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Objective: To compare the effects of weight loss vs aerobic exercise training on coronary artery disease risk factors in healthy sedentary, obese, middle-aged and older men.Design: Randomized controlled trial.Subjects: A total of 170 obese (body mass index, 30 +/- 1 kg/m2 [mean +/- SEM]), middle-aged and older (61 +/- 1 years) men.Interventions: A 9-month diet-induced weight loss interventions, 9-month aerobic exercise training program, and a weight-maintenance control group.Main Outcome Measures: Change in body composition, maximal aerobic capacity (V02 max), blood pressure, lipoprotein concentrations, and glucose tolerance.Results: Forty-four of 73 men randomized to weight loss completed the intervention and had a 10% mean reduction in weight (- 9.5 +/- 0.7 kg; P < .001), with no 22 change in VO2 max. Forty-nine of 71 men randomized to aerobic exercise completed the intervention, increased their VO2 max by a mean of 17% (P < .001), and did not change their weight, whereas the 18 men who completed in the control group had no significant changes in body composition or VO2 max. Weight loss decreased fasting glucose concentrations by 2%, insulin by 18%, and glucose and insulin areas during the oral glucose tolerance test (OGTT) by 8% and 26%, respectively (P < .01). By contrast, aerobic exercise did not improve fasting glucose or insulin concentrations or glucose responses during the OGTT but decreased insulin areas by 17% (P < .001). In analysis of variance, the decrement in fasting glucose and insulin levels and glucose areas with intervention differed between weight loss and aerobic exercise when compared with the control group (P < .05). Similarly, weight loss but not aerobic exercise increased high-density lipoprotein cholesterol levels (+ 13%) and decreased blood pressure compared with the control group. In multiple regression analyses, the improvement in lipoprotein and glucose metabolism was related primarily to the reduction in obesity.Conclusions: These results suggest that weight loss is the preferred treatment to improve coronary artery disease risk factors in overweight, middle-aged and older men. [ABSTRACT FROM AUTHOR]

Objective: To test the hypothesis that the greater beta-adrenoceptor (beta-AR)-stimulated lipolysis and sensitivity (half-maximal lipolytic response) in abdominal (ABD) adipocytes, greater gluteal (GLT) adipose tissue-lipoprotein lipase (AT-LPL) activity, and dyslipidemia associated with obesity in older women are modifiable by weight loss (WL) and are not due to menopause or aging., Research Methods and Procedures: The metabolic effects of 6 months of hypocaloric diet and low-intensity walking WL program on the regional regulation of in vitro lipolysis and AT-LPL activity in subcutaneous ABD and GLT adipocytes were measured in 34 obese (48.7 +/- 0.7% body fat, mean +/- SE) postmenopausal (59 +/- 1 years) white women., Results: The lipolytic responsiveness to the beta-AR agonist isoproterenol and basal lipolysis in the presence of 1 U/mL adenosine deaminase-uninhibited (lipolysis) were greater (p < 0.01) in ABD than GLT adipocytes before and after WL, but there were no regional differences in postreceptor (dibutyryl 3',5'-cyclic adenosine monophosphate)-stimulated lipolysis. beta-AR sensitivity was greater in ABD than GLT adipocytes before (p < 0.01) but not after WL. Regional AT-LPL did not change after WL, but the change in the activity of ABD (but not GLT) AT-LPL correlated with the baseline adenosine deaminase-uninhibited lipolysis (r = 0.38, p = 0.03). There were no relationships between the declines in plasma triglyceride or increases in high-density lipoprotein cholesterol associated with WL and the changes in regional fat cell metabolism., Discussion: Thus, despite improving lipoprotein lipid profiles in obese, postmenopausal women, WL does not affect the regulation of regional fat metabolism, and a greater tonic inhibition of basal lipolysis by endogenous adenosine may increase the activity of AT-LPL after WL and predispose older women to develop ABD adiposity.

This study determines whether changes in abdominal (ABD) and gluteal (GLT) adipose tissue lipoprotein lipase (LPL) activity in response to a 6-mo weight loss intervention, comprised of a hypocaloric diet and low-intensity walking, affect changes in body composition, fat distribution, lipid metabolism, and the magnitude of weight regain in 36 obese postmenopausal women. Average adipose tissue LPL activity did not change with an average 5.6-kg weight loss, but changes in LPL activity were inversely related to baseline LPL activity (ABD: r = -0.60, GLT: r = -0.48; P < 0.01). The loss of abdominal body fat and decreases in total and low-density lipoprotein cholesterol were greater in women whose adipose tissue LPL activity decreased with weight loss despite a similar loss of total body weight and fat mass. Moreover, weight regain after a 6-mo follow-up was less in women whose adipose tissue LPL activity decreased than in women whose LPL increased (ABD: 0.9 +/- 0.5 vs. 2.8 +/- 0.6 kg, P < 0.05; GLT: 0.2 +/- 0.5 vs. 2.8 +/- 0.5 kg, P < 0.01). These results suggest that a reduction in adipose tissue LPL activity with weight loss is associated with improvements in lipid metabolic risk factors with weight loss and with diminished weight regain in postmenopausal women.

