Edward S. Horton

Effects of Prior High-Intensity Exercise on Glucose Metabolism in Normal and Insulin-resistant Men

The effects of prior high-intensity cycle exercise (85% VO2 max) to muscular exhaustion on basal and insulinstimulated glucose metabolism were studied in obese, insulin-resistant, and normal subjects. Six obese (30.4% fat) and six lean (14.5% fat) adult males underwent two separate, two-level hyperinsulinemic-euglycemic clamp studies (100-min infusions at 40 and 400 mU/m2/min), with and without exercise 12 h earlier. Carbohydrate oxidation was estimated by indirect calorimetry using a ventilated hood system, and endogenous glucose production by D-(3-3H)-glucose infusion. Glycogen content and glycogen synthase activity (GS %l) were measured in vastus lateralis muscle biopsies before and at the end of each insulin clamp procedure. After exercise, the obese and lean subjects had comparably low muscle glycogen concentrations (0.10 versus 0.08 mg/g protein, respectively), and equal activation of muscle GS activity (54.4 versus 45.3 GS %l, respectively). In the obese subjects, insulin-stimulated glucose disposal was increased significantly, but not totally corrected to normal. In both groups there was a comparable increase in nonoxidative glucose disposal (NOGD), whereas glucose oxidation was decreased and lipid oxidation was increased. Thus, the major effect of prior exercise was to increase insulin-stimulated glucose disposal in the obese subjects and to alter the pathways of glucose metabolism to favor NOGD and decrease glucose oxidation. No correlation was found between the exercise-induced increase in GS %l and NOGD, except in the normal subjects during maximal insulin stimulation. Thus, glycogen synthase activity does not appear to be ratelimiting fpr NOGD at physiologic insulin concentrations. Our findings suggest that a single bout of glycogendepleting exercise can increase glucose disposal for at least 12–14 h in obese subjects with insulin resistance.

Acute exercise increases the number of plasma membrane glucose transporters in rat skeletal muscle

To determine whether increased glucose transport following exercise is associated with an increased number of glucose transporters in muscle plasma membranes, the D‐glucose inhabitable cytochalasin B binding technique was used to measure glucose transporters in red gastrocnemius muscle from exercised (1 h treadmill) or sedentary rats. Immediately following exercise there was a 2‐fold increase in cytochalasin B binding sites, measured in purified plasma membranes enriched 30‐fold in 5′‐nucleotidase activity. This increase in glucose transporters in the plasma membrane may explain in part, the increase in glucose transport rate which persists in skeletal muscle following exercise. Where these transporters originate, remains to be elucidated.

Metabolic studies in human obesity during overnutrition and undernutrition: Thermogenic and hormonal responses to norepinephrine

Overfeeding increases the thermogenic response of norepinephrine (NE) in normal but not in certain genetically obese rodents. It has been suggested that human obesity may be associated with a similar thermogenic defect. To determine whether there are differences in the thermogenic sensitivity to NE in human obesity, energy expenditure in response to graded infusions of NE (0.05, 0.10, 0.15, 0.20 micrograms/min/kg fat-free mass) was measured in six lean and six obese subjects (9.5 +/- 1.8 v 36.3 +/- 3.8% body fat P less than 0.005). Resting metabolic rate (RMR), thermogenic response to NE, and thermogenic response to exercise were measured during weight maintenance and during the third week of feeding 1000 extra Kcal/d in the lean and obese subjects. These components of energy expenditure were also measured in the obese subjects during the third week of a 589 Kcal/d diet. Resting metabolic rate increased during overfeeding in lean (6.6%, P less than 0.05) but not in the obese subjects (2.7%, P = NS) and fell during underfeeding in the obese (-9.1%, P less than 0.02). There was a logarithmic increment above baseline in VO2 v plasma NE concentration during the NE infusions (r = 0.75, P less than 0.005) in lean subjects which was unaltered by overfeeding. The obese exhibited equivalent VO2 responses to NE to that measured in the lean. Supine plasma NE concentrations were lower but metabolic clearance rates (MCR) of NE were similar in the obese compared to lean subjects during both weight maintenance and overfeeding. Overfeeding minimally increased plasma concentration but not MCR of NE in both groups. The thermogenic response to exercise was similar in the lean and obese subjects and was unaltered by overfeeding or underfeeding. The increments in plasma glycerol and free fatty acid in response to the NE infusions were proportional to the total fat mass of each individual and were greater in the obese subjects. Overfeeding partially suppressed the lipolytic response to NE in both groups and underfeeding increased the lipolytic response in the obese. There are no differences in thermogenic responses to NE in human obesity to account for excessive fat deposition. Overfeeding does not increase the thermogenetic responses to NE in humans as has been reported in small mammals.

