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ObjectiveTo determine whether metformin or lifestyle modification can lower rates of all-cause and cause-specific mortality in the Diabetes Prevention Program and Diabetes Prevention Program Outcomes Study.Research design and methodsFrom 1996 to 1999, 3,234 adults at high risk for type 2 diabetes were randomized to an intensive lifestyle intervention, masked metformin, or placebo. Placebo and lifestyle interventions stopped in 2001, and a modified lifestyle program was offered to everyone, but unmasked study metformin continued in those originally randomized. Causes of deaths through 31 December 2018 were adjudicated by blinded reviews. All-cause and cause-specific mortality hazard ratios (HRs) were estimated from Cox proportional hazards regression models and Fine-Gray models, respectively.ResultsOver a median of 21 years (interquartile range 20-21), 453 participants died. Cancer was the leading cause of death (n = 170), followed by cardiovascular disease (n = 131). Compared with placebo, metformin did not influence mortality from all causes (HR 0.99 [95% CI 0.79, 1.25]), cancer (HR 1.04 [95% CI 0.72, 1.52]), or cardiovascular disease (HR 1.08 [95% CI 0.70, 1.66]). Similarly, lifestyle modification did not impact all-cause (HR 1.02 [95% CI 0.81, 1.28]), cancer (HR 1.07 [95% CI 0.74, 1.55]), or cardiovascular disease (HR 1.18 [95% CI 0.77, 1.81]) mortality. Analyses adjusted for diabetes status and duration, BMI, cumulative glycemic exposure, and cardiovascular risks yielded results similar to those for all-cause mortality.ConclusionsCancer was the leading cause of mortality among adults at high risk for type 2 diabetes. Although metformin and lifestyle modification prevented diabetes, neither strategy reduced all-cause, cancer, or cardiovascular mortality rates.

Sex 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). This 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. ILS resulted in significantly higher increases (postmenopausal women: p

Coronary artery disease (CAD) is more frequent among individuals with dysglycemia. Preventive interventions for diabetes can improve cardiometabolic risk factors (CRFs), but it is unclear whether the benefits on CRFs are similar for individuals at different genetic risk for CAD. We built a 201-variant polygenic risk score (PRS) for CAD and tested for interaction with diabetes prevention strategies on 1-year changes in CRFs in 2,658 Diabetes Prevention Program (DPP) participants. We also examined whether separate lifestyle behaviors interact with PRS and affect changes in CRFs in each intervention group. Participants in both the lifestyle and metformin interventions had greater improvement in the majority of recognized CRFs compared with placebo (P < 0.001) irrespective of CAD genetic risk (P interaction > 0.05). We detected nominal significant interactions between PRS and dietary quality and physical activity on 1-year change in BMI, fasting glucose, triglycerides, and HDL cholesterol in individuals randomized to metformin or placebo, but none of them achieved the multiple-testing correction for significance. This study confirms that diabetes preventive interventions improve CRFs regardless of CAD genetic risk and delivers hypothesis-generating data on the varying benefit of increasing physical activity and improving diet on intermediate cardiovascular risk factors depending on individual CAD genetic risk profile.

ObjectiveThe GUARDIAN (Genetics UndeRlying DIAbetes in HispaNics) consortium is described, along with heritability estimates and genetic and environmental correlations of insulin sensitivity and metabolic clearance rate of insulin (MCRI).MethodsGUARDIAN is comprised of seven cohorts, consisting of 4,336 Mexican-American individuals in 1,346 pedigrees. Insulin sensitivity (SI ), MCRI, and acute insulin response (AIRg) were measured by frequently sampled intravenous glucose tolerance test in four cohorts. Insulin sensitivity (M, M/I) and MCRI were measured by hyperinsulinemic-euglycemic clamp in three cohorts. Heritability and genetic and environmental correlations were estimated within the family cohorts (totaling 3,925 individuals) using variance components.ResultsAcross studies, age, and gender-adjusted heritability of insulin sensitivity (SI , M, M/I) ranged from 0.23 to 0.48 and of MCRI from 0.35 to 0.73. The ranges for the genetic correlations were 0.91 to 0.93 between SI and MCRI; and -0.57 to -0.59 for AIRg and MCRI (all P

