Replication of the Association of BDNF and MC4R Variants With Dietary Intake in the Diabetes Prevention Program.

OBJECTIVE: Genomewide association studies (GWAS) have identified consistent associations with obesity, with a number of studies implicating eating behavior as a primary mechanism. Few studies have replicated genetic associations with dietary intake. This study evaluates the association between obesity susceptibility loci and dietary intake. METHODS: Data were obtained as part of the Diabetes Prevention Program (DPP), a clinical trial of diabetes prevention in persons at high risk of diabetes. The association of 31 genomewide association studies identified obesity risk alleles with dietary intake, measured through a food frequency questionnaire, was investigated in 3,180 participants from DPP at baseline. RESULTS: The minor allele at BDNF, identified as protective against obesity, was associated with lower total caloric intake (ß = -106.06, SE = 33.13; p = .0014) at experimentwide statistical significance (p = .0016), whereas association of MC4R rs571312 with higher caloric intake reached nominal significance (ß = 61.32, SE = 26.24; p = .0194). Among non-Hispanic white participants, the association of BDNF rs2030323 with total caloric intake was stronger (ß = -151.99, SE = 30.09; p < .0001), and association of FTO rs1421085 with higher caloric intake (ß = 56.72, SE = 20.69; p = .0061) and percentage fat intake (ß = 0.37, SE = 0.08; p = .0418) was also observed. CONCLUSIONS: These results demonstrate with the strength of independent replication that BDNF rs2030323 is associated with 100 to 150 greater total caloric intake per allele, with additional contributions of MC4R and, in non-Hispanic white individuals, FTO. As it has been argued that an additional 100 kcal/d could account for the trends in weight gain, prevention focusing on genetic profiles with high dietary intake may help to quell adverse obesity trends. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov,NCT00004992.

Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes.

BACKGROUND: Weight loss is recommended for overweight or obese patients with type 2 diabetes on the basis of short-term studies, but long-term effects on cardiovascular disease remain unknown. We examined whether an intensive lifestyle intervention for weight loss would decrease cardiovascular morbidity and mortality among such patients. METHODS: In 16 study centers in the United States, we randomly assigned 5145 overweight or obese patients with type 2 diabetes to participate in an intensive lifestyle intervention that promoted weight loss through decreased caloric intake and increased physical activity (intervention group) or to receive diabetes support and education (control group). The primary outcome was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for angina during a maximum follow-up of 13.5 years. RESULTS: The trial was stopped early on the basis of a futility analysis when the median follow-up was 9.6 years. Weight loss was greater in the intervention group than in the control group throughout the study (8.6% vs. 0.7% at 1 year; 6.0% vs. 3.5% at study end). The intensive lifestyle intervention also produced greater reductions in glycated hemoglobin and greater initial improvements in fitness and all cardiovascular risk factors, except for low-density-lipoprotein cholesterol levels. The primary outcome occurred in 403 patients in the intervention group and in 418 in the control group (1.83 and 1.92 events per 100 person-years, respectively; hazard ratio in the intervention group, 0.95; 95% confidence interval, 0.83 to 1.09; P=0.51). CONCLUSIONS: An intensive lifestyle intervention focusing on weight loss did not reduce the rate of cardiovascular events in overweight or obese adults with type 2 diabetes. (Funded by the National Institutes of Health and others; Look AHEAD ClinicalTrials.gov number, NCT00017953.).

Pioglitazone for diabetes prevention in impaired glucose tolerance.

