Evidence for spatial heterogeneity in insulin- and exercise-induced increases in glucose uptake: studies in normal subjects and patients with type 1 diabetes.

It is unknown whether resistance to insulin- or exercise-stimulated glucose uptake reflects a spatially uniform or nonuniform decrease in glucose uptake within skeletal muscle. We compared the distributions of muscle glucose uptake and blood flow in eight patients with type 1 diabetes (age 24 +/- 1 yr, body mass index 22.0 +/- 0.8 kg/m2) and seven age- and weight-matched normal subjects using positron emission tomography, [18F]-fluoro-deoxy-glucose, and [15O]-water. Both groups were studied during euglycemic hyperinsulinemia and one-legged exercise. Heterogeneity was evaluated by calculating relative dispersion (SD divided by mean * 100%) of glucose uptake (RD(g)) and flow (RD(f)) in all pixels within a region of interest in femoral muscle. At rest insulin-stimulated glucose uptake was significantly lower in the type 1 diabetic patients (42 +/- 7 micromol/kg per min) than in the normal subjects (78 +/- 9 micromol/kg per min, P < 0.001), while muscle blood flows were similar (26 +/- 1 vs. 31 +/- 3 ml/kg muscle per min, respectively). The exercise-induced increment in glucose uptake but not in blood flow was also significantly lower in the type 1 diabetic patients than in the normal subjects. Heterogeneity of glucose uptake but not of blood flow was greater in the insulin-resistant type 1 diabetic patients both at rest (RD(g) 31 +/- 1 vs. 25 +/- 2%, patients with type 1 diabetes vs. normal subjects, P < 0.05) and during exercise, compared with normal subjects (27 +/- 1 vs. 21 +/- 2%, respectively, P < 0.05). Exercise increased both glucose uptake and blood flow several-fold and significantly decreased both RD(g) and RD(f). Heterogeneity of RD(g), was inversely associated with total glucose uptake (r = -0.54, P < 0.001, pooled data) and was highest in the most insulin-resistant patients. We concluded that both glucose uptake and blood flow are characterized by heterogeneity in human skeletal muscle, whose magnitude is inversely proportional to respective mean values. This implies that an increase in glucose uptake in human skeletal muscle is not a phenomenon, by which each unit increases its glucose uptake by a fixed amount but rather a spatially heterogeneous process.

Positron emission tomography using(18)F-fluoro-deoxyglucose and euglycaemic hyperinsulinaemic glucose clamp: optimal criteria for the prediction of recovery of post-ischaemic left ventricular dysfunction. Results from the European Community Concerted Action Multicenter study on use of(18)F-fluoro-deoxyglucose Positron Emission Tomography for the Detection of Myocardial Viability.

AIMS: To assess the accuracy of positron emission tomography to predict recovery of global cardiac function after revascularization in patients with coronary artery disease. METHODS AND RESULTS: One hundred and seventy-eight patients (157 male, 58+/-10 years) with coronary artery disease and left ventricular dysfunction (mean ejection fraction 39+/-14%) were enrolled in six European centres. They underwent a common protocol for the assessment of viability using(18)F-fluoro-2-deoxyglucose (FDG) positron emission tomography during a standardized euglycaemic hyperinsulinaemic glucose clamp before revascularization by either surgery (n=140) or angioplasty (n=38). Seven patients were excluded because of incomplete revascularization of a dysfunctional region. Based on the recovery of global ejection fraction 2-6 months after revascularization, patients were classified into two groups: 82 patients who had a >5% improvement in ejection fraction postoperatively, and 89 patients without postoperative ejection fraction improvement. Optimal cut-off points for postoperative improvement of global cardiac function were computed, using receiver operating curve analysis. The highest sensitivity (79%) and specificity (55%) for predicting postoperative ejection fraction improvement by positron emission tomography was found when three or more dysfunctional segments had a relative FDG uptake >45% of normal remote myocardium (overall accuracy 67%). CONCLUSIONS: In a large cohort of coronary patients with impaired ejection fraction, FDG positron emission tomography demonstrated high sensitivity and moderate specificity to predict improvement of cardiac function after coronary revascularization.

