IntroductionWe examined the mechanisms of enhanced insulin sensitivity in 9 male healthy athletes (age, 25±1 yr; maximal aerobic power [V O2maxJ, 57.6±1.0 ml/kg per min) as compared with 10 sedentary control subjects (age, 28±2 yr; V02max, 44.1±2.3 ml/kg per min). In the athletes, whole body glucose disposal (240-min insulin clamp) was 32% (P < 0.01 ) and nonoxidative glucose disposal (indirect calorimetry) was 62% higher (P < 0.01 ) than in the controls. Muscle glycogen content increased by 39% in the athletes (P < 0.05) but did not change in the controls during insulin clamp. VO2max correlated with whole body (r = 0.60, P < 0.01) and nonoxidative glucose disposal (r = 0.64, P < 0.001). In the athletes forearm blood flow was 64% greater (P < 0.05) than in the controls, whereas their muscle capillary density was normal. Basal blood flow was related to VO2max (r = 0.63, P < 0.05) and glucose disposal during insulin infusion (r = 0.65, P < 0.05). The forearm glucose uptake in the athletes was increased by 3.3-fold (P < 0.01) in the basal state and by 73% (P < 0.05) during insulin infusion. Muscle glucose transport protein (GLUT4) concentration was 93% greater in the athletes than controls (P < 0.01 ) and it was related to VO2max (r = 0.61, P < 0.01 ) and to whole body glucose disposal (r = 0.60, P < 0.01). Muscle glycogen synthase activity was 33% greater in the athletes than in the controls (P < 0.05), and the basal glycogen synthase fractional activity was closely related to blood flow (r = 0.88, P < 0.001).In conclusion: (a) athletes are characterized by enhanced muscle blood flow and glucose uptake. (b) The cellular mechanisms of glucose uptake are increased GLUT4 protein content, glycogen synthase activity, and glucose storage as glycogen. (c) A close correlation between glycogen synthase fractional activity and blood flow suggests that they are causally related in promoting glucose disposal. (J.

OBJECTIVE -Inflammatory activity is increased in type 1 diabetes and may predispose to vascular disease. Its origin is not clear. We therefore investigated determinants of inflammation in type 1 diabetes. RESEARCH DESIGN AND METHODS -We performed a nested case-control study from the EURODIAB Prospective Complications Study of 543 European individuals having type 1 diabetes (278 men), diagnosed at Ͻ36 years of age. Case subjects (n ϭ 348) were those with one or more complications of diabetes; control subjects (n ϭ 195) were all those with no evidence of any complication. We determined levels of C-reactive protein, interleukin-6, and tumor necrosis factor-␣, combined them in a "general score of inflammatory markers," and investigated their associations with vascular risk factors and markers of endothelial dysfunction by use of multiple linear regression analysis. CONCLUSIONS -We have shown that conventional risk factors for vascular disease and endothelial adhesion molecules are important determinants of inflammation in type 1 diabetic individuals, suggesting that strategies to decrease inflammatory activity in type 1 diabetes should focus not only on control of conventional risk factors, but also on improvement of endothelial function. RESULTS Diabetes Care 26:2165-2173, 2003A therothrombosis is now widely considered a chronic inflammatory disease. In accordance, plasma markers of inflammation, such as C-reactive protein (CRP) and interleukin-6 (IL-6) levels, are positively associated with risk of vascular disease in nondiabetic individuals (1,2).Diabetes is an important risk factor for atherothrombosis, an association that is not explained by conventional risk factors. In individuals with type 2 diabetes, inflammatory activity is increased and is strongly associated with risk of atherothrombosis (3,4). Inflammatory activity is also increased in individuals with type 1 diabetes, as shown by increased concentrations of CRP (5,6) and tumor necrosis factor (TNF)-␣ (7). This elevation of inflammatory markers is thought to be due, in part, to hyperglycemia and the formation of advanced glycation end products (8). However, it is not known what other factors determine the increased inflammatory activity in type 1 diabetes. In particular, the roles of conventional risk factors (2,5,7,9 -12), including advanced glycation end products, and of endothelial dysfunction (4,5) have not been clarified. It is also not known whether the presence of microvascular complications influences the associations of conventional risk factors and endothelial dysfunction with inflammatory activity.In view of these considerations, we investigated determinants of inflammatory activity in the EURODIAB Prospective Complications Study, a representative sample of European individuals with type 1 diabetes (13). Inflammatory activity was estimated from serum concentrations of CRP, IL-6, and TNF-␣. We focused on two sets of potential determinants of inflammatory activity, namely, conventional risk factors for atherothrombosis, including estimates of g...

The overall prevalence of CVD in these IDDM patients was approximately 10%, increasing with age and duration of diabetes and with a sixfold variation between different European centers. CVD prevalence was most strongly associated with elevated triglyceride and decreased HDL cholesterol concentrations. CVD was also associated with albuminuria, but when adjusted by age, this association vanished. Increasing waist-to-hip ratio was associated with a number of adverse characteristics, particularly in IDDM men, reflecting the metabolic syndrome previously described in other populations.

Aims/hypothesis: Diabetic nephropathy is associated with insulin resistance, and low-grade inflammation and activation of the complement system may contribute to this cascade. Mannan-binding lectin (MBL) activates the complement system, and elevated MBL concentrations have been observed in normoalbuminuric type 1 diabetic patients. The aim of this study was to assess whether MBL is associated with diabetic nephropathy in type 1 diabetes, and whether there is an association between MBL and low-grade inflammatory markers or insulin resistance. Methods: A total of 191 type 1 diabetic patients from the Finnish Diabetic Nephropathy Study were divided into three groups based upon their AER. Patients with normal AER (n=67) did not take antihypertensive medication, while patients with microalbuminuria (n=62) or macroalbuminuria (n=62) were all treated with an ACE inhibitor. As a measure of insulin sensitivity we used estimated glucose disposal rate. MBL was measured by an immunofluorometric assay, C-reactive protein by a radioimmunoassay and IL-6 by high-sensitivity enzyme immunoassay. There was a significant correlation between MBL and estimated glucose disposal rate, but not between MBL and C-reactive protein or IL-6 levels in univariate analysis. However, in a multiple regression analysis, HbA1c was the single variable independently associated with MBL (β±SEM: 0.26±0.08; p=0.003). Conclusions/interpretation: MBL concentrations are increased in type 1 diabetic patients with diabetic nephropathy. MBL was not associated with low-grade inflammatory markers.

The glucose transport proteins (GLUT1 and GLUT4) facilitate glucose transport into insulin-sensitive cells. GLUT1 is insulin-independent and is widely distributed in different tissues. GLUT4 is insulin-dependent and is responsible for the majority of glucose transport into muscle and adipose cells in anabolic conditions. We suggest the hypothesis that insulin resistance is dependent on whether glucose is entering through GLUT1 or GLUT4 and on the two functional compartments of glucose 6-phosphate formation within the cell. Glucose entering the muscle cell through GLUT4 and phosphorylated by hexokinase II is mainly directed to glycogen synthesis and glycolysis. If glucose is entering through GLUT1 and phosphorylated by hexokinase I, the glucose 6-phosphate so formed is available for all metabolic pathways, including the hexosamine pathway. Hexosamines have a negative feedback effect on GLUT4, and reduced GLUT4 activity decreases insulin-mediated glucose uptake. Thus, insulin-independent glucose transport through GLUT1 can meet the basal needs of the muscle cell. If glucose entrance through GLUT1 and the activation of the hexosamine pathway is abundant, it can decrease the insulin-mediated glucose transport through GLUT4 leading to insulin resistance.