Objective: To test the effects of aerobic exercise training on glucose-stimulated insulin responses in middle-aged and older individuals., Design: A 9-month moderate-intensity aerobic exercise training trial in 17 men., Setting: An academic medical center., Intervention: Subjects walked, jogged, or cycled at 50 to 60% heart rate reserve (HRR) three times per week for 30 to 45 minutes and progressed over 6 to 9 months until subjects were training at 80 to 85% of HRR for 45 to 60 minutes three to four times per week. Training intensity was stabilized for 2 weeks before retesting. Diets were stabilized on American Heart Association Step I diets before training, and calories increased to prevent weight loss., Measurements: At baseline and after training, subjects underwent measurement of body fat (hydrodensitometry), regional fat distribution (waist-to-hip ratio (WHR)), VO2 max (maximal treadmill testing), diet intake (7-day food records), and glucose and insulin responses during 75 g, 2-hour oral glucose tolerance tests (OGTT) and 2-hour hyperglycemic (+/-7.9 mmol/L) glucose clamps., Results: Aerobic exercise training increased VO2 max by 15% and decreased body fat from 22.8 +/- 1.6 to 20.8 +/- 1.5% (P < .0001), waist circumference by 2% (P = .038), and WHR by 1% (P = .035). Fasting glucose and insulin levels, and glucose responses during the OGTT did not change, but insulin responses during the OGTT decreased 16% (P = .027) after training. Training reduced early (0-10 minutes) and late (20-120 minutes) phase insulin responses by 14% (P = .017 and .042, respectively), but did not significantly change glucose disposal (+8%, P = .398). Multiple regression analyses showed that changes in waist circumference (r2 = 0.68, P < .0001) and percent body fat (r2 = 0.08, P = .049) were independent predictors of the reductions in the late phase insulin responses with exercise training, however, changes in VO2 max were not (P = .199)., Conclusions: The decrease in glucose-stimulated insulin secretion with aerobic exercise training in middle-aged and older men appears to be mediated, at least in part, by reductions in the amount of abdominal fat. Regular physical exercise may prevent or ameliorate conditions associated with hyperinsulinemia including dyslipidemia, hypertension, and atherosclerosis in this group.

Adipose tissue lipoprotein lipase (LPL) activity is under strong genetic control in both mice and humans. This study determines whether common DNA variation in the LPL gene (PvuII and HindIII polymorphisms) is associated with adipose tissue LPL activity and metabolic risk factors in a homogeneous population of 75 overweight postmenopausal women (body mass index >25 kg/m2; age: 51-69 years old). The allele frequencies for the presence of the cut-sites for LPL HindIII and PvuII were 0.71 and 0.49, respectively. There were no associations between the HindIII polymorphism and any of the measured variables. Age, body mass index, percent body fat, waist-hip ratio, visceral and subcutaneous fat area, and gluteal (GLT) and abdominal (ABD) adipocyte size did not differ by LPL PvuII genotype. However, adipose tissue LPL activity at both GLT and ABD sites was higher in women without the LPL PvuII cut-site (-/-) compared with women who were heterozygous (+/-) or homozygous (+/+) for the cut-site (P<0.05). Total and LDL cholesterol were lower in women without the LPL PvuII cut-site (-/-) compared with women who were heterozygous or homozygous for the cut-site (P<0.05), whereas triglyceride and HDL levels were similar between LPL PvuII genotypes. Fasting glucose, but not insulin, was lower in women without the LPL PvuII cut-site (-/-). These data suggest that the LPL PvuII polymorphism is a possible marker for a functional mutation that is found in the LPL gene and that alters LPL activity in older overweight women.

The effects of long-term endurance exercise training, body composition, and cardiovascular fitness (VO2max) on the activity of adipose tissue lipoprotein lipase (AT-LPL) and lipoprotein lipids were examined in 66 healthy age-matched middle-aged and older men (mean +/- SE, 61 +/- 1 years). We compared subcutaneous abdominal (ABD) and gluteal (GLT) heparin-elutable AT-LPL activity in 19 master athletes (VO2max > 40 mL/kg/min) and 20 lean sedentary men (VO2max < 40 mL/kg/min) versus 27 obese sedentary men (VO2max < 40 mL/kg/min; body fat > 27%). Fasting insulin and leptin levels were similar in master athletes and lean sedentary men, but were lower than in obese sedentary men. There were no differences in fasting values for total cholesterol or low-density lipoprotein cholesterol (LDL-C) among the groups, but master athletes had lower triglyceride (TG) values (P < .05) and higher high-density lipoprotein cholesterol (HDL-C) and HDL2-C (P < .05) than obese and lean sedentary men. There were no regional (ABD v GLT) differences in the activity of AT-LPL in these groups, but obese sedentary men had higher levels of ABD AT-LPL (2.1 +/- 0.3 nmol/10(6) cells x min) than lean sedentary men (0.8 +/- 0.2) and master athletes (0.5 +/- 0.1, P = .01). Similar results were observed for GLT AT-LPL. Both ABD and GLT AT-LPL activity correlated positively with percent body fat (r = .46 to .54, P < .001), fasting insulin (r = .37 to .45, P < .001), and leptin (r = .61 to .65, P < .0001), but not with VO2max. In stepwise multiple regression analysis, leptin was the main independent predictor of ABD (R2 = .43, P < .0001) and GLT (R2 = .40, P < .0001) AT-LPL activity. Plasma TG correlated positively (r = .32, P < .01) and HDL-C correlated negatively (r = -.32, P = .02) with ABD AT-LPL activity, but these relationships were not significant after controlling for percent body fat or leptin. The results of this study indicate that in healthy middle-aged and older men, the major determinants of AT-LPL activity are obesity and its major associated hormones, leptin and insulin, not cardiovascular fitness, and also suggest that the higher HDL-C levels observed in endurance-trained men are not associated with increased AT-LPL activity.