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.

Preserved relative dispersion but blunted stimulation of mean flow, absolute dispersion, and blood volume by insulin in skeletal muscle of patients with essential hypertension.

BACKGROUND: We examined the integrity of the effects of insulin on mean muscle blood flow, flow heterogeneity, and blood volume in essential hypertension. METHODS AND RESULTS: Positron emission tomography, combined with [15O]H2O and [15O]CO as tracers for direct measurement of blood flow and volume in skeletal muscle, and a new bayesian iterative reconstruction algorithm allowing pixel-by-pixel quantitation of blood flow and flow dispersion, were used. Measurements were performed basally after an overnight fast and under normoglycemic hyperinsulinemic conditions in 11 newly diagnosed, untreated mildly hypertensive men (age, 35 +/- 1 years; body mass index, 25.2 +/- 0.4 kg/m2, blood pressure 141 +/- 4/96 +/- 2 mm Hg, mean +/- SE) and 11 matched normotensive men. Insulin-stimulated whole body glucose uptake was significantly decreased in the hypertensive men (41 +/- 4 mumol/kg per minute) compared with the normotensive (59 +/- 4 mumol/kg per minute, P < 0.005) men. Mean blood flow in skeletal muscle was significantly lower in the hypertensive than the normal subjects basally (1.7 +/- 0.2 versus 2.7 +/- 0.4 mL/0.1 kg per minute, P < 0.05) and during hyperinsulinemia (2.3 +/- 0.2 versus 4.2 +/- 0.8, P < 0.05). The flow response to insulin (0.6 +/- 0.2 versus 1.9 +/- 0.5 mL/0.1 kg per minute, hypertensive versus normal subjects, P < 0.05) was also significantly blunted. Muscle blood volume was significantly lower in the hypertensive than in the normal subjects, both basally (3.0 +/- 0.2 versus 3.5 +/- 0.2 mL/0.1 kg, P < 0.05) and during hyperinsulinemia (3.1 +/- 0.2 versus 4.0 +/- 0.2 mL/0.1 kg muscle, P < 0.02). The increase in muscle blood volume by insulin was significant in the normal (P < 0.05) but not the hypertensive subjects. Regional pixel-by-pixel analysis within femoral muscles revealed significant spatial heterogeneity of blood flow. Insulin increased absolute dispersion of blood flow significantly more in the normal subjects than in the hypertensive subjects (P < 0.05). CONCLUSIONS: True flow heterogeneity, as judged from the coefficients of variation (relative dispersion), was comparable between the groups basally and during hyperinsulinemia. We conclude that mean flow, its absolute dispersion, and blood volume exhibit insulin resistance in patients with essential hypertension.

Insulin resistance in essential hypertension is characterized by impaired insulin stimulation of blood flow in skeletal muscle.

OBJECTIVE: To determine whether insulin-stimulated blood flow in patients with mild essential hypertension is altered. SUBJECTS: Eleven untreated mildly hypertensive patients [aged 35 +/- 2 years, body mass index 25.1 +/- 0.4 kg/m2, mean arterial pressure 110 +/- 2 mmHg (means +/- SEM) and 10 matched normotensive subjects (mean arterial pressure 94 +/- 3 mmHg). METHODS: Blood flow was quantitated directly in skeletal muscle both basally and during supraphysiologic hyperinsulinemia (serum insulin approximately = 450 mU/l) using radiowater ([15O]H2O) and positron emission tomography. Whole-body and femoral muscle glucose uptakes were determined using the euglycemic insulin clamp technique, [18F]-2-fluoro-2-deoxy-D-glucose and positron emission tomography. RESULTS: Rates of whole-body and femoral muscle glucose uptake were significantly lower in the hypertensive than in the normotensive group. Insulin increased muscle blood flow by 91% in the normotensive group, but only by 33% in the hypertensive group. CONCLUSIONS: The ability of insulin to stimulate blood flow in patients with mild essential hypertension is impaired.

