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Insulin Resistance in Type 2 Diabetes: Association with Truncal Obesity, Impaired Fitness, and Atypical Malonyl Coenzyme A Regulation

Divisions of Medicine and Molecular Medicine, Departments of Emergency and Cardiovascular Medicine (P.N.B.), Endocrinology (S.E., J.K.), and Anesthesiology (J.P.), Karolinska Hospital and Institute, S-17176 Stockholm, Sweden; and Diabetes and Metabolism Unit (N.B.R., A.K.S.), Boston University Hospital, Boston, Massachusetts 02118

Address all correspondence and requests for reprints to: Dr. Peter Båvenholm, Department of Emergency and Cardiovascular Medicine, Division of Internal Medicine, Karolinska Hospital, S-171 76 Stockholm, Sweden. E-mail: peter.bavenholm{at}ks.se.

Abdominal obesity and physical inactivity are associated with insulin resistance in humans and contribute to the development of type 2 diabetes. Likewise, sustained increases in the concentration of malonyl coenzyme A (CoA), an inhibitor of fatty-acid oxidation, have been observed in muscle in association with insulin resistance and type 2 diabetes in various rodents. In the present study, we assessed whether these factors are present in a defined population of slightly overweight (body mass index, 26.2 kg/m²), insulin-resistant patients with type 2 diabetes. Thirteen type 2 diabetic men and 17 sex-, age-, and body mass index-matched control subjects were evaluated. Insulin sensitivity was assessed during a two-step euglycemic insulin clamp (infusion of 0.25 and 1.0 mU/kg·min). The rates of glucose administered during the low-dose insulin clamp were 2.0 ± 0.2 vs. 0.7 ± 0.2 mg/kg body weight·min (P < 0.001) in the control and diabetic subjects, respectively; rates during the high-dose insulin clamp were 8.3 ± 0.7 vs. 4.6 ± 0.4 mg/kg body weight·min (P < 0.001) for controls and diabetic subjects. The diabetic patients had a significantly lower maximal oxygen uptake than control subjects (29.4 ± 1.0 vs. 33.4 ± 1.4 ml/kg·min; P = 0.03) and a greater total body fat mass (3.7 kg), mainly due to an increase in truncal fat (16.5 ± 0.9 vs. 13.1 ± 0.9 kg; P = 0.02). The plasma concentration of free fatty acid and the rate of fatty acid oxidation during the clamps were both higher in the diabetic subjects than the control subjects (P = 0.002–0.007). In addition, during the high-dose insulin clamp, the increase in cytosolic citrate and malate in muscle, which parallels and regulates malonyl CoA levels, was significantly less in the diabetic patients (P < 0.05 vs. P < 0.001). Despite this, a similar increase in the concentration of malonyl CoA was observed in the two groups, suggesting an abnormality in malonyl CoA regulation in the diabetic subjects.

In conclusion, the results confirm that insulin sensitivity is decreased in slightly overweight men with mild type 2 diabetes and that this correlates closely with an increase in truncal fat mass and a decrease in physical fitness. Whether the unexpectedly high levels of malonyl CoA in muscle, together with the diminished suppression of plasma free fatty acid, explains the insulin resistance of the diabetic patients during the clamp remains to be determined.

This work was supported by grants from the Swedish Medical Research Council (K99-72X00034-35A), the Karolinska Institute, the Novo Nordisk Insulin Foundation, the National Institutes of Health (DK 19514 and DK 49147), and the Juvenile Diabetes Research Foundation (to N.B.R.).

Abbreviations: ACC, Acetyl CoA carboxylase; AMPK, AMP kinase; BMI, body mass index; CoA, coenzyme A; DAG, diacylglycerol; DEXA, dual-energy x-ray absorptiometry; FFA, free fatty acid; LBM, lean body mass; LCFA, long chain fatty acyl; OGTT, oral glucose tolerance test; PKC, protein kinase C; VO₂ max, maximal oxygen uptake.

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