Frank González

Effects of Exercise and Caloric Restriction on Insulin Resistance and Cardiometabolic Risk Factors in Older Obese Adults—A Randomized Clinical Trial

BACKGROUNDnThe prevalence of insulin resistance, metabolic syndrome, and cardiovascular disease is greatest in older obese patients, and effective evidence-based treatment strategies are lacking.nnnMETHODSnA prospective controlled study was conducted on 24 older (65.5 +/- 5.0 years) obese (body mass index, 34.3 +/- 5.2 kg/m(2)) adults with clinically diagnosed metabolic syndrome. We examined the effect of exercise alone (EX) or exercise combined with moderate caloric restriction (-500 kcal, EX + CR) on metabolic and cardiovascular risk factors. Measures of insulin sensitivity assessed by euglycemic hyperinsulinemic clamp and by oral glucose tolerance test, lipid profiles, blood pressure, body composition, abdominal fat, and aerobic capacity were all obtained before and after the interventions.nnnRESULTSnBoth groups experienced significant weight loss, but the reduction was greater in the EX + CR group than in the EX group (-6.8 +/- 2.7 kg vs -3.7 +/- 3.4 kg, respectively, p = .02). Both interventions improved insulin sensitivity (2.4 +/- 2.4 mg/kg FFM/min and 1.4 +/- 1.7 mg/kgFFM/min, respectively, p < .001) and indices of metabolic syndrome (systolic/diastolic blood pressure, waist circumference, glucose, and triglycerides; p < .05). High-density lipoprotein levels remained unchanged. Total abdominal, subcutaneous, and visceral fat; aerobic capacity; and total and low-density lipoprotein cholesterol were also improved. With the exception of weight loss and subcutaneous fat, there was no difference in the magnitude of improvement between the interventions.nnnCONCLUSIONnThese data suggest that exercise alone is an effective nonpharmacological treatment strategy for insulin resistance, metabolic syndrome, and cardiovascular disease risk factors in older obese adults.

Evidence of proatherogenic inflammation in polycystic ovary syndrome

Women with polycystic ovary syndrome (PCOS) have chronic low-level inflammation that can increase the risk of atherogenesis. We measured circulating proatherogenic inflammatory mediators in women with PCOS (8 lean: body mass index, 18-25 kg/m(2); 8 obese: body mass index, 30-40 kg/m(2)) and weight-matched controls (8 lean, 8 obese). Blood samples were obtained fasting and 2 hours after glucose ingestion to measure interleukin-6 (IL-6), soluble intercellular adhesion molecule-1 (sICAM-1), monocyte chemotactic protein-1 (MCP-1), C-reactive protein (CRP), matrix metalloproteinase-2, plasminogen activator inhibitor-1 (PAI-1), and activated nuclear factor kappaB in mononuclear cells. Truncal fat was determined by dual-energy x-ray absorptiometry. Fasting MCP-1 levels were elevated in lean women with PCOS compared with lean controls (159.9 +/- 14.1 vs 121.2 +/- 5.4 pg/mL, P < .02). Hyperglycemia failed to suppress matrix metalloproteinase-2 in lean women with PCOS compared with lean controls (1.7 +/- 1.2 vs -4.8 +/- 1.6 pg/mL, P < .002). Among women with PCOS, obese individuals exhibited higher fasting sICAM-1 (16.1 +/- 0.8 vs 10.5 +/- 1.0 ng/mL, P < .03) and PAI-1 (6.1 +/- 0.7 vs 3.4 +/- 0.8 ng/mL, P < .03) levels. Trend analysis revealed higher (P < .005) IL-6, sICAM-1, CRP, PAI-1, systolic and diastolic blood pressures, triglycerides, fasting insulin, and homeostasis model assessment of insulin resistance index in women with PCOS compared with weight-matched controls, and the highest levels in the obese regardless of PCOS status. Fasting MCP-1 levels correlated with activated nuclear factor kappaB during hyperglycemia (P < .05) and androstenedione (P < .004). Truncal fat correlated with fasting IL-6 (P < .004), sICAM-1 (P < .006), CRP (P < .0009), and PAI-1 (P < .02). We conclude that both PCOS and obesity contribute to a proatherogenic state; but in women with PCOS, abdominal adiposity and hyperandrogenism may exacerbate the risk of atherosclerosis.

Free fatty acid-induced hepatic insulin resistance is attenuated following lifestyle intervention in obese individuals with impaired glucose tolerance.