Myocardial efficiency during calcium sensitization with levosimendan: a noninvasive study with positron emission tomography and echocardiography in healthy volunteers.

Dynamic positron emission tomography (PET) with [11C]acetate allows noninvasive assessment of myocardial oxygen consumption. In combination with echocardiography, PET enables determination of cardiac efficiency (defined as useful cardiac work per unit of oxygen consumption). We used this approach to compare the effects of levosimendan, a Ca(2+)-dependent calcium sensitizer, with dobutamine and sodium nitroprusside in healthy male volunteers. The effects of levosimendan on k(mono), an index of oxygen consumption, and cardiac efficiency were neutral, whereas the hemodynamic profile was consistent with balanced inotropism and vasodilatation. Dobutamine enhanced cardiac efficiency at the expense of increased oxygen requirement, but the effects of nitroprusside on k(mono) and cardiac efficiency were neutral. This study shows the feasibility of PET in phase 1 pharmacodynamic studies and suggests potential energetical advantages of calcium sensitization with levosimendan.

Quantitative blood flow measurement of skeletal muscle using oxygen-15-water and PET.

UNLABELLED: The aim of the present study was to evaluate quantitation of muscle blood flow using [15O]H2O and PET. METHODS: The autoradiographic (ARG) and the steady-state methods using PET were used to measure femoral muscle blood flow. A simulation study was performed to examine the errors due to contamination of radioactivity in the blood content in muscle tissue, statistical noise and delay and the dispersion of the input curve in the ARG method. Five separate paired muscle blood flow examinations were carried out for comparison of the ARG and the steady-state techniques, including measurement of muscle blood volume in each subject. To obtain the normal range for resting muscle blood flow, additional measurements with the ARG method were performed in 16 normal subjects. RESULTS: When the integration time in ARG was increased to 200-300 sec, the errors due to arterial blood volume, statistical noise, delay and dispersion of the input curve were significantly reduced. Muscle blood flow values in the ARG (200 sec) and the steady-state studies were in good agreement, and each provided an estimated accuracy of 5%. Resting muscle blood flow averaged 3.12 +/- 1.55 ml/min.100 g muscle (range 1.43-6.72 ml/min.100 g muscle, n = 18). CONCLUSION: The ARG and the steady-state methods provided consistent blood flow values for skeletal muscle when a long tissue integration time (> or = 200 sec) was applied in the ARG study. Based on the lower effective radiation dose and the shorter total scan duration, the ARG method is favored over the steady-state method in the measurement of muscle blood flow.

Acute effects of celiprolol on muscle blood flow and insulin sensitivity: studies using [15O]-water, [18F]-fluorodeoxyglucose and positron emission tomography.

OBJECTIVE: Recently the role of peripheral vasoconstriction in the aetiology of insulin resistance has been proposed. Celiprolol is a beta 1-selective adrenoceptor antagonist with partial agonist activity at the beta 2-receptor as well as vasodilator properties. The acute effects of celiprolol on skeletal muscle blood flow and insulin sensitivity were measured in this study. METHODS: Celiprolol (2 times 0.5 mg.kg-1) or saline was given intravenously to five healthy males in random order. Muscle blood flow was measured in femoral regions using [15O]-labelled water and positron emission tomography (PET) during euglycaemic hyperinsulinaemia (serum insulin approximately 65 mU.1(-1)) after an overnight fast. Thereafter, skeletal and heart muscle glucose uptake were determined using [18F]-2-deoxy-D-glucose. RESULTS: Celiprolol increased muscle blood flow by 74%, from 3.4 to 5.9 ml.min-1.100 g-1 muscle in the basal state. It decreased peripheral resistance by 40%, from 32.0 to 19.2 mmHg.ml-1.min-1.100 g-1. Celiprolol significantly decreased diastolic blood pressure from 82 to 73 mmHg and increased heart rate from 61 to 68 beats.min-1, which suggests sympathetic activation. Insulin-stimulated glucose uptake was reduced by 46% in the whole body, from 39 to 21 mumol.kg-1.min-1 and by 59% in the femoral muscles, from 99 to 41 mumol.kg-1.min-1, with celiprolol as compared to saline. The effect on heart glucose uptake did not statistically differ between the treatments. CONCLUSION: Celiprolol given intravenously increased muscle blood flow and decreased peripheral resistance at rest. It also acutely increased heart rate probably via sympathetic activation, and decreased insulin sensitivity in the muscles of healthy male volunteers. The enhanced muscle perfusion when celiprolol is given intravenously does not explain the improved insulin sensitivity seen in the long-term oral use in dyslipidaemic hypertensive patients.

