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.

Remission of pre-diabetes to normal glucose tolerance in obese adults with high protein versus high carbohydrate diet: randomized control trial.

OBJECTIVE: Remission of pre-diabetes to normal is an important health concern which has had little success in the past. This study objective was to determine the effect on remission of pre-diabetes with a high protein (HP) versus high carbohydrate (HC) diet and effects on metabolic parameters, lean and fat body mass in prediabetic, obese subjects after 6 months of dietary intervention. RESEARCH DESIGN AND METHODS: We recruited and randomized 24 pre-diabetes women and men to either a HP (30% protein, 30% fat, 40% carbohydrate; n=12) or HC (15% protein, 30% fat, 55% carbohydrate; n=12) diet feeding study for 6 months in this randomized controlled trial. All meals were provided to subjects for 6 months with daily food menus for HP or HC compliance with weekly food pick-up and weight measurements. At baseline and after 6 months on the respective diets oral glucose tolerance and meal tolerance tests were performed with glucose and insulin measurements and dual energy X-ray absorptiometry scans. RESULTS: After 6 months on the HP diet, 100% of the subjects had remission of their pre-diabetes to normal glucose tolerance, whereas only 33.3% of subjects on the HC diet had remission of their pre-diabetes. The HP diet group exhibited significant improvement in (1) insulin sensitivity (p=0.001), (2) cardiovascular risk factors (p=0.04), (3) inflammatory cytokines (p=0.001), (4) oxidative stress (p=0.001), (5) increased percent lean body mass (p=0.001) compared with the HC diet at 6 months. CONCLUSIONS: This is the first dietary intervention feeding study, to the best of our knowledge, to report 100% remission of pre-diabetes with a HP diet and significant improvement in metabolic parameters and anti-inflammatory effects compared with a HC diet at 6 months. TRIAL REGISTRATION NUMBER: NCT0164284.

Pioglitazone is equally effective for diabetes prevention in older versus younger adults with impaired glucose tolerance.

To determine the efficacy of pioglitazone to prevent type 2 diabetes in older compared to younger adults with pre-diabetes. Six hundred two participants with impaired glucose tolerance (IGT) were randomized in double blind fashion to placebo or pioglitazone for diabetes prevention in the ACT NOW study (NEJM 364:1104-1115, 2011). Cox proportional hazard regression was used to compare time to development of diabetes over a mean of 2 years between older (≥61 years) and younger participants. We compared effects of pioglitazone versus placebo on metabolic profiles, inflammatory markers, adipokines, ß cell function (disposition index), insulin sensitivity (Matsuda index), and body composition by ANOVA. Diabetes incidence was reduced by 85 % in older and 69 % in younger subjects (p = 0.41). ß cell function (disposition index) increased by 35.0 % in the older and 26.7 % in younger subjects (p = 0.83). Insulin sensitivity (Matsuda index) increased by 3.07 (5.2-fold) in older and by 2.54 (3.8-fold) in younger participants (p = 0.58). Pioglitazone more effectively increased adiponectin in older versus younger subjects (22.9 ± 3.2 µg/mL [2.7-fold] vs. 12.7 ± 1.4 µg/mL [2.2-fold], respectively; p = 0.04). Younger subjects tended to have a greater increase in whole body fat mass compared to older subjects (3.6 vs. 3.1 kg; p = 0.061). Younger and older subjects had similar decreases in bone mineral density (0.018 ± 0.0071 vs. 0.0138 ± 0.021 g/cm2). Younger and older pre-diabetic adults taking pioglitazone had similar reductions in conversion to diabetes and older adults had similar or greater improvements in metabolic risk factors, demonstrating that pioglitazone is useful in preventing diabetes in older adults.

Diabetes Incidence and Glucose Tolerance after Termination of Pioglitazone Therapy: Results from ACT NOW.

