and oxidation pathways, haemostatic cascade, and other candidate genes.     

Effect of inhibition of the renin-angiotensin system on development of type 2 diabetes mellitus (meta-analysis of randomized trials)

The increasing prevalence and costs of type 2 diabetes mellitus (DM) make strategies to prevent its development vitally important. This analysis was conducted to determine if angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) prevent the development of DM. Medline and the Cochrane Central Register of Controlled Trials (1966 to May 2006) were queried for prospective, randomized, placebo-controlled or active-controlled trials of ACE inhibitor or ARB therapy in adults that reported rates of new-onset diabetes during follow-up. Meta-analyses of summary statistics from individual trials were performed using a random-effects model. Thirteen trials with a total of 93,451 patients were identified. Renin-angiotensin system antagonists reduced the incidence of DM from 9% in nontreated patients to 7.1% in those treated, a 26% reduction in odds (odds ratio [OR] 0.74, 95% confidence interval [CI] 0.66 to 0.81, p<0.001). The effect sizes were similar in trials that randomized only hypertensive subjects (OR 0.73, 95% CI 0.66 to 0.82, p<0.001) and trials that studied the impact of renin-angiotensin system inhibition on outcomes of patients with vascular disease or heart failure (OR 0.67, 95% CI 0.50 to 0.90, p=0.008). ACE inhibitors and ARBs had comparable effects on the development of DM. In ACE inhibitor trials, the odds of developing DM were reduced by 28% (OR 0.72, 95% CI 0.63 to 0.84, p<0.001), and in the 5 ARB studies, there was a 27% reduction (OR 0.73, 95% CI 0.64 to 0.84, p<0.001) in the odds. In conclusion, evidence accumulated to date indicates that inhibition of the renin-angiotensin system may contribute to the prevention of DM.     

盐酸丁咯地尔治疗2型糖尿病疗效观察

目的　观察盐酸丁咯地尔对糖尿病患者血粘度、红细胞变形能力、血小板聚集功能、血糖及胰岛素敏感性的影响。方法　 6 4例 2型糖尿病患者在保持原有饮食、运动、药物不变基础上随机分为两组 ,治疗组给予盐酸丁咯地尔 2 0 0 mg/d,静脉滴注 14天 ,对照组给予维生素 C、维生素 B6 静脉点滴。结果　应用盐酸丁咯地尔治疗后全血粘度、红细胞变形能力、血小板聚集功能、血糖、 Hom a- IR指数均明显改善 (P <0 .0 5～ 0 .0 1)。结论　盐酸丁咯地尔能显著改善 2型糖尿病患者血粘度、红细胞变形能力、血小板聚集功能 ,能增加胰岛素敏感性 ,有显著的协助降糖作用 ,并可能影响糖尿病患者的亚临床炎症状态。     

Increased prevalence of ventricular fibrillation in patients with type 2 diabetes mellitus

Diabetes mellitus (DM) is an independent risk for cardiovascular disease. Furthermore, patients with DM have increased risk for ventricular arrhythmia that is thought to be secondary to coronary artery disease (CAD) or congestive heart failure (CHF). We hypothesized that DM may cause ventricular arrhythmias independent of CAD or CHF. Using a large database, we evaluated the occurrence of ventricular fibrillation in patients with DM adjusting for CAD and CHF. We used patient treatment files (PTF), documents of inpatients' admissions containing discharge diagnoses (ICD-9 codes) from all Veterans Health Administration Hospitals. The patients were stratified in two groups: ICD-9 code for DM (293 124) and a control group with ICD-code for hypertension (HTN) but no DM (552 623). ICD-9 codes for ventricular fibrillation were used for this study. We performed uni- and multivariant analysis adjusting for comorbid conditions. Ventricular fibrillation was present in 563 (0.2%) vs 781 (0.1%) in the control group. Using multivariate analysis, DM remained independently associated with ventricular fibrillation (odds ratio: 1.7; confidence interval: 1.5–1.9; P < 0.000). Patients with DM have significantly higher prevalence of ventricular fibrillation independent of CAD or CHF, which in part may explain the higher risk of sudden death in patients with DM.     

