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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.

Background Many CpGs become hyper or hypo-methylated with age. Multiple methods have been developed by Horvath et al. to estimate DNA methylation (DNAm) age including Pan-tissue, Skin & Blood, PhenoAge, and GrimAge. Pan-tissue and Skin & Blood try to estimate chronological age in the normal population whereas PhenoAge and GrimAge use surrogate markers associated with mortality to estimate biological age and its departure from chronological age. Here, we applied Horvath’s four methods to calculate and compare DNAm age in 499 subjects with type 1 diabetes (T1D) from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study using DNAm data measured by Illumina EPIC array in the whole blood. Association of the four DNAm ages with development of diabetic complications including cardiovascular diseases (CVD), nephropathy, retinopathy, and neuropathy, and their risk factors were investigated. Results Pan-tissue and GrimAge were higher whereas Skin & Blood and PhenoAge were lower than chronological age (p < 0.0001). DNAm age was not associated with the risk of CVD or retinopathy over 18–20 years after DNAm measurement. However, higher PhenoAge (β = 0.023, p = 0.007) and GrimAge (β = 0.029, p = 0.002) were associated with higher albumin excretion rate (AER), an indicator of diabetic renal disease, measured over time. GrimAge was also associated with development of both diabetic peripheral neuropathy (OR = 1.07, p = 9.24E−3) and cardiovascular autonomic neuropathy (OR = 1.06, p = 0.011). Both HbA1c (β = 0.38, p = 0.026) and T1D duration (β = 0.01, p = 0.043) were associated with higher PhenoAge. Employment (β = − 1.99, p = 0.045) and leisure time (β = − 0.81, p = 0.022) physical activity were associated with lower Pan-tissue and Skin & Blood, respectively. BMI (β = 0.09, p = 0.048) and current smoking (β = 7.13, p = 9.03E−50) were positively associated with Skin & Blood and GrimAge, respectively. Blood pressure, lipid levels, pulse rate, and alcohol consumption were not associated with DNAm age regardless of the method used. Conclusions Various methods of measuring DNAm age are sub-optimal in detecting people at higher risk of developing diabetic complications although some work better than the others.

Objective In addition to slowing diabetes development among participants in the Diabetes Prevention Program (DPP), intensive lifestyle change and metformin raised HDL-cholesterol (HDL-C) compared to placebo treatment. We investigated the lifestyle and metabolic determinants as well as effects of biomarkers of inflammation, endothelial dysfunction and coagulation and their changes resulting from lifestyle and metformin interventions on the increase in HDL-C in the DPP. Methods The effects of a 1 year period of intensive lifestyle change aimed at achieving 7% weight loss or metformin 850 mg twice daily versus placebo on HDL-C were assessed in 3070 participants with impaired glucose tolerance, and on HDL particle concentration (HDL-P) and size in a subgroup of 1645 individuals. Treatment-associated changes in lifestyle and metabolic factors as well as in novel biomarkers were investigated for their associations with change in HDL-C using multiple regression analysis. Results After adjusting for BMI, insulin resistance, glycemia, dietary saturated fat, alcohol intake, physical activity and nine different biomarkers, only adiponectin accounted for the effect of intensive lifestyle change on HDL-C via an increase in large HDL-P. By contrast baseline and change in BMI and tissue plasminogen activator levels attenuated the effect of metformin on HDL-C, with adiponectin having no specific effect. Conclusion While both lifestyle and metformin interventions used to prevent diabetes increase HDL-C, the mechanisms involved differ between the two treatments and may have consequences for future risk of cardiovascular disease.

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.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.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.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 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.

IntroductionSex hormone binding globulin (SHBG) levels are reported to be inversely associated with diabetes risk. It is unknown whether diabetes prevention interventions increase SHBG and whether resultant changes in SHBG affect diabetes risk. The purpose of this analysis was to determine whether intensive lifestyle intervention (ILS) or metformin changed circulating SHBG and if resultant changes influenced diabetes risk in the Diabetes Prevention Program (DPP).Research design and methodsThis is a secondary analysis from the DPP (1996–2001), a randomized trial of ILS or metformin versus placebo on diabetes risk over a mean follow-up of 3.2 years. The DPP was conducted across 27 academic study centers in the USA. Men, premenopausal and postmenopausal women without hormone use in the DPP were evaluated. The DPP included overweight/obese persons with elevated fasting glucose and impaired glucose tolerance. Main outcomes measures were changes in SHBG levels at 1 year and risk of diabetes over 3 years.ResultsILS resulted in significantly higher increases (postmenopausal women: pConclusionsLifestyle intervention may be associated with favorable changes in circulating SHBG, which is largely due to changes in adiposity. Changes in circulating SHBG do not independently predict reductions in diabetes incidence.

