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Concept: Insulin resistance

402

Obesity and type 2 diabetes are characterized by altered gut microbiota, inflammation, and gut barrier disruption. Microbial composition and the mechanisms of interaction with the host that affect gut barrier function during obesity and type 2 diabetes have not been elucidated. We recently isolated Akkermansia muciniphila, which is a mucin-degrading bacterium that resides in the mucus layer. The presence of this bacterium inversely correlates with body weight in rodents and humans. However, the precise physiological roles played by this bacterium during obesity and metabolic disorders are unknown. This study demonstrated that the abundance of A. muciniphila decreased in obese and type 2 diabetic mice. We also observed that prebiotic feeding normalized A. muciniphila abundance, which correlated with an improved metabolic profile. In addition, we demonstrated that A. muciniphila treatment reversed high-fat diet-induced metabolic disorders, including fat-mass gain, metabolic endotoxemia, adipose tissue inflammation, and insulin resistance. A. muciniphila administration increased the intestinal levels of endocannabinoids that control inflammation, the gut barrier, and gut peptide secretion. Finally, we demonstrated that all these effects required viable A. muciniphila because treatment with heat-killed cells did not improve the metabolic profile or the mucus layer thickness. In summary, this study provides substantial insight into the intricate mechanisms of bacterial (i.e., A. muciniphila) regulation of the cross-talk between the host and gut microbiota. These results also provide a rationale for the development of a treatment that uses this human mucus colonizer for the prevention or treatment of obesity and its associated metabolic disorders.

Concepts: Bacteria, Gut flora, Nutrition, Insulin, Diabetes mellitus type 2, Diabetes mellitus, Obesity, Insulin resistance

229

 To assess diagnostic accuracy of screening tests for pre-diabetes and efficacy of interventions (lifestyle or metformin) in preventing onset of type 2 diabetes in people with pre-diabetes.

Concepts: Insulin, Diabetes mellitus type 2, Evaluation, Obesity, Diabetes, Insulin resistance, Sulfonylurea, Prevention

226

 To assess the risks of amputation, blindness, severe kidney failure, hyperglycaemia, and hypoglycaemia in patients with type 2 diabetes associated with prescribed diabetes drugs, particularly newer agents including gliptins or glitazones (thiazolidinediones).

Concepts: Diabetes mellitus type 2, Diabetes mellitus, Insulin resistance, Anti-diabetic drug, Sulfonylurea, Pioglitazone, Thiazolidinedione, Rosiglitazone

189

Self-monitoring of blood glucose among people with type 2 diabetes not treated with insulin does not appear to be effective in improving glycemic control. We investigated whether health professional review of telemetrically transmitted self-monitored glucose results in improved glycemic control in people with poorly controlled type 2 diabetes.

Concepts: Nutrition, Insulin, Diabetes mellitus type 2, Diabetes mellitus, Randomized controlled trial, Diabetes, Insulin resistance, Carbohydrate

189

The study investigated cross-sectional associations of total amount and patterns of sedentary behaviour with glucose metabolism status and the metabolic syndrome.

Concepts: Nutrition, Hypertension, Insulin, Diabetes mellitus type 2, Diabetes mellitus, Obesity, Blood sugar, Insulin resistance

186

BACKGROUND: Epidemiological studies suggest that excessive sitting time is associated with increased health risk, independent of the performance of exercise. We hypothesized that a daily bout of exercise cannot compensate the negative effects of inactivity during the rest of the day on insulin sensitivity and plasma lipids. METHODOLOGY/PRINCIPAL FINDINGS: Eighteen healthy subjects, age 21±2 year, BMI 22.6±2.6 kgm(-2) followed randomly three physical activity regimes for four days. Participants were instructed to sit 14 hr/day (sitting regime); to sit 13 hr/day and to substitute 1 hr of sitting with vigorous exercise 1 hr (exercise regime); to substitute 6 hrs sitting with 4 hr walking and 2 hr standing (minimal intensity physical activity (PA) regime). The sitting and exercise regime had comparable numbers of sitting hours; the exercise and minimal intensity PA regime had the same daily energy expenditure. PA was assessed continuously by an activity monitor (ActivPAL) and a diary. Measurements of insulin sensitivity (oral glucose tolerance test, OGTT) and plasma lipids were performed in the fasting state, the morning after the 4 days of each regime. In the sitting regime, daily energy expenditure was about 500 kcal lower than in both other regimes. Area under the curve for insulin during OGTT was significantly lower after the minimal intensity PA regime compared to both sitting and exercise regimes 6727.3±4329.4 vs 7752.0±3014.4 and 8320.4±5383.7 mU•min/ml, respectively. Triglycerides, non-HDL cholesterol and apolipoprotein B plasma levels improved significantly in the minimal intensity PA regime compared to sitting and showed non-significant trends for improvement compared to exercise. CONCLUSIONS: One hour of daily physical exercise cannot compensate the negative effects of inactivity on insulin level and plasma lipids if the rest of the day is spent sitting. Reducing inactivity by increasing the time spent walking/standing is more effective than one hour of physical exercise, when energy expenditure is kept constant.

