BACKGROUND Peripheral arterial disease (PAD) is associated with an impairment in exercise performance and muscle function that is not fully explained by the reduced leg blood flow during exercise. This study characterized the effects of PAD on muscle function, histology, and metabolism. METHODS AND RESULTS Twenty-six patients with PAD and six age-matched control subjects were studied. Ten of the PAD patients had unilateral disease, which permitted paired comparisons between their diseased and nonsymptomatic legs. All PAD patients had a lower peak treadmill walking time and peak oxygen consumption than controls. Vascular disease (diseased leg in unilateral patients and the most severely diseased leg in bilateral patients) was associated with decreased calf muscle strength compared with control values. In patients with unilateral disease, the diseased legs had a greater percentage of angular fibers (indicating chronic denervation) and a decreased type II fiber cross-sectional area (expressed as percent of total fiber area) compared with the nonsymptomatic, or control, legs. In diseased legs, gastrocnemius muscle strength was correlated with the total calf cross-sectional area (r = 0.78, p < 0.05) and type II fiber cross-sectional area (r = 0.63, p < 0.05). Activities of citrate synthase, phosphofructokinase, and lactate dehydrogenase in all 26 PAD patients (most diseased leg) did not differ from control values. Despite a wide range in citrate synthase activity in PAD patients, activity of this enzyme was not correlated with muscle strength or treadmill exercise performance. CONCLUSIONS In patients with PAD, gastrocnemius muscle weakness is associated with muscle fiber denervation and a decreased type II fiber cross-sectional area. In contrast, the PAD patients displayed substantial heterogeneity in muscle enzyme activities that was not associated with exercise performance. Denervation and type II fiber atrophy may contribute to the muscle dysfunction in patients with PAD and further confirm that the pathophysiology of chronic PAD extends beyond arterial obstruction.

Both waist circumference and sagittal diameter were good predictors of VAT in all groups. However, the nature of this relation differed such that race- and sex-specific equations will likely be required to estimate VAT from waist circumference or sagittal diameter.

In the placebo and lifestyle groups, VAT at both cuts, WHR, and WC predicted diabetes. No measure predicted diabetes in the metformin group. CT provided no important advantage over these simple measures. SAT did not predict diabetes.

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To determine whether uterine blood flow was reduced and indexes of pelvic blood flow distribution altered in normotensive pregnancy at high (3,100 m) compared with low altitude (1,600 m), we measured uterine, common iliac, and external iliac artery blood flow velocities and diameters in women during pregnancy and again postpartum. Pregnancy increased uterine artery diameter, blood flow velocity, and volumetric flow at both altitudes. Uterine artery blood flow velocity was greater (69.0 +/- 2.2 vs. 59.4 +/- 3.0 cm/s; P < 0.005) but diameter was smaller at 3,100 m than at 1,600 m (2.5 +/- 0.3 mm vs. 3.4 +/- 0.2 mm; P< 0.005), resulting in volumetric flow that was one-third lower at week 36 of pregnancy (203 +/- 48 vs. 312 +/- 22 ml/min, respectively; P < 0.01). Pregnancy increased common iliac blood flow velocity and decreased external iliac artery blood flow velocity at both altitudes. The uterine artery received a smaller percent of common iliac flow at 3,100 than at 1,600 m (46 +/- 7 vs. 74 +/- 6%; P < 0.005). Gestational age was similar but birth weight was lower at 3,100 m than at 1,600 m. Among subjects at 1,600 m, variation in uterine blood flow velocity correlated positively with infant birth weight. We concluded that reduced uterine blood flow and altered pelvic blood flow distribution during pregnancy at high altitude likely contributed to the altitude-associated reduction in infant birth weight.

The Diabetes Prevention Program is a randomized clinical trial testing strategies to prevent or delay the development of type 2 diabetes in high-risk individuals with elevated fasting plasma glucose concentrations and impaired glucose tolerance. The 27 clinical centers in the U.S. are recruiting at least 3,000 participants of both sexes, ~50% of whom are minority patients and 20% of whom are ≥65 years old, to be assigned at random to one of three intervention groups: an intensive lifestyle intervention focusing on a healthy diet and exercise and two masked medication treatment groupsmetformin or placebo-combined with standard diet and exercise recommendations. Participants are being recruited during a 2 2/3-year period, and all will be followed for an additional 3 1/3 to 5 years after the close of recruitment to a common closing date in 2002. The primary outcome is the development of diabetes, diagnosed by fasting or post-challenge plasma glucose concentrations meeting the 1997 American Diabetes Association criteria. The 3,000 participants will provide 90% power to detect a 33% reduction in an expected diabetes incidence rate of at least 6.5% per year in the placebo group. Secondary outcomes include cardiovascular disease and its risk factors; changes in glycemia, β-cell function, insulin sensitivity, obesity, diet, physical activity, and health-related quality of life; and occurrence of adverse events. A fourth treatment group-troglilazone combined with standard diet and exercise recommendations-was included initially but discontinued because of the liver toxicity of the drug. This randomized clinical trial will test the possibility of preventing or delaying the onset of type 2 diabetes in individuals at high risk. AbbreviationsADA, American Diabetes Association; DPP, Diabetes Prevention Program; FPG, fasting plasma glucose; IGT, impaired glucose tolerance; NIDDK, National Institute of Diabetes and Digestive and Kidney Diseases; OGTT, oral glucose tolerance test; WHO, World Health Organization Type 2 diabetes is a common chronic disease affecting an estimated 12% of 40-to 74-yearold people in the U.S. (1). It is a major cause of premature mortality and morbidity due to cardiovascular, renal, ophthalmic, and neurologic diseases. Although treatment of type 2 diabetes can improve hyperglycemia, normalization of glycemia and glycohemoglobin is rarely achieved or maintained. Furthermore, macro-vascular disease and its risk factors are often already present in individuals at high risk of developing type 2 diabetes (2). Therefore, a policy RESEARCH GOALS PrimaryThe primary research goal is a comparison of the efficacy and safety of each of three interventions (an intensive lifestyle intervention or standard lifestyle recommendations combined with metformin or placebo) in preventing or delaying the development of diabetes. Diabetes is diagnosed by fasting plasma glucose (FPG) or glucose tolerance testing according to the 1997 American Diabetes Association (ADA) criteria (1). SecondarySecondary research goals i...

