Search

Aim: We investigated the effect of carbohydrate availability and euglycaemic hyperinsulinaemia on intramuscular and plasma amino acids in 14 healthy men (age 26.5 +/- 0.9 years, b.m.i. 22.9 +/- 0.5 kg/m2)., Methods: Insulin was infused (1.5 mU/kg/min) for 240 min both after a carbohydrate depleting exercise and after carbohydrate loading. Muscle samples were taken before and after hyperinsulinaemia. Plasma and intramuscular amino acid concentrations were measured., Results: Insulin-mediated glucose disposal was similar after carbohydrate depletion (65.2 +/- 1.9 micromol/kg/min) and loading (66.9 +/- 2.8 micromol/kg/min). Carbohydrate depletion was associated with decreased alanine and increased branched chain amino acid (BCAA) concentrations in muscle and plasma. Blood lactate was lower after carbohydrate depletion (477 +/- 25 micromol/l) than loading (850 +/- 76 micromol/l, p < 0.001). In carbohydrate depletion, hyperinsulinaemia resulted in a greater increase in intramuscular (from 927 +/- 48 nmol/g muscle to 2029 +/- 104 nmol/g muscle, p < 0.001), than plasma (from 197 +/- 6.7 micromol/l to 267 +/- 11 micromol/l, p < 0.001) alanine. After carbohydrate loading muscle alanine did not rise significantly (from 1546 +/- 112 nmol/g muscle to 1781 +/- 71 nmol/g muscle) whereas plasma alanine decreased (from 339 +/- 26 micromol/l to 272 +/- 13 micromol/l, p < 0.05)., Conclusions: (1) Carbohydrate availability has profound effects on the interrelationship between glucose and amino acid metabolism and on the form of storage for glucose-derived carbons. (2) For most amino acids changes in plasma levels of amino acids are not related to changes in concentrations of intramuscular amino acids during hyperinsulinaemia.

1. The role of blood flow as a determinant of skeletal muscle glucose uptake is at present controversial and results of previous studies are confounded by possible direct effects of vasoactive agents on glucose uptake. Since increase in muscle blood flow can be due to increased flow velocity or recruitment of new capillaries, or both, it would be ideal to determine whether the vasoactive agent affects flow distribution or only increases the mean flow. 2. In the present study blood flow, flow distribution and glucose uptake were measured simultaneously in both legs of 10 healthy men (aged 29 +/- 1 years, body mass index 24 +/- 1 kg m-2) using positron emission tomography (PET) combined with [15O]H2O and [18F]fluoro-2-deoxy-D-glucose (FDG). The role of blood flow in muscle glucose uptake was studied by increasing blood flow in one leg with sodium nitroprusside (SNP) and measuring glucose uptake simultaneously in both legs during euglycaemic hyperinsulinaemia (insulin infusion 6 pmol kg-1 min-1). 3. SNP infusion increased skeletal muscle blood flow by 86 % (P < 0.01), but skeletal muscle flow distribution and insulin-stimulated glucose uptake (61.4 +/- 7. 5 vs. 67.0 +/- 7.5 micromol kg-1 min-1, control vs. SNP infused leg, not significant), as well as flow distribution between different tissues of the femoral region, remained unchanged. The effect of SNP infusion on blood flow and distribution were unchanged during infusion of physiological levels of insulin (duration, 150 min). 4. Despite a significant increase in mean blood flow induced by an intra-arterial infusion of SNP, glucose uptake and flow distribution remained unchanged in resting muscles of healthy subjects. These findings suggest that SNP, an endothelium-independent vasodilator, increases non-nutritive, but not nutritive flow or capillary recruitment.

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.

We examined whether hyperinsulinemia is associated with changes in the amount of L-carnitine and acetyl-L-carnitine in the muscle and whether the source of acetyl-coenzyme A (CoA) (glucose or free fatty acids [FFAs]) influences its further metabolism to acetyl-L-carnitine or through tricarboxylic acid in the skeletal muscle of man in vivo. Twelve healthy men (aged 45 +/- 2 years; body mass index, 25.2 +/- 1.0 kg/m2) were studied using a 4-hour euglycemic-hyperinsulinemic clamp (1.5 mU/kg/min) and indirect calorimetry. Although the mean muscle free L-carnitine and acetyl-L-carnitine concentrations remained unchanged during hyperinsulinemia in the group as a whole, the individual changes in muscle free L-carnitine and acetyl-L-carnitine concentrations were inversely related (r = -.72, P < .02). The basal level of acetyl-L-carnitine was inversely related to the rate of lipid oxidation (r = -.70, P < .02). In a stepwise linear regression analysis, 77% of the variation in the change of acetyl-L-carnitine concentrations was explained by the basal muscle glycogen level (inversely) and nonoxidative glucose disposal rate (directly) during hyperinsulinemia (P < .001); by adding the final FFA concentration (inverse correlation) to the model, 88% of the variation was explained (P < .001). In conclusion, (1) hyperinsulinemia does not enhance skeletal muscle free L-carnitine or acetyl-L-carnitine concentrations in-man, and (2) the acetyl group of acetyl-L-carnitine in human skeletal muscle in vivo is probably mostly derived from glucose and not through beta-oxidation from fatty acids.