The clustering of metabolic abnormalities often associated with hypertension, including insulin resistance, glucose intolerance, and dyslipidemia, in middle-aged men may be the result of a decrease in cardiovascular fitness (VO2max) and the accumulation of body fat with aging. This study examines the effects of a 6-month program of aerobic exercise training plus weight loss (AEX+WL) on VO2max, body composition, blood pressure (BP), glucose and insulin responses during an oral glucose tolerance test (OGTT), glucose infusion rates (GIR) during 3-dose hyperinsulinemic-euglycemic clamps at insulin infusion rates of 120, 600, and 3,000 pmol x m(-2) x min(-1), and plasma lipoprotein levels. Compared with eight non-obese, normotensive, sedentary men (age, 62+/-2 years; 19%+/-2% fat; BP, 117+/-4/72+/-2 mm Hg), the nine obese, hypersensitive, sedentary men studied (age, 56+/-1 year; 32%+/-1% body fat; BP, 147+/-3/93+/-2 mm Hg) initially had a larger waist girth and waist-to-hip ratio (WHR) and were more hyperinsulinemic and insulin resistant with lower GIR at the two lower insulin infusion rates of the clamp and had a 2.9-fold higher EC50, the insulin concentration producing a half-maximal increase in GIR. They had higher triglyceride (TG) and lower high-density lipoprotein cholesterol (HDL-C) levels. The AEX+WL intervention reduced body weight by 9%, percent body fat by 21%, waist girth by 9%, and WHR by 3%, and increased VO2max by 16% (P < .01 for all). This was associated with decreases of 14+/-3 mm Hg in systolic and 10+/-2 mm Hg in diastolic BP, significant changes in GIR at the low (+42%) and intermediate (+39%) insulin infusion rates and EC50 (-39%) and in glucose (-21%) and insulin (-51%) responses during OGTT (P < .02 for all). AEX+WL also lowered total cholesterol by 14% and TG by 34%, and raised HDL2-C levels twofold (P < .01 for all). Thus, a 6-month AEX+WL intervention substantially lowers BP and improves glucose and lipid metabolism in obese, sedentary, hypertensive men. This suggests that hypertension and the metabolic risk factors for cardiovascular disease associated with it can be ameliorated by AEX+WL in obese, sedentary, middle-aged men.

In women there is an increase in visceral obesity, subcutaneous abdominal adipocyte lipolysis, and risk of cardiovascular disease (CVD) associated with weight gain after menopause. The mechanisms underlying this increase in adrenoreceptor (AR)-agonist catecholamine-stimulated lipolysis and abdominal obesity in postmenopausal women were studied in intact adipocytes isolated from the abdominal and gluteal subcutaneous fat depots in 19 obese (48% +/- 1% body fat, mean +/- SE) women with a mean +/- SE age of 58 +/- 1 years. The fat cell size and adipose tissue lipoprotein lipase (ATLPL) activity were similar in both sites. The maximal lipolytic responsiveness and sensitivity to isoproterenol were higher (P < .05) in abdominal compared with gluteal adipocytes, but maximal lipolytic response to a post-AR agent was similar. Abdominal adipocytes had a higher beta-AR ([3H]-CGP-12177) and alpha2-AR ([3H]-yohimbine) affinity than gluteal cells (P < .05), lower alpha2-AR density (P < .05), but similar beta-AR density as gluteal cells. Both abdominal and gluteal cell size correlated with alpha2-AR density (P < .01), but not with beta-AR density. Thus, a higher beta-AR affinity and lower alpha2-AR relative to beta-AR density may explain the higher in vitro catecholamine-mediated lipolysis in abdominal compared with gluteal adipocytes in obese, postmenopausal women.

The relative benefits of weight loss (WL) versus aerobic exercise training (AEX) on cardiac risk factors in obese individuals remain controversial. In this study, we examined the effects of the sequential interventions of 9 months of AEX followed by weight loss with continued AEX (AEX + WL) on cardiac risk factors in 21 obese (body fat, 29.5% +/- 0.8%, mean +/- SEM) middle-aged and older men. AEX increased the maximal aerobic capacity ([VO2max] in liters per minute) of these men by 14% (P < .001), with no significant change in weight. AEX did not improve blood pressure (BP) or oral glucose tolerance, and had no significant effect on lipid concentrations. During the AEX + WL intervention, the 21 men lost 8.1 +/- 0.6 kg. Despite continued training, there was no further increase in VO2max during this intervention. Compared with AEX, AEX + WL decreased glucose and insulin responses during the oral glucose tolerance test (OGTT) by 8% (P < .05) and 30% (P < .01), respectively. AEX + WL reduced plasma triglyceride (TG) by 17% (P < .05) and low-density lipoprotein cholesterol (LDL-C) by 8% (P < .01) and increased high-density lipoprotein cholesterol (HDL-C) by 11% (3.7 mg/dL, P < .01). The sequential interventions resulted in a 20% decrease in the LDL-C/HDL-C ratio. The results demonstrate that AEX + WL had a more substantial impact than AEX alone on glucose tolerance and lipoprotein concentrations. Physicians should encourage obese patients to become physically active and lose weight to improve their cardiac risk factor profile.

