Resistance to exercise-induced increase in glucose uptake during hyperinsulinemia in insulin-resistant skeletal muscle of patients with type 1 diabetes.

Insulin and exercise have been shown to activate glucose transport at least in part via different signaling pathways. However, it is unknown whether insulin resistance is associated with a defect in the ability of an acute bout of exercise to enhance muscle glucose uptake in vivo. We compared the abilities of insulin and isometric exercise to stimulate muscle blood flow and glucose uptake in 12 men with type 1 diabetes (age 24 +/- 1 years, BMI 23.0 +/- 0.4 kg/m(2)) and in 11 age- and weight-matched nondiabetic men (age 25 +/- 1 years, BMI 22.3 +/- 0.6 kg/m(2)) during euglycemic hyperinsulinemia (1 mU. kg(-1). min(-1) insulin infusion for 150 min). One-legged exercise was performed at an intensity of 10% of maximal isometric force for 105 min (range 45-150). Rates of muscle blood flow, oxygen consumption, and glucose uptake were quantitated simultaneously in both legs using [(15)O]water, [(15)O]oxygen, [(18)F]-2-fluoro-2-deoxy-D-glucose, and positron emission tomography. Resting rates of oxygen consumption were similar during hyperinsulinemia between the groups (2.4 +/- 0.3 vs. 2.0 +/- 0.5 ml. kg(-1) muscle. min(-1); normal subjects versus patients with type 1 diabetes, NS), and exercise increased oxygen consumption similarly in both groups (25.3 +/- 4.3 vs. 20.1 +/- 3.0 ml. kg(-1) muscle. min(-1), respectively, NS). Rates of insulin-stimulated muscle blood flow and the increments in muscle blood flow induced by exercise were also similar in normal subjects (129 +/- 14 ml. kg(-1). min(-1)) and in patients with type 1 diabetes (115 +/- 12 ml. kg(-1). min(-1)). The patients with type 1 diabetes exhibited resistance to both insulin stimulation of glucose uptake (34 +/- 6 vs. 76 +/- 9 micromol. kg(-1) muscle. min(-1), P < 0.001) and also to the exercise-induced increment in glucose uptake (82 +/- 15 vs. 162 +/- 29 micromol. kg(-1) muscle. min(-1), P < 0.05). We conclude that the ability of exercise to increase insulin-stimulated glucose uptake in vivo is blunted in patients with insulin-resistant type 1 diabetes compared with normal subjects. This could be caused by either separate or common defects in exercise- and insulin-stimulated pathways.

Enhanced oxygen extraction and reduced flow heterogeneity in exercising muscle in endurance-trained men.

The aim of this study was to investigate the effects of endurance training on skeletal muscle hemodynamics and oxygen consumption. Seven healthy endurance-trained and seven untrained subjects were studied. Oxygen uptake, blood flow, and blood volume were measured in the quadriceps femoris muscle group by use of positron emission tomography and [15O]O2, [15O]H2O, and [15O]CO during rest and one-legged submaximal intermittent isometric exercise. The oxygen extraction fraction was higher (0.49 +/- 0.14 vs. 0.29 +/- 0.12; P = 0.017) and blood transit time longer (0.6 +/- 0.1 vs. 0.4 +/- 0.1 min; P = 0.04) in the exercising muscle of the trained compared with the untrained subjects. The flow heterogeneity by means of relative dispersion was lower for the exercising muscle in the trained (50 +/- 9%) compared with the untrained subjects (65 +/- 13%, P = 0.025). In conclusion, oxygen extraction is higher, blood transit time longer, and perfusion more homogeneous in endurance-trained subjects compared with untrained subjects at the same workload. These changes may be associated with improved exercise efficiency in the endurance-trained subjects.

Myocardial fatty acid oxidation in patients with impaired glucose tolerance.

