Laparoscopic Roux-en-Y gastric bypass versus laparoscopic sleeve gastrectomy: 5-year outcomes of merged data from two randomized clinical trials (SLEEVEPASS and SM-BOSS).

BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) and Roux-en-Y gastric bypass (LRYGB) are both effective surgical procedures to achieve weight reduction in patients with obesity. The trial objective was to merge individual-patient data from two RCTs to compare outcomes after LSG and LRYGB. METHODS: Five-year outcomes of the Finnish SLEEVEPASS and Swiss SM-BOSS RCTs comparing LSG with LRYGB were analysed. Both original trials were designed to evaluate weight loss. Additional patient-level data on type 2 diabetes (T2DM), obstructive sleep apnoea, and complications were retrieved. The primary outcome was percentage excess BMI loss (%EBMIL). Secondary predefined outcomes in both trials included total weight loss, remission of co-morbidities, improvement in quality of life (QoL), and overall morbidity. RESULTS: At baseline, 228 LSG and 229 LRYGB procedures were performed. Five-year follow-up was available for 199 of 228 patients (87.3 per cent) after LSG and 199 of 229 (87.1 per cent) after LRYGB. Model-based mean estimate of %EBMIL was 7.0 (95 per cent c.i. 3.5 to 10.5) percentage points better after LRYGB than after LSG  (62.7 versus 55.5 per cent respectively; P < 0.001). There was no difference in remission of T2DM, obstructive sleep apnoea or QoL improvement; remission for hypertension was better after LRYGB compared with LSG (60.3 versus 44.9 per cent; P = 0.049). The complication rate was higher after LRYGB than LSG (37.2 versus 22.5 per cent; P = 0.001), but there was no difference in mean Comprehensive Complication Index value (30.6 versus 31.0 points; P = 0.859). CONCLUSION: Although LRYGB induced greater weight loss and better amelioration of hypertension than LSG, there was no difference in remission of T2DM, obstructive sleep apnoea, or QoL at 5 years. There were more complications after LRYGB, but the individual burden for patients with complications was similar after both operations.

Weight loss after bariatric surgery normalizes brain opioid receptors in morbid obesity.

Positron emission tomography (PET) studies suggest opioidergic system dysfunction in morbid obesity, while evidence for the role of the dopaminergic system is less consistent. Whether opioid dysfunction represents a state or trait in obesity remains unresolved, but could be assessed in obese subjects undergoing weight loss. Here we measured brain µ-opioid receptor (MOR) and dopamine D2 receptor (D2R) availability in 16 morbidly obese women twice-before and 6 months after bariatric surgery-using PET with [(11)C]carfentanil and [(11)C]raclopride. Data were compared with those from 14 lean control subjects. Receptor-binding potentials (BPND) were compared between the groups and between the pre- and postoperative scans among the obese subjects. Brain MOR availability was initially lower among obese subjects, but weight loss (mean=26.1 kg, s.d.=7.6 kg) reversed this and resulted in ~23% higher MOR availability in the postoperative versus preoperative scan. Changes were observed in areas implicated in reward processing, including ventral striatum, insula, amygdala and thalamus (P's<0.005). Weight loss did not influence D2R availability in any brain region. Taken together, the endogenous opioid system plays an important role in the pathophysiology of human obesity. Because bariatric surgery and concomitant weight loss recover downregulated MOR availability, lowered MOR availability is associated with an obese phenotype and may mediate excessive energy uptake. Our results highlight that understanding the opioidergic contribution to overeating is critical for developing new treatments for obesity.

Brown adipose tissue triglyceride content is associated with decreased insulin sensitivity, independently of age and obesity.

The aim of the present study was to determine whether single-voxel proton magnetic resonance spectroscopy ((1)H-MRS) can non-invasively assess triglyceride content in both supraclavicular fat depots and subcutaneous white adipose tissue (WAT) to determine whether these measurements correlate to metabolic variables. A total of 25 healthy volunteers were studied using (18)F-fluorodeoxyglucose positron emission tomography (PET) and (15)O-H2O PET perfusion during cold exposure, and (1)H-MRS at ambient temperature. Image-guided biopsies were collected from nine volunteers. The supraclavicular triglyceride content determined by (1)H-MRS varied between 60 and 91% [mean ± standard deviation (s.d.) 77 ± 10%]. It correlated positively with body mass index, waist circumference, subcutaneous and visceral fat masses and 8-year diabetes risk based on the Framingham risk score and inversely with HDL cholesterol and insulin sensitivity (M-value; euglycaemic-hyperinsulinaemic clamp). Subcutaneous WAT had a significantly higher triglyceride content, 76-95% (mean ± s.d. 87 ± 5%; p = 0.0002). In conclusion, the triglyceride content in supraclavicular fat deposits measured by (1)H-MRS may be an independent marker of whole-body insulin sensitivity, independent of brown adipose tissue metabolic activation.