Weight loss (WL) by hypocaloric diet decreases adipocyte lipolysis and fat oxidation, adaptations that might predispose individuals to regain weight. Our hypothesis was that the addition of endurance exercise (EX) to dietary-induced WL (6 mo; 250-350 kcal/day deficit) would prevent declines in abdominal (ABD) and gluteal (GLT) adipocyte lipolysis and fat oxidation in obese older women. At baseline, the WL (n = 9) and WL+EX (n = 11) groups had similar body composition, fat distribution, aerobic fitness (VO2max), and resting fat metabolism. Reductions in body weight (WL = 11%, WL+EX = 8%), percent body fat, and intra-abdominal fat area with the interventions were similar in both groups, but VO2max increased (9%, P < 0.01) only in the WL+EX group. Basal and adrenergic receptor- and postreceptor-stimulated lipolysis in ABD and GLT adipocytes decreased (20-70%, P < 0.05) in the WL group but did not change in the WL+EX group. Fat oxidation decreased (38%, P < 0.05) in the WL group but not in the WL+EX group. The changes in fat oxidation and GLT lipolysis differed significantly between groups. Fat oxidation correlated positively with ABD and GLT adipocyte basal lipolysis at baseline (r = 0.45 and r = 0.53, P < 0.05), and the changes in fat oxidation with the interventions correlated positively with changes in ABD and GLT adipocyte basal lipolysis (r = 0.50 and r = 0.42. P < 0.05) in the entire group of women. These results indicate that exercise counteracts the decline in fat oxidation with WL, in part by maintaining adipocyte lipolytic responsiveness in some weight-reduced postmenopausal women.

The decline in glucose homeostasis with aging may be due to the physical deconditioning and obesity that often develop with aging. The independent and combined effects of aerobic exercise training (AEX) and weight loss (WL) on glucose metabolism were studied in 47 nondiabetic sedentary older men. There were 14 men in a weekly behavioral modification/WL program, 10 in a 3 times/wk AEX program, 14 in an AEX+WL program, and 9 in the control (Con) group. The 10-mo intervention increased maximal oxygen consumption (VO2max) in both the AEX and AEX+WL groups [0.33 +/- 0.05 and 0.37 +/- 0.09 (SE) l/min, respectively], but VO2max did not significantly change in the WL (0.01 +/- 0.06 l/min) and Con groups (-0.04 +/- 0.05 l/min; P > 0.05). The AEX+WL and WL groups had comparable reductions in body weight (-8.5 +/- 0.9 and -8.8 +/- 1.2 kg, respectively) and percent fat (-5.5 +/- 0.7 and -5.9 +/- 1.1%, respectively) that were significantly greater than those in the Con and AEX groups. Oral glucose tolerance tests showed significant reductions in insulin responses in the AEX, WL, and AEX+WL groups, but the decrease in insulin response in the AEX+WL group was significantly greater than that in the other three groups. The glucose area decreased significantly in the WL and AEX+WL groups but did not change in the Con or AEX groups. There were significant increases in insulin-mediated glucose disposal rates as measured by the hyperinsulinemic (600 pmol.m-2.min-1) euglycemic clamps in the AEX and AEX+WL groups [1.66 +/- 0.50 and 1.76 +/- 0.41 mg.kg fat-free mass (FFM)-1.min-1, respectively] that were significantly greater than those in the WL (0.13 +/- 0.31 mg.kg FFM-1.min-1) and Con groups (-0.05 +/- 0.51 mg.kg FFM-1.min-1; n = 5). These data suggest that AEX and WL improve glucose metabolism through different mechanisms and that the combined intervention of AEX+WL is necessary to improve both glucose tolerance and insulin sensitivity in older men.