Relationship between limb and muscle blood flow in man.

1. Since direct measurement of muscle blood flow in humans has been difficult, estimations of muscle flow have been made from measured total limb blood flow using a classic equation that predicts that the fraction of resting blood flow through muscle tissue decreases as total limb flow increases. 2. We used positron emission tomography and 15O-labelled water to directly quantify resting muscle and total limb blood flow in cross-sections of the femoral region in twenty-eight normal subjects (age, 30 +/- 8 years; body mass index, 24.1 +/- 3.3 Kg m-2) under conditions of constant environmental temperature of 22-23 degrees C. 3. Muscle blood flow averaged 3.1 +/- 1.7 ml (100 ml muscle)-1 min-1 (range, 1.1-7.5 ml (100 ml muscle)-1 min-1 and cross-sectional limb blood flow averaged 2.5 +/- 1.1 ml (100 ml limb)-1 min-1) (range, 1.0-4.8 ml (100 ml limb)-1 min-1). A linear relationship was observed between limb and muscle blood flow, and a regression equation was calculated for estimation of muscle blood flow bases on limb flow: muscle flow = (1.41 +/- 0.10) limb flow - (0.43 +/- 0.28). The slope of this equation was significantly greater than 1 (P < 0.001) indicating that the fraction of blood flow perfusing muscle tissue increases as a function of total limb flow. 4. These data provide a new equation for estimation of resting muscle blood flow in normal subjects, and demonstrate that muscle blood flow is the primary determinant of resting blood flow in man.

Insulin increases blood volume in human skeletal muscle: studies using [15O]CO and positron emission tomography.

High insulin concentrations increase blood flow in the leg, but it is unknown whether this effect is associated with a change in muscle blood volume. In the present study, we used positron emission tomography combined with inhalation of [15O]carbon monoxide to quantitate the effect of insulin on skeletal muscle blood volume in humans. The reproducibility of the method was determined from two consecutive measurements performed in the basal state in five normal subjects. The coefficient of variation of the repeated measurements was 3.0 +/- 1.8%. In 14 normal subjects [age 35 +/- 3 yr, body mass index 24.9 +/- 1.3 (SE) kg/m2], skeletal muscle blood volume was determined in the femoral region in the basal state and during euglycemic hyperinsulinemia (serum insulin 3,200 +/- 190 pmol/l). The mean muscle blood volume was 3.3 +/- 0.1 ml/0.1 kg muscle in the basal state. Insulin increased muscle blood volume by 9 +/- 2% to 3.6 +/- 0.2 ml/0.1 kg muscle (P < 0.01). The rate of whole body glucose uptake was 53 +/- 6 mumol.kg-1.min-1 and correlated with muscle blood volume during insulin stimulation (r = 0.65, P < 0.02). We conclude that high insulin concentrations exert a true vasodilatory effect in human skeletal muscle.

Insulin action on heart and skeletal muscle glucose uptake in essential hypertension.

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.

The effect of insulin and FFA on myocardial glucose uptake.