The prevalence of polycystic ovaries in women with type 2 diabetes mellitus

OBJECTIVE: Polycystic ovary syndrome (PCOS) and type 2 diabetes mellitus are both common conditions associated with insulin resistance and compensatory hyperinsulinaemia. Previous reports have noted that impaired glucose tolerance and diabetes are common in women with PCOS. In this report we present the results of the converse study: the prevalence of polycystic ovaries in premenopausal women presenting with type 2 diabetes mellitus. SUBJECTS: Subjects were recruited from a hospital Diabetes Clinic. A search of computerized records identified 49 premenopausal women with type 2 diabetes mellitus being treated with diet alone or oral hypoglycaemic agents of whom 38 (76%) patients agreed to be studied. DESIGN: A cross-sectional study recording clinical, demographic and anthropometric data. Measurements of fasting metabolic parameters, reproductive endocrine profiles and ovarian dimensions were taken. RESULTS: Eighty-two percent of women with type 2 diabetes mellitus had polycystic ovaries on ultrasound. Of these women, 52% had clinical evidence of cutaneous hyperandrogenism and/or menstrual disturbance. Correlations between metabolic and reproductive parameters were consistent with a stimulatory action of insulin on the ovary. There was no significant difference between the PCO and non-PCO groups with respect to metabolic profiles. CONCLUSIONS: Women with type 2 diabetes mellitus have a higher prevalence of polycystic ovaries than that reported in the general population. Not all women with hyperinsulinaemia due to type 2 diabetes mellitus, however, develop PCO suggesting that hyperinsulinaemia alone is not sufficient for the expression of this ovarian morphology.     

Very severely obese patients have a high prevalence of type 2 diabetes mellitus and cardiovascular disease

The prevalence of very severe obesity has increased progressively and faster than other classes of obesity over the last years. It is unclear whether the prevalence of obesity-related complications and health risks increases progressively or reaches a plateau above a certain degree of obesity. The aim of our study was to investigate whether the severity of obesity was correlated with the prevalence of type 2 diabetes mellitus (T2DM), impaired fasting glucose, impaired glucose tolerance (IGT), metabolic syndrome (MS), and cardiovascular diseases (CVDs) in a large cohort of patients with different degrees of obesity. A cross-sectional study was conducted in 938 obese patients without a previous diagnosis of diabetes. Patients were assigned to different categories of obesity: mild-moderate obesity (BMI 30–39.9 kg/m²), morbid obesity (BMI 40–49.9 kg/m²), and super-obesity (SO, BMI ≥50 kg/m²). The prevalence of IGF, IGT, screen-detected T2DM, MS, and CVD was higher in SO patients than in the other groups. Interestingly, the association between SO and either MS or CVD was independent of glucose tolerance status, indicating that factors other than glucose metabolism also favor cardio-metabolic complications in obese patients. In patients without screen-detected T2DM (n = 807), insulin sensitivity and secretion OGTT-derived indexes indicated that SO patients had the worst glucose homeostasis relative to the other categories of obesity, which was indicated by the most reduced disposition index in these patients, a predictor of future T2DM. In conclusion, SO patients have an extremely high prevalence of glucose metabolism deterioration, and cardio-metabolic complications are more prevalent in these patients compared to less obese patients.     

Fungi in patients with diabetes mellitus type 2: prevalence, species of isolated strains

