Peter G. Snell

Insulin Resistance and Body Fat Distribution in South Asian Men Compared to Caucasian Men

Objective South Asians are susceptible to insulin resistance even without obesity. We examined the characteristics of body fat content, distribution and function in South Asian men and their relationships to insulin resistance compared to Caucasians. Research Design and Methods Twenty-nine South Asian and 18 Caucasian non-diabetic men (age 27±3 and 27±3 years, respectively) underwent euglycemic-hyperinsulinemic clamp for insulin sensitivity, underwater weighing for total body fat, MRI of entire abdomen for intraperitoneal (IP) and subcutaneous abdominal (SA) fat and biopsy of SA fat for adipocyte size. Results Compared to Caucasians, in spite of similar BMI, South Asians had higher total body fat (22±6 and 15±4% of body weight; p-value<0.0001), higher SA fat (3.5±1.9 and 2.2±1.3 kg, respectively; p-value = 0.004), but no differences in IP fat (1.0±0.5 and 1.0±0.7 kg, respectively; p-value = 0.4). SA adipocyte cell size was significantly higher in South Asians (3491±1393 and 1648±864 µm2; p-value = 0.0001) and was inversely correlated with both glucose disposal rate (r-value = −0.57; p-value = 0.0008) and plasma adiponectin concentrations (r-value = −0.71; p-value<0.0001). Adipocyte size differences persisted even when SA was matched between South Asians and Caucasians. Conclusions Insulin resistance in young South Asian men can be observed even without increase in IP fat mass and is related to large SA adipocytes size. Hence ethnic excess in insulin resistance in South Asians appears to be related more to excess truncal fat and dysfunctional adipose tissue than to excess visceral fat.

Insulin Resistance and Risk Factors for Cardiovascular Disease in Young Adult Survivors of Childhood Acute Lymphoblastic Leukemia

PURPOSE To determine the prevalence of insulin resistance and other risk factors for cardiovascular disease (CVD) in young adult survivors of childhood acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS In this cross-sectional evaluation of 118 survivors of childhood ALL (median age, 23.0 years; range, 18 to 37 years), insulin resistance was estimated using the homeostasis model for assessment of insulin resistance (HOMA-IR). Sex-specific comparisons were made with a cohort of 30- to 37-year-old individuals from the same region participating in the Dallas Heart Study (DHS, N = 782). ALL survivors were stratified by treatment with and without cranial radiotherapy (CRT). RESULTS Female ALL survivors had a significantly higher HOMA-IR (CRT, mean 4.6, 95% CI, 3.6 to 5.7; no CRT, mean 3.3, 95% CI, 2.8 to 3.8) in comparison with DHS women (mean 2.4, 95% CI, 2.2 to 2.7). Eighty percent of women treated with CRT had at least three of six CVD risk factors, and they were significantly more likely to have three or more risk factors compared with DHS women (odds ratio [OR], 5.96; 95% CI, 2.15 to 16.47). Male ALL survivors had a significantly higher HOMA-IR (CRT, mean 4.0, 95% CI, 2.8 to 5.6; no CRT, mean 3.4, 95% CI, 2.9 to 3.9) in comparison with DHS men (mean 2.3, 95% CI, 2.1 to 2.6), but were not more likely to have multiple CVD risk factors. CONCLUSION ALL survivors had an increased prevalence of insulin resistance in comparison with a cohort of older individuals from the same community. Importantly, women treated with CRT seem to have an increased prevalence of multiple CVD risk factors, warranting close monitoring and risk-reducing strategies.

Cardiovascular adaptations to intense swim training in sedentary middle-aged men and women.

Central and peripheral cardiovascular adaptations to 12 weeks of intense swim training were characterized in 12 previously sedentary middle-aged men and women. Peak oxygen uptake (VO2) during upright bicycle exercise improved from 29.2 +/- 5.6 to 34.7 +/- 6.7 ml/kg/min (mean +/- SD, p less than .01) because of similar increases in peak cardiac output (CO) and calculated arteriovenous oxygen difference (both p = .02). Peak supine VO2 was 10% higher after training (p less than .005) solely because of enhanced CO (p = .005). Peak heart rate decreased in both postures; therefore stroke volume at peak exercise was greater by 10% and 18% in the upright and supine postures, respectively (p = .05 and p = .005). There was an identical 18% rise (p = .01) in peak supine left ventricular end-diastolic volume index by radionuclide ventriculography but no change in left ventricular ejection fraction or end-systolic volume index (ESVI). Peak systolic blood pressure (SBP) was unchanged in the upright posture but was 8% higher (p = .002) during recumbency despite a similar total peripheral resistance and SBP/ESVI ratio. Maximal calf conductance (Gmax), assessed separately by venous occlusion plethysmography after local ischemic exercise to fatigue, was augmented 20% (p less than .02) by training, resulting in an 18% greater hyperemic blood flow (p = .05). Peak VO2, CO, and Gmax were unchanged in five nonexercising control subjects. We conclude that in middle-aged humans, intense swim training for 12 weeks produces adaptations that include a greater capacity for vasodilatation in skeletal muscle and an enhanced cardiac pump capacity.

