Limited value of the homeostasis model assessment to predict insulin resistance in older men with impaired glucose tolerance.

OBJECTIVE: Insulin resistance (IR) in older individuals is associated with risk factors for coronary artery disease. The glucose clamp measures IR directly, but the homeostasis model assessment (HOMA) of IR, referred to here as HOMA-IR, is based on fasting glucose and insulin and is less invasive and labor intensive. This method requires validation in the elderly. RESEARCH DESIGN AND METHODS: We assessed the validity of HOMA-IR as an index of IR by comparing it to glucose infusion rates (GIRs) measured by a glucose clamp (600 pmol x m(-2) x min(-1)) in 45 obese men (61 +/- 8 years of age, mean +/- SD) with normal glucose tolerance (NGT) (n = 21) or impaired glucose tolerance (IGT) (n = 24). We also evaluated relationships between body composition, exercise capacity, and IR. RESULTS: Subjects with NGT had lower BMI (28 +/- 3 vs. 31 +/- 3 kg/m2), waist circumference (97 +/- 9 vs. 105 +/- 9 cm), waist-to-hip ratio (WHR) (0.93 +/- 0.06 vs. 0.97 +/- 0.05), and percent body fat (25 +/- 6 vs. 30 +/- 6) than subjects with IGT. Subjects with NGT also had lower areas above basal during the 2-h oral glucose tolerance test for glucose (274 +/- 95 vs. 419 +/- 124 mmol x min/l) and insulin (38,142 +/- 18,206 vs. 58,383 +/- 34,408 pmol x min/l) and lower HOMA-IR values (2.2 +/- 0.8 vs. 4.2 +/- 2.6) than subjects with IGT. GIR (micromol x kg(-1) FFM x min(-1)) was higher in subjects with NGT than in subjects with IGT (53 +/- 11 vs. 43 +/- 14). HOMA-IR correlated with GIR in subjects with NGT (r = -0.59), but not in subjects with IGT (r = -0.13). GIR correlated with VO2max in subjects with NGT (r = 0.58) and IGT (r = 0.42), but with WHR only in subjects with NGT (r = -0.53). HOMA-IR correlated with VO2max (r = -0.57) and waist circumference (r = 0.54) in subjects with NGT, but with percent body fat in subjects with IGT (r = 0.54). CONCLUSIONS: These findings indicate that HOMA-IR should not be used as an index of IR in older individuals who may be at risk for IGT, and suggest that lifestyle changes that increase VO2max and decrease body fat may reduce IR in older people.

Long-term effects of a high-carbohydrate diet and exercise on insulin action in older subjects with impaired glucose tolerance.

Carbohydrate metabolism was assessed in 20 glucose-intolerant subjects before and after 12 wk on a high-carbohydrate diet (HC) or the diet combined with exercise training (HC-EX). The diet provided 60% of energy as carbohydrate and 20% as fat. Neither treatment altered fasting glucose or insulin concentrations or their response to a meal. During a glucose clamp (216 pmol insulin/L) glucose disposal increased from 13.2 +/- 0.83 to 14.6 +/- 0.83 mumol.kg fat-free mass-1.min-1 (P < 0.05) in both groups. During more pronounced hyperinsulinemia (654 pmol/L) glucose disposal did not change significantly (49.9 +/- 3.8 to 50.7 +/- 3.8 mumol.kg fat-free mass-1.min-1). Muscle glycogen increased in the HC-EX group (78.5 +/- 8.1 to 161.1 +/- 15.7 mmol glucose/kg muscle), with no changes in the HC group. These results do not support the recommendation to increase the dietary carbohydrate content for improving postprandial glucose metabolism or insulin action in glucose-intolerant adults unless combined with exercise training, which promotes muscle glycogen storage.

Lipoprotein response to exercise training and a low-fat diet in older subjects with glucose intolerance.