BACKGROUND: Impaired glucose tolerance is associated with increased rates of cardiovascular disease and conversion to type 2 diabetes mellitus. Interventions that may prevent or delay such occurrences are of great clinical importance. METHODS: We conducted a randomized, double-blind, placebo-controlled study to examine whether pioglitazone can reduce the risk of type 2 diabetes mellitus in adults with impaired glucose tolerance. A total of 602 patients were randomly assigned to receive pioglitazone or placebo. The median follow-up period was 2.4 years. Fasting glucose was measured quarterly, and oral glucose tolerance tests were performed annually. Conversion to diabetes was confirmed on the basis of the results of repeat testing. RESULTS: Annual incidence rates for type 2 diabetes mellitus were 2.1% in the pioglitazone group and 7.6% in the placebo group, and the hazard ratio for conversion to diabetes in the pioglitazone group was 0.28 (95% confidence interval, 0.16 to 0.49; P<0.001). Conversion to normal glucose tolerance occurred in 48% of the patients in the pioglitazone group and 28% of those in the placebo group (P<0.001). Treatment with pioglitazone as compared with placebo was associated with significantly reduced levels of fasting glucose (a decrease of 11.7 mg per deciliter vs. 8.1 mg per deciliter [0.7 mmol per liter vs. 0.5 mmol per liter], P<0.001), 2-hour glucose (a decrease of 30.5 mg per deciliter vs. 15.6 mg per deciliter [1.6 mmol per liter vs. 0.9 mmol per liter], P<0.001), and HbA(1c) (a decrease of 0.04 percentage points vs. an increase of 0.20 percentage points, P<0.001). Pioglitazone therapy was also associated with a decrease in diastolic blood pressure (by 2.0 mm Hg vs. 0.0 mm Hg, P=0.03), a reduced rate of carotid intima-media thickening (31.5%, P=0.047), and a greater increase in the level of high-density lipoprotein cholesterol (by 7.35 mg per deciliter vs. 4.5 mg per deciliter [0.4 mmol per liter vs. 0.3 mmol per liter], P=0.008). Weight gain was greater with pioglitazone than with placebo (3.9 kg vs. 0.77 kg, P<0.001), and edema was more frequent (12.9% vs. 6.4%, P=0.007). CONCLUSIONS: As compared with placebo, pioglitazone reduced the risk of conversion of impaired glucose tolerance to type 2 diabetes mellitus by 72% but was associated with significant weight gain and edema. (Funded by Takeda Pharmaceuticals and others; ClinicalTrials.gov number, NCT00220961.).

Intensive lifestyle intervention reduces urinary incontinence in overweight/obese men with type 2 diabetes: results from the Look AHEAD trial.

PURPOSE: We determined the effect of an intensive lifestyle intervention on the prevalence, incidence and resolution of bothersome nocturia, increased daytime urinary voiding and urinary incontinence in overweight/obese men with type 2 diabetes after 1 year in the Look AHEAD trial. MATERIALS AND METHODS: A subset of male Look AHEAD participants was selected for this secondary data analysis. Overall 1,910 men with an average (mean ± SD) age of 59.9 ± 6.7 years and body mass index of 35.2 ± 5.5 kg/m(2) were randomized to an intensive lifestyle intervention or diabetes support and education group. All participants self-reported information regarding incontinence, nocturia and daytime urinary voiding at entry and 1 year. RESULTS: After 1 year the intensive lifestyle intervention group lost significantly more weight than the diabetes support and education group (9.4% ± 7.0% vs 0.7% ± 4.5%, respectively; p <0.001). The odds of prevalent urinary incontinence at 1 year were reduced by 38% in the intensive lifestyle intervention group compared to the diabetes support and education group. The prevalence of urinary incontinence decreased from 11.3% to 9.0% in the intensive lifestyle intervention group and increased from 9.7% to 11.6% in the diabetes support and education group. The intensive lifestyle intervention group also had increased odds of urinary incontinence resolving (OR 1.93, 95% CI 1.04-3.59, p = 0.04 and 56.0% vs 40.7%, p = 0.03) and trend toward reduced odds of new onset, incident urinary incontinence (OR 0.66, 95% CI 0.42-1.02, p = 0.06) compared with the diabetes support and education arm. In contrast, no differences between intensive lifestyle intervention and diabetes support and education were seen at 1 year for frequency of nocturia or frequency of daytime voiding. CONCLUSIONS: Intensive lifestyle intervention should be considered for the treatment of urinary incontinence in overweight/obese men with type 2 diabetes.

Look inside Look AHEAD: why the glass is more than half-full.

Look AHEAD is the only long-term study in a large cohort of subjects with type 2 diabetes that assessed the effect of intensive lifestyle, predominantly diet and exercise, on a number of outcomes. While Look AHEAD was not able to detect a significant effect of intensive lifestyle modification on cardiovascular outcomes, it clearly demonstrated numerous beneficial and sustained effects on health outcomes that are relevant to this population. Without the exceptional retention of study participants, it would have been difficult to detect these benefits. Our review provides a perspective on aspects related to exercise, diet, and weight loss in relation to cardiovascular outcomes and potential future research.