Familial partial lipodystrophy: Complications of obesity in the non-obese?

Abstract The increased frequency of metabolic perturbations in overweight individuals whose fat is predominantly central, as compared with those whose fat is more generalized in distribution suggests that characteristics of fat other than an excess promote the morbidity of the obese. In this report we describe the location and quantity of body fat together with the status of carbohydrate and lipid metabolism in 8 females affected with familial partial lipodystrophy, a rare condition in which peripheral subcutaneous fat is mostly absent while there is retention or an increase in central adiposity. The 8 subjects had normal or reduced amounts of body fat as determined by body density measurements. Computerized axial tomograms in two subjects showed that there was normal to increased amounts of intra-abdominal fat and irregular pockets of subcutaneous fat overlying the abdomen. Plasma triglycerides varied but were elevated in all subjects ranging from 171 to 3720 mg/dl (normal = 103 ± 36). Mild sustained elevations in mean systolic blood pressure (> 135 mm Hg) occurred in 4. Two of the 8 had fasting hyperglycemia (>140 mg/dL) and a third was intolerant to oral, but not to intravenous glucose. Fasting serum insulin concentrations were uniformly elevated (22 to 51 uU/ml) and, in most instances, responded to both glucose and arginine with exaggerated increments, but there was no delay in insulin release. Mild insulin resistance was documented by the failure to respond to standard insulin injections, and there were decreased insulin receptors on erythrocytes. Basal plasma glucagon concentrations were generally elevated, did not suppress during oral glucose administrations and rose 2 to 5 times basal levels during intravenous infusion of arginine. These studies emphasize that the various complications of the obese, especially those with centralized obesity, are seen in a non-obese condition characterized by an increase in the ratio of central to peripheral fat.

The effect of diet on thermogenesis in acquired lipodystrophy.

Abstract We tested the effect of variation of intake of carbohydrate, fat, protein, and total calories on the metabolic rate and thyroid hormones in an 18-yr-old female with total acquired lipodystrophy and a 23-yr-old normal female control subject. The lipodystrophic subjects resting metabolic rates, when expressed as W/m 2 body surface area, were elevated and varied directly with the caloric intake. The metabolic rates were highest after 3 days of the protein-supplemented diet and lowest after a 3 day fast. Serum triiodothyronine (T 3 ) concentrations of the lipodystrophic subject were within the normal range but varied directly with the caloric content of the diet. T 3 was highest during the period of protein supplementation and lowest after the 3 day fast. The resting metabolic rate rose beyond the normal range in the control subject only after 3 days of the protein-supplemented diet and fell to low normal values after the 3 day fast. In contrast to the finding in the lipodystrophic subject, T 3 concentrations were stable after each 3–6 day dietary alteration. We conclude that there is relative metabolic lability in the lipodystrophic subject, and this may be related to the diminished capacity to store energy as fat. Metabolic rates, when calculated as W/kg estimated lean mass, were normal in the lipodystrophic subject, consuming reduced amounts of food (1800 cal/day). The role, if any, of T 3 in modulating these processes is unclear. The subject with lipodystrophy may demonstrate a form of dietary-induced thermogenesis.

Spontaneous and experimental human obesity: Effects of diet and adipose cell size on lipolysis and lipogenesis☆

Abstract We examined the hypothesis that adipose tissue from lean and obese subjects might provide different internal signals in response to changes in stored calories. Adipose tissue was obtained before weight gain in nonobese subjects and after weight gain in five of the same individuals. Adipose tissue was removed before and after weight loss in seven obese patients. Two isocaloric diets were fed to both groups for 2–3 wk each; one diet was high in carbohydrate, and the other contained a low carbohydrate content. Incorporation of radioactivity from pyruvate into fatty acids in vitro was lower with the low-carbohydrate diet than with the high-carbohydrate diet. It was also significantly reduced after weight gain in the nonobese subjects but was not significantly altered in the obese. There were no significant effects of diet or weight gain on the enzymatic activities in the nonobese subjects. The large fat cells from both groups of subjects had an increased sensitivity to the lipolytic effects of isoproterenol as compared with the smaller fat cells. Variations in carbohydrate intake had no effect on the lipolytic response to isoproterenol. The dose response of fat cells to dibutyryl-cyclic-3′,5′-AMP did not change after weight gain in the nonobese males, but was significantly reduced on both levels of carbohydrate after weight loss in the obese (i.e., when studying the smaller fat cells). These studies suggest that differences in the metabolism of adipose tissue between obese and lean subjects persist when differences in the size of fat cells and caloric intake are controlled.

