A genomewide search for type 2 diabetes-susceptibility genes in indigenous Australians

The prevalence of type 2 diabetes among Australian residents is 7.5%; however, prevalence rates up to six times higher have been reported for indigenous Australian communities. Epidemiological evidence implicates genetic factors in the susceptibility of indigenous Australians to type 2 diabetes and supports the hypothesis of the thrifty genotype, but, to date, the nature of the genetic predisposition is unknown. We have ascertained clinical details from a community of indigenous Australian descent in North Stradbroke Island, Queensland. In this population, the phenotype is characterized by severe insulin resistance. We have conducted a genomewide scan, at an average resolution of 10 cM, for type 2 diabetes-susceptibility genes in a large multigeneration pedigree from this community. Parametric linkage analysis undertaken using FASTLINK version 4.1p yielded a maximum two-point LOD score of +2.97 at marker D2S2345. Multipoint analysis yielded a peak LOD score of +3.9

Prediction of Golgi Type II membrane proteins based on their transmembrane domains

Motivation: A major issue in cell biology today is how distinct intracellular regions of the cell, like the Golgi Apparatus, maintain their unique composition of proteins and lipids. The cell differentially separates Golgi resident proteins from proteins that move through the organelle to other subcellular destinations. We set out to determine if we could distinguish these two types of transmembrane proteins using computational approaches. Results: A new method has been developed to predict Golgi membrane proteins based on their transmembrane domains. To establish the prediction procedure, we took the hydrophobicity values and frequencies of different residues within the transmembrane domains into consideration. A simple linear discriminant function was developed with a small number of parameters derived from a dataset of Type II transmembrane proteins of known localization. This can discriminate between proteins destined for Golgi apparatus or other locations (post-Golgi) with a success rate of 89.3% or 85.2%, respectively on our redundancy-reduced data sets.

Metformin & lifestyle intervention prevent Type 2 diabetes: lifestyle intervention has the greater effect

Diabetes mellitus is now occurring in epidemic proportions in many countries. Owing to the limited effectiveness of drug prophylaxis of diabetic complications after diabetes has developed, it may be more appropriate to investigate ways to prevent the onset of diabetes. A recent trial published by the Diabetes Prevention Programme Research Group investigated whether lifestyle changes or metformin were effective in delaying the onset of diabetes in subjects with impaired glucose tolerance. The goals of the intensive lifestyle intervention were to achieve and maintain a weight reduction of 7% through a low-calorie, low-fat diet and to engage in physical activity of moderate intensity, such as brisk walking, for at least 150 min/week. The effectiveness of the intensive lifestyle intervention on body weight was initially quite good but decreased over time. Metformin caused some weight loss but to a lesser extent than the intensive lifestyle intervention. Both therapies decreased the fasting plasma glucose levels to a similar extent initially. The intensive lifestyle intervention decreased plasma glycosylated haemoglobin levels to a greater extent than metformin. Both intensive lifestyle intervention and metformin reduced the incidence of diabetes, with the lifestyle intervention having the greater effect.

Prolonged retention after aggregation into secretory granules of human R183H-growth hormone (GH), a mutant that causes autosomal dominant GH deficiency type II

Human R183H-GH causes autosomal dominant GH deficiency type II. Because we show here that the mutant hormone is fully bioactive, we have sought to locate an impairment in its progress through the secretory pathway as assessed by pulse chase experiments. Newly synthesized wild-type and R183H-GH were stable when expressed transiently in AtT20 cells, and both formed equivalent amounts of Lubrol-insoluble aggregates within 40 min after synthesis. There was no evidence for intermolecular disulfide bond formation in aggregates of wild-type hormone or the R183H mutant. Both wildtype and R183H-GH were packaged into secretory granules, assessed by the ability of 1 mm BaCl2 to stimulate release and by immunocytochemistry. The mutant differed from wildtype hormone in its retention in the cells after packaging into secretory granules; 50% more R183H-GH than wild-type aggregates were retained in AtT20 cells 120 min after synthesis, and stimulated release of R183H-GH or a mixture of R183H-GH and wild-type that had been retained in the cell was reduced. The longer retention of R183H-GH aggregates indicates that a single point mutation in a protein contained in secretory granules affects the rate of secretory granule release.

Left ventricular mass in patients with type 2 diabetes is independently associated with central but not peripheral pulse pressure

An increase in left ventricular mass (LVM) occurs in the presence of type 2 diabetes, apparently independent of hypertension (1), but the determinants of this process are unknown. Brachial blood pressure is not representative of that at the ascending aorta (2) because the pressure wave is amplified from central to peripheral arteries. Central blood pressure is probably more clinically important since local pulsatile pressure determines adverse arterial and myocardial remodeling (3,4). Thus, an inaccurate assessment of the contribution of arterial blood pressure to LVM may occur if only brachial blood pressure is taken into consideration. In this study we sought the contribution of central blood pressure (and other interactive factors known to affect wave reflection, e.g., glycemic control and total arterial compliance) to LVM in patients with type 2 diabetes.