Comparison of vertebral bone marrow fat assessed by 1H MRS and inphase and out-of-phase MRI among family members.

UNLABELLED: Inphase and out-of-phase magnetic resonance imaging is a robust and fast method which can provide similar vertebral bone marrow fat estimation as (1)H proton magnetic resonance spectroscopy, indicating that this technique is a potentially useful tool in both research and clinical practice. INTRODUCTION: The importance of evaluating bone marrow fat lies in the fact that osteoporosis and obesity, two disorders of body composition, are growing in prevalence. Bone fat mass can be reliably assessed using proton magnetic resonance spectroscopy ((1)H MRS), but this method is technically demanding and needs advanced post-processing unlike inphase and out-of-phase magnetic resonance imaging (MRI), which is a robust and fast method. METHODS: We compared vertebral bone marrow fat (BMF) content assessed by inphase and out-of-phase MRI and (1)H MRS using a 1.5-T MRI scanner in mothers (n = 34, aged 49.4 years), fathers (n = 31, aged 53.1 years) and their daughters (n = 40, aged 20.3 years) who participated in the CALEX family study. Signal intensity on the inphase and out-of-phase MRI was analyzed from the same location and size of the single-voxel (1)H MRS measurement. RESULTS: Positive correlations were found between (1)H MRS and inphase and out-of-phase MRI in the axial plane (r = 0.746, p < 0.001) and sagittal plane (r = 0.804, p < 0.001). The mean differences between (1)H MRS and inphase and out-of-phase MRI in the axial and sagittal planes were relatively small, at 4.13 and 2.67 %, and the agreement between techniques was 89.4 and 93.2 %, respectively. Girls had a significantly lower vertebral BMF than mothers and fathers with both methods (for all, p < 0.001). CONCLUSIONS: We conclude that inphase and out-of-phase MRI can provide similar vertebral BMF estimation as (1)H MRS, indicating that this technique is a potentially useful tool in both research and clinical practice.

Brown adipose tissue thermogenesis in humans.

The prevalence of obesity and type 2 diabetes is at epidemic proportions. Classical interventions aimed at targeting obesity, such as reducing energy intake or increasing exercise, are often not effective over the long term. In contrast to white adipocytes, which store energy, brown adipocytes generate heat via mitochondrial uncoupling protein 1, thereby acting as a defence against hypothermia and, potentially, obesity. In this issue of Diabetologia, Admiraal et al compare brown adipose tissue activation during cold exposure between two different ethnic groups: South Asians and Europids. The prevalence of abdominal obesity and type 2 diabetes differs among various ethnic groups and decreased BAT metabolic activity could be one causal factor. As yet, the clinical impact of this 'rediscovered' organ is largely unknown, but has potential as a drug target for obesity.

Validation of [18F]fluorodeoxyglucose and positron emission tomography (PET) for the measurement of intestinal metabolism in pigs, and evidence of intestinal insulin resistance in patients with morbid obesity.

AIMS/HYPOTHESIS: The role of the intestine in the pathogenesis of metabolic diseases is gaining much attention. We therefore sought to validate, using an animal model, the use of positron emission tomography (PET) in the estimation of intestinal glucose uptake (GU), and thereafter to test whether intestinal insulin-stimulated GU is altered in morbidly obese compared with healthy human participants. METHODS: In the validation study, pigs were imaged using [(18)F]fluorodeoxyglucose ([(18)F]FDG) and the image-derived data were compared with corresponding ex vivo measurements in tissue samples and with arterial-venous differences in glucose and [(18)F]FDG levels. In the clinical study, GU was measured in different regions of the intestine in lean (n = 8) and morbidly obese (n = 8) humans at baseline and during euglycaemic hyperinsulinaemia. RESULTS: PET- and ex vivo-derived intestinal values were strongly correlated and most of the fluorine-18-derived radioactivity was accumulated in the mucosal layer of the gut wall. In the gut wall of pigs, insulin promoted GU as determined by PET, the arterial-venous balance or autoradiography. In lean human participants, insulin increased GU from the circulation in the duodenum (from 1.3 ± 0.6 to 3.1 ± 1.1 µmol [100 g](-1) min(-1), p < 0.05) and in the jejunum (from 1.1 ± 0.7 to 3.0 ± 1.5 µmol [100 g](-1) min(-1), p < 0.05). Obese participants failed to show any increase in insulin-stimulated GU compared with fasting values (NS). CONCLUSIONS/INTERPRETATION: Intestinal GU can be quantified in vivo by [(18)F]FDG PET. Intestinal insulin resistance occurs in obesity before the deterioration of systemic glucose tolerance.

