Plasma Free Fatty Acid Uptake and Oxidation Are Already Diminished in Subjects at High Risk for Developing Type 2 Diabetes

Marco Mensink 0 Ellen E. Blaak 0 Marleen A. van Baak 0 Anton J.M. Wagenmakers 0 Wim H.M. Saris 0 0 From the Department of Human Biology, Nutrition and Toxicology Research Institute Maastricht (NUTRIM), Maastricht University , Maastricht , the Neth- erlands. Department of Human Biology, Nutrition and Toxicology Research Institute (NUTRIM), Maastricht University , P.O. Box 616, 6200 MD Maastricht , The Netherlands The objective of this study was to investigate to what extent disturbances in fatty acid metabolism found in type 2 diabetes are already present in subjects at high risk for developing diabetes (i.e., impaired glucose tolerance [IGT]). Components of fatty acid metabolism were measured in male subjects with IGT during postabsorptive conditions and during 60 min of exercise (50% VO2max) with the use of the stable isotope tracer [U-13C]palmitate in combination with indirect calorimetry, and those values were compared with previously published findings in male type 2 diabetic and male obese subjects. No differences were found between groups in energy expenditure and in total fat and carbohydrate oxidation. Rate of appearance and rate of disappearance of plasma free fatty acid (FFA) were lower in subjects with IGT and type 2 diabetes compared with obese subjects (P < 0.05). Plasma FFA oxidation was lower in subjects with IGT and type 2 diabetes compared with obese subjects at rest and tended to be lower during exercise (rest: 3.7 0.3, 4.4 0.6, and 6.9 1.0 mol kg fat-free mass [FFM]1 min1 , P < 0.01; exercise: 15.0 1.7, 14.1 1.9, and 19.6 1.5 mol kg FFM1 min1 for IGT, type 2 diabetic, and obese subjects, respectively, P 0.07). Triglyceridederived fatty acid oxidation, however, was elevated in subjects with IGT and type 2 diabetes during exercise (3.6 1.4, 1.4 1.4, and - 4.0 2.0 mol kg FFM1 min1 for IGT, type 2 diabetic, and obese subjects, respectively; P < 0.05). These data demonstrate that male subjects with a prediabetic condition (IGT) have the same defects in fatty acid utilization as subjects with type 2 diabetes, suggesting that these disturbances may play an important role in the progression from IGT to type 2 diabetes. Diabetes 50:2548 -2554, 2001 - Ihave been identified as an important factor associncreased circulating levels of plasma free fatty acid (FFA), a common finding in type 2 diabetic subjects, ated with insulin resistance and development of type 2 diabetes, and they seem to be related to common risk factors for coronary heart diseases, including hypertriglyceridemia, hyperapo B, and increased coagulation activity (1). In the liver, an increased delivery of FFA can impair insulin-mediated suppression of hepatic glucose output (2), increase synthesis of VLDL (1), and diminish hepatic insulin clearance (3). Chronically elevated levels of circulating FFA may also reduce insulin secretion by the -cell of the pancreas (4,5). Elevated FFA concentrations may result from increased fasting rates of lipolysis, which seem to result from both the enlarged adipose tissue stores and an impaired insulinmediated suppression of lipolysis (6). On the other hand, defects in FFA uptake and/or oxidation could also result in elevated circulating levels of FFA. Colberg et al. (7) reported that in viscerally obese women, there was a negative relation between visceral fat content and postabsorptive FFA utilization by skeletal muscle. Similar results were shown by Kelley and associates (8,9) using the leg-balance technique in combination with indirect calorimetry. They reported a diminished uptake of plasma FFA and a diminished oxidation rate of fatty acids in the postabsorptive state in patients with type 2 diabetes in comparison with lean healthy subjects. We have shown in obese type 2 diabetic patients that the uptake and oxidation of plasma FFA are diminished in the forearm muscles in the postabsorptive state and during -adrenergic stimulation (10). Type 2 diabetic subjects also had a diminished plasma FFA oxidation and a higher triglyceridederived fatty acid oxidation at the whole-body level as compared with weight-matched control subjects during rest and moderate-intensity exercise (50% VO2max) (11). Skeletal muscle is believed to be the main site responsible for the impaired fatty acid utilization and oxidation because of its large mass and since lipids are the principal oxidative substrate of skeletal muscle after an overnight fast and during moderate-intensity exercise. An imbalance between FFA uptake and FFA could easily lead to fat accumulation within skeletal muscle. Indeed, skeletal muscle triglyceride content is increased up to sixfold in patients with diabetes (12,13). Furthermore, the content of intramuscular triglycerides (IMTGs) shows a strong negaVO2max (ml/min) VO2max (ml/kg FFM/min) Data are means SE. *Significantly different from obese (P 0.05, Sheffe post hoc test); significantly different from IGT (P post hoc test). ANOVA, analysis of variance; WHR, waist-to-hip ratio. tive correlation with the degree of insulin resistance (i.e., insulin-stimulated glucose disposal) (14,15). Thus, there is a lot of evidence indicating that disturbances in muscle fatty acid utilization may play an important role in the etiology of insulin resistance and type 2 diabetes. However, it is difficult to assess the pathophysiological abnormalities leading to type 2 diabetes when the type 2 diabetic state has already developed, since it is impossible to differentiate between primary factors and adaptational responses. Subjects with impaired glucose tolerance (IGT) have an elevated risk for the development of type 2 diabetes. Within 10 years, up to 50% of individuals with IGT become diabetic (16). If the disturbances in skeletal muscle fatty acid metabolism described above are already present in the glucose-intolerant state, this could indicate that the defects might be important etiological factors in the development of type 2 diabetes. Therefore, the objective of this study was to investigate to what extent disturbances in fatty acid metabolism found in the diabetic state are already present in subjects at high risk for developing type 2 diabetes (i.e., IGT). We measured components of fatty acid metabolism with the use of stable isotope tracers in combination with indirect calorimetry in subjects with IGT and compared those values with previously published findings in type 2 diabetic subjects and obese subjects during postabsorptive conditions and during 60 min of moderate-intensity exercise (11). RESEARCH DESIGN AND METHODS Subjects. Seven obese normoglycemic, seven IGT, and seven type 2 diabetic male subjects were studied. IGT was determined during a 2-h oral glucose tolerance test (OGTT) according to the World Health Organization criteria of 1985. Type 2 diabetes was diagnosed with an OGTT. Diabetic subjects were treated with diet alone (n 3) or diet together with sulfonylureas (n 4); blood glucoselowering medication was withheld for 2 days before the experiment (...truncated)