Pioglitazone slows progression of atherosclerosis in prediabetes independent of changes in cardiovascular risk factors.

OBJECTIVE: To determine whether changes in standard and novel risk factors during the Actos Now for Prevention of Diabetes trial explained the slower rate of carotid intima media thickness (CIMT) progression with pioglitazone treatment in persons with prediabetes. METHODS AND RESULTS: CIMT was measured in 382 participants at the beginning and up to 3 additional times during follow-up of the Actos Now for Prevention of Diabetes trial. During an average follow-up of 2.3 years, the mean unadjusted annual rate of CIMT progression was significantly (P=0.01) lower with pioglitazone treatment (4.76×10(-3) mm/year; 95% CI: 2.39×10(-3)-7.14×10(-3) mm/year) compared with placebo (9.69×10(-3) mm/year; 95% CI: 7.24×10(-3)-12.15×10(-3) mm/year). High-density lipoprotein cholesterol, fasting and 2-hour glucose, HbA(1c), fasting insulin, Matsuda insulin sensitivity index, adiponectin, and plasminogen activator inhibitor-1 levels improved significantly with pioglitazone treatment compared with placebo (P<0.001). However, the effect of pioglitazone on CIMT progression was not attenuated by multiple methods of adjustment for traditional, metabolic, and inflammatory risk factors and concomitant medications, and was independent of changes in risk factors during pioglitazone treatment. CONCLUSIONS: Pioglitazone slowed progression of CIMT, independent of improvement in hyperglycemia, insulin resistance, dyslipidemia, and systemic inflammation in prediabetes. These results suggest a possible direct vascular benefit of pioglitazone.

Venous serum bicarbonate concentration predicts arterial pH in adults with diabetic ketoacidosis.

OBJECTIVE: The initial assessment of metabolic acidosis in subjects with diabetic ketoacidosis (DKA) is arterial blood gas analysis. This process is expensive, painful, and technically difficult. Furthermore, blood gas analysis may not be available in some facilities, especially in developing countries where DKA-associated morbidity and mortality remain high. Therefore, we investigated the utility of venous bicarbonate concentration obtained from a basic metabolic panel in predicting arterial pH in adults with DKA. METHODS: We performed a retrospective analysis of clinical and biochemical data of 396 adults admitted to 2 community teaching hospitals with DKA. We determined the correlation between arterial pH and venous serum parameters. Using multiple logistic regression, we obtained a predictive formula for arterial pH from serum venous bicarbonate level. RESULTS: The patient population was 59.0% male and had a mean age of 36.7 ± 13.3 years. We derived that arterial pH = 6.97 + (0.0163 x bicarbonate), and by applying this equation, we determined that serum venous bicarbonate concentration of ≤20.6 mEq/L predicted arterial pH ≤7.3 with over 95% sensitivity and 92% accuracy. CONCLUSION: Venous serum bicarbonate obtained from the basic metabolic panel is an affordable and reliable way of estimating arterial pH in adults with DKA. Validation of this formula in a prospective study would offer a more accessible means of estimating metabolic acidosis in adults with DKA, especially in developing countries where DKA incidence and mortality remain high.

Human cardiovascular disease IBC chip-wide association with weight loss and weight regain in the look AHEAD trial.

BACKGROUND/AIMS: The present study identified genetic predictors of weight change during behavioral weight loss treatment. METHODS: Participants were 3,899 overweight/obese individuals with type 2 diabetes from Look AHEAD, a randomized controlled trial to determine the effects of intensive lifestyle intervention (ILI), including weight loss and physical activity, relative to diabetes support and education, on cardiovascular outcomes. Analyses focused on associations of single nucleotide polymorphisms (SNPs) on the Illumina CARe iSelect (IBC) chip (minor allele frequency >5%; n = 31,959) with weight change at year 1 and year 4, and weight regain at year 4, among individuals who lost ≥ 3% at year 1. RESULTS: Two novel regions of significant chip-wide association with year-1 weight loss in ILI were identified (p < 2.96E-06). ABCB11 rs484066 was associated with 1.16 kg higher weight per minor allele at year 1, whereas TNFRSF11A, or RANK, rs17069904 was associated with 1.70 kg lower weight per allele at year 1. CONCLUSIONS: This study, the largest to date on genetic predictors of weight loss and regain, indicates that SNPs within ABCB11, related to bile salt transfer, and TNFRSF11A, implicated in adipose tissue physiology, predict the magnitude of weight loss during behavioral intervention. These results provide new insights into potential biological mechanisms and may ultimately inform weight loss treatment.