Essential hypertension is characterized by skeletal muscle insulin resistance but it is unknown whether insulin resistance also affects heart glucose uptake. We quantitated whole body (euglycemic insulin clamp) and heart and skeletal muscle (positron emission tomography and 18F-fluoro-2-deoxy-D-glucose) glucose uptake rates in 10 mild essential hypertensive (age 33 +/- 1 yr, body mass index 23.7 +/- 0.8 kg/m2, blood pressure 146 +/- 3/97 +/- 3 mmHg, VO2max 37 +/- 3 ml/kg per min) and 14 normal subjects (29 +/- 2 yr, 22.5 +/- 0.5 kg/m2, 118 +/- 4/69 +/- 3 mmHg, 43 +/- 2 ml/kg per min). Left ventricular mass was similar in the hypertensive (155 +/- 15 g) and the normotensive (164 +/- 13 g) subjects. In the hypertensives, both whole body (28 +/- 3 vs 44 +/- 3 mumol/kg per min, P < 0.01) and femoral (64 +/- 11 vs 94 +/- 8 mumol/kg muscle per min, P < 0.05) glucose uptake rates were decreased compared to the controls. In contrast, heart glucose uptake was 33% increased in the hypertensives (939 +/- 51 vs 707 +/- 46 mumol/kg muscle per min, P < 0.005), and correlated with systolic blood pressure (r = 0.66, P < 0.001) and the minute work index (r = 0.48, P < 0.05). We conclude that insulin-stimulated glucose uptake is decreased in skeletal muscle but increased in proportion to cardiac work in essential hypertension. The increase in heart glucose uptake in mild essential hypertensives with a normal left ventricular mass may reflect increased oxygen consumption and represent an early signal which precedes the development of left ventricular hypertrophy.

Unlabelled: We examined the interrelationship of lipid and glucose metabolism in the basal state and during insulin stimulus in 19 healthy men (27 +/- 2 years, body mass index 23.6 +/- 0.6 kg/m2). In each subject, we performed a 4-h euglycaemic (5.3 +/- 0.1 mmol/l) hyperinsulinaemic (647 +/- 21 pmol/l) insulin clamp with indirect calorimetry in the basal state and during insulin infusion, and muscle biopsies before and at the end of the clamp. In the basal state, serum non-esterified fatty acid levels correlated directly with lipid oxidation (r = 0.56, p < 0.05) and indirectly with glucose oxidation (r = -0.80, p < 0.001). Lipid and glucose oxidation rates were inversely related in the basal state (r = -0.47, p < 0.05) and during insulin infusion (r = -0.65, p < 0.01). Basal lipid oxidation and glycogen synthase total activity correlated inversely (r = -0.54, p < 0.05). Lipid oxidation both in the basal state (r = -0.61, p < 0.01) and during insulin infusion (r = -0.62, p < 0.05) was inversely related to muscle glycogen content after the insulin clamp. Fasting plasma triglyceride concentration correlated directly to fasting insulin (r = 0.55, p < 0.05) and C-peptide (r = 0.50, p < 0.03) concentrations and inversely to non-oxidative glucose disposal rate at the end of clamp (r = -0.54, p < 0.05)., In Conclusion: 1) Serum non-esterified fatty acid concentration enhances lipid and reduces glucose oxidation. 2) Lipid oxidation is inversely related to total glycogen synthase activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Myocardial and skeletal muscle glucose uptake was examined in 9 type 2 diabetic patients and 13 control subjects using PET and the insulin clamp technique. All subjects had clinically stable coronary heart disease. To simulate the clinical situation, diabetic patients were kept slightly hyperglycemic during the clamp study. Consequently, there were no differences in skeletal muscle or total body glucose disposal between the two groups. With PET, myocardial glucose uptake was 12-20-fold greater than that in skeletal muscle in both groups. However, in the diabetic patients, myocardial glucose uptake was 39% lower (p < 0.05) than in the control subjects. These data suggest a defect in myocardial glucose utilization in type 2 diabetes and emphasize the need for standardized metabolic conditions in diabetic patients during 18FDG PET imaging.