In addition to direct stimulation of glucose uptake and metabolism in cardiac myocytes, insulin inhibits lipolysis and, thereby, reduces serum free fatty acid (FFA) concentrations. This, in turn, has been suggested to enhance myocardial glucose utilization. To study the mechanism of insulin action on myocardial glucose uptake (MGU) in vivo, five patients with stable coronary artery disease were studied with positron emission tomography (PET) and [18F]FDG. All patients underwent two PET studies after a 12-h fast, once during low serum FFA but high insulin concentrations (during insulin clamp), and once during low serum FFA and low insulin concentrations (in the fasting state after two oral doses of 250 mg of an antilipolytic drug, acipimox). The MGU in the normal myocardium was measured using dynamic PET imaging. Plasma glucose concentrations were comparable during the insulin clamp and after administration of acipimox (5.0 +/- 0.4 v 5.2 +/- 0.3 mmol/l, n.s.). Serum insulin concentrations were high during clamp but remained in low fasting concentrations after acipimox (74 +/- 9 mU/l v 6 +/- 5 mU/l, P = 0.0001). Serum FFA concentrations were similar during both approaches (230 +/- 110 v 200 +/- 40 mumol/l, respectively, n.s.). No difference in cardiac work load was detected between the approaches. The calculated MGU values in normal myocardium were similar during both approaches (57 +/- 23 mumol/min/100 g v 61 +/- 14 mumol/min/100 g, respectively, n.s.). The MGU values correlated inversely to serum FFA concentration (r = -0.87, P = 0.001) and directly to myocardial work load (r = 0.73, P = 0.016) but not to serum insulin concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

Gender and insulin sensitivity in the heart and in skeletal muscles. Studies using positron emission tomography.

Good insulin sensitivity is independently associated with a low risk for coronary heart disease, but it is unclear whether this risk factor differs between men and women. We compared insulin sensitivity of glucose uptake directly in muscle and heart tissues between healthy women (age 29 +/- 2 years, body mass index [BMI] 22 +/- 1 kg/m2, VO2max 39 +/- 4 ml.kg-1.min-1) and men matched for age (31 +/- 2 years), BMI (23 +/- 1 kg/m2), and VO2max (44 +/- 3 ml.kg-1.min-1) using [18F]fluoro-2-deoxy-D-glucose and positron emission tomography under hyperinsulinemic (insulin infusion rate 1 mU.kg-1.min-1) normoglycemic conditions. Whole body insulin sensitivity was 41% greater in women (52 +/- 6 mumol.kg body wt-1.min-1) than in men (37 +/- 3 mumol.kg body wt-1.min-1, P < 0.05). This difference was explained by a 47% greater rate of glucose uptake by femoral muscles (113 +/- 10 vs. 77 +/- 7 mumol.kg muscle-1.min-1, women vs. men, P < 0.01). Insulin-stimulated glucose uptake rates in the heart were similar in women (738 +/- 58) and men (749 +/- 62 mumol.kg muscle-1.min-1). Femoral muscle insulin sensitivity was closely correlated with whole body insulin sensitivity (r = 0.84, P < 0.001). Gender and VO2max together explained 68% of the variation in femoral muscle glucose uptake. We conclude that women are more sensitive to insulin than equally fit men because of enhanced muscle but not heart insulin sensitivity.

Effect of antilipolysis on heart and skeletal muscle glucose uptake in overnight fasted humans.

We quantitated how lowering of free fatty acid (FFA) by an antilipolytic agent (acipimox) in the fasting state changes glucose uptake in heart and skeletal muscles. Glucose uptake in these tissues was measured two times in seven normal subjects, once after acipimox and once after placebo, using positron emission tomography-derived [18F]fluoro-2-deoxy-D-glucose kinetics. Plasma glucose and insulin remained at their fasting concentrations in both studies. Fasting FFA concentrations were 60% lower after acipimox (238 +/- 39) than placebo (645 +/- 78 mumol/l, P < 0.001). Glucose uptake increased 6 +/- 2-fold in the heart by acipimox (344 +/- 49 vs. 108 +/- 40 mumol.kg muscle-1.min-1, P < 0.002) and 1.5-fold in arm muscles (27.7 +/- 2.6 vs. 18.6 +/- 1.2 mumol.kg muscle-1.min-1, P < 0.02). Heart (r = -0.93, P < 0.001) and arm (r = -0.82, P < 0.001) glucose uptakes were inversely related to serum FFA. We conclude that serum FFA are inversely related to glucose uptake in heart and arm skeletal muscles after an overnight fast. These data indicate that compensatory glycogenolysis, although it may occur, does not prevent operation of the glucose-FFA cycle under fasting conditions.