Association of an intensive lifestyle intervention with remission of type 2 diabetes.

CONTEXT: The frequency of remission of type 2 diabetes achievable with lifestyle intervention is unclear. OBJECTIVE: To examine the association of a long-term intensive weight-loss intervention with the frequency of remission from type 2 diabetes to prediabetes or normoglycemia. DESIGN, SETTING, AND PARTICIPANTS: Ancillary observational analysis of a 4-year randomized controlled trial (baseline visit, August 2001-April 2004; last follow-up, April 2008) comparing an intensive lifestyle intervention (ILI) with a diabetes support and education control condition (DSE) among 4503 US adults with body mass index of 25 or higher and type 2 diabetes. INTERVENTIONS: Participants were randomly assigned to receive the ILI, which included weekly group and individual counseling in the first 6 months followed by 3 sessions per month for the second 6 months and twice-monthly contact and regular refresher group series and campaigns in years 2 to 4 (n=2241) or the DSE, which was an offer of 3 group sessions per year on diet, physical activity, and social support (n=2262). MAIN OUTCOME MEASURES: Partial or complete remission of diabetes, defined as transition from meeting diabetes criteria to a prediabetes or nondiabetic level of glycemia (fasting plasma glucose <126 mg/dL and hemoglobin A1c <6.5% with no antihyperglycemic medication). RESULTS Intensive lifestyle intervention participants lost significantly more weight than DSE participants at year 1 (net difference, -7.9%; 95% CI, -8.3% to -7.6%) and at year 4 (-3.9%; 95% CI, -4.4% to -3.5%) and had greater fitness increases at year 1 (net difference, 15.4%; 95% CI, 13.7%-17.0%) and at year 4 (6.4%; 95% CI, 4.7%-8.1%) (P < .001 for each). The ILI group was significantly more likely to experience any remission (partial or complete), with prevalences of 11.5% (95% CI, 10.1%-12.8%) during the first year and 7.3% (95% CI, 6.2%-8.4%) at year 4, compared with 2.0% for the DSE group at both time points (95% CIs, 1.4%-2.6% at year 1 and 1.5%-2.7% at year 4) (P < .001 for each). Among ILI participants, 9.2% (95% CI, 7.9%-10.4%), 6.4% (95% CI, 5.3%-7.4%), and 3.5% (95% CI, 2.7%-4.3%) had continuous, sustained remission for at least 2, at least 3, and 4 years, respectively, compared with less than 2% of DSE participants (1.7% [95% CI, 1.2%-2.3%] for at least 2 years; 1.3% [95% CI, 0.8%-1.7%] for at least 3 years; and 0.5% [95% CI, 0.2%-0.8%] for 4 years). CONCLUSIONS: In these exploratory analyses of overweight adults, an intensive lifestyle intervention was associated with a greater likelihood of partial remission of type 2 diabetes compared with diabetes support and education. However, the absolute remission rates were modest. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00017953.

Effects of oral and intravenous fat load on blood pressure, endothelial function, sympathetic activity, and oxidative stress in obese healthy subjects.

We compared the effects of high and low oral and intravenous (iv) fat load on blood pressure (BP), endothelial function, autonomic nervous system, and oxidative stress in obese healthy subjects. Thirteen obese subjects randomly received five 8-h infusions of iv saline, 20 (32 g, low iv fat) or 40 ml/h intralipid (64 g, high iv fat), and oral fat load at 32 (low oral) or 64 g (high oral). Systolic BP increased by 14 ± 10 (P = 0.007) and 12 ± 9 mmHg (P = 0.007) after low and high iv lipid infusions and by 13 ± 17 (P = 0.045) and 11 ± 11 mmHg (P = 0.040) after low and high oral fat loads, respectively. The baseline flow-mediated dilation was 9.4%, and it decreased by 3.8 ± 2.1 (P = 0.002) and 4.1 ± 3.1% (P < 0.001) after low and high iv lipid infusion and by 3.8 ± 1.8 (P = 0.002) and 5.0 ± 2.5% (P < 0.001) after low and high oral fat load, respectively. Oral and iv fat load stimulated oxidative stress, increased heart rate, and decreased R-R interval variability. Acute iv fat load decreased blood glucose by 6-10 mg/dl (P < 0.05) without changes in insulin concentration, whereas oral fat increased plasma insulin by 3.7-4.0 µU/ml (P < 0.01) without glycemic variations. Intravenous saline and both oral and iv fat load reduced leptin concentration from baseline (P < 0.01). In conclusion, acute fat load administered orally or intravenously significantly increased blood pressure, altered endothelial function, and activated sympathetic nervous system by mechanisms not likely depending on changes in leptin, glucose, and insulin levels in obese healthy subjects. Thus, fat load, independent of its source, has deleterious hemodynamic effects in obese subjects.