AIMS/HYPOTHESIS: Fatty acids are an important source of energy in the myocardium. Abnormal myocardial fatty acid metabolism could contribute to the deterioration of cardiac function frequently observed in patients with Type II (non-insulin-dependent) diabetes mellitus. In our previous study, myocardial total uptake of non-esterified fatty acid (NEFA) was measured in patients with impaired glucose tolerance and found to be normal. This study aimed to investigate the subsequent metabolic steps and beta-oxidation of NEFA. METHODS: A total of 6 men with impaired fasting glucose (age 50 +/- 2 years, BMI 29 +/- 1 kg/m2, means +/- SEM) and 6 healthy men (50 +/- 1 years, 25 +/- 1 kg/ m2) were studied in the fasting state. Myocardial blood flow was measured with [15O]H2O and positron emission tomography and myocardial NEFA metabolism with [11C]palmitic acid. RESULTS: Myocardial blood flow was normal and not different between the impaired glucose tolerance and the control group (78 +/- 6 vs 73 +/- 13 ml/100 g/ min, NS). The [11C]palmitic acid uptake indices were similar between the groups (10.4 +/- 0.5 vs 11.2 +/- 0.8 ml/100 g/min, respectively, NS). The clearance of [11C]-palmitate from the myocardium, an index of NEFA beta-oxidation, was similar between the groups (half-times of activity 17.6 +/- 1.6 vs 19.5 +/- 2.3 min, respectively, NS) CONCLUSION/INTERPRETATION: The results indicate that myocardial NEFA uptake and beta-oxidation are not altered in patients with IGT. Thus, it is not likely that altered NEFA metabolism contributes to the deterioration of the cardiac function in patients with IGT or Type II diabetes.

Muscle blood flow and flow heterogeneity during exercise studied with positron emission tomography in humans.

Blood flow is the main regulator of skeletal muscle's oxygen supply, and several studies have shown heterogeneous blood flow among and within muscles. However, it remains unclear whether exercise changes the heterogeneity of flow in exercising human skeletal muscle. Muscle blood flow and spatial flow heterogeneity were measured simultaneously in exercising and in the contralateral resting quadriceps femoris (QF) muscle in eight healthy men using H2(15)O and positron emission tomography. The relative dispersion (standard deviation/mean) of blood flow was calculated as an index of spatial flow heterogeneity. Average muscle blood flow in QF was 29 (10) ml x (kg muscle)(-1) x min(-1) at rest and 146 (54) ml x (kg muscle)(-1) x min(-1) during exercise (P = 0.008 for the difference). Blood flow was significantly (P < 0.001) higher in the vastus medialis and the vastus intermedius than in the vastus lateralis and the rectus femoris, both in the resting and the exercising legs. Flow was more homogeneous in the exercising vastus medialis and more heterogeneous (P < 0.001) in the exercising vastus lateralis (P = 0.01) than in the resting contralateral muscle. Flow was more homogeneous (P < 0.001) in those exercising muscles in which flow was highest (vastus intermedius and vastus medialis) as compared to muscles with the lowest flow (vastus lateralis and the rectus femoris). These data demonstrate that muscle blood flow varies among different muscles in humans both at rest and during exercise. Muscle perfusion is spatially heterogeneous at rest and during exercise, but responses to exercise are different depending on the muscle.

Myocardial oxygen consumption is unchanged but efficiency is reduced in patients with essential hypertension and left ventricular hypertrophy.

BACKGROUND: Patients with hypertension and left ventricular hypertrophy (LVH) are prone to develop heart failure. We tested the hypothesis that compensatory LVH is associated with normalization of myocardial oxygen consumption and that this occurs at the expense of a decrease in the ratio between cardiac work and oxygen consumption (efficiency). METHODS AND RESULTS: Nine hypertensive men with LVH (LVH+) (age 42+/-2 years), left ventricular mass index (LVMI) 161+/-8 g/m(2), blood pressure (BP) 145+/-16/88+/-10 mm Hg (mean+/-SD); 8 hypertensive men without LVH (LVH-) (age 39+/-5 years, LVMI 107+/-15 g/m(2), BP 140+/-15/90+/-11 mm Hg); and 10 normotensive men (CONT) were studied. Myocardial blood flow, oxygen consumption, and glucose uptake were measured during euglycemic hyperinsulinemia using PET techniques. LV dimensions, volumes, and workload were determined by echocardiography, and efficiency was calculated. Myocardial workload (2.5+/-0.8 versus 3.0+/-0.6 versus 2. 3+/-0.5 mm Hg. mL. min(-1). g(-1) for CONT versus LVH- versus LVH+; P<0.05, LVH- versus LVH+), myocardial blood flow (0.84+/-0.16 versus 1.06+/-0.22 versus 0.81+/-0.09 mL. g(-1). min, respectively; P<0.05, LVH- versus other groups) and oxygen consumption (0.09+/-0.02 versus 0.14+/-0.03 versus 0.11+/-0.01 ml. g(-1). min(-1), respectively; P<0. 05, LVH- versus other groups) were increased in the LVH- group. Myocardial efficiency was reduced in the LVH+ group (18.1+/-4.1% versus 15.1+/-2.3% versus 13.5+/-1.9%, respectively; P<0.05, LVH+ versus CONT). CONCLUSIONS: Myocardial oxygen consumption per unit weight is increased in hypertensive patients without LVH but is normal in those with LVH. The normalization of oxygen consumption via hypertrophy occurs at the expense of efficiency, which may predispose hypertensive patients with LVH to heart failure.