High-volume exercise program in obese bariatric surgery patients: a randomized, controlled trial.

Weight regain is a problem among many bariatric surgery patients. Whether a high‐volume exercise program (HVEP), a strategy to limit weight regain, is feasible in these patients is unknown. The feasibility of an HVEP in obese post‐bariatric‐surgery patients was determined by randomizing 33 Roux‐en‐Y gastric bypass (RYGB) and gastric banding (GB) surgery patients with a mean BMI of 41 ± 6 kg/m2 to an HVEP or control group for 12 weeks. The HVEP group was instructed to expend ≥2,000 kcal/week in moderate‐intensity exercise. All patients were counseled to limit energy intake. Treatment effect was assessed by repeated measures analysis. During the last 4 weeks of the study, 53% of the HVEP group expended ≥2,000 kcal/week and 82% expended ≥1,500 kcal/week. Step count, reported time spent and energy expended during moderate physical activity, maximal oxygen consumption relative to weight, and incremental area under the postprandial blood glucose curve were significantly improved over 12 weeks in the HVEP group compared to controls (group‐by‐week effect: P = 0.009–0.03). Both groups reported significant improvement in some quality‐of‐life scales. Changes in weight, energy and macronutrient intake, resting energy expenditure (REE), fasting lipids and glucose, and fasting and postprandial insulin concentrations were not different between the two groups. HVEP is feasible in about 50% of the patients and enhances physical fitness and reduces postprandial blood glucose in bariatric surgery patients.

Comparison of efficacy and safety of leptin replacement therapy in moderately and severely hypoleptinemic patients with familial partial lipodystrophy of the Dunnigan variety.

CONTEXT Leptin replacement therapy improves metabolic complications in patients with lipodystrophy and severe hypoleptinemia (SH), but whether the response is related to the degree of hypoleptinemia remains unclear. OBJECTIVE The aim of the study was to compare efficacy of leptin therapy in familial partial lipodystrophy, Dunnigan variety (FPLD) patients with SH (serum leptin<7th percentile of normal) vs. those with moderate hypoleptinemia (MH; serum leptin in 7th to 20th percentiles). DESIGN, SETTING, AND PATIENTS We conducted an open-label, parallel group, observational study in 14 SH (mean±sd, serum leptin, 1.9±1.1 ng/ml) and 10 MH (serum leptin, 5.3±1.0 ng/ml) women with FPLD. INTERVENTION Patients received 0.08 mg/kg·d of metreleptin by twice daily sc injections for 6 months. MAIN OUTCOME MEASURES The primary outcome variable was change in fasting serum triglycerides. Other secondary variables were fasting plasma glucose and insulin, insulin sensitivity, hemoglobin A1c, and hepatic triglyceride content. RESULTS Median fasting serum triglycerides decreased from 228 to 183 mg/dl in the SH group (P=0.04) and from 423 to 339 mg/dl in the MH group (P=0.02), but with no difference between the groups (P value for interaction=0.96). Hepatic triglyceride levels similarly declined significantly from 8.8 to 4.9% in the SH group and from 23.7 to 9.2% in the MH group (P value for interaction=0.9). Loss of body weight and body fat occurred in both groups. Fasting glucose, insulin, glucose tolerance, and hemoglobin A1c levels did not change. K value on insulin tolerance test improved slightly in the SH group (0.98 to 1.24%; P=0.01), but not in the MH group (1.1 to 1.27%; P=0.4). CONCLUSION Metreleptin replacement therapy is equally effective in FPLD patients with both SH and MH in reducing serum and hepatic triglyceride levels, but did not improve hyperglycemia.

The frequency of anemia and iron deficiency in the runner

The current consensus is that runners commonly experience a mild anemia influenced by iron deficiency. We compared hematologic parameters of 72 (35 males and 37 females) runners with 48 (27 males and 21 females) nonrunners and assessed the impact of iron supplementation. Male runners had lower hemoglobin (Hb) values than male nonrunners (14.8 vs 15.3 g.dl-1) (P less than 0.05) regardless of iron usage. Female runners had higher (P = 0.05) Hb values than female controls (13.5 vs 12.8 g.dl-1). Female runners off iron had Hbs similar to controls off iron (P = 0.30). Iron parameters (total serum iron, TSI; total iron-binding capacity, TIBC; percent saturation of the TIBC, %sat TIBC; and serum ferritin) of runners vs controls, runners vs runners (on or off iron), and nonrunners vs nonrunners (on or off iron) were comparable except 1) male runners off iron had lower (P less than 0.05) %sat TIBC values (26%) than male runners on iron (34%) and 2) female runners taking iron had ferritin values (32 ng.ml-1) similar to those of female nonrunners taking iron (39 ng.ml-1) but higher (P less than 0.05) than their counterparts off iron (15 and 15 ng.ml-1, respectively). This study concludes that running affects Hb in a variable manner and suggests that the runners iron status is similar to that of the general population.