To determine the tissue localization of insulin resistance in type 1 diabetic patients, whole body and regional glucose uptake rates were determined under euglycemic hyperinsulinemic conditions. Leg, arm, and heart glucose uptake rates were measured using positron emission tomography-derived 2-deoxy-2-[18F]-fluoro-D-glucose kinetics and the three-compartment model described by Sokoloff et al. (L. Sokoloff, M. Reivich, C. Kennedy, M.C. DesRosiers, C.S. Patlak, K.D. Pettigrew, O. Sakurada, and M. Shinohara. J. Neurochem. 28: 897-916, 1977) in eight type 1 diabetic patients and eight matched normal subjects. Whole body glucose uptake was quantitated by the euglycemic insulin clamp technique. Whole body glucose uptake was approximately 31% lower in the diabetic patients (P < 0.01) than in the normal subjects, thus confirming the presence of whole body insulin resistance. The rate of glucose uptake was approximately 45% lower in leg muscle when measured in the femoral region (55 +/- 7 vs. 102 +/- 13 mumol.kg muscle-1.min-1, diabetic patients vs. normal subjects, P < 0.05) and approximately 27% lower in the arm muscles (66 +/- 4 vs. 90 +/- 13 mumol.kg muscle-1.min-1, respectively, P < 0.05), whereas no difference was observed in heart glucose uptake [789 +/- 80 vs. 763 +/- 58 mumol.kg muscle-1.min-1 not significant (NS)]. Whole body glucose uptake correlated with glucose uptake in femoral (r = 0.93, P < 0.005) and arm muscles (r = 0.66, P < 0.05) but not with glucose uptake in the heart (r = 0.04, NS). We conclude that insulin resistance in type 1 diabetic patients is localized to skeletal muscle, whereas heart glucose uptake is unaffected.(ABSTRACT TRUNCATED AT 250 WORDS)

Positron emission tomography permits noninvasive measurement of regional glucose uptake in vivo in humans. We employed this technique to determine the effect of FFA on glucose uptake in leg, arm, and heart muscles. Six normal men were studied twice under euglycemic hyperinsulinemic (serum insulin approximately 500 pmol/liter) conditions, once during elevation of serum FFA by infusions of heparin and Intralipid (serum FFA 2.0 +/- 0.4 mmol/liter), and once during infusion of saline (serum FFA 0.1 +/- 0.01 mmol/liter). Regional glucose uptake rates were measured using positron emission tomography-derived 18F-fluoro-2-deoxy-D-glucose kinetics and the three-compartment model described by Sokoloff (Sokoloff, L., M. Reivich, C. Kennedy, M. C. Des Rosiers, C. S. Patlak, K. D. Pettigrew, O. Sakurada, and M. Shinohara. 1977. J. Neurochem. 28: 897-916). Elevation of plasma FFA decreased whole body glucose uptake by 31 +/- 2% (1,960 +/- 130 vs. 2,860 +/- 250 mumol/min, P less than 0.01, FFA vs. saline study). This decrease was due to inhibition of glucose uptake in the heart by 30 +/- 8% (150 +/- 33 vs. 200 +/- 28 mumol/min, P less than 0.02), and in skeletal muscles; both when measured in femoral (1,594 +/- 261 vs. 2,272 +/- 328 mumol/min, 25 +/- 13%) and arm muscles (1,617 +/- 411 to 2,305 +/- 517 mumol/min, P less than 0.02, 31 +/- 6%). Whole body glucose uptake correlated with glucose uptake in femoral (r = 0.75, P less than 0.005), and arm muscles (r = 0.69, P less than 0.05) but not with glucose uptake in the heart (r = 0.04, NS). These data demonstrate that the glucose-FFA cycle operates in vivo in both heart and skeletal muscles in humans.

We have previously demonstrated that interferon administration impairs glucose tolerance and causes insulin resistance in healthy man. Whether this is a direct effect of interferon is not known. The present study was undertaken to examine directly the effect of interferon alpha on insulin binding and action on glucose transport in isolated human adipocytes. Different concentrations of interferon alpha (range 10(-3)-10(5) IU ml-1) and different incubation times (0-5-24 h) with interferon were employed. Acute and 5-h and 24-h exposure of human adipocytes to 10(-2)-10 IU ml-1 of interferon increased the high affinity binding of 125I-insulin (P less than 0.05). In contrast, human interferon alpha had no effect on insulin binding in rat adipocytes. In short-term studies interferon had no effect on 14C-glucose transport clearance. 24-h preincubation of human adipocytes with 10(-2), 10, 10(4) IU ml-1 interferon increased maximally-insulin stimulated 14C-glucose transport clearance (P less than 0.05) and glucose transport responsiveness to insulin was enhanced by 24% (P less than 0.05) in cells exposed to 10(-2) IU ml-1 interferon. After 5 and 24-h preincubations with interferon we observed modest changes in glucose transport sensitivity to moderate concentrations of insulin (50-100 pM) with upregulation in the presence of 10(-2)-10 IU ml-1 interferon and downregulation in the presence of 10(4)-10(5) IUm ml-1 interferon (P less than 0.05). The insulin sensitivity index (ED50) did not change.(ABSTRACT TRUNCATED AT 250 WORDS)