Effects of weight loss intervention on erectile function in older men with type 2 diabetes in the Look AHEAD trial.

INTRODUCTION: Overweight men with diabetes often report erectile dysfunction (ED), but few studies have examined effects of weight loss on this problem. AIM: This study examined 1-year changes in erectile function (EF) in overweight/obese men with type 2 diabetes participating in the Look AHEAD (Action for Health in Diabetes) trial. METHODS: Participants in Look AHEAD were randomly assigned to a control condition involving diabetes support and education (DSE) or to intensive lifestyle intervention (ILI) involving group and individual sessions to reduce weight and increase physical activity. Men from five of the clinical sites in Look AHEAD completed the International Index of Erectile Function (IIEF) at baseline (N = 372) and at 1 year (N = 306) (82%). MAIN OUTCOME MEASURES: Changes in EF as reported on the EF subscale of the IIEF. RESULTS: At 1 year, the ILI group lost a greater percent of initial body weight (9.9% vs. 0.6 %) and had greater improvements in fitness (22.7% vs. 4.6%) than DSE. EF improved more in ILI (17.3 +/- 7.6 at baseline; 18.6 +/- 8.1 at 1 year) than in DSE (18.3 +/- 7.6 at baseline; 18.4 +/- 8.0 at 1 year); P = 0.04 and P = 0.06 after adjusting for baseline differences. Using established norms for none (i.e., normal EF), and three grades (i.e., mild, moderate, and severe) ED, 8% of men in ILI reported a worsening of EF from baseline to 1 year, 70% stayed in the same category, and 22% reported improvements. In contrast, 20% of DSE reported worsening, 57% stayed in the same category, and 23% improved (P = 0.006). CONCLUSION: In this sample of older overweight/obese diabetic men, weight loss intervention was mildly helpful in maintaining EF.

History of Cardiovascular Disease, Intensive Lifestyle Intervention, and Cardiovascular Outcomes in the Look AHEAD Trial.

OBJECTIVE: To examine the effects of an intensive lifestyle intervention (ILI) on cardiovascular disease (CVD), the Action for Health in Diabetes (Look AHEAD) trial randomized 5,145 participants with type 2 diabetes and overweight/obesity to a ILI or diabetes support and education. Although the primary outcome did not differ between the groups, there was suggestive evidence of heterogeneity for prespecified baseline CVD history subgroups (interaction P = 0.063). Event rates were higher in the ILI group among those with a CVD history (hazard ratio 1.13 [95% CI: 0.90-1.41]) and lower among those without CVD (hazard ratio 0.86 [95% CI: 0.72-1.02]). METHODS: This study conducted post hoc analyses of the rates of the primary composite outcome and components, adjudicated cardiovascular death, nonfatal myocardial infarction (MI), stroke, and hospitalization for angina, as well as three secondary composite cardiovascular outcomes. RESULTS: Interaction P values for the primary and two secondary composites were similar (0.060-0.064). Of components, the interaction was significant for nonfatal MI (P = 0.035). This interaction was not due to confounding by baseline variables, different intervention responses for weight loss and physical fitness, or hypoglycemic events. In those with a CVD history, statin use was high and similar by group. In those without a CVD history, low-density lipoprotein cholesterol levels were higher (P = 0.003) and statin use was lower (P ≤ 0.001) in the ILI group. CONCLUSIONS: Intervention response heterogeneity was significant for nonfatal MI. Response heterogeneity may need consideration in a CVD-outcome trial design.

Intravenous intralipid-induced blood pressure elevation and endothelial dysfunction in obese African-Americans with type 2 diabetes.