Background Hyperglycemia leading to increased oxidative stress is implicated in the increased risk for the development of macrovascular and microvascular complications in patients with type 1 diabetes mellitus. Methods and Results A random subcohort of 349 participants was selected from the DCCT / EDIC (Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications) cohort. This included 320 controls and 29 cardiovascular disease cases that were augmented with 98 additional known cases to yield a case cohort of 447 participants (320 controls, 127 cases). Biosamples from DCCT baseline, year 1, and closeout of DCCT , and 1 to 2 years post‐ DCCT ( EDIC years 1 and 2) were measured for markers of oxidative stress, including plasma myeloperoxidase, paraoxonase activity, urinary F 2α isoprostanes, and its metabolite, 2,3 dinor‐8 iso prostaglandin F 2α . Following adjustment for glycated hemoblobin and weighting the observations inversely proportional to the sampling selection probabilities, higher paraoxonase activity, reflective of antioxidant activity, and 2,3 dinor‐8 iso prostaglandin F 2α , an oxidative marker, were significantly associated with lower risk of cardiovascular disease (−4.5% risk for 10% higher paraoxonase, P iso prostaglandin F 2α , P =0.0092). In contrast, the oxidative markers myeloperoxidase and F 2α isoprostanes were not significantly associated with cardiovascular disease after adjustment for glycated hemoblobin. There were no significant differences between DCCT intensive and conventional treatment groups in the change in all biomarkers across time segments. Conclusions Heightened antioxidant activity (rather than diminished oxidative stress markers) is associated with lower cardiovascular disease risk in type 1 diabetes mellitus, but these biomarkers did not change over time with intensification of glycemic control. Clinical Trial Registration URL : https://www.clinicaltrials.gov . Unique identifiers: NCT 00360815 and NCT 00360893.

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.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.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.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.

Hyperglycemic crises of diabetic ketoacidosis and nonketotic hyperglycemia are associated with elevation of counterregulatory hormones and proinflammatory cytokines, markers of lipid peroxidation, and oxidative stress. To investigate if other conditions besides hyperglycemia could evoke such a prompt increase in cytokine levels, lipid peroxidation, and oxidative stress markers, we induced hypoglycemic stress by standard insulin tolerance test and measured proinflammatory cytokines, markers of lipid peroxidation, reactive oxygen species (ROS), and counterregulatory hormones. Insulin tolerance test was performed in 13 healthy male subjects with no history of infection, cardiovascular risk factors, or abnormal glucose. At baseline and at 30, 45, 60, 120, and 240 minutes after insulin injection, the following parameters were measured: glucose, cortisol, corticotropin, epinephrine (EP), norepinephrine (NE), growth hormone, tumor necrosis factor (TNF)– α , interleukin (IL) 1 β , IL-6, IL-8, free fatty acids, white blood cells, lipid peroxidation markers by thiobarbituric acid assay, and ROS by dichlorofluorescein method. The peak value of white blood cell count at 120 minutes was significantly associated with the peak values of NE at 30 minutes and cortisol at 60 minutes. By comparing the area under the curve of measured parameters, EP emerged as significant predictor of TNF- α ( P = .05) and IL-8 ( P = .027). Cortisol emerged as predictor of IL-1 β significantly ( P = .05). Corticotropin predicted area under the curve of IL-6 with borderline significance ( P = .06). In the present study, insulin-induced hypoglycemia in nondiabetic male subjects is associated with increased proinflammatory cytokines (TNF- α , IL-1 β , IL-6, and IL-8), markers of lipid peroxidation, ROS, and leukocytosis. Elevations of NE, EP, corticotropin, and cortisol in hypoglycaemia are associated with the elevation of the proinflammatory cytokines and leukocytosis.

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.

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.

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 β-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.

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

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.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.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.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.

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 β-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 β-cell function (ln insulin secretion/insulin resistance index) predicted the development of diabetes (r = 0.49; P < 0.0001).

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.

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 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.

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.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.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).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.).

It is unknown whether intensive lifestyle modification (ILS) or metformin changes sex steroids among premenopausal women without a history of polycystic ovarian syndrome (PCOS).We examined 1-year intervention impact on sex steroids (estradiol, testosterone, dehydroepiandrosterone, and androstenedione [A4]) and SHBG and differences by race/ethnicity.A subgroup of Diabetes Prevention Program participants who were premenopausal, not using estrogen, without a history of PCOS or irregular menses, and who reported non-Hispanic white (NHW), Hispanic, or African-American race/ethnicity (n = 301).Randomization arms were 1) ILS with the goals of weight reduction of 7% of initial weight and 150 minutes per week of moderate intensity exercise, 2) metformin 850 mg twice a day, or 3) placebo.Neither intervention changed sex steroids compared to placebo. ILS, but not metformin, increased median SHBG by 3.1 nmol/L (~11%) compared to decreases of 1.1 nmol/L in the placebo arm (P.05). This comparison remained significant after adjustment for changes in covariates including waist circumference. However, associations with glucose were not significant. Median baseline A4 was lower in Hispanics compared to NHWs (5.7 nmol/L vs 6.5 nmol/L, P.05) and increases in A4 were greater in Hispanics compared to NHWs (3.0 nmol/ vs 1.2 nmol/L, P.05), and these differences did not differ significantly by intervention arm. No other racial/ethnic differences were significant.Among premenopausal glucose-intolerant women, no intervention changed sex steroids. ILS increased SHBG, although associations with glucose were not significant. SHBG and sex steroids were similar by race/ethnicity, with the possible exception of lower baseline A4 levels in Hispanics compared to NHWs.