The purpose of this study was to determine the effect of aerobic exercise training (Ex), a low-fat diet (LF, 19% fat), or combined interventions (LF-Ex) on lipoprotein cholesterol (LDL, HDL, and VLDL) and triglyceride (TG) concentrations in glucose-intolerant subjects while their weight was maintained. Baseline dietary fat and carbohydrate composition, body composition, body mass index, age, and lipoprotein cholesterol were not different among groups. Aerobic capacity increased in both exercise groups (P < 0.01) and remained unchanged in the LF group. Body composition was unaltered and change in body weight (kg) was small: Ex, -0.8 +/- 0.4, (P < 0.05); LF, +0.4 +/- 0.4; (NS); LF-Ex, -1.4 +/- 0.4 (P < 0.01). Exercise alone did not significantly affect lipoprotein cholesterol or TG concentrations. In LF and LF-Ex, respectively, decreases (P < 0.02) in total cholesterol (-0.66 +/- 0.24 and -0.42 +/- 0.21 mmol/L), HDL (-0.14 +/- 0.07 and -0.26 +/- 0.04), and LDL (-0.60 +/- 0.25 and -0.23 +/- 0.13) were seen after 12 wk, whereas VLDL and TG remained unchanged. Our data indicate that beneficial effects of exercise training on lipid indexes are not observed in subjects with impaired glucose tolerance on either an average US diet or a low-fat diet if substantial changes in weight or body composition do not occur.

Short-term exercise enhances insulin-stimulated GLUT-4 translocation and glucose transport in adipose cells.

This investigation examined the effects of short-term exercise training on insulin-stimulated GLUT-4 glucose transporter translocation and glucose transport activity in rat adipose cells. Male Wistar rats were randomly assigned to a sedentary (Sed) or swim training group (Sw, 4 days; final 3 days: 2 x 3 h/day). Adipose cell size decreased significantly but minimally (approximately 20%), whereas total GLUT-4 increased by 30% in Sw vs. Sed rats. Basal 3-O-methyl-D-[14C]glucose transport was reduced by 62%, whereas maximally insulin-stimulated (MIS) glucose transport was increased by 36% in Sw vs. Sed rats. MIS cell surface GLUT-4 photolabeling was 44% higher in the Sw vs. Sed animals, similar to the increases observed in MIS glucose transport activity and total GLUT-4. These results suggest that increases in total GLUT-4 and GLUT-4 translocation to the cell surface contribute to the increase in MIS glucose transport with short-term exercise training. In addition, the results suggest that the exercise training-induced adaptations in glucose transport occur more rapidly than previously thought and with minimal changes in adipose cell size.

Exercise training and the glucose transport system in obese SHHF/Mcc-fa(cp) rats.

The effects of a similar exercise training stimulus on maximal insulin-stimulated (MIS) plasma membrane glucose transporter number and glucose transport were determined in lean and obese SHHF/Mcc-facp rats. Six-week-old lean and obese male rats were randomly divided into four groups: lean sedentary (LSed), obese sedentary (OSed), lean exercise (LEx), and obese exercise (OEx). An 8- to 12-wk treadmill running program equalized daily muscular work for LEx and OEx. Plasma membranes were isolated from control and MIS muscles of mixed fiber types. MIS significantly increased glucose transport (3.4- and 2.8-fold) in LSed and OSed, respectively. MIS significantly increased glucose transporter number (2.5-fold) in LSed, but there was no increase in glucose transporter number in OSed. Peak oxygen uptake and citrate synthase activity were increased a similar amount for LEx and OEx groups, demonstrating a similar training stimulus. MIS significantly and similarly increased glucose transport in LEx and OEx (4.4- and 5.1-fold, respectively). The effects of MIS on plasma membrane glucose transporter number in the exercise-trained rats were similar to the responses observed in the sedentary lean and obese groups. MIS significantly increased glucose transporter number (2.6-fold) in LEx, whereas there was no increase in glucose transporter number in OEx. The reduction in MIS glucose transport in OSed appears to be related to a defect in the processes associated with the translocation of glucose transporters to the plasma membrane. Exercise training of the obese rats apparently did not alter this defect. Similar increases in peak oxygen uptake, citrate synthase, and MIS glucose transport in LEx and OEx groups suggest that insulin resistance does not limit the ability of the glucose transport system to adapt to exercise training in the obese male SHHF/Mcc-facp rats.