OBJECTIVE: Increased free fatty acids (FFAs) are leading candidates in the pathogenesis of insulin resistance and hypertension in obese subjects. We evaluated the effect of sustained elevations of FFA on blood pressure, endothelial function, insulin secretion, inflammatory markers, and renin-angiotensin system. RESEARCH DESIGN AND METHODS: Twenty-four obese, African-American, normotensive diabetic subjects received a sequential 48-h infusion of Intralipid (20%, 40 ml/h) plus heparin (250 units/h) or normal saline (40 ml/h) plus heparin (250 units/h). RESULTS: Blood pressure was significantly increased within 4 h of lipid infusion and reached a peak increment of 13 mm Hg in systolic and 5 mm Hg in diastolic blood pressure at 24 h (P < 0.01). Compared to baseline, lipid infusion reduced flow-mediated dilatation by 11% at 24 h and 18% at 48 h (P < 0.001). FFA and triglyceride levels increased from a baseline of 0.5 +/- 0.2 mmol/liter and 135 +/- 76 mg/dl to 1.8 +/- 1.0 mmol/liter and 376 +/- 314 mg/dl at 48 h, respectively (P < 0.01). C-Reactive protein increased by 35% at 24 h and by 110% at 48 h of lipid infusion. There were no significant changes in plasma renin and aldosterone levels during lipid or saline infusions. CONCLUSION: Increased FFA levels result in a rapid and sustained elevation in blood pressure, impaired endothelial function, and increased inflammatory markers in obese subjects with type 2 diabetes. The model of FFA-induced hypertension may be useful in examining disease mechanisms associated with the development of hypertension in obese subjects.

The association of ENPP1 K121Q with diabetes incidence is abolished by lifestyle modification in the diabetes prevention program.

CONTEXT: Insulin resistance is an important feature of type 2 diabetes. Ectoenzyme nucleotide pyrophosphatase phosphodiesterase 1 (ENPP1) inhibits insulin signaling, and a recent meta-analysis reported a nominal association between the Q allele in the K121Q (rs1044498) single nucleotide polymorphism in its gene ENPP1 and type 2 diabetes. OBJECTIVE AND INTERVENTION: We examined the impact of this polymorphism on diabetes incidence as well as insulin secretion and sensitivity at baseline and after treatment with a lifestyle intervention or metformin vs. placebo in the Diabetes Prevention Program (DPP). DESIGN, SETTING, PARTICIPANTS, AND OUTCOME: We genotyped ENPP1 K121Q in 3548 DPP participants and performed Cox regression analyses using genotype, intervention, and interactions as predictors of diabetes incidence. RESULTS: Fasting glucose and glycated hemoglobin were higher in QQ homozygotes at baseline (P < 0.001 for both). There was a significant interaction between genotype at rs1044498 and intervention under the dominant model (P = 0.03). In analyses stratified by treatment arm, a positive association with diabetes incidence was found in Q allele carriers compared to KK homozygotes [hazard ratio (HR), 1.38; 95% confidence interval (CI), 1.08-1.76; P = 0.009] in the placebo arm (n = 996). Lifestyle modification eliminated this increased risk. These findings persisted after adjustment for body mass index and race/ethnicity. Association of ENPP1 K121Q genotype with diabetes incidence under the additive and recessive genetic models showed consistent trends [HR, 1.10 (95% CI, 0.99-1.23), P = 0.08; and HR, 1.16 (95% CI, 0.92-1.45), P = 0.20, respectively] but did not reach statistical significance. CONCLUSIONS: ENPP1 K121Q is associated with increased diabetes incidence; the DPP lifestyle intervention eliminates this increased risk.

Erectile dysfunction in type 2 diabetic men: relationship to exercise fitness and cardiovascular risk factors in the Look AHEAD trial.