Regional differences in blood flow, glucose uptake and fatty acid uptake within quadriceps femoris muscle during dynamic knee-extension exercise.

The purpose of the present study was to investigate the regional differences in glucose and fatty acid uptake within skeletal muscle during exercise. Blood flow (BF), glucose uptake (GU) and free fatty acid uptake (FFAU) were measured in four different regions (vastus lateralis, VL; rectus femoris, RF; vastus intermedius, VI; and vastus medialis, VM) of the quadriceps femoris (QF) muscle during low-intensity, knee-extension exercise using positron emission tomography. BF was higher in VI than in VL, RF and VM (P < 0.05). FFAU was higher in VI (P < 0.001) but also in VM (P < 0.05) compared with VL and RF. In contrast, GU was higher in RF compared with VL (P < 0.05) but was not significantly different to VM or VI (both P = NS). FFAU within these four muscle regions correlated significantly with BF (r = 0.951, P < 0.05), whereas no significant relationship was observed between GU and BF (r = 0.352, P = NS). Therefore, skeletal muscle FFAU, but not GU, appears to be associated with BF during low-intensity exercise. The present results also indicate considerable regional differences in substrate use within working QF muscle. As such, an important methodological outcome from these results is that one sample from a specific part of the QF muscle does not represent the response in the entire QF muscle group.

Similar patterns of myocardial metabolism and perfusion in patients with type 2 diabetes and heart disease of ischaemic and non-ischaemic origin.

AIMS/HYPOTHESIS: Type 2 diabetes and insulin resistance are often associated with the co-occurrence of coronary atherosclerosis and cardiac dysfunction. The aim of this study was to define the independent relationships between left ventricular dysfunction or ischaemia and patterns of myocardial perfusion and metabolism in type 2 diabetes. METHODS: Twenty-four type 2 diabetic patients--12 with coronary artery disease (CAD) and preserved left ventricular function and 12 with non-ischaemic heart failure (HF)--were enrolled in a cross-sectional study. Positron emission tomography (PET) was used to assess myocardial blood flow (MBF) at rest, after pharmacological stress and under euglycaemic hyperinsulinaemia. Insulin-mediated myocardial glucose disposal was determined with 2-deoxy-2-[(18)F]fluoroglucose PET. RESULTS: There was no difference in myocardial glucose uptake (MGU) between the healthy myocardium of CAD patients and the dysfunctional myocardium of HF patients. MGU was strongly influenced by levels of systemic insulin resistance in both groups (CAD, r = 0.85, p = 0.005; HF, r = 0.77, p = 0.01). In HF patients, there was an inverse association between MGU and the coronary flow reserve (r = -0.434, p = 0.0115). A similar relationship was observed in non-ischaemic segments of CAD patients. Hyperinsulinaemia increased MBF to a similar extent in the non-ischaemic myocardial of CAD and HF patients. CONCLUSIONS/INTERPRETATION: In type 2 diabetes, similar metabolic and perfusion patterns can be detected in the non-ischaemic regions of CAD patients with normal cardiac function and in the dysfunctional non-ischaemic myocardium of HF patients. This suggests that insulin resistance, rather than diagnosis of ischaemia or left ventricular dysfunction, affects the metabolism and perfusion features of patients with type 2 diabetes.

The effect of revascularization of atherosclerotic renal artery stenosis on coronary flow reserve and peripheral endothelial function.