To examine mechanisms of insulin resistance, nine patients (age 33 +/- 4 yr, body mass index 22 +/- 1 kg/m2) with acute bacterial or viral infections and in six matched normal subjects were studied. Endogenous glucose appearance (Ra), glucose disappearance (Rd), and recycling, the percentage of plasma lactate originating from plasma glucose, total glucose oxidation, and whole body and forearm muscle Rd were measured after an overnight fast in the basal state and during physiological hyperinsulinemia (serum insulin approximately 215 pmol/L). Basally Ra, Rd, glucose recycling, and oxidation were similar in both groups. During hyperinsulinemia, insulin stimulated plasma Rd approximately 35% less (17.6 +/- 1.3 vs. 26.8 +/- 3.6 mumol/kg.min, P less than 0.01, patients vs. normal subjects), and inhibited endogenous Ra less in the patients (from 13.3 +/- 0.8 to 5.3 +/- 0.8 mumol/kg.min) than in the normal subjects (from 12.8 +/- 1.0 to 2.1 +/- 1.2 mumol/kg.min, P less than 0.01). The decrease in whole body Rd was largely explained by a approximately 75% reduction in muscle Rd (5.6 +/- 1.5 vs. 20.8 +/- 3.3 mumol/kg muscle.min, P less than 0.01, patients vs. normal subjects). The defect in Rd was confined to nonoxidative (4.8 +/- 1.1 vs. 11.0 +/- 3.0 mumol/kg.min, P less than 0.01, patients vs. normal subjects) but not to oxidative glucose metabolism. The percentage of plasma lactate derived from plasma glucose during hyperinsulinemia averaged 63 +/- 6% in the patients and 79 +/- 5% in the normal subjects, indicating that glycogenolysis did not excessively dilute glycolytic carbons in the patients. We conclude that during natural infections in humans, abnormal glucose metabolism is confined to the insulin-stimulated state and involves a marked defect in muscle glucose uptake and glycogen synthesis, as well as a less marked hepatic defect.

The content of GLUT4 glucose transporter mRNA and protein were measured in samples of the vastus lateralis muscle of normal volunteers subjected to a 4-h hyperinsulinaemic, euglycaemic clamp. Plasma glucose concentration was clamped at 5.3 +/- 0.1 mmol/l, and serum insulin concentration was maintained at 740 +/- 5 pmol/l. Whole body glucose uptake averaged 38.3 +/- 2.2 mumol.kg-1.min-1, 62% of this being due to disposal via non-oxidative pathways. A significant correlation existed between basal levels of GLUT4 protein and the rate of whole body glucose disposal (r = 0.77, p less than 0.02) and non-oxidative glucose disposal (r = 0.80, p less than 0.02). There was no correlation between GLUT4 protein content and oxidative glucose disposal (r = 0.08, NS). These observations are consistent with an important role for skeletal muscle GLUT4 protein in whole body glucose disposal.