INTRODUCTION: Determinants of erectile dysfunction in diabetic men have not been adequately investigated as potential mediators of change. AIM: To determine the prevalence and correlates of erectile dysfunction (ED) in overweight men with type 2 diabetes in the multicenter, Look AHEAD trial (Action for Health in Diabetes). MAIN OUTCOME MEASURES: International Index of Erectile Function (IIEF), self-reported use of phosphodiesterase type 5 inhibitors, laboratory measures of adiposity, cardiometabolic parameters, and exercise fitness. METHODS: Male participants aged 45-75 in the Look AHEAD trial in a committed relationship were recruited for an ongoing study of sexual function and diabetes. Eligible participants completed the IIEF questionnaire and provided updated information on use of medical treatments for sexual dysfunction. Baseline sexual function results for participants in the male ancillary study are reported here; intervention data and results for female participants are presented elsewhere. RESULTS: A total of 373 eligible male participants completed all sexual function questionnaires, of whom 263 (68.7%) were sexually active at the time of the study. Almost half (49.8%) of the men reported mild or moderate degrees of ED, and 24.8% had complete ED. Among sexually active participants, 42.6% had sought medical help for their problem, and 39.7% reported use of ED medications. ED was significantly associated with age (odds ratio [OR] = 1.05; confidence interval [CI]: 1.01-1.10) baseline HbA(1c) (OR = 1.31; CI: 1.05-1.63), hypertension history (OR = 2.41; CI: 1.34-4.36), and metabolic syndrome (OR = 3.05, CI: 1.31-7.11). Of note, cardiorespiratory fitness was found to be protective of ED in a multivariable analysis (OR = 0.61; P < 0.001). CONCLUSIONS: ED is prevalent in this sample of obese, type 2 diabetic men in the Look AHEAD study. Cardiovascular risk factors were highly associated with ED in this population, and cardiorespiratory fitness was protective in this analysis.

Actos Now for the prevention of diabetes (ACT NOW) study.

BACKGROUND: Impaired glucose tolerance (IGT) is a prediabetic state. If IGT can be prevented from progressing to overt diabetes, hyperglycemia-related complications can be avoided. The purpose of the present study was to examine whether pioglitazone (ACTOS) can prevent progression of IGT to type 2 diabetes mellitus (T2DM) in a prospective randomized, double blind, placebo controlled trial. METHODS/DESIGN: 602 IGT subjects were identified with OGTT (2-hour plasma glucose = 140-199 mg/dl). In addition, IGT subjects were required to have FPG = 95-125 mg/dl and at least one other high risk characteristic. Prior to randomization all subjects had measurement of ankle-arm blood pressure, systolic/diastolic blood pressure, HbA1C, lipid profile and a subset had frequently sampled intravenous glucose tolerance test (FSIVGTT), DEXA, and ultrasound determination of carotid intima-media thickness (IMT). Following this, subjects were randomized to receive pioglitazone (45 mg/day) or placebo, and returned every 2-3 months for FPG determination and annually for OGTT. Repeat carotid IMT measurement was performed at 18 months and study end. Recruitment took place over 24 months, and subjects were followed for an additional 24 months. At study end (48 months) or at time of diagnosis of diabetes the OGTT, FSIVGTT, DEXA, carotid IMT, and all other measurements were repeated.Primary endpoint is conversion of IGT to T2DM based upon FPG >or= 126 or 2-hour PG >or= 200 mg/dl. Secondary endpoints include whether pioglitazone can: (i) improve glycemic control (ii) enhance insulin sensitivity, (iii) augment beta cell function, (iv) improve risk factors for cardiovascular disease, (v) cause regression/slow progression of carotid IMT, (vi) revert newly diagnosed diabetes to normal glucose tolerance. CONCLUSION: ACT NOW is designed to determine if pioglitazone can prevent/delay progression to diabetes in high risk IGT subjects, and to define the mechanisms (improved insulin sensitivity and/or enhanced beta cell function) via which pioglitazone exerts its beneficial effect on glucose metabolism to prevent/delay onset of T2DM. TRIAL REGISTRATION: clinical trials.gov identifier: NCT00220961.

Thirty years of personal experience in hyperglycemic crises: diabetic ketoacidosis and hyperglycemic hyperosmolar state.