Determinants of exercise capacity in patients with type 2 diabetes

OBJECTIVE - Type 2 diabetes is associated with reduced exercise capacity, but the cause of this association is unclear. We sought the associations of impaired exercise capacity in type 2 diabetes. RESEARCH DESIGN AND METHODS - Subclinical left ventricular (LV) dysfunction was sought from myocardial strain rate and the basal segmental diastolic velocity (Em) of each wall in 170 patients with type 2 diabetes (aged 56 +/- 10 years, 91 men), good quality echocardiographic images, and negative exercise echocardiograms. The same measurements were made in 56 control subjects (aged 53 +/- 10 years, 29 men). Exercise capacity was calculated in metabolic equivalents, and heart rate recovery (HRR) was measured as the heart rate difference between peak and 1 min after exercise. In subjects with type 2 diabetes, exercise capacity was correlated with clinical, therapeutic, biochemical, and echocardiographic variables, and significant independent associations were sought using a multiple linear regression model. RESULTS - Exercise capacity, strain rate, Em, and HRR were significantly reduced in type 2 diabetes. Exercise capacity was associated with age (r- = -0.37, P < 0.001), male sex (r = 0.26, P = 0.001), BMI (r = -0.19, P = 0.012), HbA(1c) (AlC; r = -0.22, P = 0.009), Em (r = 0.43, P < 0.001), HRR (r = 0.42, P < 0.001), diabetes duration (r = -0.18, P = 0.021), and hypertension history (r = -0.28, P < 0.001). Age (P < 0.001), male sex (P = 0.007), BMI (P = 0.001), Em (P = 0.032), HRR (P = 0.013), and AlC (P = 0.0007) were independent predictors of exercise capacity. CONCLUSIONS - Reduced exercise capacity in patients with type 2 diabetes is associated with diabetes control, subclinical LV dysfunction, and impaired HRR.

The relative benefits of endurance and strength training on the metabolic factors and muscle function of people with type 2 diabetes mellitus

Objective: To compare the effects of a 4-month strength training (ST) versus aerobic endurance training (ET) program on metabolic control, muscle strength, and cardiovascular endurance in subjects with type 2 diabetes mellitus (T2D). Design: Randomized controlled trial. Setting: Large public tertiary hospital. Participants: Twenty-two T21) participants (I I men, I I women; mean age +/- standard error, 56.2 +/- 1.1 y; diabetes duration, 8.8 +/- 3.5y) were randomized into a 4-month ST program and 17 T2D participants (9 men, 8 women; mean age, 57.9 +/- 1.4y; diabetes duration, 9.2 +/- 1.7y) into a 4-month ET program. Interventions: ST (up to 6 sets per muscle group per week) and ET (with an intensity of maximal oxygen consumption of 60% and a volume beginning at 15min and advancing to a maximum of 30min 3X/wk) for 4 months. Main Outcome Measures: Laboratory tests included determinations of blood glucose, glycosylated hemoglobin (Hb A(1c)), insulin, and lipid assays. Results: A significant decline in Hb A, was only observed in the ST group (8.3% +/- 1.7% to 7.1% +/- 0.2%, P=.001). Blood glucose (204 +/- 16mg/dL to 147 +/- 8mg/dL, P <.001) and insulin resistance (9.11 +/- 1.51 to 7.15 +/- 1.15, P=.04) improved significantly in the ST group, whereas no significant changes were observed in the ET group. Baseline levels of total cholesterol (207 +/- 8mg/dL to 184 +/- 7mg/dL, P <.001), low-density lipoprotein cholesterol (120 +/- 8mg/dL to 106 +/- 8mg/dL, P=.001), and triglyceride levels (229 +/- 25mg/dL to 150 +/- 15mg/dL, P=.001) were significantly reduced and high-density lipoprotein cholesterol (43 +/- 3mg/dL to 48 +/- 2mg/dL, P=.004) was significantly increased in the ST group; in contrast, no such changes were seen in the ET group. Conclusions: ST was more effective than ET in improving glycemic control. With the added advantage of an improved lipid profile, we conclude that ST may play an important role in the treatment of T2D.

Urinary albumin levels in the normal range determine arterial wall thickness in adults with Type 2 diabetes: a FIELD substudy

Aim Cardiovascular disease (CVD) rates are substantially higher among patients with Type 2 diabetes than in the general population. The objective of this study was to identify the determinants of carotid intima media thickness (IMT) in patients with Type 2 diabetes. Methods We measured the thickness of the intima media layer of the carotid artery, a strong predictor of the risk of future vascular events, in 397 Type 2 diabetic patients drawn from the Fenofibrate Intervention and Event Lowering in Diabetes study, prior to treatment allocation. Results The mean IMT was 0.78 mm [interquartile range (IQR) 0.23 mm], and the maximum IMT was 1.17 mm (IQR 0.36 mm). By multivariate analysis, age, sex, duration of diabetes, triglycerides, and total cholesterol were independently correlated with IMT, as was urine albumin-creatinine ratio (ACR) (P < 0.001). The effect of ACR on IMT was further examined by tertile. Clinically significant differences in IMT were associated with ACR > 0.65 mg/mmol, approximately one-fifth the standard clinical threshold for microalbuminuria (P < 0.01). Long-term diabetes, independent of other parameters, was associated with a 50% increase in age-related thickening. Conclusions IMT in people with Type 2 diabetes is independently and continuously related to urine albumin levels and to the duration of diabetes. These results support previous data linking urine albumin measurements within the normal range with increased ischaemic cardiac mortality in the setting of Type 2 diabetes, and strongly suggest that urine albumin levels within this range should trigger a formal evaluation for CVD.