OBJECTIVE To study the effects of high-protein versus high-carbohydrate diets on various metabolic end points (glucoregulation, oxidative stress [dichlorofluorescein], lipid peroxidation [malondialdehyde], proinflammatory cytokines [tumor necrosis factor-α and interleukin-6], adipokines, and resting energy expenditure [REE]) with high protein–low carbohydrate (HP) and high carbohydrate–low protein (HC) diets at baseline and after 6 months of dietary intervention. RESEARCH DESIGN AND METHODS We recruited obese, premenopausal women aged 20–50 years with no diabetes or prediabetes who were randomized to HC (55% carbohydrates, 30% fat, and 15% protein) or HP (40% carbohydrates, 30% fat, and 30% protein) diets for 6 months. The diets were provided in prepackaged food, which provided 500 kcal restrictions per day. The above metabolic end points were measured with HP and HC diet at baseline and after 6 months of dietary intervention. RESULTS After 6 months of the HP versus HC diet (12 in each group), the following changes were significantly different by Wilcoxon rank sum test for the following parameters: dichlorofluorescein (−0.8 vs. −0.3 µmol/L, P < 0.0001), malondialdehyde (−0.4 vs. −0.2 μmol/L, P = 0.0004), C-reactive protein (−2.1 vs. −0.8 mg/L, P = 0.0003), E-selectin (−8.6 vs. −3.7 ng/mL, P = 0.0007), adiponectin (1,284 vs. 504 ng/mL, P = 0.0011), tumor necrosis factor-α (−1.8 vs. −0.9 pg/mL, P < 0.0001), IL-6 (−1.3 vs. −0.4 pg/mL, P < 0.0001), free fatty acid (−0.12 vs. 0.16 mmol/L, P = 0.0002), REE (259 vs. 26 kcal, P < 0.0001), insulin sensitivity (4 vs. 0.9, P < 0.0001), and β-cell function (7.4 vs. 2.1, P < 0.0001). CONCLUSIONS To our knowledge, this is the first report on the significant advantages of a 6-month hypocaloric HP diet versus hypocaloric HC diet on markers of β-cell function, oxidative stress, lipid peroxidation, proinflammatory cytokines, and adipokines in normal, obese females without diabetes.

Genome-wide association studies have provided new insights into the genetic factors that contribute to the development of obesity. We hypothesized that these genetic markers would also predict magnitude of weight loss and weight regain after initial weight loss. Established obesity risk alleles available on the Illumina CARe iSelect (IBC) chip were characterized in 3899 overweight or obese participants with type 2 diabetes from the Look AHEAD (Action for Health in Diabetes), a randomized trial to determine the effects of intensive lifestyle intervention (ILI) and diabetes support and education (DSE) on cardiovascular morbidity and mortality. Primary analyses examined the interaction between 13 obesity risk polymorphisms in eight genes and randomized treatment arm in predicting weight change at year 1, and weight regain at year 4 among individuals who lost 3% or more of their baseline weight by year 1. No single-nucleotide polymorphisms (SNPs) were significantly associated with magnitude of weight loss or interacted with treatment arm at year 1. However, fat mass and obesity associated gene (FTO) rs3751812 predicted weight regain within DSE (1.56 kg per risk allele, P=0.005), but not ILI (P=0.761), resulting in SNP × treatment arm interaction (P=0.009). In a partial replication of prior research, the obesity risk (G) allele at BDNF rs6265 was associated with greater weight regain across treatment arms (0.773 kg per risk allele), although results were of borderline statistical significance (P=0.051). Variations in the FTO and BDNF loci may contribute risk of weight regain after weight loss.

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 Conclusion— 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.

OBJECTIVES: 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 (β = −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 (β = 61.32, SE = 26.24; p = .0194). Among non-Hispanic white participants, the association of BDNF rs2030323 with total caloric intake was stronger (β = −151.99, SE = 30.09; p < .0001), and association of FTO rs1421085 with higher caloric intake (β = 56.72, SE = 20.69; p = .0061) and percentage fat intake (β = 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.

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, β 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). β 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. Electronic supplementary material The online version of this article (doi:10.1007/s11357-016-9946-6) contains supplementary material, which is available to authorized users.