CONTEXT: Thiazolidinediones have proven efficacy in preventing diabetes in high-risk individuals. However, the effect of thiazolidinediones on glucose tolerance after cessation of therapy is unclear. OBJECTIVE: To examine the effect of pioglitazone (PIO) on incidence of diabetes after discontinuing therapy in ACT NOW. Design, Settings and Patients: Two-hundred ninety-three subjects (placebo [PLAC], n = 138; PIO, n = 152) completed a median followup of 11.7 mo after study medication was stopped. RESULTS: Diabetes developed in 138 (12.3%) of PLAC vs 17 of 152 PIO patients (11.2%; P = not significant, PIO vs PLAC). However, the cumulative incidence of diabetes from start of study medication to end of washout period remained significantly lower in PIO vs PLAC (10.7 vs 22.3%; P < .005). After therapy was discontinued, 23.0% (35/152) of PIO-treated patients remained normal-glucose tolerant (NGT) vs 13.8% (19/138) of PLAC-treated patients (P = .04). Insulin secretion/insulin resistance index (I0-120/G0-120 × Matsuda index) was markedly lower in subjects with impaired glucose tolerance (IGT) who converted to diabetes during followup vs those who remained IGT or NGT. The decline in-cell function (insulin secretion/insulin resistance index) was similar in subjects with IGT who developed diabetes, irrespective of whether they were treated with PIO or PLAC. CONCLUSIONS: 1) The protective effect of PIO on incidence of diabetes attenuates after discontinuation of therapy, 2) cumulative incidence of diabetes in individuals exposed to PIO remained significantly (56%) lower than PLAC and a greater number of PIO-treated individuals maintained NGT after median followup of 11.4 mo, and 3) low insulin secretion/insulin resistance index is a strong predictor of future diabetes following PIO discontinuation.

The evolution of diabetic ketoacidosis: An update of its etiology, pathogenesis and management.

The prognosis of diabetic ketoacidosis has undergone incredibly remarkable evolution since the discovery of insulin nearly a century ago. The incidence and economic burden of diabetic ketoacidosis have continued to rise but its mortality has decreased to less than 1% in good centers. Improved outcome is attributable to a better understanding of the pathophysiology of the disease and widespread application of treatment guidelines. In this review, we present the changes that have occurred over the years, highlighting the evidence behind the recommendations that have improved outcome. We begin with a discussion of the precipitants and pathogenesis of DKA as a prelude to understanding the rationale for the recommendations. A brief review of ketosis-prone type 2 diabetes, an update relating to the diagnosis of DKA and a future perspective are also provided.

A novel insulin resistance index to monitor changes in insulin sensitivity and glucose tolerance: the ACT NOW study.

OBJECTIVE: The objective was to test the clinical utility of Quantose M(Q) to monitor changes in insulin sensitivity after pioglitazone therapy in prediabetic subjects. Quantose M(Q) is derived from fasting measurements of insulin, α-hydroxybutyrate, linoleoyl-glycerophosphocholine, and oleate, three nonglucose metabolites shown to correlate with insulin-stimulated glucose disposal. RESEARCH DESIGN AND METHODS: Participants were 428 of the total of 602 ACT NOW impaired glucose tolerance (IGT) subjects randomized to pioglitazone (45 mg/d) or placebo and followed for 2.4 years. At baseline and study end, fasting plasma metabolites required for determination of Quantose, glycated hemoglobin, and oral glucose tolerance test with frequent plasma insulin and glucose measurements to calculate the Matsuda index of insulin sensitivity were obtained. RESULTS: Pioglitazone treatment lowered IGT conversion to diabetes (hazard ratio = 0.25; 95% confidence interval = 0.13-0.50; P < .0001). Although glycated hemoglobin did not track with insulin sensitivity, Quantose M(Q) increased in pioglitazone-treated subjects (by 1.45 [3.45] mg·min(-1)·kgwbm(-1)) (median [interquartile range]) (P < .001 vs placebo), as did the Matsuda index (by 3.05 [4.77] units; P < .0001). Quantose M(Q) correlated with the Matsuda index at baseline and change in the Matsuda index from baseline (rho, 0.85 and 0.79, respectively; P < .0001) and was progressively higher across closeout glucose tolerance status (diabetes, IGT, normal glucose tolerance). In logistic models including only anthropometric and fasting measurements, Quantose M(Q) outperformed both Matsuda and fasting insulin in predicting incident diabetes. CONCLUSIONS: In IGT subjects, Quantose M(Q) parallels changes in insulin sensitivity and glucose tolerance with pioglitazone therapy. Due to its strong correlation with improved insulin sensitivity and its ease of use, Quantose M(Q) may serve as a useful clinical test to identify and monitor therapy in insulin-resistant patients.

Impact of an intensive lifestyle intervention on use and cost of medical services among overweight and obese adults with type 2 diabetes: the action for health in diabetes.

OBJECTIVE: To assess the relative impact of an intensive lifestyle intervention (ILI) on use and costs of health care within the Look AHEAD trial. RESEARCH DESIGN AND METHODS: A total of 5,121 overweight or obese adults with type 2 diabetes were randomly assigned to an ILI that promoted weight loss or to a comparison condition of diabetes support and education (DSE). Use and costs of health-care services were recorded across an average of 10 years. RESULTS: ILI led to reductions in annual hospitalizations (11%, P = 0.004), hospital days (15%, P = 0.01), and number of medications (6%, P < 0.001), resulting in cost savings for hospitalization (10%, P = 0.04) and medication (7%, P < 0.001). ILI produced a mean relative per-person 10-year cost savings of $5,280 (95% CI 3,385-7,175); however, these were not evident among individuals with a history of cardiovascular disease. CONCLUSIONS: Compared with DSE over 10 years, ILI participants had fewer hospitalizations, fewer medications, and lower health-care costs.

