Uno Wegelius

Glucose-free fatty acid cycle operates in human heart and skeletal muscle in vivo.

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.

Coronary Flow Reserve Is Impaired in Young Men With Familial Hypercholesterolemia

OBJECTIVES We sought to investigate whether functional abnormalities in coronary vasomotion exist in young adults by studying 15 men (age 31 +/- 8 years [mean +/- SD]) with familial hypercholesterolemia (FH) and a matched group of 20 healthy control subjects. BACKGROUND Precursors of morphologic coronary artery disease are known to be present in adolescents and young adults with a high risk factor profile. METHODS Myocardial blood flow was measured at the basal state and during dipyridamole-induced hyperemia using positron emission tomography and oxygen-15-labeled water. RESULTS Serum total and low density lipoprotein cholesterol concentrations were higher in the patients than in the control subjects (mean +/- SD): 7.7 +/- 1.9 versus 5.3 +/- 1.5 mmol/liter (298 +/- 73 vs. 205 +/- 58 mg/dl) and 6.1 +/- 1.8 versus 3.5 +/- 1.4 mmol/liter (236 +/- 70 vs. 135 +/- 54 mg/dl), respectively (both p < 0.001). The baseline myocardial blood flow was similar in the patients and control subjects: 0.92 +/- 0.24 versus 0.83 +/- 0.13 ml/g per min, respectively (p = 0.21). A significant increase in flow was observed in both groups after dipyridamole infusion, but the flow at maximal vasodilation was 29% lower in the patients: 3.19 +/- 1.59 versus 4.49 +/- 1.27 ml/g per min (p = 0.011). Consequently, coronary flow reserve (the ratio of hyperemia flow to basal flow) was 35% lower in the patients than in the control subjects: 3.5 +/- 1.6 versus 5.4 +/- 1.5 (p = 0.0008). Total coronary resistance during hyperemia was higher in the patients than in the control subjects: 36 +/- 25 versus 21 +/- 10 mm Hg/min per g per ml (p = 0.045). Coronary flow reserve was inversely associated with serum total cholesterol concentration: r = -0.43 (p = 0.009). CONCLUSIONS Coronary flow reserve is reduced in young men with FH, and, consequently, coronary resistance during hyperemia is increased. The results demonstrate very early impairment of coronary vasomotion in hypercholesterolemic patients.

Different alterations in the insulin-stimulated glucose uptake in the athlete's heart and skeletal muscle.

Physical training increases skeletal muscle insulin sensitivity. Since training also causes functional and structural changes in the myocardium, we compared glucose uptake rates in the heart and skeletal muscles of trained and untrained individuals. Seven male endurance athletes (VO2max 72 +/- 2 ml/kg/min) and seven sedentary subjects matched for characteristics other than VO2max (43 +/- 2 ml/kg/min) were studied. Whole body glucose uptake was determined with a 2-h euglycemic hyperinsulinemic clamp, and regional glucose uptake in femoral and arm muscles, and myocardium using 18F-fluoro-2-deoxy-D-glucose and positron emission tomography. Glucose uptake in the athletes was increased by 68% in whole body (P < 0.0001), by 99% in the femoral muscles (P < 0.01), and by 62% in arm muscles (P = 0.06), but it was decreased by 33% in the heart muscle (P < 0.05) as compared with the sedentary subjects. The total glucose uptake rate in the heart was similar in the athletes and control subjects. Left ventricular mass in the athletes was 79% greater (P < 0.001) and the meridional wall stress smaller (P < 0.001) as estimated by echocardiography. VO2max correlated directly with left ventricular mass (r = 0.87, P < 0.001) and inversely with left ventricular wall stress (r = -0.86, P < 0.001). Myocardial glucose uptake correlated directly with the rate-pressure product (r = 0.75, P < 0.02) and inversely with left ventricular mass (r = -0.60, P < 0.05) or with the whole body glucose disposal (r = -0.68, P < 0.01). Thus, in athletes, (a) insulin-stimulated glucose uptake is enhanced in the whole body and skeletal muscles, (b) whereas myocardial glucose uptake per muscle mass is reduced possibly due to decreased wall stress and energy requirements or the use of alternative fuels, or both.

