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OBJECTIVE--Recently, the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research Trial demonstrated that treatment with the angiotensin receptor blocker (ARB) valsartan for 5 years resulted in a relative reduction [...]

OBJECTIVE--Increased intramuscular triacylglycerol (IMTG) storage is a characteristic of the obese insulin-resistant state. We aimed to investigate whether a blunted fasting or β-adrenergically mediated lipolysis contributes to this increased IMTG storage in obesity. RESEARCH DESIGN AND METHODS--Forearm skeletal muscle lipolysis was investigated in 13 lean and 10 obese men using [²[H.sub.5]]glycerol combined with the measurement of arteriovenous differences before and during β-adrenergic stimulation using the nonselective β-agonist isoprenaline (ISO). Muscle biopsies were taken from the vastus lateralis muscle before and during ISO to investigate hormone-sensitive lipase (HSL) protein expression and serine phosphorylation. RESULTS--Baseline total glycerol release across the forearm was significantly blunted in obese compared with lean subjects (P = 0.045). This was accompanied by lower HSL protein expression (P = 0.004), HSL phosphorylation on PKA sites [Ser.sup.563] (P = 0.041) and [Ser.sup.659] (p = 0.09), and HSL phosphorylation on the AMPK site [Ser.sup.565] (P = 0.007), suggesting a blunted skeletal muscle lipolysis in obesity. Total forearm glycerol uptake during baseline did not differ significantly between groups, whereas higher net fatty acid uptake across the forearm was observed in the obese (P = 0.064). ISO induced an increase in total glycerol release from skeletal muscle, which was not significantly different between groups. Interestingly, this was accompanied by an increase in HSL [Ser.sup.659] phosphorylation in obese subjects during ISO compared with baseline (P = 0.008). CONCLUSIONS--Obesity is accompanied by impaired fasting glycerol release, lower HSL protein expression, and serine phosphorylation. It remains to be determined whether this is a primary factor or an adaptation to the obese insulin-resistant state. Diabetes 57:1834-1841, 2008, The obese insulin-resistant state is characterized by increased triacylglycerol (TAG) storage in adipose and nonadipose tissues (ectopic fat), such as skeletal muscle (1). A strong link between increased intramuscular TAG [...]

Despite consistent evidence that abnormalities of fatty acid delivery and storage underlie the metabolic defects of insulin resistance, physiological pathways by which fat is stored in adipose tissue and skeletal muscle are not clear. We used a combination of stable isotope labeling and arteriovenous difference measurements to elucidate pathways of postprandial fat deposition in adipose tissue and skeletal muscle in healthy humans. A test meal containing [U-[sup.13]C]palmitate was combined with intravenous infusion of [²[H.sub.2]]palmitate to label plasma fatty acids and VLDL-triglyceride. Both dietary (chylomicron) and VLDL-triglyceride were cleared across adipose tissue and muscle, though with greater fractional extraction of the chylomicron-triglyceride. In adipose tissue there was significant uptake of plasma nonesterified fatty acids (NEFAs) in the postprandial but not the fasting state. However, this was minor in comparison with chylomicron-triglyceride fatty acids. We modeled the fate of fatty acids released by lipoprotein lipase (LPL). There was clear preferential uptake of these fatty acids compared with plasma NEFAs. In muscle, there was unexpected evidence for release of LPL-derived fatty acids into the plasma. With this integrative physiological approach, we have revealed hidden complexities in pathways of fatty acid uptake in adipose tissue and skeletal muscle., Disturbances in fat metabolism, most notably raised plasma concentrations of nonesterified fatty acids (NEFAs) and triglycerides, have been implicated in the pathophysiology of type 2 diabetes and consequent cardiovascular disease [...]

The current study investigated the fate of a [[U-.sup.13]C] palmitate tracer extracted by forearm muscle in type 2 diabetic and control subjects. We studied seven healthy lean male subjects and [...]

Recently, a role for uncoupling protein-3 (UCP3) in carbohydrate metabolism and in type 2 diabetes has been suggested. Mice overexpressing UCP3 in skeletal muscle showed reduced fasting plasma glucose levels, improved glucose tolerance after an oral glucose load, and reduced fasting plasma insulin levels. However, data regarding the expression of UCP3 in patients with type 2 diabetes is inconsistent, and so far, there have been no reports of UCP3 protein content. Here we compared, for the first time, the protein levels of UCP3 in vastus lateralis muscle in 14 male type 2 diabetic patients (age 49.8 ± 2.1 years; BMI 27.2 ± 1.2 kg/[m.sup.2]; mean ± SE) with 16 male control subjects (age 48.0 ± 1.9 years; BMI 23.4 ± 0.6 kg/[m.sup.2]). We found that UCP3 protein levels were twice as low in patients with type 2 diabetes compared with control subjects (117 ± 16 vs. 58 ± 12 AU; P = 0.007). There was no correlation between UCP3 content and BMI. In conclusion, UCP3 content is lower in type 2 diabetic patients compared with healthy control subjects. These results are consistent with a role for UCP3 in glucose homeostasis and suggest a role for UCP3 in type 2 diabetes., The human uncoupling protein UCP3 uncouples oxidative phosphorylation from ATP production and is therefore thought to play a role in human energy metabolism and obesity (1). Recently, a role for [...]

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 post-absorptive conditions and during 60 min of exercise (50% V[O.sub.2max]) with the use of the stable isotope tracer [U-[sup.13]C]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 µmol x kg fat-free mass [[FFM].sup.-1] x [min.sup.-1], P < 0.01; exercise: 15.0 ± 1.7, 14.1 ± 1.9, and 19.6 ± 1.5 µmol x kg FF[M.sup.-1] x [min.sup.-1] for IGT, type 2 diabetic, and obese subjects, respectively, P = 0.07). Triglyceride-derived 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 µmol x kg FF[M.sup.-1] x [min.sup.-1] 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., Increased circulating levels of plasma free fatty acid (FFA), a common finding in type 2 diabetic subjects, have been identified as an important factor associated with insulin resistance and development [...]

OBJECTIVE--To investigate the relation between serum concentration of 25-hydroxyvitamin D [25(OH)D] and insulin action and secretion. RESEARCH DESIGN AND METHODS--In a cross-sectional study of 446 Pan-European subjects with the metabolic [...]

OBJECTIVE -- We investigated whether circulating adipokine concentrations can be altered by lifestyle intervention according to general recommendations in subjects at risk for diabetes as well as the potential of [...]

The present study was intended to investigate the different components of fatty acid utilization during a 60-min period of moderate-intensity cycling exercise (50% of [VO.sub.2max]) in eight male type 2 [...]