This study determines whether there are regional differences in lipolysis and whether adipocyte lipolysis is associated with the degree of visceral adiposity and its metabolic complications in 32 obese (28-37 kg/m2), nondiabetic, postmenopausal women. In vitro lipolysis was measured in the basal state and after addition of epinephrine (Epi), Epi plus yohimbine, Epi plus propranolol, and N6,2'-O-dibutyryl adenosine 3',5'-cyclic monophosphate (DBcAMP) in abdominal (ABD) and gluteal (GLT) adipocytes. Upper body obese [UBO, waist-to-hip ratio (WHR) > or = 0.80, n = 19] women had a greater intra-abdominal fat area (IA, 199 +/- 50 vs. 142 +/- 28 cm2) and Epi-stimulated lipolysis (ABD: 1.60 +/- 1.10 vs. 0.95 +/- 0.54 mumol glycerol.10(6) cells-1.2h; GLT: 1.14 +/- 0.70 vs. 0.66 +/- 0.42 mumol glycerol.10(6) cells-1.2 h) than lower body obese (LBO, WHR < 0.80, n = 13) women. The UBO women also had lower high-density lipoprotein cholesterol (1.39 +/- 0.40 vs. 1.64 +/- 0.39 mmol/l, P < 0.05), higher plasma triglycerides (1.89 +/- 0.48 vs. 1.44 +/- 0.56 mmol/l, P < 0.05), and higher fasting insulin levels (154 +/- 57 vs. 118 +/- 33 pmol/l, P < 0.05) than LBO women. Basal, adrenergic receptor-mediated, and DBcAMP-stimulated lipolytic rates in ABD and GLT adipocytes were positively correlated with IA (r = 0.44-0.76, P < 0.05, n = 28). In both UBO and LBO women, Epi-stimulated lipolysis was higher (+30%, P < 0.05) in ABD than GLT adipocytes. These results show that, in postmenopausal women, visceral obesity is associated with increased rates of lipolysis in both ABD and GLT subcutaneous adipocytes. The findings also indicate that Epi-stimulated lipolysis is greater in ABD than GLT adipocytes regardless of fat distribution.

Older individuals have higher plasma insulin and norepinephrine (NE) levels than the young. This may be due to biological aging; however, these changes also may be due in part to the increase in abdominal obesity that often accompanies aging. The latter possibility was tested by examining the effects of weight loss on plasma insulin and NE levels in 11 healthy men aged 52 to 72 years who had mild to moderate obesity (body mass index [BMI], 27 to 36 kg/m2). Plasma insulin levels were measured during an oral glucose tolerance test, and on a second day NE levels were measured during supine rest and upright posture. Subjects lost 10 +/- 5 kg (mean +/- SD) and decreased their waist to hip ratio ([WHR] an index of the pattern of regional fat distribution) 2.8% (P < .01) over 9 +/- 3 months through mild caloric restriction. This resulted in a 23% decrease (P < .05) in fasting insulin levels and a 48% decrease (P < .01) in 2-hour insulin levels. Weight loss also resulted in a 31% decrease (P < .001) in supine plasma NE levels and an 8% decrease (P < .05) in supine diastolic blood pressure (BP). Decreases in supine plasma NE levels correlated with changes in WHR (r = .61, P < .05), but did not correlate with changes in other measures of body composition or with changes in glucose and insulin levels. These results suggest that higher plasma NE levels are related to the distribution of body fat to upper-body or abdominal sites in obese older men.

The effect of long-term aerobic exercise training on insulin action was determined in older individuals by comparing insulin sensitivity and maximal responsiveness in 11 master athletes [63.5 +/- 1.9 (SE) yr] and 10 age- and body fat-matched sedentary individuals. Maximal aerobic power was higher and the waist-to-hip ratio (WHR) was lower in the athletes, but there were no differences in body weight, percent body fat, or fat-free mass between groups. Fasting plasma glucose levels and glucose and insulin responses during oral glucose tolerance tests were lower in the athletes. The insulin concentration producing a half-maximal increase in glucose disposal (EC50) during a three-step hyperinsulinemic-euglycemic glucose clamp was 41% lower in the athletes than in controls (483 +/- 30 vs. 822 +/- 132 pmol/l, P < 0.05), whereas maximal responsiveness was comparable (81.0 +/- 4.4 vs. 85.5 +/- 8.3 mumol.kg fat-free mass-1.min-1, P = not significant). The EC50 correlated with maximal aerobic power (r = -0.62, P < 0.01) and WHR (r = 0.52, P < 0.05), but in multiple regression analyses WHR was the only variable independently related to EC50. These results indicate that long-term aerobic exercise training is associated with enhanced insulin sensitivity and a lower WHR in older individuals. This finding suggests that regular aerobic exercise may prevent the age-associated increase in abdominal obesity and insulin resistance.

Healthy older (64 +/- 1 years, mean +/- SEM) athletic (maximal oxygen consumption [VO2max] > 40 mL/kg/min) normocholesterolemic men with no prior history of coronary artery disease (CAD) were recruited for cardiovascular and metabolic studies. Thirty-three percent had asymptomatic exercise-induced ST segment depression on their exercise electrocardiogram (ECG), consistent with silent myocardial ischemia (SI). We hypothesized that abnormalities in high-density lipoprotein (HDL) and postprandial triglyceride (TG) metabolism may increase their risk for CAD. Compared with 12 nonischemic controls of comparable age, percent body fat, and VO2max, the 13 men with SI had decreased fasting HDL cholesterol ([HDL-C] 41 +/- 2 v 50 +/- 2 mg/dL, P < .001) and %HDL2b subspecies levels as measured by gradient gel electrophoresis (22 +/- 2 v 34 +/- 3, P < .001). Fasting plasma TG and low-density lipoprotein cholesterol (LDL-C) levels were the same in both groups. Although plasma glucose levels during an oral glucose tolerance test (OGTT) were similar in both groups, the total insulin area was higher in men with SI (P < .05). After consumption of a standard high-fat meal (680 kcal/m2 body surface area of a formula in which 86% of the calories were derived from fat), postprandial plasma TG, chylomicron-TG, and very-low-density lipoprotein (VLDL)-TG levels and postprandial areas were higher in men with SI (P < .001).(ABSTRACT TRUNCATED AT 250 WORDS)