ObjectiveWe aimed to identify factors that are independently associated with the metabolic clearance rate of insulin (MCRI) and to examine the association of MCRI with incident type 2 diabetes in nondiabetic Hispanics and African Americans.Research design and methodsWe investigated 1,116 participants in the Insulin Resistance Atherosclerosis Study (IRAS) Family Study with baseline examinations from 2000 to 2002 and follow-up examinations from 2005 to 2006. Insulin sensitivity (S(I)), acute insulin response (AIR), and MCRI were determined at baseline from frequently sampled intravenous glucose tolerance tests. MCRI was calculated as the ratio of the insulin dose over the incremental area under the curve of insulin. Incident diabetes was defined as fasting glucose ≥126 mg/dL or antidiabetic medication use by self-report.ResultsWe observed that S(I) and HDL cholesterol were independent positive correlates of MCRI, whereas fasting insulin, fasting glucose, subcutaneous adipose tissue, visceral adipose tissue, and AIR were independent negative correlates (all P < 0.05) at baseline. After 5 years of follow-up, 71 (6.4%) participants developed type 2 diabetes. Lower MCRI was associated with a higher risk of incident diabetes after adjusting for demographics, lifestyle factors, HDL cholesterol, indexes of obesity and adiposity, and insulin secretion (odds ratio 2.01 [95% CI 1.30-3.10], P = 0.0064, per one-SD decrease in loge-transformed MCRI).ConclusionsOur data showed that lower MCRI predicts the incidence of type 2 diabetes.

Weight-loss interventions generally improve lipid profiles and reduce cardiovascular disease risk, but effects are variable and may depend on genetic factors. We performed a genetic association analysis of data from 2,993 participants in the Diabetes Prevention Program to test the hypotheses that a genetic risk score (GRS) based on deleterious alleles at 32 lipid-associated single-nucleotide polymorphisms modifies the effects of lifestyle and/or metformin interventions on lipid levels and nuclear magnetic resonance (NMR) lipoprotein subfraction size and number. Twenty-three loci previously associated with fasting LDL-C, HDL-C, or triglycerides replicated (P = 0.04-1 × 10(-17)). Except for total HDL particles (r = -0.03, P = 0.26), all components of the lipid profile correlated with the GRS (partial |r| = 0.07-0.17, P = 5 × 10(-5)-1 10(-19)). The GRS was associated with higher baseline-adjusted 1-year LDL cholesterol levels (β = +0.87, SEE ± 0.22 mg/dl/allele, P = 8 × 10(-5), P(interaction) = 0.02) in the lifestyle intervention group, but not in the placebo (β = +0.20, SEE ± 0.22 mg/dl/allele, P = 0.35) or metformin (β = -0.03, SEE ± 0.22 mg/dl/allele, P = 0.90; P(interaction) = 0.64) groups. Similarly, a higher GRS predicted a greater number of baseline-adjusted small LDL particles at 1 year in the lifestyle intervention arm (β = +0.30, SEE ± 0.012 ln nmol/L/allele, P = 0.01, P(interaction) = 0.01) but not in the placebo (β = -0.002, SEE ± 0.008 ln nmol/L/allele, P = 0.74) or metformin (β = +0.013, SEE ± 0.008 nmol/L/allele, P = 0.12; P(interaction) = 0.24) groups. Our findings suggest that a high genetic burden confers an adverse lipid profile and predicts attenuated response in LDL-C levels and small LDL particle number to dietary and physical activity interventions aimed at weight loss.