Background Findings from the Look AHEAD trial showed no significant reductions in the primary outcome of cardiovascular disease incidence in adults with type 2 diabetes randomly assigned to an intensive lifestyle intervention for weight loss compared with those randomly assigned to diabetes support and education (control). We examined whether the incidence of cardiovascular disease in Look AHEAD varied by changes in weight or fitness. Methods Look AHEAD was a randomised clinical trial done at 16 clinical sites in the USA, recruiting patients from Aug 22, 2001, to April 30, 2004. In the trial, 5145 overweight or obese adults aged 45-76 years with type 2 diabetes were assigned (1:1) to an intensive lifestyle intervention or diabetes support and education. In this observational, post-hoc analysis, we examined the association of magnitude of weight loss and fitness change over the first year with incidence of cardiovascular disease. The primary outcome of the trial and of this analysis was a composite of death from cardiovascular causes, non-fatal acute myocardial infarction, non-fatal stroke, or admission to hospital for angina. The secondary outcome included the same indices plus coronary artery bypass grafting, carotid endartectomy, percutaneous coronary intervention, hospitalisation for congestive heart failure, peripheral vascular disease, or total mortality. We adjusted analyses for baseline differences in weight or fitness, demographic characteristics, and risk factors for cardiovascular disease. The Look AHEAD trial is registered with ClinicalTrials.gov, number NCT00017953. Findings For the analyses related to weight change, we excluded 311 ineligible participants, leaving a population of 4834; for the analyses related to fitness change, we excluded 739 participants, leaving a population of 4406. In analyses of the full cohort (ie, combining both study groups), over a median 10·2 years of follow-up (IQR 9·5-10·7), individuals who lost at least 10% of their bodyweight in the first year of the study had a 21% lower risk of the primary outcome (adjusted hazard ratio [HR] 0·79, 95% CI 0·64-0·98; p=0·034) and a 24% reduced risk of the secondary outcome (adjusted HR 0·76, 95% CI 0·63-0·91; p=0·003) compared with individuals with stable weight or weight gain. Achieving an increase of at least 2 metabolic equivalents in fitness change was associated with a significant reduction in the secondary outcome (adjusted HR 0·77, 95% CI 0·61-0·96; p=0·023) but not the primary outcome (adjusted HR 0·78, 0·60-1·03; p=0·079). In analyses treating the control group as the reference group, participants in the intensive lifestyle intervention group who lost at least 10% of their bodyweight had a 20% lower risk of the primary outcome (adjusted HR 0·80, 95% CI 0·65-0·99; p=0·039), and a 21% lower risk of the secondary outcome (adjusted HR 0·79, 95% CI 0·66-0·95; p=0·011); however, change in fitness was not significantly associated with a change in the primary outcome. Interpretation The results of this post-hoc analysis of Look AHEAD suggest an association between the magnitude of weight loss and incidence of cardiovascular disease in people with type 2 diabetes. These findings suggest a need to continue to refine approaches to identify individuals who are most likely to benefit from lifestyle interventions and to develop strategies to improve the magnitude of sustained weight loss with lifestyle interventions. Funding US National Institute of Diabetes and Digestive and Kidney Diseases.

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.

The hyperglycemic emergencies, diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar state (HHS) are potentially fatal complications of uncontrolled diabetes mellitus. The incidence of DKA and the economic burden of its treatment continue to rise, but its associated mortality rate which was uniformly high has diminished remarkably over the years. This Improvement in outcome is largely due to better understanding of the pathogenesis of hyperglycemic emergencies and the application of evidence-based guidelines in the treatment of patients. In this article, we present a critical review of the evidence behind the recommendations that have resulted in the improved prognosis of patients with hyperglycemic crises. A succinct discussion of the pathophysiology and important etiological factors in DKA and HHS are provided as a prerequisite for understanding the rationale for the effective therapeutic maneuvers employed in these acute severe metabolic conditions. The evidence for the role of preventive measures in DKA and HHS is also discussed. The unanswered questions and future research needs are also highlighted.

OBJECTIVE Rates of severe obesity (BMI ≥40 kg/m2) are on the rise, and effective treatment options are needed. We examined the effect of an intensive lifestyle intervention (ILI) on weight loss, cardiovascular disease (CVD) risk, and program adherence in participants with type 2 diabetes who were severely obese compared with overweight (BMI 25 to RESEARCH DESIGN AND METHODS Participants in the Action for Health in Diabetes (Look AHEAD) trial were randomly assigned to ILI or diabetes support and education (DSE). DSE participants received a less intense educational intervention, whereas ILI participants received an intensive behavioral treatment to increase physical activity (PA) and reduce caloric intake. This article focuses on the 2,503 ILI participants (age 58.6 ± 6.8 years). RESULTS At 1 year, severely obese participants in the ILI group lost −9.04 ± 7.6% of initial body weight, which was significantly greater (P < 0.05) than ILI participants who were overweight (−7.43 ± 5.6%) and comparable to class I (−8.72 ± 6.4%) and class II obese (−8.64 ± 7.4%) participants. All BMI groups had comparable improvements in fitness, PA, LDL cholesterol, triglycerides, blood pressure, fasting glucose, and HbA1c at 1 year. ILI treatment session attendance was excellent and did not differ among weight categories (severe obese 80% vs. others 83%; P = 0.43). CONCLUSIONS Severely obese participants in the ILI group had similar adherence, percentage of weight loss, and improvement in CVD risk compared with less obese participants. Behavioral weight loss programs should be considered an effective option for this population.

Several types of evidence suggest that menopause could be associated with more rapid progression of glucose intolerance. First, postmenopause may be a relatively androgenic state compared to premenopause due to cessation of ovarian estrogen production and continuation of androgen production. 1 Second, greater levels of endogenous androgens are associated with glucose intolerance in both premenopausal and postmenopausal women.2 Third, postmenopausal estrogen therapy reduces fasting plasma glucose (FPG) levels. 3 It is unknown if menopause per se is associated with higher glucose levels, particularly among women who are already glucose intolerant. As diabetes is typically defined by glucose levels, the presence of impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) are strong risk factors for diabetes, and the menopausal state may not have any additional effect. While several longitudinal studies have found no association between menopause and glucose, 4–6 these studies did not measure the associations between menopause and key mediators of glucose tolerance, specifically insulin secretion and insulin resistance, or other biomarkers. Furthermore, these studies did not compare diabetes risk among the population of women with bilateral oophorectomy as opposed to natural menopause. Bilateral oophorectomy reduces testosterone levels7 and high testosterone is a risk factor for diabetes in women.2 Finally, it is also unknown if diabetes prevention interventions are more effective in premenopausal compared to postmenopausal women. If menopause status is a risk factor for diabetes among women who are already high-risk, or modifies response to diabetes prevention interventions, this has implications for targeted diabetes prevention interventions. The Diabetes Prevention Program (DPP) was a randomized trial of diabetes prevention interventions among adults with IFG and IGT. Using data from the DPP, we examined diabetes risk associated with menopause status, comparing women who were premenopausal with women who were postmenopausal at baseline. We also examined if menopause status modified the effect of DPP interventions on a number of metabolic variables, including adiposity, insulin metabolism, glucose, adiponectin, C-reactive protein (CRP), fibrinogen, and tissue plasminogen activator antigen (tPA). Finally, we examined whether the associations between natural menopause and diabetes risk differed from those of bilateral oophorectomy and diabetes risk before and after consideration of hormone therapy (HT).