The hyperinsulinemic euglycemic glucose clamp is widely used to quantitate in vivo insulin action. Modification of this technique by sequentially infusing multiple doses of insulin allows determination of insulin sensitivity and maximal responsiveness; however, the validity of this approach has not been determined in older individuals. In this study, glucose disposal rates during a sequential three-dose clamp at insulin infusion rates of 20, 100, and 500 mU/m2.min were compared to those obtained during a single-dose 100 mU/m2.min clamp in eight healthy older men. There were no differences in plasma insulin levels (256 +/- 46 vs. 261 +/- 32 microU/ml) or glucose disposal rates (11.0 +/- 3.6 vs. 10.8 +/- 3.0 mg/kgfat-free mass.min) during the 100 mU/m2.min infusion of the three-dose clamp and the one-dose clamp. In four subjects with impaired glucose tolerance, the EC50 (insulin concentration producing a half-maximal response) was higher and Mmax (maximal glucose disposal) lower than in subjects with normal glucose tolerance, suggesting impairments in both insulin sensitivity and responsiveness in older subjects with impaired glucose tolerance. Future studies using this modification of the hyperinsulinemic euglycemic glucose clamp to determine insulin sensitivity and responsiveness may lead to an improved understanding of the insulin resistance of aging and the pathogenesis of diseases such as diabetes and hypertension.

The relationships of body composition and physical fitness [maximal aerobic capacity (VO2max)] to the decline in insulin sensitivity with age were examined in healthy older (47-73 yr; n = 36) and young (19-36 yr; n = 13) men. In 18 older men with normal glucose tolerance (OGTT), glucose disposal rates (M) during hyperinsulinemic euglycemic clamps correlated negatively with the waist to hip ratio (WHR; r = -0.77; P < .001) and percent body fat (r = -0.46; P < 0.05) and positively with VO2max (r = 0.54; P < 0.05), but not with age. Similar relationships existed in the 36 older men with a spectrum of OGTT responses; however, only WHR was independently related to M (r2 = 0.32; P < 0.01). In the older men with normal OGTT, M (mean +/- SEM, 7.88 +/- 0.43 mg/kg fat-free mass.min) was not different from that in the young men (8.56 +/- 0.47; P = NS). Furthermore, in older and young men with normal OGTT matched for WHR, percent fat, or VO2max, glucose disposal was comparable at sequential 15-min intervals during the clamp and in its relationship to insulin concentrations at the tissue level (multicompartmental analysis). In contrast, despite higher steady state plasma insulin levels during the clamp, M was significantly lower in the older men with a higher WHR, greater percent fat, lower VO2max, or impaired OGTT. Thus, in healthy older men up to the age of 73 yr, insulin sensitivity and glucose tolerance are affected primarily by the regional body fat distribution, not age, obesity, or VO2max.

This study examines the relationships between parameters of the time course of plasma free fatty acid (FFA) concentration during a euglycemic, hyperinsulinemic clamp (100 mU/m2.min) and the age, body composition, and physical fitness, indexed as maximal aerobic capacity (VO2 max), of three groups of healthy men: (A) 20 obese older men (32% +/- 1% fat, aged 60 +/- 2 years, mean +/- SEM); (B) 11 lean older men (19% +/- 1% fat, aged 63 +/- 2 years); and (C) 11 lean younger men (16% +/- 2% fat, aged 27 +/- 2 years). The time course was modeled as a delayed exponential decline from an initial level to a plateau level. The plateau level was 72% +/- 2%, 72% +/- 2%, and 68% +/- 3% of the initial level in groups A, B, and C, respectively. The delay was shorter in the younger men than in the older men (7.6 +/- 0.9 minutes in group C v 13.2 +/- 1.0 in group A and 11.9 +/- 1.6 minutes in group B), but correlated more strongly with percent fat, waist to hip ratio (WHR), or VO2max than with age. The magnitude of the rate constant of the exponential, k, was smaller in obese than in lean men (3.2 +/- 0.2 h-1 in group A v 5.3 +/- 0.6 h-1 in group B and 6.4 +/- 0.6 h-1 in group C), and was independently predicted only by percent fat in the older men and only by VO2max when the older and younger groups were combined.(ABSTRACT TRUNCATED AT 250 WORDS)

The age-related declines in the antilipolytic and lipogenic actions of insulin were studied in adipocytes from rats aged 2, 6, 12, and 24 months. Since adenosine modulates insulin action, its concentration was controlled by treatment of adipocytes with adenosine deaminase and addition of the non-metabolizable adenosine analog, N6-[(R)-(-)1-methyl-2-phenethyl] adenosine (PIA). Inhibition of isoproterenol-stimulated lipolysis by PIA increased significantly by 6 months of age. Decreasing the concentration of PIA rendered the adipocytes from the 6-, 12-, and 24-mo-old rats less sensitive to the antilipolytic effect of insulin. Basal and insulin-stimulated lipogenesis decreased with aging. PIA increased insulin-stimulated lipogenesis at 0.2 ng/ml insulin only in the 2-month-old rats. PIA reduced insulin-stimulated lipogenesis at higher insulin doses in the oldest rats. These results suggest that aging causes quantitative declines in maximal lipolysis and basal and maximal lipogenesis. Maturation may cause a decline in sensitivity to insulin, but adenosine in sufficient concentration reverses the acquired resistance to the antilipolytic effect of insulin.