GLUT4 trafficking in insulin-stimulated rat adipose cells: evidence that heterotrimeric GTP-binding proteins regulate the fusion of docked GLUT4-containing vesicles.

Agents that activate the G-protein G(i) (e.g. adenosine) increase, and agents that activate G(s) [e.g. isoprenaline (isoproterenol)] decrease, steady-state insulin-stimulated glucose transport activity and cell-surface GLUT4 in isolated rat adipose cells without changing plasma membrane GLUT4 content. Here we have further examined the effects of R(s)G(s) and R(i)G(i) ligands (in which R(s) and R(i) are G(s)- and G(i)-coupled receptors respectively) on insulin-stimulated cell-surface GLUT4 and the kinetics of GLUT4 trafficking in these same cells. Rat adipose cells were preincubated for 2 min with or without isoprenaline (200 nM) and adenosine deaminase (1 unit/ml), to stimulate G(s) and decrease the stimulation of G(i) respectively, followed by 0-20 min with insulin (670 nM). Treatment with isoprenaline and adenosine deaminase decreased insulin-stimulated glucose transport activity by 58%. Treatment with isoprenaline and adenosine deaminase also resulted in similar decreases in insulin-stimulated cell-surface GLUT4 as assessed by both bis-mannose photolabelling of the substrate-binding site and biotinylation of the extracellular carbohydrate moiety when evaluated under similar experimental conditions. After stimulation with insulin in the absence of G(s) and the presence of G(i) agents, a distinct sequence of plasma membrane events took place, starting with an increase in immunodetectable GLUT4, then an increase in the accessibility of GLUT4 to bis-mannose photolabel, and finally an increase in glucose transport activity. Pretreatment with isoprenaline and adenosine deaminase before stimulation with insulin did not affect the time course of the increase in immunodetectable GLUT4 in the plasma membrane, but did delay both the increase in accessibility of GLUT4 to photolabel and the increase in glucose transport activity. These results suggest that R(s)G(s) and R(i)G(i) modulate insulin-stimulated glucose transport by influencing the extent to which GLUT4 is associated with occluded vesicles attached to the plasma membrane during exocytosis, perhaps by regulating the fusion process through which the GLUT4 in docked vesicles becomes exposed on the cell surface.

Weight gain and adipose tissue metabolism after smoking cessation in women.

BACKGROUND: Cigarette smoking increases the risk of cardiovascular disease, and is an important preventable cause of death and illness. One major deterrent to smoking cessation is a gain in body weight. Understanding the mechanisms that contribute to this weight gain may maximize the success of long-term smoking cessation. We hypothesized that smoking cessation is associated with an increase in adipose tissue lipoprotein lipase (AT-LPL) activity and/or a decrease in lipolysis, two metabolic factors that determine the balance between fat storage and fat utilization, and thus affect the propensity for weight gain. MATERIALS AND METHODS: Ten premenopausal women (37.1+/-6.2 y, 31.7+/-6.4 kg/m(2) body mass index (BMI), mean+/-s.d.) participated in a 4 week smoking cessation program. Measurements of body weight, waist and hip circumferences, adipose cell metabolism and resting metabolic rate were obtained at baseline and after 4 weeks of smoking cessation. RESULTS: Of the 10 women who began the intervention, five successfully completed the smoking cessation intervention. After 4 weeks of smoking cessation, there were significant increases in body weight (95.1+/-13.9-97.7+/-14.4 kg, P<0.05), with no change in waist and hip circumferences or resting energy expenditure. Gluteal AT-LPL activity significantly increased in all women by 2.8-fold (1.65+/-1.30-4.72+/-3.34 nmol/g/min, P<0.05). Abdominal AT-LPL activity increased in four out of the five women, but did not reach statistical significance (1.14+/-0.88-3.50+/-3.76 nmol/g/min, P=0.14). The increase in body weight correlated with the increase in gluteal AT-LPL activity (r=0.89, P<0.05), as well as the baseline activity of gluteal AT-LPL (r=0.86, P=0.06). There were no changes in basal or stimulated lipolysis in the gluteal or abdominal fat depots. CONCLUSIONS: These results suggest that smoking cessation is associated with significant increases in body weight, as well as changes in adipose cell metabolism, in particular increases in AT-LPL activity. This increase in LPL activity may contribute to the increase in body weight associated with smoking cessation.