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.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.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; P0.001). Conversion to normal glucose tolerance occurred in 48% of the patients in the pioglitazone group and 28% of those in the placebo group (P0.001). 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], P0.001), 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], P0.001), and HbA(1c) (a decrease of 0.04 percentage points vs. an increase of 0.20 percentage points, P0.001). 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, P0.001), and edema was more frequent (12.9% vs. 6.4%, P=0.007).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.).

The prevalence of type 2 diabetes continues to increase at an alarming rate around the world, with even more people being affected by prediabetes. Although the pathogenesis and long-term complications of type 2 diabetes are fairly well known, its treatment has remained challenging, with only half of the patients achieving the recommended hemoglobin A(1c) target. This narrative review explores the pathogenetic rationale for the treatment of type 2 diabetes, with the view of fostering better understanding of the evolving treatment modalities. The diagnostic criteria including the role of hemoglobin A(1c) in the diagnosis of diabetes are discussed. Due attention is given to the different therapeutic maneuvers and their utility in the management of the diabetic patient. The evidence supporting the role of exercise, medical nutrition therapy, glucose monitoring, and antiobesity measures including pharmacotherapy and bariatric surgery is discussed. The controversial subject of optimum glycemic control in hospitalized and ambulatory patients is discussed in detail. An update of the available pharmacologic options for the management of type 2 diabetes is provided with particular emphasis on newer and emerging modalities. Special attention has been given to the initiation of insulin therapy in patients with type 2 diabetes, with explanation of the pathophysiologic basis for insulin therapy in the ambulatory diabetic patient. A review of the evidence supporting the efficacy of the different preventive measures is also provided.

Observational studies in hospitalized patients with and without diabetes indicate that hyperglycemia is a predictor of poor clinical outcome and mortality.1–4 Early randomized controlled trials of intensified insulin therapy in patients with surgical and medical acute critical illness reported a reduction on the risk of multiorgan failure and systemic infections,3–5 as well as short- and long-term mortality.1,4 Recent randomized controlled trials, however, have failed to confirm the previously suggested benefits of intensive glucose control,6 and the large multicenter normoglycaemia in intensive care evaluation and survival using glucose algorithm regulation (NICE-SUGAR) study reported an absolute increase in mortality rate with intensive glucose control.7 In addition, intensified insulin therapy in critically-ill patients has been shown to be associated with a higher rate of severe hypoglycemic events than less aggressive glycemic control protocols.7–10 These results have led to a heightened interest in improving the quality and safety of the management of diabetes and hyperglycemia in the hospital. The use of intravenous continuous insulin infusion (CII) is the preferred route of insulin administration for the management of hyperglycemia in the critical care setting.1,11 Numerous examples of successful CII algorithms in achieving glycemic control are reported in the literature.4,5,12 Traditionally, order forms to “titrate drip” to achieve a target blood glucose (BG) range using an established algorithm or by the application of mathematical rules have been used in clinical practice. Recently, computer-based algorithms aiming to direct the nursing staff adjusting insulin infusion rate have become commercially available.13,14 It is not known, however, if computer-based algorithms are superior to standard paper form-based protocols in achieving glucose control and in reducing hypoglycemic events in critically-ill patients. Accordingly, this multicenter randomized study aimed to determine differences in glycemic control and hypoglycemic events between treatment with a computer-guided CII device and a standard column-based paper algorithm in critically-ill patients in the medical intensive care unit (ICU).

OBJECTIVE Most patients with ketosis-prone type 2 diabetes (KPD) discontinue insulin therapy and remain in near-normoglycemic remission. The aim of this study was to determine the effect of glucotoxicity on β-cell function during remission in obese patients with KPD. RESEARCH DESIGN AND METHODS Age- and BMI-matched obese African Americans with a history of KPD (n = 8), severe hyperglycemia but without ketosis (ketosis-resistant type 2 diabetes, n = 7), and obese control subjects (n = 13) underwent intravenous infusion of 10% dextrose at a rate of 200 mg per m2/min for 20 h. β-Cell function was assessed by changes in insulin and C-peptide concentrations during dextrose infusion and by changes in acute insulin response (AIR) and first-phase insulin release (FPIR) to arginine stimulation before and after dextrose infusion. RESULTS The mean ± SD time to discontinue insulin therapy was 7.1 ± 1.7 weeks in KPD and 9.6 ± 2.3 weeks in ketosis-resistant type 2 diabetes (NS). During a 20-h dextrose infusion, changes in insulin, C-peptide, and the C-peptide–to–glucose ratio were similar among diabetic and control groups. During dextrose infusion, subjects with ketosis-resistant type 2 diabetes had greater areas under the curve for blood glucose than subjects with KPD and control subjects (P < 0.05). The AIR and FPIR to arginine stimulation as well as glucose potentiation to arginine assessed before and after dextrose infusion were not different among the study groups. CONCLUSIONS Near-normoglycemia remission in obese African American patients with KPD and ketosis-resistant type 2 diabetes is associated with a remarkable recovery in basal and stimulated insulin secretion. At near-normoglycemia remission, patients with KPD displayed a pattern of insulin secretion similar to that of patients with ketosis-resistant type 2 diabetes and obese nondiabetic subjects.