In 77 diabetic patients the detection of fungi was carried out in the oral cavity, digestive tract, genital organs and skin lesions. Patient age ranged from 39 to 82 years, with the Body Mass Index (BMI) from 22 to the highest values of 46.5. Diabetes control was assessed by determination of the glucose level in serum after overnight fasting and after lunch, as well as by determination of the HbA(1c) level. Fungi were diagnosed in 61 patients (79.6%). The total of 111 fungal strains were isolated in 319 cultures evaluated from 12 biological materials. Fungal strains were detected in the highest percentage in oral cavity (77.9%), in the lower percentage in anus (33.8%), vagina discharge (11.6%) and the region of vulva (14.3%). Fungi were observed in one focus--exclusively in the oral cavity--in 28 (36.4%) patients, whereas they occurred in multifocal infections in 33 (42.9%) patients. The isolated fungal strains were classified into 4 genera (Candida, Saccharomyces, Trichosporon, Aspergillus) and 12 species. The most frequently detected fungi were C. albicans (55.2%), followed by C. glabrata (12.4%), C parapsilosis (10.5%) and C. tropicalis (9.5%). Relatively low percentage of fungi identified in vagina was associated, among others, with the fact that most of the female patients with diabetes were at the postmenopausal period. In all the patients in whom fungi were isolated from the vagina contents, these fungi were also found in other ontocenoses. The increase in percentage of fungal strains from genera other than Candida in patients with a higher risk is of clinical importance, as some of them are resistant in vitro to azole derivatives e.g. fluconazole. The digestive tract is thought to be the most frequent fungal habitat. A considerable prevalence of fungi, multifocal infections, particularly related to oral cavity and anus, and occurrence of high percentage of strains different from C. albicans species of Candida genus in female patients with type 2 diabetes indicate the necessity of the special mode of diagnostic and therapeutic management.     

Effects of short-term modest weight loss on fasting and post-prandial lipoprotein sub-fractions in type 2 diabetes mellitus patients

OBJECTIVE: We assessed the efficacy of a modest weight loss (1.5 +/- 0.3 kg) and simultaneous rapid improvement in glycemic control on fasting an post-prandial lipoprotein sub-fractions in nine overweight (BMI=28 +/- 1.7 kg/m(2)) well controlled Type 2 diabetic patients (HbA(1c)=7.3 +/- 0.1%). MATERIAL AND METHODS: They followed a non-drastical hypocaloric balanced diet (1 561 +/- 39 kcal/day) over ten days in hospital. The fat content of the diet was significantly lowered from 96 +/- 12 g/day to 62 +/- 4 g/day (p<0.03). Plasma lipid and lipoprotein levels were measured in fasting and four hours after standard breakfast and four hours after standard lunch twice before and after ten days of hospitalization. The sub-fractions of very low density and low density lipoprotein were obtained by cumulative flotation ultracentrifugation. RESULTS: This weight loss reduced two well known independent cardiovascular risk factors such as the post-prandial glycemic excursions (p<0.05) and the post-prandial lipemia (p<0.05). Multiple linear regression analyses identified weight loss as an independent variable accounting for the ability to predict post-prandial capillary triglyceride clearance (p<0.05). Improvements in post-prandial glycemic excursions which was also entered as a parameter did not appear as a variable being able to predict these changes (p=0.4). In addition to the 23% improvement in post-prandial capillary triglyceride clearance (p<0.02), a decrement in post-prandial VLDL-2 triglyceride enrichment was found (p<0.05). Finally, fasting and post-prandial LDL-3 cholesterol levels were diminished (p<0.05) and the LDL-2/LDL-3 mass ratio post-prandial kinetics were improved (p<0.05). CONCLUSIONS: Even a modest weight loss in overweight, average controlled type 2 diabetic patients can achieve a significant improvement in two cardiovascular risk factors, namely post-prandial triglyceride excursions and the LDL-2/LDL-3 mass ratio kinetics independently from glycemic control improvements.     

Application of radioimmunoassay to the renin-angiotensin system and to aldosterone

Many of the factors regulating the renin-angiotensin system have been defined by means of a bioassay method based on the hypertensive effect, in the nephrectomized rat, of angiotensin II generated by the action of renin on its plasma substrate. The bioassay has now been largely replaced by a simpler and more sensitive radioimmunoassay based on the generation of angiotensin I in the same system. The radioimmunoassay of aldosterone in plasma has been possible using antisera developed to aldosterone-albumin conjugates. Cross-reactivity to other steroids is low, but their greater abundance in plasma necessitates chromatographic purification before the immunoassay step. The radioimmunoassay of aldosterone in plasma is simpler and more sensitive than measurement by double isotopic techniques. Simultaneous measurement of renin activity and aldosterone in plasma, now possible by radioimmunoassay, should provide a more precise definition of the interrelationship of the two hormonal systems.