Enhancement of myocardial [fluorine-18]fluorodeoxyglucose uptake by a nicotinic acid derivative.

UNLABELLED: Recently, the euglycemic hyperinsulinemic clamp technique was shown to give excellent image quality during metabolic steady-state conditions. Acipimox is a new potent nicotinic acid derivative that rapidly reduces serum free fatty acid (FFA) levels by inhibiting lipolysis in peripheral tissue. METHODS: To compare the effects of acipimox administration and insulin clamp on [18F]fluorodeoxyglucose ([18F]FDG) uptake and myocardial glucose utilization, five nondiabetic and seven type II diabetic patients who had had previous myocardial infarctions were studied twice: once during a clamp study and once after the administration of acipimox (2 x 250 mg orally). All patients also underwent resting SPECT perfusion imaging prior to PET scans. RESULTS: The patients tolerated acipimox well. Although fasting plasma glucose levels were higher in diabetic patients (9.2 +/- 3.4 versus 5.5 +/- 0.3 mM, p = 0.03), they were decreased both during clamping and after acipimox; during imaging, no significant differences between the groups and approaches were detected. By visual analysis, the image quality and myocardial [18F]FDG uptake patterns were similar during clamping and after acipimox. Compared with the relative [18F]FDG uptake values obtained during clamping, acipimox yielded similar results in normal, mismatch and scar segments (r = 0.88, p = 0.0001). Similar rMGU values were also obtained during both approaches. CONCLUSION: Thus, PET imaging with [18F]FDG after the administration of acipimox is a simple and feasible method for clinical viability studies both in nondiabetic and diabetic patients. It results in excellent image quality and gives rMGU levels similar to the insulin clamp technique.

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.

Myocardial viability: fluorine-18-deoxyglucose positron emission tomography in prediction of wall motion recovery after revascularization.

To assess the value of positron emission tomography (PET) imaging with fluorine-18-deoxyglucose ([18F]FDG) in predicting cardiac wall motion recovery after revascularization, 48 consecutive patients with previous myocardial infarction were studied. The normalized [18F]FDG uptake at rest was assessed semiquantitatively and compared to perfusion at rest as studied by SPECT imaging. Wall motion was analyzed with echocardiography before and after revascularization. Wall motion recovery occurred in 27 (30%) of the revascularized 90 dysfunctional segments. Preserved [18F]FDG uptake (mean +/- 2 SD) was commonly found in dysfunctional segments, but only 54% of these segments recovered after revascularization. Subnormal [18F]FDG uptake identified accurately the segments with no potential to recover (predictive value 100%). By using an optimized threshold value for normalized [18F]FDG uptake, the sensitivity of 85% and specificity of 84% to predict functional recovery were reached simultaneously. However, in the segments with moderately or severely reduced perfusion at rest, the diagnostic accuracy of [18F]FDG uptake for viability was 100%. The results of this study show that the presence of viable tissue indicated by preserved [18F]FDG uptake does not inevitably imply functional recovery after revascularization. However, acceptable diagnostic accuracy for viability might be reached by [18F]FDG alone, providing that appropriate uptake limits are used. The combined evaluation of [18F]FDG uptake and perfusion enables precise assessment of myocardial viability.

In vivo effects of insulin on tumor and skeletal muscle glucose metabolism in patients with lymphoma.