Evidence for Dissociation of Insulin Stimulation of Blood Flow and Glucose Uptake in Human Skeletal Muscle: Studies Using [15O]H2O, [18F]fluoro-2-deoxy-D-glucose, and Positron Emission Tomography

We determined the effect of insulin on muscle blood flow and glucose uptake in humans using [15O]H2O, [18F]fluoro-2-deoxy-D-glucose ([18F]FDG), and positron emission tomography (PET). Femoral muscle blood flow was measured in 14 healthy volunteers (age 34 ± 8 years, BMI 24.6 ± 3.4 kg/m2 [means ± SD]) before and at 75 min during a 140-min high-dose insulin infusion (serum insulin 2,820 ± 540 pmol/l) under normoglycemic conditions. A dynamic scan of the femoral region was performed using PET for 6 min after injection of [15O]H2O to determine the 15O concentration in tissue. Regional femoral muscle blood flow was calculated using an autoradiographic method from the dynamic data obtained with PET and [15O]H2O. Femoral muscle glucose uptake was measured during hyperinsulinemia immediately after the flow measurement using PET-derived [18F]FDG kinetics and a three-compartment model. Whole-body glucose uptake was quantitated using the euglycemic insulin clamp technique. In the basal state, 84 ± 8% of blood flow was confined to skeletal muscle. Insulin increased leg blood flow from 29 ± 14 to 54 ± 29 ml · kg−1 leg · min−1 (P < 0.001) and muscle flow from 31 ± 18 to 58 ± 35 ml · kg−1 muscle · min−1 (P < 0.005). Under insulin-stimulated conditions, 81 ± 8% of blood flow was in muscle tissue (NS versus basal). Skeletal muscle explained 70 ± 25% of the increase in leg blood flow. No correlation was observed between blood flow and glucose uptake when analyzed individually in identical regions of interest within femoral muscles. These data demonstrate that skeletal muscle accounts for most of the insulin-induced increase in blood flow. Insulin-stimulated rates of blood flow and glucose uptake do not colocalize in the same regions of muscle tissue, suggesting that insulins hemodynamic and metabolic effects are differentially regulated.

Repeated fluorodeoxyglucose positron emission tomography of the brain in infants with suspected hypoxic-ischaemic brain injury

Positron emission tomography (PET) permits the study of cerebral metabolism in vivo. We performed repeated PET studies with fluorine-18 fluorodeoxyglucose (FDG) as a tracer to measure cerebral glucose metabolism for estimation of neurological prognosis in infants with suspected hypoxic-ischaemic brain injury. Fourteen infants (gestational age 35.3 ± 4.67 weeks) were examined during the neonatal period (at age 38.4±2.7 weeks) and again at the age of 3.5±0.7 months; one further infant was studied only once at the age of 2.5 months. All children also underwent ultrasound examinations. Electroencephalography and computed tomography or magnetic resonance imaging were performed according to their clinical condition and their neurological development has been followed. FDG accumulated most actively in the subcortical areas (thalami, brainstem and cerebellum) and the sensorimotor cortex during the neonatal period. The repeated PET study showed that the uptake of FDG was markedly high and increased in all brain sections of infants with normal development (n=11), whereas those with delayed development (n=4) had significantly lower values (P≤0.005).

Cerebral metabolic rate for glucose after neonatal hypoglycaemia

OBJECTIVE We studied the effect of neonatal hypoglycaemia on the local cerebral metabolic rate for glucose (LCMRglc). MATERIALS AND METHODS Eight newborn infants with neonatal hypoglycaemia were studied. The LCMRglc in the whole brain, in five cerebral regions and in skeletal muscles were quantitated using positron emission tomography (PET) and 2-[18F]Fluoro-2-deoxy-D-glucose (FDG). The PET studies were performed at the age of 5.3 +/- 6.2 days during normoglycaemia. The LCMRglc of these infants were compared to the age-adjusted LCMRglc of eight infants with suspected hypoxic-ischaemic brain injury but with normal neurological development. RESULTS After neonatal hypoglycaemia the age-adjusted LCMRglc in the whole brain was not lower than LCMRglc of the control infants (5.33 +/- 0.60 mumol/100 g/min vs. 6.71 +/- 0.60 mumol/100 g/min). Also the metabolic rate for glucose (MRglc) in the skeletal muscles was similar in hypoglycaemic and control infants (5.56 +/- 2.48 mumol/100 g/min vs. 6.99 +/- 2.41 mumol/100 g/min). CONCLUSION MRglc in brain and in skeletal muscle seems to be normal after neonatal hypoglycaemia, although larger group of patients with more severe hypoglycaemia are needed to confirm this finding.