Helen P. Hazuda

Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes

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

Prospective Analysis of The Insulin-Resistance Syndrome (Syndrome X)

Many studies have shown that hyperinsulinemia and/or insulin resistance are related to various metabolic and physiological disorders including hypertension, dyslipidemia, and non-insulin-dependent diabetes mellitus. This syndrome has been termed Syndrome X. An important limitation of previous studies has been that they all have been cross sectional, and thus the presence of insulin resistance could be a consequence of the underlying metabolic disorders rather than its cause. We examined the relationship of fasting insulin concentration (as an indicator of insulin resistance) to the incidence of multiple metabolic abnormalities in the 8-yr follow-up of the cohort enrolled in the San Antonio Heart Study, a population-based study of diabetes and cardiovascular disease in Mexican Americans and non-Hispanic whites. In univariate analyses, fasting insulin was related to the incidence of the following conditions: hypertension, decreased high-density lipoprotein cholesterol concentration, increased triglyceride concentration, and non-insulin-dependent diabetes mellitus. Hyperinsulinemia was not related to increased low-density lipoprotein or total cholesterol concentration. In multivariate analyses, after adjustment for obesity and body fat distribution, fasting insulin continued to be significantly related to the incidence of decreased high-density lipoprotein cholesterol and increased triglyceride concentrations and to the incidence of non-insulin-dependent diabetes mellitus. Baseline insulin concentrations were higher in subjects who subsequently developed multiple metabolic disorders. These results were not attributable to differences in baseline obesity and were similar in Mexican Americans and non-Hispanic whites. These results support the existence of a metabolic syndrome and the relationship of that syndrome to multiple metabolic disorders by showing that elevations of insulin concentration precede the development of numerous metabolic disorders.

Long-term effects of a lifestyle intervention on weight and cardiovascular risk factors in individuals with type 2 diabetes mellitus: Four-year results of the look AHEAD trial

BACKGROUND Lifestyle interventions produce short-term improvements in glycemia and cardiovascular disease (CVD) risk factors in individuals with type 2 diabetes mellitus, but no long-term data are available. We examined the effects of lifestyle intervention on changes in weight, fitness, and CVD risk factors during a 4-year study. METHODS The Look AHEAD (Action for Health in Diabetes) trial is a multicenter randomized clinical trial comparing the effects of an intensive lifestyle intervention (ILI) and diabetes support and education (DSE; the control group) on the incidence of major CVD events in 5145 overweight or obese individuals (59.5% female; mean age, 58.7 years) with type 2 diabetes mellitus. More than 93% of participants provided outcomes data at each annual assessment. RESULTS Averaged across 4 years, ILI participants had a greater percentage of weight loss than DSE participants (-6.15% vs -0.88%; P < .001) and greater improvements in treadmill fitness (12.74% vs 1.96%; P < .001), hemoglobin A(1c) level (-0.36% vs -0.09%; P < .001), systolic (-5.33 vs -2.97 mm Hg; P < .001) and diastolic (-2.92 vs -2.48 mm Hg; P = .01) blood pressure, and levels of high-density lipoprotein cholesterol (3.67 vs 1.97 mg/dL; P < .001) and triglycerides (-25.56 vs -19.75 mg/dL; P < .001). Reductions in low-density lipoprotein cholesterol levels were greater in DSE than ILI participants (-11.27 vs -12.84 mg/dL; P = .009) owing to greater use of medications to lower lipid levels in the DSE group. At 4 years, ILI participants maintained greater improvements than DSE participants in weight, fitness, hemoglobin A(1c) levels, systolic blood pressure, and high-density lipoprotein cholesterol levels. CONCLUSIONS Intensive lifestyle intervention can produce sustained weight loss and improvements in fitness, glycemic control, and CVD risk factors in individuals with type 2 diabetes. Whether these differences in risk factors translate to reduction in CVD events will ultimately be addressed by the Look AHEAD trial. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00017953.

Incidence of Type II Diabetes in Mexican Americans Predicted by Fasting Insulin and Glucose Levels, Obesity, and Body-Fat Distribution

Few data exist on predictors of non-insulin-dependent (type II) diabetes mellitus. We examined body mass index (BMI), ratio of subscapular-to-triceps skin fold (centrality index), and fasting glucose and insulin concentrations as predictors of decompensation to type II diabetes in Mexican Americans, a population at high risk for this disorder. Twenty-eight of 474 initially nondiabetic Mexican Americans developed type II diabetes after 8 yr of follow-up. Converters to diabetes were older and had higher BMIs, centrality indices, and fasting glucose and insulin concentrations than nonconverters. Subjects in the highest quartile of the insulin distribution had 6.6 times the risk of developing type II diabetes as subjects in the remaining three quartiles combined (95% confidence interval [CI] = 3.14–13.7). In multivariate analysis, fasting glucose (odds ratio [OR] = 5.80, 95% CI = 2.57–13.1) and insulin (OR = 3.12, 95% CI = 1.36–7.14) remained significantly related to conversion to diabetes. However, BMI and centrality index, which were significantly related to conversion in the univariate analysis, were no longer significant in the multivariate analysis once glucose and insulin concentrations were taken into consideration, suggesting that the effect of these variables may be mediated by insulin resistance. Nearly half of the incident cases developed in a subset of the population who were simultaneously in the highest quartile of both fasting insulin and glucose concentrations (population-attributable risk 44.2%). Our results support the insulin resistance/pancreatic exhaustion theory of type II diabetes.