It has been proposed that the increase produced by insulin in electrical potential differences across membranes of target cells may be a mechanism by which the cell surface insulin-receptor complex causes at least some of the metabolic effects of insulin. If insulin-induced hyperpolarization is a transducer of common effector responses it must precede those responses. The problem has not been addressed previously, so that rapid responses to insulin have not been sought. Two methods were used. In one method, the bathing solution was changed rapidly so as to include insulin in supramaximal concentrations, and a series of measurements of membrane potentials. Er, were made. Insulin hyperpolarized by 9.4 mV within 1 min. In the other method, nanoliter amounts of highly concentrated insulin solution were ejected from a micropipette onto the surface of an impaled muscle fiber. In 21 out of 32 insulin injections, hyperpolarization occurred with 1 s; in 11 control injections there was no change. This is the most rapid response to insulin yet reported, and is consistent with the hypothesis that insulin-induced hyperpolarization may transduce effector responses.

Increased temperature produces a red shift and decreased fluorescence intensity of the emission peak of 1,8-anilinonaphthalene sulfonic acid (ANS) in suspensions of biomembrane vesicles. These changes have been attributed to a conjectured increase in polarity of the microenvironment of ANS. If the conjecture is correct, fluorescence lifetimes must be decreased with warming. We showed than ANS binds to both protein and lipid protein of sarcolemma, that there are two kinds of sarcolemma-lipid ANS-binding sites, and that there are three fluorescence lifetimes of excited sarcolemma-bound ANS. The three fluroescence lifetimes were unchanged on warming, or decreased too little to account for the observations. Fluorescence lifetime data were consistent with the notion that the effect of increasing temperature is to decrease the amount of ANS bound to sarcolemma. From studies of liposomes prepared from lipid extracts of sarcolemma, and of proteins from sarcolemma it was deduced that warming reducted the amount of ANS bound to both of these sarcolemma components, probably mainly by reducing binding capacity. There might also be a shift of affinities such that the ratio, KA sarcolemma lipid/KA sarcolemma protein, is larger at higher temperature. Except at very small concentration ratios of ANS/sarcolemma, more than twice as much ANS was bound to sarcolemma lipids as to proteins.

Insulin hyperpolarizes. This raises the questions: is hyperpolarization a means by which insulin exerts some of its other effects, and can electrically induced hyperpolarization mimic insulin action on membrane functions? A technique was devised to study the latter question. The technique permits electrical hyperpolarization of a segment of whole muscle. Rat caudofemoralis muscle was threaded into a triple sucrose-gap chamber. Continuous flow of sucrose displaced interstitial fluid of muscle segments in the gaps. In one electrolyte compartment between gaps was placed an anode and in the other a cathode. The muscle segment in the anodal compartment was hyperpolarized continuously for 30 min, probably by about 1.5 mV. Uptake of deoxyglucose was increased in the hyperpolarized muscle segment. This increase, by 39%, was highly significant. It was probably smaller than the twofold increase elicited by insulin (100 mU/ml), but not than the possible effect produced by 10 mU/ml. The effect of hyperpolarization was specific for the D-glucose transport system because uptake of L-glucose was not altered.

We are testing the hypothesis that hyperpolarization is a transducer of insulin action. We listed three criteria that must be met if the hypothesis is to be demonstrated to be correct. So far, questions based on the first two of these criteria have been subjected to test. We have answered, in part, the second condition: electrically-produced hyperpolarization in the absence of insulin was insulinomimetic insofar as it increased specific D-glucose transport. Now we have addressed the first criterion. Insulin-induced hyperpolarization can occur in less than 1 sec, a response more rapid than any other reported effect of insulin. The data are consistent with the hypothesis that hyperpolarization is a transducer of insulin action.

Catecholamines and a number of peptide hormones either hyperpolarize or depolarize surface membranes of target cells. For catecholamines there is no consistent relationship between alpha and beta-adrenergic action and the direction of the change in transmembrane electrical potential difference. Examples of all possible mechanisms have been reported to underlie the altered electrical potentials. The question of what roles hormone-induced altered polarization may play is linked to the question of why a large transmembrane electrical field strength is a general property of cells. It is suggested that the normal, or resting, field strength serves to maintain an array of configuration of membrane dipoles (proteins: transport systems, enzyme systems), and that hormone-induced changes in the field strength serve to command an altered array of configuration of membrane dipoles with a different set of functions. Insulin hyperpolarizes rat skeletal muscle. The mechanism is not by activation of a ouabain-sensitive electrogenic pump, but probably by reduced permeability to Na+. Insulin-induced hyperpolarization precedes other reported effects of insulin. Electrically produced hyperpolarization of a segment of whole muscle (rat), in the absence of insulin, stimulates specific D-glucose transport. Thus, it is possible that insulin-induced hyperpolarization is part of the transduction chain, signaling from the insulin-receptor complex to instruct effector responses to insulin.