Determinants of erectile dysfunction in diabetic men have not been adequately investigated as potential mediators of change.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).International Index of Erectile Function (IIEF), self-reported use of phosphodiesterase type 5 inhibitors, laboratory measures of adiposity, cardiometabolic parameters, and exercise fitness.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.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; P0.001).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.

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.

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.

Diabetic ketoacidosis (DKA) and the hyperosmolar hyperglycemic state (HHS) are the two most serious acute metabolic complications of diabetes. DKA is responsible for more than 500,000 hospital days per year (1,2) at an estimated annual direct medical expense and indirect cost of 2.4 billion USD (2,3). Table 1 outlines the diagnostic criteria for DKA and HHS. The triad of uncontrolled hyperglycemia, metabolic acidosis, and increased total body ketone concentration characterizes DKA. HHS is characterized by severe hyperglycemia, hyperosmolality, and dehydration in the absence of significant ketoacidosis. These metabolic derangements result from the combination of absolute or relative insulin deficiency and an increase in counterregulatory hormones (glucagon, catecholamines, cortisol, and growth hormone). Most patients with DKA have autoimmune type 1 diabetes; however, patients with type 2 diabetes are also at risk during the catabolic stress of acute illness such as trauma, surgery, or infections. This consensus statement will outline precipitating factors and recommendations for the diagnosis, treatment, and prevention of DKA and HHS in adult subjects. It is based on a previous technical review (4) and more recently published peer-reviewed articles since 2001, which should be consulted for further information. View this table: Table 1 Diagnostic criteria for DKA and HHS Recent epidemiological studies indicate that hospitalizations for DKA in the U.S. are increasing. In the decade from 1996 to 2006, there was a 35% increase in the number of cases, with a total of 136,510 cases with a primary diagnosis of DKA in 2006—a rate of increase perhaps more rapid than the overall increase in the diagnosis of diabetes (1). Most patients with DKA were between the ages of 18 and 44 years (56%) and 45 and 65 years (24%), with only 18% of patients

OBJECTIVE—The purpose of this study was to assess the efficacy of an insulin priming dose with a continuous insulin infusion versus two continuous infusions without a priming dose. RESEARCH DESIGN AND METHODS—This prospective randomized protocol used three insulin therapy methods: 1) load group using a priming dose of 0.07 units of regular insulin per kg body weight followed by a dose of 0.07 unit · kg−1 · h−1 i.v. in 12 patients with diabetic ketoacidosis (DKA); 2) no load group using an infusion of regular insulin of 0.07 unit · kg body weight−1 · h−1 without a loading dose in 12 patients with DKA, and 3) twice no load group using an infusion of regular insulin of 0.14 · kg−1 · h−1 without a loading dose in 13 patients with DKA. Outcome was based on the effects of insulin therapy on biochemical and hormonal changes during treatment and recovery of DKA. RESULTS—The load group reached a peak in free insulin value (460 μU/ml) within 5 min and plateaued at 88 μU/ml in 60 min. The twice no load group reached a peak (200 μU/ml) at 45 min. The no load group reached a peak (60 μU/ml) in 60–120 min. Five patients in the no load group required supplemental insulin doses to decrease initial glucose levels by 10%; patients in the twice no load and load groups did not. Except for these differences, times to reach glucose ≤250 mg/dl, pH ≥7.3, and HCO3− ≥15 mEq/l did not differ significantly among the three groups. CONCLUSIONS—A priming dose in low-dose insulin therapy in patients with DKA is unnecessary if an adequate dose of regular insulin of 0.14 unit · kg body weight−1 · h−1 (about 10 units/h in a 70-kg patient) is given.

Objective To review current consensus and controversy regarding whether obesity is a ‘disease’, examine the pathogenic potential of adipose tissue to promote metabolic disease and explore the merits of ‘adiposopathy’ and ‘sick fat’ as scientifically and clinically useful terms in defining when excessive body fat may represent a ‘disease’.

Abstract Many protocols have been used in clinical and research settings for collecting systolic blood pressure (SBP) measurements to calculate the ankle–brachial index (ABI); however, it is not known how useful it is to replicate measurements and which measures best reflect cardiovascular risk. Standardized measurements of ankle and arm SBP from 5140 overweight or obese individuals with type 2 diabetes were used to estimate sources of variation. Measurement characteristics of leg-specific ABI, as calculated using a standard algorithm based on the highest SBP of the dorsalis pedis or posterior tibial arteries, were projected using simulations. Coefficients of variability ranged from 2% to 3% when single SBP measurements were used and ABI was overestimated by 2–3%. Taking two SBP measurements at each site reduced standard errors and bias each by 30–40%. The sensitivity of detecting low ABI ranges exceeded 90% for ABI within 0.05 of the 0.90 clinical cut-point. The average and the minimum of the two (i.e. right and left) leg-specific ABI values had similar U-shaped relationships with Framingham risk scores; however, the average leg ABI had slightly greater precision. Replicating SBP measurements reduces the error and bias of ABI. Averaging leg-specific values may increase power for characterizing cardiovascular disease risk.