Myocardial blood flow, oxygen consumption, and fatty acid uptake in endurance athletes during insulin stimulation.

We have previously demonstrated reduced myocardial glucose uptake rates in hearts of endurance athletes, which could be due to increased use of alternative fuels or reduced energy demands. In the present study myocardial blood flow, oxygen consumption, and free fatty acid uptake were measured with [(15)O]H(2)O, [(15)O]O(2), [(18)F]FTHA, and positron emission tomography (PET) in 9 endurance athletes and 11 sedentary men during euglycemic hyperinsulinemia. Compared with sedentary men, athletes had 33% lower myocardial blood flow, 27% lower oxygen consumption, and 20% lower estimated myocardial work per gram of tissue. Myocardial fatty acid uptake rates were not significantly different in endurance athletes (0.83 +/- 0.29) and sedentary men (1.0 +/- 0.31 micromol. 100 g(-1). min(-1), P = 0.232). In conclusion, myocardial blood flow and oxygen consumption per unit mass of myocardium are reduced at rest in endurance athletes. This can be explained by reduced energy requirements per gram of tissue due to anatomic and physiological changes of the athlete's heart.

Impaired free fatty acid uptake in skeletal muscle but not in myocardium in patients with impaired glucose tolerance: studies with PET and 14(R,S)-[18F]fluoro-6-thia-heptadecanoic acid.

Free fatty acids (FFAs) are an important substrate for myocardial and skeletal muscle metabolism, and increased availability and oxidation of FFA are suggested to be associated with insulin resistance. This study was undertaken to assess whether myocardial or muscle uptake of FFA is altered in patients with impaired glucose tolerance (IGT). Eight healthy men (control group; age 48+/-1 years, BMI 25+/-1 kg/m2, mean +/- SE) and eight men with IGT (glucose-intolerant group; age 49+/-1 years, BMI 29+/-1 kg/m2) were studied in the fasting state. Myocardial oxygen consumption and blood flow and myocardial and femoral muscle FFA uptake rates were measured with positron emission tomography (PET) and [15O]O2, [15O]H2O, [15O]CO, and 14(R, S)-[18F]fluoro-6-thia-heptadecanoic acid ([18F]FTHA), a fatty acid tracer trapped into the cell after undergoing initial steps of beta-oxidation. Serum glucose and insulin concentrations were higher in the glucose-intolerant group during the PET study, but FFA concentrations were comparable between the groups. No differences between the groups were observed in the myocardial blood flow, oxygen consumption, fractional FTHA uptake rates, or FFA uptake indices (5.6+/-0.4 vs. 5.2+/-0.4 pmol x 100 g(-1) x min(-1), glucose-intolerant versus control, NS). In the femoral muscle, fractional FTHA uptake (0.0062+/-0.0003 vs. 0.0072+/-0.0003 min(-1), P = 0.044) and FFA uptake indices (0.30+/-0.02 vs. 0.43+/-0.04 min(-1), P = 0.020) were significantly lower in the glucose-intolerant group than in the control group. In conclusion, when studied at the fasting state and normal serum FFA concentrations, subjects with IGT have similar myocardial but lowered femoral muscle FFA uptake. This finding argues against the hypothesis that an increased oxidation of serum FFA, via the competition of glucose and FFA as fuel sources, is the primary cause for impaired peripheral glucose utilization and insulin resistance commonly observed in IGT.