1. Catecholamines can nearly double (Na+ + K+)-ATPase acts effect is not mediated by cyclic AMP and is not beta-adrenergic. 3. Orthodihydroxybenzene compounds and their orthoquinone derivatives enhance (Na+ + K+)-ATPase activity. 4. Enhancement of (Na+ + K+)-ATPase activity by catechols is not due to increased availability of ATP. 5. It is suggested that catechols and their orthoquinones somehow alter or protect the configuration of the enzyme so that it becomes more active or so protect the configuration of the enzyme so that it becomes more active or so that its activity is maintained under conditions in which its activity is otherwise diminished.

These experiments were designed to test the hypothesis that insulin-induced hyperpolarization is a link in the chain of events leading to stimulation of glucose transport. External potassium concentration, [K+]o, was increased by equimolar substitution of KCl for NaCl, a method known to cause cell swelling, and by substitution of [K+]o for [Na+]o with maintenance of constant [K+]o X [Cl-]o product, a method that does not cause cell swelling. When there was constant KCl product, even at 76.8 meq [K+]o insulin continued to hyperpolarize, although by only approximately 44% as much as in normal [K+]o, and insulin-stimulated 2-deoxyglucose uptake was only approximately 60% of that at normal [K+]o. With equimolar substitution of KCl for NaCl: electrical potential difference across cell membranes of surface fibers of rat caudofemoralis muscle decreased with logarithm [K+]o, in the presence or absence of insulin. Insulin-induced hyperpolarization decreased as [K+]o increased and disappeared at 36 mM [K+]o. The amount of insulin bound to its receptors in 1 h was not affected by [K+]o over the range studied. Insulin effects on membrane potential and on 2-deoxyglucose uptake, as both were altered by [K+]o, correlated well. As the probe moved in depth through the first six fibers there was stepwise decrease in depolarization in high [K+]o in the absence of insulin. Insulin hyperpolarized the deepest of these fibers, even when it did not hyperpolarize the outermost. The decrease in insulin-induced hyperpolarization as [K+]o increases is consistent with the hypothesis that insulin hyperpolarizes by decreasing the ratio PNa/PK.

The sarcolemmal fraction prepared from rat skeletal muscle consists of osmotically active vesicles that accumulate D-glucose in preference to L-glucose, apparently by facilitated diffusion into intravesicular space. Stereospecific D-glucose uptake by these vesicles is a saturable rpocess, inhibited by phloridzin, by cytochalasin B, and by certain sugars, and enhanced by counterflow. An additional leak pathway permits entry of both D- and L-glucose into the vesicles. Stereospecific D-glucose transport by sarcolemmal vesicles is enhanced to a small extent by insulin, provided the hormone is administered prior to cell disruption. In membranes prepared from insulin-pretreated muscle, Ca2+ produces a small further enhancement. Local anesthetics preferentially inhibit stereospecific D-glucose transport. Apparent uptake of both D- and L-glucose is greater when vesicles are suspended in salt solutions rather than sucrose, an effect attributed to increased functional vesicular volume.

Antibodies to insulin receptors have been reported to have some insulinlike metabolic effects. If insulin-induced electrical hyperpolarization of skeletal muscle is part of the transduction chain between receptor and certain metabolic responses, then receptor antiserum should hyperpolarize. The Jacobs antiserum (rabbit antiserum against rat liver insulin receptor) hyperpolarized rat caudofemoralis muscle. Maximum effect, about 4.5 mV, occurred at 1:10,000 dilution, half maximum at about 1:40,000. Maximum effect of antiserum was only as great as half maximum hyperpolarization by insulin on this muscle. 2-Deoxyglucose uptake was also stimulated by antiserum but required greater concentration than for hyperpolarization, and the stimulation was only by about one-third the maximum effect of insulin.

1. Intact rat extensor digitorum longus muscles soaked in L-isoproterenol plus 10(-5) M ouabain gained less sarcoplasmic Na+ than did muscles soaked in ouabain alone. Half maximal effect was produced by 10(-8) M L-isoproterenol. 2. D-Isoproterenol and oxidized L-isoproterenol were only 3 and 1%, respectively, as potent as L-isoproterenol. Other catechols tested had no effect. 3. The effect of L-isoproterenol on sarcoplasmic Na+ content appears to be a beta-adrenergic function in that it was blocked by propranolol, but not by phentolamine, and could be mimicked by dibutyryl cyclic AMP or by caffeine. 4. Reduced gain in sarcoplasmic Na+ was accompanied by reduced loss of sarcoplasmic K+. 5. L-Isoproterenol increased loss of sarcoplasmic Na+ in the absence of ouabain, in muscles recovering from cold treatment. 6. Results suggest that the beta-adrenergic system stimulates a coupled Na-K+ pump. 7. A model is proposed in which stimulation of the Na+-K+ pump in response to beta-adrenergic agents involves a number of intermediate steps, identified tentatively.