Lifestyle and metformin interventions have a durable effect to lower CRP and tPA levels in the diabetes prevention program except in those who develop diabetes.

OBJECTIVE: We evaluate whether lifestyle and metformin interventions used to prevent diabetes have durable effects on markers of inflammation and coagulation and whether the effects are influenced by the development of diabetes. RESEARCH DESIGN AND METHODS: The Diabetes Prevention Program was a controlled clinical trial of 3,234 subjects at high risk for diabetes who were randomized to lifestyle, metformin, or placebo interventions for 3.4 years. Diabetes was diagnosed semiannually by fasting glucose and annually by oral glucose tolerance testing. In addition to baseline testing, anthropometry was performed every 6 months; fasting insulin yearly; and hs-CRP, tissue plasminogen activator (tPA), and fibrinogen at 1 year and end of study (EOS). RESULTS: CRP and tPA levels were unchanged in the placebo group but fell in the lifestyle and metformin groups at 1 year and remained lower at EOS. These reductions were not seen in those who developed diabetes over the course of the study despite intervention. Fibrinogen was lower at 1 year in the lifestyle group. Differences in weight and weight change explained most of the influence of diabetes on the CRP response in the lifestyle group, but only partly in the placebo and metformin groups. Weight, insulin sensitivity, and hyperglycemia differences each accounted for the influence of diabetes on the tPA response. CONCLUSIONS: Lifestyle and metformin interventions have durable effects to lower hs-CRP and tPA. Incident diabetes prevented these improvements, and this was accounted for by differences in weight, insulin resistance, and glucose levels.

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.

Baseline adiponectin levels do not influence the response to pioglitazone in ACT NOW.

OBJECTIVE: Plasma adiponectin levels are reduced in type 2 diabetes mellitus (T2DM) and other insulin-resistant states. We examined whether plasma adiponectin levels at baseline and after pioglitazone treatment in impaired glucose tolerance (IGT) subjects were associated with improved insulin sensitivity (SI) and glucose tolerance status. RESEARCH DESIGN AND METHODS: A total of 602 high-risk IGT subjects in ACT NOW were randomized to receive pioglitazone or placebo with a median follow-up of 2.4 years. RESULTS: Pioglitazone reduced IGT conversion to diabetes by 72% in association with improved ß-cell function by 64% (insulin secretion/insulin resistance index) and increased tissue sensitivity by 88% (Matsuda index). In pioglitazone-treated subjects, plasma adiponectin concentration increased threefold from 13 ± 0.5 to 38 ± 2.5 µg/mL (P < 0.001) and was strongly correlated with the improvement in SI (r = 0.436, P < 0.001) and modestly correlated with glucose area under the curve during oral glucose tolerance test (r = 0.238, P < 0.005) and insulin secretion/insulin resistance index (r = 0.306, P < 0.005). The increase in adiponectin was a strong predictor of reversion to normal glucose tolerance and prevention of T2DM. In the placebo group, plasma adiponectin did not change and was not correlated with changes in glucose levels. There was an inverse association between baseline plasma adiponectin concentration and progression to diabetes in the placebo group but not in the pioglitazone group. CONCLUSIONS: Baseline adiponectin does not predict the response to pioglitazone. The increase in plasma adiponectin concentration after pioglitazone therapy in IGT subjects is strongly related to improved glucose tolerance status and enhanced tissue sensitivity to insulin.

Evaluation of early weight loss thresholds for identifying nonresponders to an intensive lifestyle intervention.

OBJECTIVE: Weight losses in lifestyle interventions are variable, yet prediction of long-term success is difficult. The utility of using various weight loss thresholds in the first 2 months of treatment for predicting 1-year outcomes was examined. METHODS: Participants included 2327 adults with type 2 diabetes (BMI:35.8 ± 6.0) randomized to the intensive lifestyle intervention (ILI) of the Look AHEAD trial. ILI included weekly behavioral sessions designed to increase physical activity and reduce caloric intake. 1-month, 2-month, and 1-year weight changes were calculated. RESULTS: Participants failing to achieve a ≥2% weight loss at Month 1 were 5.6 (95% CI:4.5, 7.0) times more likely to also not achieve a ≥10% weight loss at Year 1, compared to those losing ≥2% initially. These odds were increased to 11.6 (95% CI:8.6, 15.6) when using a 3% weight loss threshold at Month 2. Only 15.2% and 8.2% of individuals failing to achieve the ≥2% and ≥3% thresholds at Months 1 and 2, respectively, go on to achieve a ≥10% weight loss at Year 1. CONCLUSIONS: Given the association between initial and 1-year weight loss, the first few months of treatment may be an opportune time to identify those who are unsuccessful and utilize rescue efforts. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00017953.