We tested whether FFAs influence glucose uptake by human peripheral tissues in vivo. Whole body glucose uptake, FFA turnover, energy expenditure and substrate oxidation rates, forearm glucose and FFA uptake, and nonoxidative glycolysis (net release of alanine and lactate) were measured in 14 normal male subjects in the basal state (0-240 min; serum insulin, approximately 5 microU/mL) and during euglycemic hyperinsulinemia (240-360 min; approximately 75 microU/mL) on 2 separate occasions, once during elevation of plasma FFA by infusions of Intralipid and heparin (plasma FFA, 4.6 +/- 0.1 vs. 4.2 +/- 0.4 mmol/L; 180-240 vs. 300-360 min) and once during infusion of saline (plasma FFA, 0.50 +/- 0.07 vs. 0.02 +/- 0.07 mmol/L, respectively). In the basal state, whole body glucose disposal remained unchanged, but the fate of glucose was significantly altered toward diminished oxidation (7.3 +/- 0.8 vs. 5.6 +/- 0.5 mumol/kg.min; P less than 0.05, saline vs. Intralipid) and increased nonoxidative glycolysis (P less than 0.05). Elevation of plasma FFA significantly increased forearm glucose uptake (1.0 +/- 0.6 vs. 2.4 +/- 0.7 mumol/kg.min; P less than 0.01) and nonoxidative glycolysis (net release of alanine and lactate, 0.4 +/- 0.5 vs. 1.2 +/- 0.4 mumol glucose equivalents/kg.min; P less than 0.05). During hyperinsulinemia, FFA decreased whole body glucose disposal (38 +/- 2 vs. 30 +/- 3 mumol/kg.min; P less than 0.001) due to a decrease in glucose oxidation (13 +/- 1 vs. 7 +/- 1 mumol/kg.min; P less than 0.01, saline vs. Intralipid), and forearm glucose uptake (31 +/- 4 vs. 24 +/- 6 mumol/kg.min; P less than 0.01, saline vs. Intralipid). Under these conditions, 7 +/- 2% and 3 +/- 1% (P less than 0.05) of forearm glucose uptake could be accounted for by nonoxidative glycolysis in the Intralipid and saline studies, respectively. In summary, 1) elevation of plasma FFA concentrations suppresses the rate of carbohydrate oxidation to a rate that, both basally and during hyperinsulinemia, is similar to that reported for insulin-independent glucose oxidation in the brain; 2) basally, forearm glucose uptake is increased by FFA; and 3) during hyperinsulinemia, FFA inhibit glucose uptake by forearm tissues. We conclude that the interaction between glucose and FFA fuels in human forearm tissues is dependent upon the ambient insulin concentration; the increase in basal glucose uptake would be compatible with the increase need of glucose for FFA reesterification; the decrease in insulin-stimulated glucose uptake supports operation of the glucose-FFA cycle in human forearm tissues.

Patients with type 1 diabetes are characterized by an average 40% reduction in the insulin sensitivity. In newly diagnosed patients, insulin resistance is due to insulin deficiency and its metabolic consequences. After the beginning of insulin therapy, insulin sensitivity transiently improves, but deteriorates again after 6-9 months of insulin therapy. Insulin resistance is mainly due to a reduction in glucose uptake by muscle tissue. There are similar relative reductions in both oxidative and nonoxidative glucose disposal. When glucose disposal is determined under similar plasma glucose and insulin concentrations, glucose oxidation, the activity of pyruvate dehydrogenase and glycogen synthase are all reduced. If glucose disposal rate in diabetic patients is normalized by glucose mass action, both oxidative and nonoxidative glucose disposal and glycogen synthase activity become normal. As the normalization of glucose disposal occurs in the face of unchanged muscle glucose-6-phosphate concentrations, this suggest that reduced glucose disposal is secondary to reduced glucose transport in type 1 diabetes.

Under non-steady-state conditions, glucose turnover rates determined with tritiated glucose tracers are often underestimated. To examine whether isotope discrimination or a tracer contaminant can contribute to this, we compared the turnover rates of unlabelled and tritiated glucose under isotopic steady-state conditions. The turnover rates were measured in 20 healthy subjects at two insulin concentrations (79 +/- 3 mU.l-1 and 704 +/- 62 mU.l-1). Euglycaemia was maintained by infusing unlabelled glucose mixed with (3(3)H)- or (6(3)H)-glucose. In both studies, the isotopically determined glucose disposal rate was virtually identical to the exogenous glucose infusion rate (low insulin 7.66 +/- 0.48 vs 7.58 +/- 0.44 mg.kg-1.min-1, high insulin 13.36 +/- 0.74 vs 13.55 +/- 0.98 mg.kg-1.min-1). The individual values were correlated in both the low (r = 0.85, p less than 0.001) and high dose insulin (r = 0.81, p less than 0.001) studies. Tritiated glucose specific activities were also compared in arterialized and deep venous blood across forearm tissues during the high-dose insulin infusion. Glucose specific activities were similar in arterialized and deep venous blood when analysed with HPLC and conventional methods. In summary: (1) Under isotopic steady-state conditions the turnover rates of unlabelled and labelled glucoses are similar. (2) Unlabelled and labelled glucose are handled identically across forearm tissues. (3) We found no tracer impurity in our tritiated glucose preparations. We conclude that (3(3)H)- and (6(3)H)-glucose tracers can be used to reliably measure glucose turnover rates in man.