The thermogenic role of exercise in the treatment of morbid obesity: a critical evaluation.

Exercise induces negative energy balance either directly or by enhancing meal thermogenesis, increasing resting metabolic rate, and/or decreasing food intake. A quantitative evaluation of these effects in programs of weight control led to the following conclusions: 1) energy cost of exercise per se is minimal, 2) effects on thermic of food are negligible, and 3) exercise training may be advantageous in conjunction with low-calorie diet programs because it helps to maintain resting metabolic rate and fat-free mass. However, exercise may not prevent, and may even accentuate, the fall in metabolic rate in programs of severe calorie restriction, thus hampering weight reduction. Overall, exercise should not be envisioned as a sole agent to induce negative energy balance, but it is an essential element in comprehensive programs for morbidly obese patients due to its effects on lipids, carbohydrate metabolism, and cardiovascular system.

Effects of Loop Diuretics on Carbohydrate Metabolism and Electrolyte Excretion

Abstract: The effects of two loop diuretics, bumetanide and furosemide, on carbohydrate metabolism and electrolyte balance were assessed in 11 normal male subjects in a double‐blind manner. Glucose, insulin, glucagon, and growth hormone responses to 5‐hour glucose tolerance test and arginine infusion were measured during the control and drug treatment periods. Three other non‐insulin‐dependent diabetic subjects, receiving diuretic drug for six weeks, underwent a similar protocol. Kaliuresis and natriuresis due to diuretic administration were significant only on day 1 of treatment. There were no significant changes in total body potassium by 40K counting; net potassium loss by balance study was minimal in both the acutely treated subjects and the chronically treated patients. Effects of bumetanide and furosemide on water and electrolyte excretion did not differ. Glucose tolerance was significantly improved with bumetanide but not with furosemide. Plasma insulin, glucagon, and growth hormone levels during the oral glucose tolerance test were unaffected by either drug. Insulin levels with arginine infusion were significantly increased, and growth hormone levels decreased with bumetanide but not with furosemide. No evidence of impaired carbohydrate metabolism in the three chronically treated diabetic subjects was seen. It is concluded that the effects of bumetanide and furosemide on potassium balance and glucose utilization were minimal in this experimental setting.

Exercise in the Treatment of NIDDM: Applications for GDM?

Physical training is associated with lower plasma insulin concentrations and increased sensitivity to insulin in skeletal muscle and adipose tissue of individuals with non-insulin-dependent diabetes mellitus (NIDDM). The benefits of exercise to individuals with NIDDM in terms of increased insulin sensitivity could be applied to reversing the insulin resistance associated with gestational diabetes mellitus (GDM). Exercise may also benefit women with GDM by acting as an adjunct to diet in preventing excessive weight gain and preventing or decreasing the severity of hypertension and/or hyperlipidemia during pregnancy. Regular physical exercise should be considered as a potential approach to the prevention and treatment of GDM.

Exercise training normalizes glucose metabolism in a rat model of impaired glucose tolerance

The purpose of this study was to characterize an animal model of impaired glucose tolerance produced by streptozocin treatment of rats (45 mg/kg, intravenously [i.v.]) and selection of animals with plasma glucose concentrations less than 150 mg/dL. In addition, we determined the effects of physical training on glucose tolerance and metabolism in these animals. During 10 weeks of monitoring, it was determined that these animals have nearly normal plasma glucose concentrations; however, they have an impaired glucose tolerance when challenged with an oral glucose load. They also have normal fasting insulin, free fatty acid, and triglyceride concentrations, normal body weight and food consumption patterns, and normal rates of skeletal muscle glucose uptake, but impaired basal and insulin-stimulated glucose metabolism in isolated adipose cells. Ten weeks of exercise training normalized both the impaired glucose tolerance and adipose cell function present in the untrained streptozocin-treated rats. Low-dose streptozocin treatment of rats with appropriate selection of animals based on plasma glucose concentrations appears to be an excellent model of impaired glucose tolerance for studies of factors affecting insulin resistance and altered glucose metabolism.