0021-972X/91/7204-0801$03.00/0 Journal of Clinical Endocrinology and Metabolism Copyright © 1991 by The Endocrine Society

Vol. 72, No. 4 Printed in U.S.A.

Reduced Glucose-Induced Thermogenesis Is Present in Noninsulin-Dependent Diabetes Mellitus without Obesity* BARRY GUMBINERf, ANNE W. THORBURN$, AND ROBERT R. HENRY Department of Medicine, University of California, San Diego, California and Veterans Administration Medical Center, San Diego, California 92161

ABSTRACT. Decreased glucose-induced thermogenesis has been observed in all forms of obesity. However, some studies implicate insulin resistance rather than obesity per se as the mechanism by which glucose-induced thermogenesis is reduced. To establish the role of insulin resistance in reduced thermogenesis independent of obesity, we compared energy expenditure in 9 nonobese individuals with noninsulin-dependent diabetes mellitus (NIDDM) to 16 nonobese control subjects using indirect calorimetry and the hyperinsulinemic clamp technique. To document the presence of insulin resistance and reduced glucoseinduced thermogenesis in nonobese NIDDM, 6 individuals from each group were studied under identical conditions of hyperinsulinemia (120 mU/m 2 min) and euglycemia (~5 mmol/1). Both glucose uptake (0.482 ± 0.042 vs. 0.737 ± 0.040 g/min) and energy expenditure above basal (0.04 ± 0.02 vs. 0.10 ± 0.02 kcal/ min) were decreased in nonobese NIDDM compared to control subjects (both P < 0.05). To determine whether decreased glucose-induced thermogenesis could be overcome by correcting for reduced glucose uptake, the 9 nonobese NIDDM individuals were age- and weight-matched to 9 control subjects and clamps were performed at matched rates of glucose uptake. During a 40

mU/m2-min insulin infusion, the nonobese NIDDM individuals were studied at hyperglycemia (17.5 ± 1.9 mmol/L) and compared to the control subjects at euglycemia (5.1 ±0.1 mmol/L; P < 0.05). Under these conditions, both groups achieved similar rates of glucose uptake (0.698 ± 0.040 vs. 0.688 ± 0.038 g/min, NIDDM and control subjects, respectively) and similar rates of energy expenditure above basal (0.08 ± 0.03 vs. 0.06 ± 0.02 kcal/ min, P = NS). During 600 mU/m 2 min clamps performed at hyperglycemia (19.0 ± 1.2 vs. 14.5 ± 1.1 mmol/L, NIDDM vs. control subjects, respectively; P < 0.05), rates of maximal glucose uptake (1.538 ± 0.093 us. 1.518 ± 0.047 g/min) and energy expenditure above basal (0.34 ± 0.03 vs. 0.31 ± 0.03 kcal/min) were also similar (P = NS). In conclusion nonobese NIDDM is associated with both decreased rates of glucose uptake and decreased glucose-induced thermogenesis. Decreased glucose substrate availability, due to impaired insulin action, appears to be the critical determinant of glucose-induced thermogenesis in nonobese NIDDM. These data indicate that decreased thermogenesis in NIDDM is a consequence of insulin resistance and can occur independent of obesity. (J Clin Endocrinol Metab 72: 801-807, 1991)

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HE increase in energy expenditure associated with oral and iv glucose administration is a well described phenomenon (1-8). In obese conditions [obese noninsulin-dependent diabetes mellitus (NIDDM) (8-13) and obese glucose tolerant individuals (8, 12-15)], this thermogenic response is diminished. Based on this observation, investigators have proposed that reduced glucoseinduced thermogenesis may lead to obesity. However,

insulin resistance is another metabolic characteristic common to these individuals and recent studies suggest that defects in energy expenditure are a consequence of impaired insulin action associated with the obese state (9, 11, 15). Due to diminished tissue uptake of glucose, less substrate is available to traverse the metabolic pathways that induce increased energy expenditure. When impaired glucose uptake in obese NIDDM and obese glucose tolerant individuals is corrected experimentally, glucose-induced thermogenesis is normalized (9,11, 15). Therefore, these studies suggest that reduced glucoseinduced thermogenesis is not a cause of obesity per se but a consequence of the insulin resistance associated with the obese state. This would also suggest that reduced glucose-induced thermogenesis should be manifested in nonobese conditions associated with insulin resistance and such a defect could be corrected under conditions of increased glucose uptake. To elucidate the role of insulin resistance in the reduction of glucose-induced thermo-

Received September 2,1990. Address all correspondence and requests for reprints to: Barry Gumbiner, M.D., Veterans Administration Medical Center, Medical Research Service (lllG), 3350 La Jolla Village Drive, San Diego, California 92161. * This study was supported in part by the Medical Research Service of the Veterans Administration, the American Diabetes Association, Grants DK-38949 from the National Institute of Diabetes and Digestive and Kidney Disease and Grant MOl-RR-00827 from the General Clinical Research Branch, Division of Research Resources, NIH. t Recipient of an American Diabetes Association, California Affiliate, Fellowship Award. X Neil Hamilton Fairley Fellow funded by National Health and Medical Research Council of Australia.

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GUMBINER ET AL.

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JCE & M • 1991 Vol 72 • No 4

genesis independent of obesity, energy expenditure was measured by indirect calorimetry in nonobese NIDDM individuals under various glucose clamp conditions to: 1) document decreased glucose-induced thermogenesis and 2) normalize thermogenesis by experimentally correcting reduced glucose uptake.

Materials and Methods

Caiorimetry

Subjects

Sampling

Nine nonobese males with NIDDM and 16 nonobese male control subjects participated in the studies. Some of the results presented in this report are derived from data previously reported (16-18). All control subjects were healthy, receiving no medication, had no family history of NIDDM, and had normal glucose tolerance based on an oral glucose tolerance test (19). The nonobese NIDDM individuals were frankly diabetic as manifested by fasting hyperglycemia (19). Mean duration of NIDDM was 9 ± 3 yr. All NIDDM subjects were otherwise healthy, and were free of significant diabetic complications. Diabetic therapy was discontinued at least 2 weeks before the studies and mean hemogloblin Ale was 9.6 ± 1.3% (4.1-8.1% normal range) when studies were initiated. The groups were similar in age, weight, and fat-free mass (FFM), body mass index (Table 1). By history, the level of physical fitness was comparable between the groups. The protocol was approved by the Committee on Human Investigation of the University of California, San Diego and the Veterans Administration Medical Center (San Diego, CA). Written informed consent was obtained from each subject. Protocol (Fig. 1)

Subjects were admitted to the Special Diagnostic and Treatment Unit of the Veterans Administration Medical Center in San Diego and consumed a weight-maintenance standardized solid diet containing 55% of calories as carbohydrate, 30% as fat and 15% as protein for at least 24 h before each study. Study 1:120 mU/m2-min hyperinsulinemic euglycemic clamp Six NIDDM subjects and six control subjects underwent a 120 mU/m2-min hyperinsulinemic euglycemic clamp in combination with indirect calorimetry to document the presence of decreased glucose-induced thermogenesis in nonobese NIDDM compared to controls under identical conditions of hyperinsuTABLE 1. Clinical and metabolic characteristics

Age (yr) Weight (kg) FFM (kg) Body mass index (kg/m2) Fasting serum glucose (mmol/L) Fasting serum insulin (/zU/ml) 'P

Reduced glucose-induced thermogenesis is present in noninsulin-dependent diabetes mellitus without obesity.

Decreased glucose-induced thermogenesis has been observed in all forms of obesity. However, some studies implicate insulin resistance rather than obes...
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