CONTEXT: Diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar state (HHS) cause major morbidity and significant mortality in patients with diabetes mellitus. For more than 30 yr, our group, in a series of prospective, randomized clinical studies, has investigated the pathogenesis and evolving strategies of the treatment of hyperglycemic crises. This paper summarizes the results of these prospective studies on the management and pathophysiology of DKA. SETTING: Our earliest studies evaluated the comparative efficacy of low-dose vs. pharmacological amounts of insulin and the use of low-dose therapy by various routes in adults and later in children. Subsequent studies evaluated phosphate and bicarbonate therapy, lipid metabolism, ketosis-prone type 2 patients, and use of rapid-acting insulin analogs as well as leptin status, cardiac risk factors, proinflammatory cytokines, and the mechanism of activation of T lymphocytes in hyperglycemic crises. MAIN OUTCOME: The information garnered from these studies resulted in the creation of the 2001 American Diabetes Association (ADA) technical review on DKA and HHS as well as the ADA Position and Consensus Paper on the therapy for hyperglycemic crises. CONCLUSIONS: Areas of future research include prospective randomized studies to do the following: 1) establish the efficacy of bicarbonate therapy in DKA for a pH less than 6.9; 2) establish the need for a bolus insulin dose in the initial therapy of DKA; 3) determine the pathophysiological mechanisms for the absence of ketosis in HHS; 4) investigate the reasons for elevated proinflammatory cytokines and cardiovascular risk factors; and 5) evaluate the efficacy and cost benefit of using sc regular insulin vs. more expensive insulin analogs on the general ward for the treatment of DKA.

Evidence for strict inpatient blood glucose control: time to revise glycemic goals in hospitalized patients.

Inpatient hyperglycemia in patients with and without a history of diabetes is common and is associated with increased hospital morbidity and mortality. The objectives of this communication are to examine results of randomized clinical trials of strict inpatient glucose control in medical and surgical intensive care units and to provide guidelines for achieving and maintaining glycemic control in patients admitted to critical and noncritical settings. We propose a more conservative approach of glycemic control than current American Association of Clinical Endocrinology recommendations until results of prospective, multicenter, randomized studies become available.

Transcriptome and proteome expressions involved in insulin resistance in muscle and activated T-lymphocytes of patients with type 2 diabetes.

We analyzed the genes expressed (transcriptomes) and the proteins translated (pro- teomes) in muscle tissues and activated CD4(+) and CD8(+) T-lymphocytes (T-cells) of five Type 2 diabetes (T2DM) subjects using Affymetrix microarrays and mass spectrometry, and compared them with matched non-diabetic controls. Gene expressions of insulin receptor (INSR), vitamin D receptor, insulin degrading enzyme, Akt, insulin receptor substrate-1 (IRS-1), IRS-2, glucose transporter 4 (GLUT4), and enzymes of the glycolytic pathway were decreased at least 50% in T2DM than in controls. However, there was greater than two-fold gene upregulation of plasma cell glycoprotein-1, tumor necrosis factor alpha (TNFalpha, and gluconeogenic enzymes in T2DM than in controls. The gene silencing for INSR or TNFalpha resulted in the inhibition or stimulation of GLUT4, respectively. Proteome profiles corresponding to molecular weights of the above translated transcriptomes showed different patterns of changes between T2DM and controls. Meanwhile, changes in transcriptomes and proteomes between muscle and activated T-cells of T2DM were comparable. Activated T-cells, analogous to muscle cells, expressed insulin signaling and glucose metabolism genes and gene products. In conclusion, T-cells and muscle in T2DM exhibited differences in expression of certain genes and gene products relative to non-diabetic controls. These alterations in transcriptomes and proteomes in T2DM may be involved in insulin resistance.

Narrative review: ketosis-prone type 2 diabetes mellitus.

Several investigators have reported that more than half of African-American persons with new diagnoses of diabetic ketoacidosis have clinical, metabolic, and immunologic features of type 2 diabetes during follow-up. These patients are usually obese, have a strong family history of diabetes, have a low prevalence of autoimmune markers, and lack a genetic association with HLA. Their initial presentation is acute, with a few days to weeks of polyuria, polydipsia, and weight loss and lack of a precipitating cause of metabolic decompensation. At presentation, they have markedly impaired insulin secretion and insulin action, but intensified diabetic management results in significant improvement in beta-cell function and insulin sensitivity sufficient to allow discontinuation of insulin therapy within a few months of follow-up. On discontinuation of insulin therapy, the period of near-normoglycemic remission may last for a few months to several years. The absence of autoimmune markers and the presence of measurable insulin secretion have proven useful in predicting near-normoglycemic remission and long-term insulin dependence in adult patients with a history of diabetic ketoacidosis. This clinical presentation is commonly reported in African and African-American persons but is also observed in Hispanic persons and those from other minority ethnic groups. The underlying mechanisms for beta-cell dysfunction in ketosis-prone type 2 diabetes are not known; however, preliminary evidence suggests an increased susceptibility to glucose desensitization.