BACKGROUND: Patients with atherosclerotic renovascular disease (ARVD) are at increased risk of heart disease because of associated hypertension, coronary artery disease, cardiac failure and chronic kidney disease. Although suggested to be beneficial, the cardiac effects of renal artery revascularization have not been well characterized. Our aim was to analyze the effects of percutaneous dilatation of renal artery stenosis (RAS) in ARVD patients on coronary and peripheral vascular function. METHODS: Nineteen ARVD patients [11 females and 8 males, age at study entry (mean ± SD) 69 ± 10 years] were treated by dilatation of unilateral (n = 9) or bilateral (n = 10) RAS, mainly because of uncontrolled or refractory hypertension. The patients were studied before and after the procedure (103 ± 29 days). They underwent echocardiography and peripheral artery endothelial function testing using flow-mediated dilatation (FMD) of brachial artery at rest and during reactive hyperemia. Myocardial blood flow was measured using quantitative PET perfusion imaging at baseline and during dipyridamole-induced hyperemia. RESULTS: Peripheral endothelial function, tested by FMD, as well as systolic blood pressure and left ventricular mass were improved in patients with bilateral RAS. However, myocardial perfusion and coronary flow reserve (CFR) did not change after the RAS dilatation. CONCLUSION: This is the first study to analyze the stage of myocardial perfusion and CFR in ARVD patients. Although peripheral endothelial function, systolic blood pressure and left ventricular hypertrophy were improved in patients with bilateral RAS by revascularization of RAS, it did not have any effect on coronary perfusion.

Basal and cold-induced fatty acid uptake of human brown adipose tissue is impaired in obesity.

Fatty acids (FA) are important substrates for brown adipose tissue (BAT) metabolism, however, it remains unclear whether there exists a difference in FA metabolism of BAT between lean and obese healthy humans. In this study we evaluated supraclavicular BAT fatty acid uptake (FAU) along with blood perfusion in lean and obese subjects during cold exposure and at room temperature using positron emission tomography (PET)/computed tomography (CT). Additionally, tissue samples were taken from supraclavicular region (typical BAT region) from a subset of subjects to evaluate histological presence of BAT. Non-shivering cold stress elevated FAU and perfusion of BAT in lean, but not in obese subjects. Lean subjects had greater FAU in BAT compared to obese subjects during cold exposure and interestingly also at room temperature. The higher BAT FAU was related to younger age and several indicators of superior systemic metabolic health. The subjects who manifested BAT histologically had several folds higher BAT FAU compared to subjects with no such histological manifestation. Together, obese subjects have less active tissue in supraclavicular region both in basal and cold-activated state and the FA metabolism of BAT is blunted in obesity.

Non-invasive estimation of hepatic glucose uptake from [18F]FDG PET images using tissue-derived input functions.

PURPOSE: The liver is perfused through the portal vein and hepatic artery. Quantification of hepatic glucose uptake (HGU) using PET requires the use of an input function for both the hepatic artery and portal vein. The former can be generally obtained invasively, but blood withdrawal from the portal vein is not practical in humans. The aim of this study was to develop and validate a new technique to obtain quantitative HGU by estimating the input function from PET images. METHODS: Normal pigs (n = 12) were studied with [18F]FDG PET, in which arterial and portal blood time-activity curves (TAC) were determined invasively to serve as reference measurements. The present technique consisted of two characteristics, i.e. using a model input function and simultaneously fitting multiple liver tissue TACs from images by minimizing the residual sum of square between the tissue TACs and fitted curves. The input function was obtained from the parameters determined from the fitting. The HGU values were computed by the estimated and measured input functions and compared between the methods. RESULTS: The estimated input functions were well reproduced. The HGU values, ranging from 0.005 to 0.02 ml/min per ml, were not significantly different between the two methods (r = 0.95, p < 0.001). A Bland-Altman plot demonstrated a small overestimation by the image-derived method with a bias of 0.00052 ml/min per g for HGU. CONCLUSION: The results presented demonstrate that the input function can be estimated directly from the PET image, supporting the fully non-invasive assessment of liver glucose metabolism in human studies.

Exercise training alters lipoprotein particles independent of brown adipose tissue metabolic activity.

INTRODUCTION: New strategies for weight loss and weight maintenance in humans are needed. Human brown adipose tissue (BAT) can stimulate energy expenditure and may be a potential therapeutic target for obesity and type 2 diabetes. However, whether exercise training is an efficient stimulus to activate and recruit BAT remains to be explored. This study aimed to evaluate whether regular exercise training affects cold-stimulated BAT metabolism and, if so, whether this was associated with changes in plasma metabolites. METHODS: Healthy sedentary men (n = 11; aged 31 [SD 7] years; body mass index 23 [0.9] kg m-2; VO2 max 39 [7.6] mL min-1 kg-1) participated in a 6-week exercise training intervention. Fasting BAT and neck muscle glucose uptake (GU) were measured using quantitative [18F]fluorodeoxyglucose positron emission tomography-magnetic resonance imaging three times: (1) before training at room temperature and (2) before and (3) after the training period during cold stimulation. Cervico-thoracic BAT mass was measured using MRI signal fat fraction maps. Plasma metabolites were analysed using nuclear magnetic resonance spectroscopy. RESULTS: Cold exposure increased supraclavicular BAT GU by threefold (p < 0.001), energy expenditure by 59% (p < 0.001) and plasma fatty acids (p < 0.01). Exercise training had no effect on cold-induced GU in BAT or neck muscles. Training increased aerobic capacity (p = 0.01) and decreased visceral fat (p = 0.02) and cervico-thoracic BAT mass (p = 0.003). Additionally, training decreased very low-density lipoprotein particle size (p = 0.04), triglycerides within chylomicrons (p = 0.04) and small high-density lipoprotein (p = 0.04). CONCLUSIONS: Although exercise training plays an important role for metabolic health, its beneficial effects on whole body metabolism through physiological adaptations seem to be independent of BAT activation in young, sedentary men.