OBJECTIVEnThe objective of the study was to examine the effects of an exercise/diet lifestyle intervention on free fatty acid (FFA)-induced hepatic insulin resistance in obese humans.nnnRESEARCH DESIGN AND METHODSnObese men and women (n = 23) with impaired glucose tolerance were randomly assigned to either exercise training with a eucaloric (EU; approximately 1800 kcal; n = 11) or hypocaloric (HYPO; approximately 1300 kcal; n = 12) diet for 12 wk. Hepatic glucose production (HGP; milligrams per kilogram fat-free mass(-1) per minute(-1)) and hepatic insulin resistance were determined using a two-stage sequential hyperinsulinemic (40 mU/m(2) . min(-1)) euglycemic (5.0 mm) clamp with [3-(3)H]glucose. Measures were obtained at basal, during insulin infusion (INS; 120 min), and insulin plus intralipid/heparin infusion (INS/FFA; 300 min).nnnRESULTSnAt baseline, basal HGP was similar between groups; hyperinsulinemia alone did not completely suppress HGP, whereas INS/FFA exhibited less suppression than INS (EU, 4.6 +/- 0.8, 2.0 +/- 0.5, and 2.6 +/- 0.4; HYPO, 3.8 +/- 0.5, 1.2 +/- 0.3, and 2.3 +/- 0.4, respectively). After the intervention the HYPO group lost more body weight (P < 0.05) and fat mass (P < 0.05). However, both lifestyle interventions reduced hepatic insulin resistance during basal (P = 0.005) and INS (P = 0.001) conditions, and insulin-mediated suppression of HGP during INS was equally improved in both groups (EU: -42 +/- 22%; HYPO: -50 +/- 20%, before vs. after, P = 0.02). In contrast, the ability of insulin to overcome FFA-induced hepatic insulin resistance and HGP was improved only in the HYPO group (EU: -15 +/- 24% vs. HYPO: -58 +/- 19%, P = 0.02).nnnCONCLUSIONSnBoth lifestyle interventions are effective in reducing hepatic insulin resistance under basal and hyperinsulinemic conditions. However, the reversal of FFA-induced hepatic insulin resistance is best achieved with a combined exercise/caloric-restriction intervention.

Decreased Visfatin after Exercise Training Correlates with Improved Glucose Tolerance

UNLABELLEDnNampt/pre-B-cell colony-enhancing factor/visfatin (visfatin) release from adipocytes has recently been suggested to be nutrient responsive and linked to systemic nicotinamide adenine dinucleotide biosynthesis and regulation of pancreatic beta-cell function.nnnPURPOSEnWe hypothesized that if visfatin does play a role in the insulin response, then the exercise training-induced reduction in insulin response to an oral glucose load would correlate with reduced plasma visfatin.nnnMETHODSnSixteen obese men and women (age = 65 +/- 1 yr, body mass index = 33.4 +/- 1.5 kg x m(-2)) volunteered to participate in a 12-wk supervised exercise program (5 d x wk(-1), 60 min x d(-1) at 85% of HRmax). Visceral (VAT) and subcutaneous adipose tissue (SAT) were measured by computed tomographic scans. A 2-h 75-g oral glucose tolerance test was performed to determine the effect of exercise training on the insulin response to a glucose load. Fasting plasma visfatin was measured by enzyme-linked immunosorbent assay.nnnRESULTSnExercise training resulted in an increase in (.)VO2max (21.1 +/- 0.9 vs 24.2 +/- 1.1 mL x kg(-1) x min(-1), P < 0.001), a decrease in body weight (96.4 +/- 4.1 vs 92.4 +/- 3.7 kg, P < 0.001), VAT (191 +/- 16 vs 144 +/- 16 cm, P < 0.001), and SAT (369 +/- 34 vs 309 +/- 41 cm, P < 0.02). Area under the glucose (450 +/- 31 vs 392 +/- 33 mmol x L(-1) x 2 h(-1), P < 0.01) and insulin (45,767 +/- 6142 vs 35,277 +/- 4997 pmol x L(-1) x 2 h(-1), P < 0.003) response curves were decreased after training. After intervention, plasma visfatin levels were significantly reduced (16.9 +/- 2.2 vs 14.5 +/- 1.8 ng x mL(-1), P < 0.05), and the change in visfatin was associated with the corresponding change in insulin (r = 0.56, P < 0.05) and glucose AUC (r = 0.53, P < 0.05).nnnCONCLUSIONnThe exercise-induced reduction of plasma visfatin is most likely the result of weight loss and body composition changes. The potential regulatory role of visfatin in mediating the pancreatic insulin response to oral glucose requires further investigation.

Elevated circulating levels of macrophage migration inhibitory factor in polycystic ovary syndrome.