When caloric intake exceeds caloric expenditure, the positive caloric balance and storage of energy in adipose tissue often causes adipocyte hypertrophy and visceral adipose tissue accumulation. These pathogenic anatomic abnormalities may incite metabolic and immune responses that promote Type 2 diabetes mellitus, hypertension and dyslipidemia. These are the most common metabolic diseases managed by clinicians and are all major cardiovascular disease risk factors. 'Disease' is traditionally characterized as anatomic and physiologic abnormalities of an organ or organ system that contributes to adverse health consequences. Using this definition, pathogenic adipose tissue is no less a disease than diseases of other body organs. This review describes the consequences of pathogenic fat cell hypertrophy and visceral adiposity, emphasizing the mechanistic contributions of genetic and environmental predispositions, adipogenesis, fat storage, free fatty acid metabolism, adipocyte factors and inflammation. Appreciating the full pathogenic potential of adipose tissue requires an integrated perspective, recognizing the importance of 'cross-talk' and interactions between adipose tissue and other body systems. Thus, the adverse metabolic consequences that accompany fat cell hypertrophy and visceral adiposity are best viewed as a pathologic partnership between the pathogenic potential adipose tissue and the inherited or acquired limitations and/or impairments of other body organs. A better understanding of the physiological and pathological interplay of pathogenic adipose tissue with other organs and organ systems may assist in developing better strategies in treating metabolic disease and reducing cardiovascular disease risk.

OBJECTIVE—The effectiveness of intentional weight loss in reducing cardiovascular disease (CVD) events in type 2 diabetes is unknown. This report describes 1-year changes in CVD risk factors in a trial designed to examine the long-term effects of an intensive lifestyle intervention on the incidence of major CVD events. RESEARCH DESIGN AND METHODS—This study consisted of a multicentered, randomized, controlled trial of 5,145 individuals with type 2 diabetes, aged 45–74 years, with BMI >25 kg/m2 (>27 kg/m2 if taking insulin). An intensive lifestyle intervention (ILI) involving group and individual meetings to achieve and maintain weight loss through decreased caloric intake and increased physical activity was compared with a diabetes support and education (DSE) condition. RESULTS—Participants assigned to ILI lost an average 8.6% of their initial weight vs. 0.7% in DSE group (P < 0.001). Mean fitness increased in ILI by 20.9 vs. 5.8% in DSE (P < 0.001). A greater proportion of ILI participants had reductions in diabetes, hypertension, and lipid-lowering medicines. Mean A1C dropped from 7.3 to 6.6% in ILI (P < 0.001) vs. from 7.3 to 7.2% in DSE. Systolic and diastolic pressure, triglycerides, HDL cholesterol, and urine albumin-to-creatinine ratio improved significantly more in ILI than DSE participants (all P < 0.01). CONCLUSIONS—At 1 year, ILI resulted in clinically significant weight loss in people with type 2 diabetes. This was associated with improved diabetes control and CVD risk factors and reduced medicine use in ILI versus DSE. Continued intervention and follow-up will determine whether these changes are maintained and will reduce CVD risk.

To identify the risk factors for recurrent diabetic ketoacidosis (DKA) in a city hospital.We performed a retrospective analysis of sequential adult admissions for DKA at Bronx Lebanon Hospital Center in New York between July 1, 2001, and June 30, 2004. The patients were divided into cohorts, which were compared with use of analysis of variance and X2 tests. Multivariate logistic regression analysis was performed where indicated.In 168 patients (96 men and 72 women), 219 episodes of DKA occurred. The mean age (+/- SD) of the overall study group was 38.6 +/- 14.8 years. Fifty-four patients (32%) had type 2 diabetes, and 44 patients (26%) had new-onset diabetes. The recurrence rate of DKA was 169% in cocaine users and 39% in nonusers (P0.0001). Active use of cocaine, noncompliance, and Hispanic ethnicity emerged as independent risk factors for recurrent DKA-odds ratio (OR) = 4.38, P = 0.001; OR = 1.96, P = 0.05; and OR = 0.40, P = 0.005, respectively. The commonest precipitants of DKA were noncompliance (44%) and infection (26%). Noncompliance was associated with use of cocaine, use of cannabis, and cigarette smoking (P = 0.008, 0.04, and 0.01, respectively). In 91 of the hospital admissions for DKA (42%), the patients were active smokers.Active use of cocaine is an independent risk factor for recurrent DKA, as are noncompliance and Hispanic ethnicity. Of these 3 factors, cocaine showed the strongest association with DKA. Therefore, toxicology screening in patients with recurrent DKA may be prudent and worthwhile.

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.