Exercise training down-regulates ob gene expression in the genetically obese SHHF/Mcc-fa(cp) rat.

The recently cloned obesity gene (ob) encodes a protein, leptin, which is secreted from adipose tissue and interacts with hypothalamic receptors to decrease appetite, increase energy expenditure, and reduce body lipid stores. The levels of ob mRNA are increased in several models of obesity, consistent with the hypothesis that obese animals may be resistant to the actions of leptin. The present study examined the impact of increased energy expenditure through exercise training on ob mRNA gene expression and body composition in the SHHF/Mc-fa(cp) male rat, a rodent model of obesity, insulin resistance, and type II diabetes. Six week old lean and obese animals were trained 8-12 weeks by treadmill running at 70% peak oxygen uptake, 5 days/wk, for 1.5 hr/day. After endurance training, exercised rats had significantly lower total body fat compared to sedentary rats of the same age, despite maintaining the same body weight. In the obese SHHF/Mcc-fa(cp) rat, the level of ob mRNA expression was markedly increased by four fold in subcutaneous adipose tissue compared to lean controls (p<0.05). In response to exercise training, there was a significant 85 % decrease in ob mRNA in exercised-training lean rats (p < 0.05) compared with non-exercised controls, while in obese-exercised rats, ob gene expression was significantly reduced only by 50% relative to non-exercised obese rats (p < 0.05). These results demonstrate that exercise training reduces fat mass and ob mRNA in lean and obese rats, and supports the hypothesis of a feedback loop between the adipocyte and hypothalamus that attempts to maintain body weight at a constant level by reducing ob gene expression in response to increased energy expenditure.

Exercise increases muscle GLUT-4 levels and insulin action in subjects with impaired glucose tolerance.

A decline in insulin sensitivity is associated with aging, inactivity, and obesity. The effects of exercise training on glucose homeostasis independent of weight loss in older glucose-intolerant individuals are not well established. We examined the effects of exercise training on oral glucose tolerance, insulin action, and concentration of the GLUT-4 glucose transporters in skeletal muscle. Exercise training at 50 and 75% of heart rate reserve was performed for 12 wk in 18 individuals (age = 64 +/- 2, body fat = 37.0 +/- 1.5%). Peripheral insulin action was determined 96 h after the last exercise bout using a two-step hyperinsulinemic-euglycemic glucose clamp (insulin = 192 and 708 pmol/l). Percent body fat and fat-free mass (FFM) were unchanged with training. Diet composition, assessed by diet record, did not change over the 12 wk. Improved oral glucose tolerance was observed, as exhibited by lower plasma glucose concentrations after training (P < 0.05), whereas plasma insulin response remained unchanged. The rate of glucose disposal was unchanged during the low insulin concentration but increased 11.0% at the high insulin concentration (P < 0.05) after training (54.4 +/- 4.4 vs. 60.4 +/- 5.5 mumol.kg FFM-1.min-1). Skeletal muscle glycogen and GLUT-4 concentration increased 24 and 60%, respectively, with training. There was no direct relationship between the change in GLUT-4 protein and the change in glucose disposal rate. These findings demonstrate that chronic exercise training without changes in body composition improves peripheral insulin action in subjects with impaired glucose tolerance.(ABSTRACT TRUNCATED AT 250 WORDS)