Women with polycystic ovary syndrome (PCOS) have chronic low level inflammation which can increase the risk of atherogenesis. We evaluated the status of circulating macrophage migration inhibitory factor (MIF), a proinflammatory cytokine involved in atherogenesis, in women with PCOS and weight-matched controls. Two-way analysis of variance models adjusted for age were fit to evaluate the effect of PCOS status (PCOS vs. controls) and weight-class (obese vs. lean) on MIF and other parameters. MIF levels were significantly (p<0.001) higher in women with PCOS (lean: 37.7+/-10.6 ng/ml; obese: 54.6+/-15.2 ng/ml) compared to controls (lean: 4.8+/-0.6 ng/ml; obese: 17.5+/-8.0 ng/ml) regardless of weight-class. CRP levels were significantly (p<0.001) higher in obese subjects (PCOS: 6.2+/-1.9 mg/l; controls: 6.7+/-1.4 mg/l) compared to lean subjects (PCOS: 0.9+/-0.4 mg/l; controls: 0.2+/-01 mg/l) after controlling for PCOS status. MIF levels directly correlated with % truncal fat (r=0.41, p<0.05), and plasma levels of CRP (r=0.42, p=0.05), LH (r=0.45, p=0.04), testosterone (r=0.53, p<0.008), androstendione (r=0.58, p<0.005). IS(OGTT) inversely correlated with plasma levels of MIF (r=-0.51, p<0.02) and CRP (r=-0.73, p<0.001). Circulating MIF is elevated in PCOS independent of obesity, but both PCOS and obesity contribute to a proatherogenic state. In PCOS, abdominal adiposity and hyperandrogenism may exacerbate the risk of atherosclerosis.

Obese Reproductive-Age Women Exhibit a Proatherogenic Inflammatory Response During Hyperglycemia

Objective: The objective was to determine if physiological hyperglycemia induces a proatherogenic inflammatory response in mononuclear cells (MNCs) in obese reproductive‐age women.

Effects of aging on basal fat oxidation in obese humans

Basal fat oxidation decreases with age. In obesity, it is not known whether this age-related process occurs independently of changes in body composition and insulin sensitivity. Therefore, body composition, resting energy expenditure, basal substrate oxidation, and maximal oxygen consumption (VO(2)max) were measured in 10 older (age, 60 +/- 4 years; mean +/- SEM) and 10 younger (age, 35 +/- 4 years) body mass index-matched, obese, normal glucose-tolerant individuals. Fasting blood samples were also collected. Older subjects had slightly elevated fat mass (32.2 +/- 7.1 vs 36.5 +/- 6.7 kg, P = .16); however, waist circumference was not different between groups (104.3 +/- 10.3 vs 102.1 +/- 12.6 cm, P = .65). Basal fat oxidation was 22% lower (1.42 +/- 0.14 vs 1.17 +/- 0.22 mg/kg fat-free mass per minute, P = .03) in older subjects. The VO(2)max was also decreased in older individuals (44.6 +/- 7.1 vs 38.3 +/- 6.0 mL/kg fat-free mass per minute, P = .03); but insulin sensitivity, lipemia, and leptinemia were not different between groups (P > .05). Fat oxidation was most related to age (r = -0.61, P = .003) and VO(2)max (r = 0.52, P = .01). These data suggest that aging per se is responsible for reduced basal fat oxidation and maximal oxidative capacity in older obese individuals, independent of changes in insulin resistance, body mass, and abdominal fat. This indicates that age, in addition to obesity, is an independent risk factor for weight gain and for the metabolic complications of elevated body fat.

Exercise Training and Dietary Glycemic Load May Have Synergistic Effects on Insulin Resistance in Older Obese Adults

Background/Aims: The aim of this study was to assess the combined effects of exercise and dietary glycemic load on insulin resistance in older obese adults. Methods: Eleven men and women (62 ± 2 years; 97.6 ± 4.8 kg; body mass index 33.2 ± 2.0) participated in a 12-week supervised exercise program, 5 days/week, for about 1 h/day, at 80–85% of maximum heart rate. Dietary glycemic load was calculated from dietary intake records. Insulin resistance was determined using the euglycemic (5.0 mM) hyperinsulinemic (40 mU/m2/min) clamp. Results: The intervention improved insulin sensitivity (2.37 ± 0.37 to 3.28 ± 0.52 mg/kg/min, p < 0.004), increased VO2max (p < 0.009), and decreased body weight (p < 0.009). Despite similar caloric intakes (1,816 ± 128 vs. 1,610 ± 100 kcal/day), dietary glycemic load trended towards a decrease during the study (140 ± 10 g before, vs. 115 ± 8 g during, p < 0.04). The change in insulin sensitivity correlated with the change in glycemic load (r = 0.84, p < 0.009). Four subjects reduced their glycemic load by 61 ± 8%, and had significantly greater increases in insulin sensitivity (78 ± 11 vs. 23 ± 8%, p < 0.003), and decreases in body weight (p < 0.004) and plasma triglycerides (p < 0.04) compared to the rest of the group. Conclusion: The data suggest that combining a low-glycemic diet with exercise may provide an alternative and more effective treatment for insulin resistance in older obese adults.