We searched for metabolic crossover points in muscle glucose metabolite profiles during maintenance of matched glucose fluxes across forearm muscle in insulin-resistant type I (insulin-dependent) diabetic patients and nondiabetic subjects. To classify subjects as insulin sensitive or insulin resistant, whole-body and forearm glucose disposal, oxidative and nonoxidative glucose disposal (indirect calorimetry), and glycogen synthesis (muscle glycogen content in needle biopsies) were measured under euglycemic conditions at two insulin concentrations. Whole-body and forearm muscle glucose disposal were significantly reduced in diabetic patients compared with control subjects. The reduction in total glucose disposal was due to similar relative reductions in oxidative and nonoxidative glucose disposal, pointing toward rate limitation early in glucose metabolism. The defect in nonoxidative glucose disposal was at least partly due to a defect in muscle glycogen synthesis, because muscle glycogen content failed to increase in response to an increase in the plasma insulin concentration in the diabetic patients. The most-insulin-resistant type 1 diabetic patients were restudied under conditions where, by glucose mass action, whole-body glucose disposal was forced to be similar to that in the control subjects. Matching glucose fluxes in the two groups resulted in similar rates of forearm and whole-body oxidative and nonoxidative glucose disposal and muscle glycogen synthesis, but it did not result in accumulation of free intracellular glucose, glucose-6-phosphate, glucose-1-phosphate, fructose-6-phosphate, or lactate in muscle. These data imply that the rate-limiting defect for glucose disposal in skeletal muscle of type I diabetic patients is at the level of glucose transport.

To evaluate the mechanism of insulin resistance in type 1 diabetes mellitus, we measured insulin sensitivity in vivo and insulin action in adipocytes in vitro. The study groups consisted of 18 insulin-treated type 1 diabetic patients and 14 matched normal subjects. In each subject, insulin-mediated glucose disposal in vivo was measured by the euglycemic clamp technique. An open surgical biopsy was performed in 9 diabetic and 7 healthy subjects to obtain abdominal sc adipose tissue for the measurement of [125I]insulin binding, D-[14C]-glucose transport, oxidation, and lipogenesis. During the euglycemic clamp studies, similar steady state plasma glucose (4.8 mmol/liter) and insulin (80 mU/liter = 700 pM) levels were maintained in both groups. The rate of glucose metabolism (M) was 43% lower in the diabetic patients (4.75 +/- 0.34 mg/kg X min) than in the normal subjects (8.27 +/- 0.43 mg/kg X min; P less than 0.001). [125I]Insulin binding to adipocytes was reduced in the diabetic patients (26% reduction in tracer binding; P less than 0.05) due to a reduction in receptor number. Insulin binding was not related to the M value at any insulin concentration. Basal and insulin-stimulated rates of glucose transport were not significantly different in diabetic and normal subjects. The basal glucose oxidation rate was reduced by 50% (P less than 0.02), and maximal glucose oxidation was reduced by 49% (P less than 0.03) in the diabetic patients (237 +/- 30 vs. 359 +/- 49 pmol/30,000 cells X 90 min, basal vs. maximal glucose oxidation, respectively) compared to those in normal subjects (513 +/- 101 vs. 700 +/- 133 pmol/30,000 cells X 90 min). The percentage responses of glucose oxidation and glucose transport to insulin were similar in both groups. Glucose oxidation rates at basal (r = 0.68; P less than 0.01), half-maximally (ED50; r = 0.70; P less than 0.01), and maximally (r = 0.64; P less than 0.05) effective insulin concentrations were positively related to the M value. Basal and insulin-stimulated rates of lipogenesis were comparable between the diabetic and normal subjects. In conclusion, insulin-mediated glucose disposal in vivo is reduced in conventionally treated type 1 diabetic patients. In vitro, adipocytes from diabetes bound slightly less insulin at tracer insulin concentrations, but the magnitude of this reduction was not related to impairment of glucose metabolism in vivo. Of the pathways of glucose metabolism studied, the rate of glucose oxidation was most affected. A significant relationship was found between the M value and the rate of in vitro glucose oxidation.(ABSTRACT TRUNCATED AT 400 WORDS)

We studied the effect of physical training on in vivo tissue sensitivity to insulin and insulin binding to monocytes in six previously untrained healthy adults. Physical training (one hour of cycle-ergometer exercise four times per week for six weeks) failed to alter body weight but resulted in a 20 per cent increase (P less than 0.02) in maximal aerobic power (VO2 max) and a 30 per cent increase (P less than 0.01) in insulin-mediated glucose uptake (determined by the insulin clamp technique). The increase in insulin sensitivity correlated directly with the rise in VO2 max (P less than 0.05). Binding of [125I]insulin to monocytes also rose by 35 per cent after physical training (P less than 0.02), primarily because of an increase in the concentration of insulin receptors. Our data indicate that physical training increases tissue sensitivity to insulin in proportion to the improvement in physical fitness. Physical training may have a role in the management of insulin-resistant states, such as obesity and maturity-onset diabetes, that is independent of its effects on body weight.