BACKGROUND: The anabolic properties of insulin have been suggested for use to reverse malnutrition associated with cancer. The host and tumor sensitivities to insulin are critical for such treatments, which aim to improve patient nutrition. The authors studied insulin effects on tumor and skeletal muscle metabolism with 2-[18F]-fluoro-2-deoxy-D-glucose ([18F]FDG) and positron emission tomography (PET). METHODS: Six patients with lymphoma twice underwent [18F]FDG-PET imaging: once after fasting overnight and once during euglycemic hyperinsulinemic clamp. The dynamic uptake of the glucose analogue [18F]FDG was measured in diseased nodes and upper arm skeletal muscle in both metabolic states. The [18F]FDG uptake in muscle and the whole body glucose use during euglycemic hyperinsulinemic clamp were compared with those of weight-matched healthy subjects studied under similar circumstances. RESULTS: In lymphomatous tissue, [18F]FDG uptake rates were similar in overnight fasting and euglycemic hyperinsulinemic clamp (38 +/- 10 versus 41 +/- 9 mumol/100 g/minute, not significant), whereas glucose uptake in skeletal muscle was increased by insulin (1.7 +/- 0.2 versus 3.8 +/- 0.5 mumol/100 g/minute, P = 0.012). Both basal (2.3 +/- 0.2 mumol/100 g/minute, P = 0.061) and insulin-stimulated (8.5 +/- 1.9 mumol/100 g/minute, P = 0.055) skeletal arm muscle glucose uptake rates were higher in control subjects than in patients. Whole body glucose use was 55% lower in patients than in control subjects (17 +/- 3 mumol/kg/minute versus 38 +/- 3 mumol/kg/minute, P = 0.002), consistent with insulin resistance in cancer. CONCLUSIONS: We found that insulin does not induce major changes in glucose uptake of lymphomatous tissue. Although insulin sensitivity of skeletal muscle was also reduced in patients with lymphoma, the net insulin effect may counteract imbalance between glucose uptake of tumor and muscle, offering a potential means to circumvent at least some metabolic abnormalities found in cancer.

Heart and skeletal muscle glucose disposal in type 2 diabetic patients as determined by positron emission tomography.

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.

The value of quantitative analysis of glucose utilization in detection of myocardial viability by PET.

To study whether absolute quantitation of regional myocardial glucose utilization (rMGU) enhances detection of myocardial viability, 70 nondiabetic patients with prior myocardial infarction and angiographically confirmed coronary artery disease were studied with [18F]FDG PET after oral glucose loading. Forty-eight patients were also revascularized and underwent echocardiography after revascularization to detect wall motion recovery. The rMGU was calculated in eight myocardial segments in each patient and the results were compared to normalized (relative) [18F]FDG uptake values. In normal segments (n = 225), rMGU was 56 +/- 18 mumole/min/100 g (mean +/- s.d.) and relative [18F]FDG uptake 97% +/- 12%. The interindividual variation of rMGU in normal myocardium was greater than the intraindividual variation (s.d. 31% versus 11%). The respective values for relative [18F]FDG uptake were 9% and 10%. Both rMGU and [18F]FDG uptake were significantly reduced in segments with scarring observed visually during bypass surgery (29 +/- 19 mumole/min/100 g and 45% +/- 22%, n = 26). The rMGU and [18F]FDG uptake were higher in segments that recovered after revascularization (53 +/- 17 mumole/min/100/g and 110% +/- 21%, n = 27) than in those that did not (37 +/- 20 mumole/min/100 g and 65% +/- 24%, n = 63). However, due to larger variability of rMGU values, normalized [18F]FDG uptake was superior to rMGU in separating normal and scar segments as well as in predicting wall motion recovery. We conclude that rMGU variability is notable and is caused mainly by variations between patients. Interindividual variation is reduced by normalization, which results in more accurate assessment of myocardial viability. Thus, static imaging and semiquantitative analysis are sufficient for the clinical assessment of myocardial viability.