Effect of rowing ergometry and oral volume loading on cardiovascular structure and function during bed rest

This study examined the effectiveness of a short-duration but high-intensity exercise countermeasure in combination with a novel oral volume load in preventing bed rest deconditioning and orthostatic intolerance. Bed rest reduces work capacity and orthostatic tolerance due in part to cardiac atrophy and decreased stroke volume. Twenty seven healthy subjects completed 5 wk of -6 degree head down bed rest. Eighteen were randomized to daily rowing ergometry and biweekly strength training while nine remained sedentary. Measurements included cardiac mass, invasive pressure-volume relations, maximal upright exercise capacity, and orthostatic tolerance. Before post-bed rest orthostatic tolerance and exercise testing, nine exercise subjects were given 2 days of fludrocortisone and increased salt. Sedentary bed rest led to cardiac atrophy (125 ± 23 vs. 115 ± 20 g; P < 0.001); however, exercise preserved cardiac mass (128 ± 38 vs. 137 ± 34 g; P = 0.002). Exercise training preserved left ventricular chamber compliance, whereas sedentary bed rest increased stiffness (180 ± 170%, P = 0.032). Orthostatic tolerance was preserved only when exercise was combined with volume loading (-10 ± 22%, P = 0.169) but not with exercise (-14 ± 43%, P = 0.047) or sedentary bed rest (-24 ± 26%, P = 0.035) alone. Rowing and supplemental strength training prevent cardiovascular deconditioning during prolonged bed rest. When combined with an oral volume load, orthostatic tolerance is also preserved. This combined countermeasure may be an ideal strategy for prolonged spaceflight, or patients with orthostatic intolerance.

Physical Inactivity An Easily Modified Risk Factor

The classic modifiable risk factors for the development of coronary heart disease (CHD), derived from the Framingham Heart Study and other long-term epidemiological studies, are increased blood pressure, elevated plasma cholesterol, and cigarette smoking. However, evidence has been accumulating for many years suggesting that physical inactivity or the lack of exercise is also a potent force in this field. The pioneering studies by Morris et al from England1,2 and Paffenbarger et al from the United States 3,4

Randomized comparison of the effects of rosiglitazone vs. placebo on peak integrated cardiovascular performance, cardiac structure, and function

AIMS To assess the effect of rosiglitazone on cardiovascular performance and cardiac function. METHODS AND RESULTS One hundred and fifty type 2 diabetes patients with cardiovascular disease (CVD) or ≥ 1 other CVD risk factor were randomized to receive rosiglitazone vs. placebo for 6 months. The primary outcome was peak oxygen uptake indexed to fat-free mass (VO(2peak)-FFM) during maximum exercise. A subset of 102 subjects underwent cardiac magnetic resonance imaging (cMRI). On hundred and eight subjects completed the study, including 75 completing the cMRI substudy. No significant differences were observed in mean VO(2peak)-FFM between rosiglitazone and placebo (26.1 ± 7.0 vs. 27.6 ± 6.6 mL/kg-FFM/min; P = 0.26). Compared with placebo, the rosiglitazone group had lower hematocrit (38 vs. 41%; P < 0.001) and more peripheral oedema (53.7 vs. 33.3%; P = 0.03). In the cMRI substudy, compared with placebo, the rosiglitazone group had larger end-diastolic volume (128.1 vs. 112.0 mL; P = 0.01) and stroke volume (83.7 vs. 72.9 mL; P = 0.01), and a trend toward increased peak ventricular filling rate (79.4 vs. 60.5; P = 0.07). CONCLUSION Rosiglitazone increased peripheral oedema but had no pernicious effects on cardiovascular performance or cardiac function, with modest improvement in selected cMRI measures. Changes in indirect markers of plasma volume suggest expansion with rosiglitazone. TRIAL REGISTRATION clinicaltrials.gov identifier: NCT00424762.

Reduced cardiorespiratory fitness in adult survivors of childhood acute lymphoblastic leukemia

Adult survivors of childhood acute lymphoblastic leukemia (ALL) are at increased cardiovascular risk. Studies of factors including treatment exposures that may modify risk of low cardiorespiratory fitness in this population have been limited.