Acute exercise increases insulin binding to its receptors on blood cells. Whether the enhanced insulin binding explains the exercise-induced increase in glucose uptake is unclear, since insulin binding and glucose uptake have not been measured simultaneously in a target tissue of insulin. In this study, we determined insulin binding and the rate of glucose transport in adipocytes obtained by needle biopsy from 10 healthy men before and after 3 h of cycle-ergometric exercise. During the exercise, plasma glucose (P less than 0.01) and insulin (P less than 0.001) fell and serum free fatty acid level rose 4.3-fold (P less than 0.001). 125I-insulin binding to adipocytes remained unchanged during exercise. The rate of basal glucose transport clearance fell from 28.1 +/- 5.7 fl.cell-1.s-1 to 22.9 +/- 5.6 fl.cell-1.s-1 (P less than 0.005), and the insulin-stimulated increase in glucose transport rate rose from 196 +/- 26 to 279 +/- 33% (P less than 0.025) during the exercise. Thus, in the adipocytes during exercise, the basal glucose transport rate and the responsiveness of glucose transport to insulin changed in the absence of alterations in insulin binding. These data indicate that the exercise-induced changes in insulin binding show tissue specificity and do not always parallel alterations in glucose transport.

To examine the effect of various carbohydrates on the metabolic and hormonal response to exercise, 75 g glucose, fructose, or placebo were given to nine well-trained males (VO2 max 60 +/- 1 ml . kg-1 . min-1) 45 min before cycle ergometer exercise performed at 75% VO2 max for 30 min. After glucose ingestion, the rise in plasma glucose was 3-fold (P less than 0.005) in plasma insulin 2.5-fold (P less than 0.01) greater than after fructose. During exercise, after glucose administration plasma glucose fell from 5.3 +/- 0.3 to 2.5 +/- 0.2 mmol/l (P less than 0.001) and after fructose from 4.5 +/- 0.1 to 3.9 +/- 0.3 mmol/l (P less than 0.05). The fall in plasma glucose was closely related to the preexercise levels of plasma insulin (r = 0.82, P less than 0.001) and glucose (r = 0.81, P less than 0.001). Both glucose and fructose ingestion decreased the FFA levels by 40-50% (P less than 0.005) and during exercise they remained 30-40% lower after carbohydrate than placebo administration (P less than 0.02). This study suggests that glucose ingestion prior to exercise results in hypoglycemia during vigorous exercise, this rapid fall in plasma glucose is mediated, at least in part, by hyperinsulinemia, and fructose ingestion is associated with a modest rise in plasma insulin and does not result in hypoglycemia during exercise.

We compared the effects of two ethanol doses on glucose kinetics and assessed the role of acetate as a mediator of ethanol-induced insulin resistance. Ten normal males were studied on four occasions, during which either a low (blood ethanol 4 +/- 1 mmol/l) or moderate (14 +/- 1 mmol/l) ethanol, acetate, or saline dose was administered. Both ethanol doses similarly inhibited (0.4-0.5 mg.kg-1.min-1, P less than 0.01) basal glucose production. The decrease in Ra was matched by a comparable decrease in glucose utilization (Rd), resulting in maintenance of normoglycemia. During hyperinsulinemia (approximately 70 microU/ml), glucose disposal was lower (1.2-1.7 mg.kg-1.min-1, P less than 0.01) in the moderate than the low-dose ethanol or saline studies. During acetate infusion, the blood acetate level was comparable with those in the ethanol studies. Acetate had no effect on glucose kinetics. In conclusion, 1) in overnight fasted subjects, ethanol does not cause hypoglycemia because its inhibitory effect on Ra is counterbalanced by equal inhibition of Rd;2) basal Ra and Rd are maximally inhibited already by small ethanol doses, whereas inhibition of insulin-stimulated glucose disposal requires a moderate ethanol dose; and 3) acetate is not the mediator of ethanol-induced insulin resistance.

The effect of guar gum on glucose and lipid metabolism and on body insulin sensitivity was examined in nine type 1 diabetic patients treated with continuous subcutaneous insulin infusion. The study was done in a randomized, double-blind, crossover fashion with either guar gum or a placebo added to the usual diet four times per day for 4 wk each. Blood glucose levels after breakfast and lunch and daily insulin requirements were significantly lower during the guar-gum than the placebo diet. After a 4-wk guar-gum supplementation, blood glucose response to a test meal was significantly reduced by guar gum compared with the placebo. Hemoglobin A1 (HbA1) and insulin sensitivity remained unchanged. Serum total cholesterol fell by 21% (p less than 0.025). Thus, guar gum can reduce postprandial blood glucose, insulin requirements, and serum total cholesterol levels in type 1 diabetic patients.