Fueling the Obesity Epidemic? Artificially Sweetened Beverage Use and Long-term Weight Gain

We have examined the relationship between artificially sweetened beverage (ASB) consumption and long‐term weight gain in the San Antonio Heart Study. From 1979 to 1988, height, weight, and ASB consumption were measured among 5,158 adult residents of San Antonio, Texas. Seven to eight years later, 3,682 participants (74% of survivors) were re‐examined. Outcome measures were incidence of overweight/obesity (OW/OBinc) and obesity (OBinc) (BMI ≥ 25 and ≥ 30 kg/m2, respectively), and BMI change by follow‐up (ΔBMI, kg/m2). A significant positive dose‐response relationship emerged between baseline ASB consumption and all outcome measures, adjusted for baseline BMI and demographic/behavioral characteristics. Consuming >21 ASBs/week (vs. none) was associated with almost‐doubled risk of OW/OB (odds ratio (OR) = 1.93, P = 0.007) among 1,250 baseline normal‐weight (NW) individuals, and doubled risk of obesity (OR = 2.03, P = 0.0005) among 2,571 individuals with baseline BMIs <30 kg/m2. Compared with nonusers (+1.01 kg/m2), ΔBMIs were significantly higher for ASB quartiles 2–4: +1.46 (P = 0.003), +1.50 (P = 0.002), and +1.78 kg/m2 (P < 0.0001), respectively. Overall, adjusted ΔBMIs were 47% greater among artificial sweetner (AS) users than nonusers (+1.48 kg/m2 vs. +1.01 kg/m2, respectively, P < 0.0001). In separate analyses—stratified by gender; ethnicity; baseline weight category, dieting, or diabetes status; or exercise‐change category—ΔBMIs were consistently greater among AS users. These differences, though not significant among exercise increasers, or those with baseline diabetes or BMI >30 kg/m2 (P = 0.069), were significant in all 13 remaining strata. These findings raise the question whether AS use might be fueling—rather than fighting—our escalating obesity epidemic.

Do Upper-Body and Centralized Adiposity Measure Different Aspects of Regional Body-Fat Distribution? Relationship to Non-Insulin-Dependent Diabetes Mellitus, Lipids, and Lipoproteins

Both central and upper-body adiposity are associated with high rates of type II non-insulin-dependent diabetes mellitus (NIDDM), high triglyceride levels, and low high-density lipoprotein (HDL) cholesterol levels. Previous data have also suggested that central and upperbody adiposity are relatively uncorrelated and hence may measure different aspects of regional body fat distribution. We assessed body mass index (BMI), the ratio of subscapular-to-triceps skinfold (STR), the ratio of waist-to-hip circumference (WHR), lipids, lipoproteins, and glucose tolerance in 738 Mexican Americans (ages 25-64 yr), who participated in the San Antonio Heart Study, a population-based study of diabetes and cardiovascular risk factors. NIDDM was diagnosed according to National Diabetes Data Group criteria. In general, STR and WHR were associated with high NIDDM rates, low HDL cholesterol levels, and high triglyceride levels, although WHR was somewhat more predictive of these than STR. In females, BMI, WHR, and STR all made independent contributions to prediction of NIDDM and HDL cholesterol; in males, WHR and STR both made independent contributions to prediction of triglyceride levels. This suggests that both indices may measure different aspects of body-fat distribution. Investigators should consider measuring both of these indicators of body-fat distribution in studies of diabetes and other cardiovascular risk factors, although if only a single measure is feasible, WHR appears to be preferable.