Both obesity and genetics contribute to cardiovascular disease (CVD). We examined whether a genetic risk score (GRS) prospectively predicted cardiovascular morbidity and mortality among overweight/obese individuals with type 2 diabetes and whether behavioural weight loss could diminish this association.Look AHEAD (Action for Health in Diabetes) is a randomised 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 among overweight/obese individuals with type 2 diabetes. Of the participants, 4,016 provided consent for genetic analyses and had DNA samples passing quality control procedures. These secondary data analyses focused on whether a GRS derived from 153 single nucleotide polymorphisms (SNPs) associated with coronary artery disease in the most recent genome-wide association study predicted cardiovascular morbidity and mortality over a median of 9.6 years of follow-up, and whether ILI would diminish this association.The GRS significantly predicted the primary composite endpoint of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalisation for angina in the full sample (HR, 95% CI per 1 SD increase in GRS: 1.19 [1.10, 1.28]) and among individuals with no known history of CVD at baseline (HR 1.18 [95% CI 1.07, 1.30]). In no case did ILI significantly alter this association.A GRS comprised of SNPs significantly predicts cardiovascular morbidity and mortality over 9.6 years of follow-up in Look AHEAD. Lifestyle intervention did not alter the genetic association.NCT00017953; NCT01270763.

Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) are the two most serious acute metabolic complications of diabetes. Most patients with DKA have autoimmune type 1 diabetes; however, patients with type 2 diabetes are also at risk during the catabolic stress of acute illness such as trauma, surgery, or infection. Table 1 outlines the diagnostic criteria and electrolyte and fluid deficits for both disorders. The mortality rate in patients with DKA is

OBJECTIVE—To evaluate barriers to and strategies for medication adherence and predictors of adherence and the primary outcome in the Diabetes Prevention Program (DPP). RESEARCH DESIGN AND METHODS—Within a randomized, controlled primary prevention study for type 2 diabetes, we collected data on study medication adherence, its predictors, and health outcomes in 27 clinical centers across mainland U.S. and Hawaii. Medication arm participants included 2,155 adults with impaired glucose tolerance randomly assigned to either metformin or matched placebo treatment arms. Structured interviews were used to promote medication adherence and to collect data regarding adherence. Adherence was measured by pill count. The primary DPP outcome of type 2 diabetes was assessed by fasting plasma glucose and oral glucose tolerance test. RESULTS—Older age-groups were more adherent than the youngest group (P = 0.01) in the metformin group. The most frequently reported barrier to adherence was “forgetting” (22%). Women reported more adverse effects of metformin (15 vs. 10%, P = 0.002) in the metformin group. Odds of nonadherence increased as participants reported more than one barrier (odds ratio 19.1, P < 0.001). Odds of adherence increased as participants reported multiple strategies to take medication (2.69, P < 0.0001). There was a 38.2% risk reduction for developing diabetes for those adherent to metformin compared with those adherent to placebo (P < 0.0003). CONCLUSIONS—DPP medication adherence results are unique in primary prevention for a chronic disease in a large multiethnic sample. Our finding that adherence was associated with risk reduction for diabetes supports the development of brief interventions in clinical settings where medication adherence is a challenge.

Tight glycemic control is recommended for patients in the ICU, as hyperglycemia is associated with increased morbidity and mortality.Observational cohort of patients admitted to a 12-bed, inner-city, medical ICU (MICU).A total of 1,185 of 1,506 patients from July 1, 1999, to December 31, 2002, selected based on a diagnosis other than diabetic ketoacidosis or glycemia280 mg/dL or80 mg/dL.To determine if the highest serum glucose level within 24 h after ICU admission is associated with increased hospital mortality when adjusted for confounders.Age, gender, race, worst values within 24 h after ICU admission to construct the acute physiology and chronic health evaluation (APACHE) II score, and highest glucose within 24 h after ICU admission. Hospital mortality was the primary outcome. Admitting diagnosis, MICU length of stay (LOS), and hospital LOS were obtained. Glucose, albumin (n = 867), and lactic acid (n = 319) were stratified for analysis.Univariate analysis identified factors included in the multivariate model.Patients were predominantly African-American (79%) and men (56%; mean age, 49.2 years). The mean ICU admission highest glucose level was 139 +/- 43.7 mg/dL (+/- SD). MICU LOS and hospital LOS were 6.2 days and 12.9 days, respectively, and 50% of patients received mechanical ventilation. MICU and hospital mortality were 18% and 20%, respectively; standardized mortality ratio was 66%. On univariate analysis, survivors (n = 945) and nonsurvivors (n = 240) showed APACHE II score, mechanical ventilation, hypoalbuminemia, lactic acidemia, and logistic organ dysfunction system score to be hospital mortality predictors; however, the highest admission serum glucose level was not. Logistic regression estimated APACHE II score/per point (odds ratio, 1.06; 95% confidence interval, 1.02 to 1.11), mechanical ventilation (odds ratio, 3.06; 95% confidence interval, 1.34 to 6.96), severe hypoalbuminemia (2 g/dL) [odds ratio, 2.98; 95% confidence interval, 1.3 to 7.02], and severe lactic acidemia (or = 8 mmol/L) [odds ratio, 7.3; 95% confidence interval, 2.14 to 24.9], but not ICU admission hyperglycemia, to be associated with hospital mortality.Conventional factors of disease severity, but not highest glucose value during the first 24 h after ICU admission, predict hospital mortality in an inner-city MICU.