Acute infections provoke insulin resistance. These experiments were designed to study the severity, duration, and mechanisms of insulin resistance caused by acute infections. First, we studied eight patients [mean age, 29 +/- 11 (+/- SD) yr; body mass index, 23 +/- 2 kg/m2] with acute viral or bacterial infections during the acute stage of their infection and 1-3 months after recovery. The rate of glucose infusion required to maintain normoglycemia during hyperinsulinemia (approximately 500 pmol/L) was used as a measure of insulin action. During infection, the glucose requirements in the patients [21 +/- 2 (+/- SE) mumol/kg.min] were 52% less than those in weight- and age-matched normal subjects (44 +/- 2 mumol/kg.min; P less than 0.001). Compared to data from a large group of normal subjects, the resistance to insulin during infection corresponded to that predicted for a weight-matched 84-yr-old normal person or an age-matched obese person with a body mass index of 37 kg/m2. One to 3 months after recovery, the patients' glucose requirements were still significantly lower (37 +/- 3 mumol/kg.min; P less than 0.02) than those in matched normal subjects. To assess the mechanism of insulin resistance, seven additional patients were studied during the acute stage of infection using a low dose insulin infusion (plasma insulin, 215 pmol/L) combined with a [3-3H]glucose infusion and indirect calorimetry. Again, the glucose requirements were 59% lower in the patients (14 +/- 2 mumol/kg.min) than in matched normal subjects (34 +/- 2 mumol/kg.min; P less than 0.001). This decrease was due to a defect in glucose utilization (18 +/- 2 vs. 37 +/- 1 mumol/kg.min; P less than 0.001, patients vs. normal subjects) rather than impaired suppression of glucose production (4 +/- 1 vs. 3 +/- 1 mumol/kg.min, respectively). Total carbohydrate oxidation rates were similar in both groups (16 +/- 2 vs. 14 +/- 1 mumol/kg.min, respectively), whereas the apparent glucose storage was neglible in the patients (2 +/- 1 mumol/kg.min) compared to that in normal subjects (22 +/- 2 mumol/kg.min; P less than 0.001). We conclude that acute infections induce severe and long-lasting insulin resistance, which is localized to glucose-utilizing pathways. The rate of carbohydrate oxidation is normal during infections, whereas the rate of nonoxidative glucose disposal, as determined by indirect calorimetry, is nearly zero. The apparent blockade in glucose storage could result from diminished glycogen synthesis, accelerated glycogenolysis, or both.

We examined the influence of various carbohydrates of fuel homeostasis and glycogen utilization during prolonged exercise. Seventy-five grams of glucose, fructose, or placebo were given orally to eight healthy males 45 min before ergometer exercise performed for 2 h at 55% of maximal aerobic power (VO2max). After glucose ingestion, the rises in plasma glucose (P less than 0.01) and insulin (P less than 0.001) were 2.4- and 5.8-fold greater than when fructose was consumed. After 30 min of exercise following glucose ingestion, the plasma glucose concentration had declined to a nadir of 3.9 +/- 0.3 mmol/l, and plasma insulin had returned to basal levels. The fall in plasma glucose was closely related to the preexercise glucose (r = 0.98, P less than 0.001) and insulin (r = 0.66, P less than 0.05) levels. The rate of endogenous glucose production and utilization rose similarly by 2.8-fold during exercise in fructose group and were 10-15% higher than in placebo group (P less than 0.05). Serum free fatty acid levels were 1.5- to 2-fold higher (P less than 0.01) after placebo than carbohydrate ingestion. Muscle glycogen concentration in the quadriceps femoris fell in all three groups by 60-65% (P less than 0.001) during exercise. These data indicate that fructose ingestion, though causing smaller perturbations in plasma glucose, insulin, and gastrointestinal polypeptide (GIP) levels than glucose ingestion, was no more effective than glucose or placebo in sparing glycogen during a long-term exercise.

The rate of hepatic glucose production (Ra) and peripheral utilization (Rd) was determined in 8 insulin-dependent diabetic subjects in basal state and during 40 min cycle ergometric exercise. The patients were treated with continuous sc infusion of either semisynthetic human or porcine (Actrapid) insulin. Basal rate of glucose production was comparable during human (2.29 +/- 0.19 mg/kg/min) and porcine (2.18 +/- 0.12 mg/kg/min) insulin therapy. In response to exercise, Ra rose 30 to 40% (P less than 0.05), to 2.85 +/- 0.35 vs 3.18 +/- 0.42 mg/kg/min, similarly during both studies. The peak rise in Rd (to 3.20 +/- 0.32 during human vs 3.78 +/- 0.44 mg/kg/min during porcine insulin) was comparable in both groups and not significantly different from the rise in Ra. Consequently, blood glucose levels remained unchanged. During the exercise tests, the metabolic conditions were stable and comparable in both studies, as indicated by similar levels of blood glucose, plasma free insulin HbA1, serum lipids and insulin binding to erythrocytes. In conclusion, semisynthetic human insulin is equally effective as porcine insulin in regulating glucose kinetics in the basal state and during exercise.