Inflammation may play a role in the pathogenesis of cardiovascular disease and type 2 diabetes, and it has been suggested that the protective effects of whole-grain consumption could be mediated by an effect on inflammation, although few studies have examined the relationships between grain intakes and inflammatory protein concentrations. Our objectives in this study were to examine the associations of whole grain and refined grain intake with plasminogen activator inhibitor type 1 (PAI-1), C-reactive protein (CRP), and fibrinogen plasma concentrations. Cross-sectional data from the Insulin Resistance Atherosclerosis Study were used to perform multiple regression analyses using dietary information on whole and refined grain intakes from a FFQ and clinical measures of plasma inflammatory protein concentrations in participants free of type 2 diabetes. After adjustment for demographic, lifestyle, and dietary variables, whole-grain intake was inversely related to log PAI-1 ([beta] = -0.102; SEM = 0.038; P = 0.0077) and log CRP ([beta] = -0.102; SEM = 0.048; P= 0.0340). Adding insulin sensitivity, waist circumference, and 2-h postload glucose to the model attenuated both associations to nonsignificance. Refined grain was positively related to log PAI-1 in the multivariate model ([beta] = 0.076; SEM = 0.034; P = 0.0251) and the relationship remained unchanged by additional adjustment for metabolic variables. Fibrinogen concentrations were not related to whole or refined grain intake. In summary, whole grain intake was inversely related to PAI-1 and CRP plasma concentrations, but these relationships were attenuated by the addition of metabolic variables to the model. Refined grain intake was positively independently related to plasma PAI-1 concentrations. doi: 10.3945/jn.109.116640.

The article reports that objective is to determine metabolite clusters associated with adherence to a DASH-like diet in the Insulin Resistance Atherosclerosis Study cohort and explore if the clusters predicted 5-year incidence of T2DM. The current study included 570 non-diabetic multi-ethnic participants aged 40-69 years.

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ahj.2008.05.017 Byline: Robert M. Califf (a)(b), Mitradev Boolell (c), Steven M. Haffner (d), M. Angelyn Bethel (e)(f), John McMurray (g), Anil Duggal (h), Rury R. Holman (i) Abstract: Patients with impaired glucose tolerance (IGT) have increased risk for developing type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). Lifestyle modification and medication can prevent or delay progression to diabetes (PD), but whether such interventions also reduce the risk of CVD has not been rigorously tested. The Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial is a multinational, randomized, double-blind, 2 x 2 factorial trial in subjects with IGT (on a screening oral glucose tolerance test [OGTT]) aged [greater than or equal to]50 years with known CVD or aged [greater than or equal to]55 years with [greater than or equal to]1 CVD risk factor. Enrollment began in January 2002 and was completed January 2004, with 9,518 patients randomized to receive 1 of 4 possible treatment combinations as follows: nateglinide with valsartan, nateglinide with valsartan-placebo, nateglinide-placebo with valsartan, or nateglinide-placebo with valsartan-placebo. All subjects are participating in a clinic-based and telephone-based lifestyle intervention aimed at reducing weight and dietary fat and increasing physical activity. The 3 coprimary end points are new onset of T2DM, a 'core' composite of major cardiovascular events (death, myocardial infarction, stroke, or hospitalization for heart failure), and an 'extended' composite including the components of the core composite plus coronary revascularization and hospitalization for unstable angina. The study was designed to evaluate whether reducing postprandial hyperglycemia, blockade of the renin-angiotensin-aldosterone system, or both interventions reduce the risk of T2DM or cardiovascular events in patients with IGT. Author Affiliation: (a) Duke Transitional Medicine Institute, Durham NC (b) Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC (c) Novartis Pharma AG, Basel, Switzerland (d) University of Texas Health Science Center, San Antonio, TX (e) Division of Endocrinology, Department of Medicine, Duke University Medical Center, Durham, NC (f) Duke Clinical Research Institute, Duke University Medical Center, Durham, NC (g) Department of Medicine, British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, Scotland, UK (h) Novartis Pharma Corp, East Hanover, NJ (i) Diabetes Trials Unit, Oxford Centre for Diabetes, Endocrinology, and Metabolism, University of Oxford, Oxford, UK Article History: Received 12 May 2004; Accepted 20 May 2008 Article Note: (footnote) This study is funded by Novartis Pharma AG, Basel, Switzerland.

A randomized controlled trial is used to evaluate the effect of pioglitazone vs glimepiride on changes in carotid artery intima-media thickness (CIMT) of the common carotid artery in patients with type 2 diabetes mellitus (DM). The results have shown that over an 18-month treatment period in patients with type 2 DM, pioglitazone slowed the progression of CIMT when compared to glimepiride.