Hyperinsulinemia in a Population at High Risk for Non-Insulin-Dependent Diabetes Mellitus

The prevalence of non-insulin-dependent diabetes mellitus (NIDDM) is higher in Mexican Americans than in non-Hispanic white Americans, even after adjustment for the formers greater overall and more centralized adiposity. We postulated that this excess risk of NIDDM could be due to resistance to insulin. We performed oral glucose-tolerance tests with measurements of serum insulin concentrations in 225 Mexican Americans and 180 non-Hispanic whites without diabetes as part of the San Antonio Heart Study, a population-based study of risk factors for diabetes. Changes in serum insulin concentrations in response to the glucose challenge were quantified by the area under the serum insulin curve. Overall adiposity was characterized by body-mass index, and regional body-fat distribution by the ratio of subscapular to triceps skinfolds and the ratio of waist to hip circumference. After adjustment for these indicators of adiposity and also for differences in glucose tolerance, Mexican Americans were found to have significantly greater areas under the serum insulin curve than non-Hispanic whites. These data suggest that, like other populations at high risk for NIDDM such as Pima Indians and Micronesians, Mexican Americans have more hyperinsulinemia than can be accounted for by their adiposity.

Hyperinsulinemia, upper body adiposity, and cardiovascular risk factors in non-diabetics

Previous studies have suggested that hyperinsulinemia and upper body adiposity are each separately associated with elevated BP and triglyceride (TG) levels, and with lower high density lipoprotein (HDL) cholesterol levels. The joint effect of hyperinsulinemia and upper body adiposity on lipids, lipoproteins, and BP, however, has not been previously studied. We hypothesized that the effect of body fat distribution on cardiovascular risk factors might be mediated through hyperinsulinemia. We measured BP, lipids and lipoproteins, HDL subfractions, and insulin and glucose concentrations as part of the San Antonio Heart Study, a population-based study of diabetes and cardiovascular risk factors. Insulinemia and glycemia were assessed as the sum of the fasting, half-hour, one-hour, and two-hour insulin and glucose levels, respectively, measured during a standardized oral glucose tolerance test. Individuals who had diabetes according to National Diabetes Data Group criteria were excluded from the analyses. In univariate analyses, both hyperinsulinemia and waist-to-hip ratio (WHR), a measure of upper body adiposity, were positively associated with TG and negatively associated with total HDL and HDL2 cholesterol levels. However, when the effects of glycemia and insulinemia were controlled for by analysis of variance, WHR was no longer significantly related to TG levels. By contrast, WHR continued to be inversely related to total HDL and HDL2 cholesterol even after adjustment for glycemia and insulinemia. Hyperinsulinemia was only weakly related to HDL cholesterol. These results suggest that insulinemia and glycemia might mediate the effects of upper body adiposity on TG, although not on HDL and HDL2 cholesterol. Hyperinsulinemia was also positively associated with diastolic and systolic BP in men.

Increased Insulin Concentrations in Nondiabetic Offspring of Diabetic Parents

Abstract Insulin resistance is thought by many to be the primary defect that results in non-insulin-dependent diabetes mellitus (NIDDM). An implication of this theory is that prediabetic persons have higher serum insulin levels than normal subjects. We assessed serum insulin concentrations in a cohort of 1497 nondiabetic Mexican Americans, a population at high risk for NIDDM, according to whether their parents or siblings had diabetes. It was assumed that prediabetic persons would be more likely to have strong family histories of diabetes. We found a stepwise increase in fasting insulin levels in nondiabetics with neither, one, or both parents with diabetes (69.8, 77.8, and 94.6 pmol per liter, respectively; P = 0.002). Similar results were observed for insulin sum (the total of insulin concentrations in the fasting state and at 30, 60, and 120 minutes after a 75-g oral glucose load). The differences in insulin sums according to family history remained statistically significant in analyses of covariance, ...

Prevalence of Diabetes in Mexican Americans: Relationship to Percent of Gene Pool Derived from Native American Sources

We have estimated the prevalence of non-insulin-dependent diabetes mellitus (NIDDM) in Mexican Americans and Anglos in three San Antonio neighborhoods. The age-adjusted NIDDM rates (both sexes pooled) for Mexican Americans were 14.5%, 10%, and 5% for residents of a low-income barrio, a middle-income transitional neighborhood, and a high-income suburb, respectively. In Mexican American women, though not in men, obesity also declined from barrio to suburbs. We have previously shown, however, that, although obesity is an important cause of NIDDM in Mexican Americans, there is a two- to fourfold excess in the rate of NIDDM in this ethnic group over and above that which can be attributed to obesity. We therefore speculated that genetic factors might also contribute to excess NIDDM in this ethnic group. The percent native American admixture of Mexican Americans as estimated from skin color measurements was 46% in the barrio, 27% in the transitional neighborhood, and 18% in the suburbs. The NIDDM rates in Mexican Americans thus paralleled the proportion of native American genes. Furthermore, the San Antonio Mexican American rates were intermediate between the NIDDM rates of “fullblooded” Pima Indians (49.9%), who presumably have close to 100% native American genes, and the San Antonio Anglo population (3.0%) and the predominantly Anglo HANES II population (3.1%), both of which presumably have few if any native American genes. The association of genetic admixture with NIDDM rates suggests that much of the epidemic of NIDDM in Mexican Americans is confined to that part of the population with a substantial native American heritage.