Insulin action on heart and skeletal muscle glucose uptake in weight lifters and endurance athletes.

There are no studies comparing myocardial metabolism between endurance- and resistance-trained athletes. We used 2-deoxy-2-[18F]fluoro-D-glucose and positron emission tomography combined with the euglycemic hyperinsulinemic clamp technique to compare the ability of insulin to stimulate myocardial, skeletal muscle, and whole body glucose uptake between weight lifters (n = 8), endurance athletes (n = 8), and sedentary men (n = 9). Maximal aerobic power (ml. kg- 1. min- 1) was higher in the endurance athletes (71 +/- 2, P < 0.001) than the weight lifters (42 +/- 2) and the sedentary men (42 +/- 2). Skeletal muscle glucose uptake (micromol. kg muscle- 1. min- 1) was enhanced in the endurance athletes (125 +/- 16, P < 0.01) but was similar in weight lifters (59 +/- 12) and sedentary (63 +/- 7) men. The rate of glucose uptake per unit mass of myocardium (micromol. kg- 1. min- 1) was similarly decreased in endurance athletes (544 +/- 50) and weight lifters (651 +/- 45) compared with sedentary men (1,041 +/- 78, P < 0.001 vs. endurance athletes and weight lifters). Both groups of athletes had increased left ventricular mass. Consequently, total left ventricular glucose uptake was comparable in all groups. These data demonstrate that aerobic but not resistance training is associated with enhanced insulin sensitivity in skeletal muscle. Despite this, cardiac changes are remarkably similar in weight lifters and endurance athletes and are characterized by an increase in left ventricular mass and diminished insulin-stimulated glucose uptake per heart mass.

Effects of insulin on blood flow and volume in skeletal muscle of patients with IDDM: studies using [15O]H2O, [15O]CO, and positron emission tomography.

Exaggerated vasoconstriction and blunted vasodilation of peripheral resistance arteries to various vasoactive agents characterize patients with IDDM. We characterized the hemodynamic effects of insulin in skeletal muscle in patients with IDDM. Muscle blood flow and blood volume were measured basally and during a high-dose insulin infusion (5 mU x kg(-1) x min[-1]) in seven normotensive patients with IDDM (age, 30 +/- 6 years; BMI, 24.5 +/- 2.0 kg/m2; blood pressure, 124 +/- 12/78 +/- 11 mmHg) and nine matched normal subjects, using [15O]H2O, [15O]CO, and positron emission tomography (PET). Whole-body insulin sensitivity was determined using the euglycemic insulin clamp technique. Insulin-stimulated whole-body glucose uptake was significantly lower in the patients with IDDM (45 +/- 15 micromol x kg(-1) x min[-1]) than in the normal subjects (62 +/- 14 micromol x kg(-1) x min[-1]) (P < 0.05). Insulin increased muscle blood flow by 111 +/- 69% above basal from 3.0 +/- 2.0 to 5.8 +/- 3.0 ml x 100 g(-1) muscle x min(-1) (P < 0.005) in the normal subjects, but only by 42 +/- 30% from 2.0 +/- 0.9 to 2.9 +/- 1.4 ml x 100 g(-1) muscle x min(-1) (P < 0.005) in patients with IDDM (P < 0.05 for change in flow in IDDM vs. normal subjects). The calculated muscle vascular resistances were comparable basally, but higher during hyperinsulinemia in the patients with IDDM (37 +/- 17 mmHg x 100 g x min x ml[-1]) than in the normal subjects (16 +/- 7 mmHg x 100 g x min x ml[-l]) (P < 0.05). Muscle blood volume increased significantly by insulin in both groups without any difference between the groups. We conclude that the ability of supraphysiological concentrations of insulin to stimulate muscle blood flow is blunted in patients with IDDM, because of the inability of insulin to stimulate linear flow velocity rather than blood volume in skeletal muscle. This defect adds yet another defect to the list of abnormalities in vascular function in IDDM, which might predispose these patients to develop hypertension.