Concepts: Insulin, Diabetes mellitus, Obesity, Overweight, Glucose tolerance test, Impaired fasting glycaemia, Insulin resistance, Impaired glucose tolerance

183

Although loss of functional β-cell mass is a hallmark of diabetes, no treatment approaches that halt this process are currently available. We recently identified thioredoxin-interacting protein (TXNIP) as an attractive target in this regard. Glucose and diabetes upregulate β-cell TXNIP expression, and TXNIP overexpression induces β-cell apoptosis. In contrast, genetic ablation of TXNIP promotes endogenous β-cell survival and prevents streptozotocin (STZ)- and obesity-induced diabetes. Finding an oral medication that could inhibit β-cell TXNIP expression would therefore represent a major breakthrough. We were surprised to discover that calcium channel blockers inhibited TXNIP expression in INS-1 cells and human islets and that orally administered verapamil reduced TXNIP expression and β-cell apoptosis, enhanced endogenous insulin levels, and rescued mice from STZ-induced diabetes. Verapamil also promoted β-cell survival and improved glucose homeostasis and insulin sensitivity in BTBR ob/ob mice. Our data further suggest that this verapamil-mediated TXNIP repression is conferred by reduction of intracellular calcium, inhibition of calcineurin signaling, and nuclear exclusion and decreased binding of carbohydrate response element-binding protein to the E-box repeat in the TXNIP promoter. Thus, for the first time, we have identified an oral medication that can inhibit proapoptotic β-cell TXNIP expression, enhance β-cell survival and function, and prevent and even improve overt diabetes.

Concepts: DNA, Gene, Gene expression, Insulin, Diabetes mellitus, Glucose, Insulin resistance, Calcium channel blocker

177

Despite a considerable amount of data available on the relationship between dietary glycemic index (GI) or load (GL) and cardiovascular disease (CVD) risk factors, in aggregate, the area remains unsettled. The aim of the present review was to summarize the effect of diets differing in GI/GL on CVD risk factors, by examining randomized controlled-feeding trials that provided all food and beverages to adult participants. The studies included a low and high GI/GL diet phase for a minimum of four weeks duration, and reported at least one outcome related to CVD risk; glucose homeostasis, lipid profile or inflammatory status. Ten publications representing five trials were identified. The low GI/GL compared to the high GI/GL diet unexpectedly resulted in significantly higher fasting glucose concentrations in two of the trials, and a lower area under the curve for glucose and insulin in one of the two studies during an oral glucose tolerance test. Response of plasma total, low density lipoprotein and high density lipoprotein cholesterol concentrations was conflicting in two of the studies for which data were available. There was either weak or no effect on inflammatory markers. The results of the five randomized controlled trials satisfying the inclusion criteria suggest inconsistent effects of the GI/GL value of the diet on CVD risk factors.

Concepts: Nutrition, Atherosclerosis, Diabetes mellitus, Cardiovascular disease, Low-density lipoprotein, Blood sugar, Insulin resistance, Glycemic index

176

Type 1 diabetes is associated with increased cardiovascular disease (CVD). Decreased endothelial progenitor cells (EPCs) number plays a pivotal role in reduced endothelial repair and development of CVD. We aimed to determine if cardioprotective effect of metformin is mediated by increasing circulating endothelial progenitor cells (cEPCs), pro-angiogenic cells (PACs) and decreasing circulating endothelial cells (cECs) count whilst maintaining unchanged glycemic control.

Concepts: Atherosclerosis, Diabetes mellitus type 2, Diabetes mellitus, Diabetes mellitus type 1, Blood vessel, Diabetes, Endothelial progenitor cell, Insulin resistance

176

OBJECTIVE The possible interaction of serum 25-hydroxyvitamin D [25(OH)D] and obesity in regard to type 2 diabetes and insulin resistance has not been well studied. To explore the effect modification of obesity on the association between 25(OH)D and insulin resistance/type 2 diabetes, data were examined from a nationally representative sample. RESEARCH DESIGN AND METHODS The analytic sample for the type 2 diabetes analysis (n = 12,900) was limited to participants from the National Health and Nutrition Examination Survey (NHANES) 2001-2006 over 20 years of age. Participants >20 years of age assigned to the morning session and free of diabetes were limited to the insulin resistance analysis (n = 5,806). Multiplicative interaction was assessed through a cross-product interaction term in a multiple logistic regression model. The presence of additive interaction between insufficient 25(OH)D and obesity (indicated by BMI or waist circumference) was evaluated by calculation of the relative excess risk due to interaction (RERI) and attributable proportion due to interaction (AP). RESULTS There was no multiplicative interaction of insufficient 25(OH)D and obesity on type 2 diabetes or insulin resistance. Furthermore, none of the RERI or AP values were statistically significant in the diabetes analysis. However, there was strong additive interaction between abdominal obesity and insufficient 25(OH)D (RERI 6.45 [95% CI 1.03-11.52]) in regard to insulin resistance. In addition, 47% of the increased odds of insulin resistance can be explained by interaction between insufficient 25(OH)D and high BMI (AP 0.47 [95% CI 0.08-0.87]). CONCLUSIONS Within a cross-sectional, nationally representative sample, abdominal obesity and insufficient 25(OH)D interact to synergistically influence the risk of insulin resistance.

Concepts: Regression analysis, Vitamin D, Insulin, Diabetes mellitus type 2, Diabetes mellitus, Obesity, Insulin resistance, Metabolic syndrome