Long-term impact of behavioral weight loss intervention on cognitive function.

BACKGROUND: It is unknown whether intentional weight loss provides long-term benefits for cognitive function. METHODS: An ancillary study to a randomized controlled clinical trial was conducted in overweight and obese individuals (N = 978), aged 45-76 years at enrollment, with type 2 diabetes. An intensive behavioral intervention designed to promote and maintain weight loss through caloric restriction and increased physical activity was compared with diabetes support and education. Standardized assessments of cognitive function were collected an average of 8.1 years after trial enrollment. RESULTS: Participants assigned to intensive lifestyle intervention lost a mean (SE) 11.1% (0.4%) and 7.2% (0.5%) of weight at Years 1 and 8, respectively, compared with 1.0% (0.2%) and 3.3% (0.5%) in the control group (p < .001). Covariate-adjusted mean composite cognitive function test scores were similar for the two groups (p = .69), and no significant differences were found for any individual cognitive test. There was some evidence of a differential effect (nominal interaction p = .008) for a prespecified comparison: Intensive lifestyle intervention was associated with a relative mean benefit for composite cognitive function of 0.276 (95% confidence interval: 0.033, 0.520) SDs among individuals with body mass index less than 30 kg/m(2) at baseline compared with a relative mean deficit of 0.086 (-0.021, 0.194) SDs among individuals with body mass more than or equal to 30 kg/m(2). CONCLUSIONS: Eight years of intensive lifestyle intervention did not alter cognitive function in obese adults with type 2 diabetes; however, there was evidence for benefit among overweight but not obese individuals. Changes in cognition were not assessed in this cross-sectional study.

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.

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.

Prediction of diabetes based on baseline metabolic characteristics in individuals at high risk.

OBJECTIVE: Individuals with impaired glucose tolerance (IGT) are at high risk for developing type 2 diabetes mellitus (T2DM). We examined which characteristics at baseline predicted the development of T2DM versus maintenance of IGT or conversion to normal glucose tolerance. RESEARCH DESIGN AND METHODS: We studied 228 subjects at high risk with IGT who received treatment with placebo in ACT NOW and who underwent baseline anthropometric measures and oral glucose tolerance test (OGTT) at baseline and after a mean follow-up of 2.4 years. RESULTS: In a univariate analysis, 45 of 228 (19.7%) IGT individuals developed diabetes. After adjusting for age, sex, and center, increased fasting plasma glucose, 2-h plasma glucose, G0-120 during OGTT, HbA1c, adipocyte insulin resistance index, ln fasting plasma insulin, and ln I0-120, as well as family history of diabetes and presence of metabolic syndrome, were associated with increased risk of diabetes. At baseline, higher insulin secretion (ln [I0-120/G0-120]) during the OGTT was associated with decreased risk of diabetes. Higher ß-cell function (insulin secretion/insulin resistance or disposition index; ln [I0-120/G0-120 × Matsuda index of insulin sensitivity]; odds ratio 0.11; P < 0.0001) was the variable most closely associated with reduced risk of diabetes. CONCLUSIONS: In a stepwise multiple-variable analysis, only HbA1c and ß-cell function (ln insulin secretion/insulin resistance index) predicted the development of diabetes (r = 0.49; P < 0.0001).

Do genetic modifiers of high-density lipoprotein cholesterol and triglyceride levels also modify their response to a lifestyle intervention in the setting of obesity and type-2 diabetes mellitus?: The Action for Health in Diabetes (Look AHEAD) study.