Nonalcoholic fatty liver disease (NAFLD) is associated with obesity and insulin resistance. The condition disproportionately affects Hispanic Americans. The aims of this study were to examine the risk factors and heritability of NAFLD in 795 Hispanic American and 347 African‐American adults participating in the Insulin Resistance Atherosclerosis Study (IRAS) Family Study. Computed tomography (CT) scans of the abdomen were evaluated centrally for measures of liver–spleen (LS) density ratio and abdominal fat distribution. Other measures included insulin sensitivity (SI) calculated from a frequently sampled intravenous glucose tolerance test and various laboratory measures. Statistical models which adjust for familial relationships were estimated separately for the two ethnic groups. Heritability was calculated using a variance components approach. The mean age of the cohort was 49 years (range 22–84); 66% were female. NAFLD (LS ratio <1) was more common in Hispanic Americans (24%) than African Americans (10%). NAFLD was independently associated with SI and visceral adipose tissue (VAT) area in both ethnic groups, although the proportion of explained variance was considerably higher in the Hispanic models. Adiponectin contributed significantly in the African‐American models whereas triglycerides (TGs) and plasminogen activator inhibitor 1 (PAI‐1) contributed only in the Hispanic models. Liver density was modestly heritable in both ethnic groups (h2 ∼0.35). In summary, the prevalence of NAFLD was twofold greater in Hispanic than African Americans. Certain correlates of NAFLD were similar between the ethnic groups, whereas others were distinct. NAFLD was modestly heritable. These findings suggest that NAFLD may have a differing environmental and/or genetic basis in these ethnic groups.

The researchers conducted this study to test the hypothesis that risk of type 2 diabetes is less following reductions in body size and central adiposity. The Diabetes Prevention Program (DPP) recruited and randomized individuals with impaired glucose tolerance to treatment with placebo, metformin, or lifestyle modification. Height, weight, waist circumference, and subcutaneous and visceral fat at L2-L3 and L4-L5 by computed tomography were measured at baseline and at 1 year. Cox proportional hazards models assessed by sex the effect of change in these variables over the 1st year of intervention upon development of diabetes over subsequent follow-up in a subset of 758 participants. Lifestyle reduced visceral fat at L2-L3 (men ؊24.3%, women ؊18.2%) and at L4-L5 (men ؊22.4%, women ؊17.8%), subcutaneous fat at L2-L3 (men ؊15.7%, women ؊11.4%) and at L4-L5 (men ؊16.7%, women ؊11.9%), weight (men ؊8.2%, women ؊7.8%), BMI (men ؊8.2%, women ؊7.8%), and waist circumference (men ؊7.5%, women ؊6.1%). Metformin reduced weight (؊2.9%) and BMI (؊2.9%) in men and subcutaneous fat (؊3.6% at L2-L3 and ؊4.7% at L4-L5), weight (؊3.3%), BMI (؊3.3%), and waist circumference (؊2.8%) in women. Decreased diabetes risk by lifestyle intervention was associated with reductions of body weight, BMI, and central body fat distribution after adjustment for age and self-reported ethnicity. Reduced diabetes risk with lifestyle intervention may have been through effects upon both overall body fat and central body fat but with metformin appeared to be independent of body fat. Diabetes 56:1680-1685, 2007 T ype 2 diabetes has rapidly become a global health problem (1). Moreover, diabetes is a major cause of morbidity and mortality from coronary artery, cerebrovascular, retinal, neurological, and renal complications (2,3). One solution may be to prevent or delay diabetes in at-risk populations (4 -6). The Diabetes Prevention Program (DPP), a multicenter randomized clinical trial, showed that this could be accomplished with lifestyle intervention or metformin among individuals with impaired glucose tolerance. At the end of 3.2 years, diabetes incidence rates were 10.8, 7.7, and 5.0 per 100 person-years in the placebo, metformin, and lifestyle intervention groups, respectively (this average duration of follow-up is 4 months longer than that reported in the primary outcome report [6]). Treatment effects were consistent by sex and race/ethnicity. Individuals who have type 2 diabetes are usually overweight or obese. Moreover, a central pattern of body fat distribution, particularly an increased amount of intraabdominal or visceral fat, is an independent risk factor for type 2 diabetes (7-17). The effect of lifestyle modification and metformin on body size and central obesity was assessed in the DPP by both anthropometric measurements and computed tomography (CT).In this article, we tested the hypothesis that reductions in body size and central adiposity over the 1st year are associated with a decreased risk in developing type 2 diabetes over subsequent fo...