BACKGROUND: High-density lipoprotein cholesterol (HDL-C) and triglycerides are cardiovascular risk factors susceptible to lifestyle behavior modification and genetics. We hypothesized that genetic variants identified by genome-wide association studies as associated with HDL-C or triglyceride levels modify 1-year treatment response to an intensive lifestyle intervention, relative to a usual care of diabetes mellitus support and education. METHODS AND RESULTS: We evaluated 82 single-nucleotide polymorphisms, which represent 31 loci demonstrated by genome-wide association studies to be associated with HDL-C and triglycerides, in 3561 participants who consented for genetic studies and met eligibility criteria. Variants associated with higher baseline HDL-C levels, cholesterol ester transfer protein (CETP) rs3764261 and hepatic lipase (LIPC) rs8034802, were found to be associated with HDL-C increases with intensive lifestyle intervention (P=0.0038 and 0.013, respectively) and had nominally significant treatment interactions (P=0.047 and 0.046, respectively). The fatty acid desaturase-2 rs1535 variant, associated with low baseline HDL-C (P=0.017), was associated with HDL-C increases with intensive lifestyle intervention (0.0037) and had a nominal treatment interaction (P=0.035). Apolipoprotein B (rs693) and LIPC (rs8034802) single-nucleotide polymorphisms showed nominally significant associations with HDL-C and triglyceride changes with intensive lifestyle intervention and a treatment interaction (P<0.05). Phosphatidylglycerophosphate synthase-1 single-nucleotide polymorphisms (rs4082919) showed the most significant triglyceride treatment interaction in the full cohort (P=0.0009). CONCLUSIONS: This is the first study to identify genetic variants modifying lipid responses to a randomized lifestyle behavior intervention in overweight or obese individuals with diabetes mellitus. The effects of genetic factors on lipid changes may differ from the effects on baseline lipids and are modifiable by behavioral intervention.

Prevention of diabetes with pioglitazone in ACT NOW: physiologic correlates.

We examined the metabolic characteristics that attend the development of type 2 diabetes (T2DM) in 441 impaired glucose tolerance (IGT) subjects who participated in the ACT NOW Study and had complete end-of-study metabolic measurements. Subjects were randomized to receive pioglitazone (PGZ; 45 mg/day) or placebo and were observed for a median of 2.4 years. Indices of insulin sensitivity (Matsuda index [MI]), insulin secretion (IS)/insulin resistance (IR; ΔI0-120/ΔG0-120, ΔIS rate [ISR]0-120/ΔG0-120), and ß-cell function (ΔI/ΔG × MI and ΔISR/ΔG × MI) were calculated from plasma glucose, insulin, and C-peptide concentrations during oral glucose tolerance tests at baseline and study end. Diabetes developed in 45 placebo-treated vs. 15 PGZ-treated subjects (odds ratio [OR] 0.28 [95% CI 0.15-0.49]; P < 0.0001); 48% of PGZ-treated subjects reverted to normal glucose tolerance (NGT) versus 28% of placebo-treated subjects (P < 0.005). Higher final glucose tolerance status (NGT > IGT > T2DM) was associated with improvements in insulin sensitivity (OR 0.61 [95% CI 0.54-0.80]), IS (OR 0.61 [95% CI 0.50-0.75]), and ß-cell function (ln IS/IR index and ln ISR/IR index) (OR 0.26 [95% CI 0.19-0.37]; all P < 0.0001). Of the factors measured, improved ß-cell function was most closely associated with final glucose tolerance status.

Effect of intensive lifestyle intervention on sexual dysfunction in women with type 2 diabetes: results from an ancillary Look AHEAD study.

OBJECTIVE: Sexual dysfunction is a prevalent problem in obese women with type 2 diabetes. This study examined the effects of intensive lifestyle intervention (ILI) in these women. RESEARCH DESIGN AND METHODS: Look AHEAD is a 16-center, randomized, controlled trial evaluating the health effects of ILI compared with a control group (diabetes support and education [DSE]). The Look AHEAD Sexual Function Ancillary study included 375 female participants at five Look AHEAD sites. Participants completed the Female Sexual Function Inventory (FSFI) and Beck Depression Inventory (BDI), and assessments of weight and cardiovascular risk factors at baseline and 1 year were made. RESULTS: At baseline, 50% of the 229 participants who reported being sexually active met criteria for female sexual dysfunction (FSD); only BDI score was related to FSD. One-year weight losses were greater in the ILI group than in the DSE group (7.6 vs. 0.45 kg; P<0.001). Among women with FSD at baseline, those in the ILI group (N=60) compared with those in the DSE group (N=53) were significantly more likely to remain sexually active (83 vs. 64%; P<0.008), reported greater improvement in total FSFI scores and in most FSFI domains (P<0.05), and were more likely to experience remission of FSD (28 vs. 11%; P<0.04) at 1 year. No significant differences between ILI and DSE were seen in women who did not have FSD at baseline. CONCLUSIONS: Participation in ILI appeared to have beneficial effects on sexual functioning among obese women with diabetes, particularly in those who had FSD at baseline.