Amino-acid-based peritoneal dialysis solution improves amino-acid transport into skeletal muscle.

Abnormalities of amino-acid (AA) and protein metabolism are known to occur in chronic kidney disease (CKD). Protein malnutrition may contribute to impaired prognosis of dialysis patients. A crucial step in protein metabolism is AA transport into the cells. We compared the effects of an AA-containing peritoneal dialysis (PD) solution to glucose-based solutions on skeletal muscle AA uptake. Thirteen nondiabetic PD patients were studied twice in a random order and in a crossover manner both in the fasting state and during euglycemic insulin stimulation using [(11)C]methylaminoisobutyrate ([(11)C]MeAIB) and positron emission tomography (PET). Before both PET study days, patients had been using either glucose-based PD solutions only or one daily bag of AA solution in addition to glucose-based PD solutions for at least 6 weeks. Skeletal muscle AA uptake was calculated with graphical analysis. AA-containing PD solution increased plasma AA concentrations from 2.18+/-0.34 to 3.08+/-0.55 mmol l(-1) in the fasting state (P=0.0002) and from 1.88+/-0.15 to 2.42+/-0.30 mmol l(-1) during insulin stimulation (P<0.0001). As compared to PD treatment using glucose-based solutions only, skeletal muscle AA uptake was significantly higher during treatment containing AA solution both in the fasting state (15.2+/-5.8 vs 20.0+/-5.6 micromol kg(-1) min(-1), respectively, P=0.0057) and during insulin stimulation (16.8+/-4.5 vs 21.1+/-4.9 micromol kg(-1) min(-1), respectively, P=0.0046). In conclusion, PD treatment with an AA-containing PD solution is associated with a significant increase in skeletal muscle AA uptake both in the fasting state and during insulin stimulation.

Twenty-four-month alpha-galactosidase A replacement therapy in Fabry disease has only minimal effects on symptoms and cardiovascular parameters.

Fabry disease is an X-linked lysosomal storage disease caused by deficiency of alpha-galactosidase A enzyme activity. Decreased enzyme activity leads to accumulation of glycosphingolipids in different tissues including endothelial cells and smooth-muscle cells and cardiomyocytes, and cardiovascular complications are common in the disease. Since 2001, specific enzyme replacement therapy (ERT) with alpha-galactosidase A has been available. It has been reported to improve clinical symptoms and quality of life. However, limited and controversial data on its efficacy to cardiac involvement have been published. Nine patients (5 male) with Fabry disease were included in an open-label prospective follow-up study of 24-month ERT. Comprehensive cardiovascular evaluation was performed by MRI, stress echocardiography and quality of life assessment. Plasma globotriaosylceramide decreased from 6.2 to 1.4 microg/ml during ERT (p<0.05). The only other measured parameters that changed significantly were resting heart rate that decreased from 79 to 67 bpm (p<0.01) and end-systolic volume that decreased by 12.4 ml (p<0.05). The other parameters consisting of quality of life, self-estimated cardiovascular condition, diastolic function, exercise capacity, ECG parameters, ejection fraction and ventricular mass did not change. ERT has only minimal effect on symptoms and cardiovascular morphology and function in Fabry disease. Therefore, effective conventional medical therapy is still of major importance in Fabry disease. Larger ERT studies are warranted, especially in women, to solve current open questions, such as the age at which ERT should be started, optimal dosage and intervals between infusions. Furthermore, longer follow-up studies are needed to assess the effects of ERT on prognosis.

Insulin resistance of glucose uptake in skeletal muscle cannot be ameliorated by enhancing endothelium-dependent blood flow in obesity.

We tested the hypothesis that endothelium-dependent vasodilatation is a determinant of insulin resistance of skeletal muscle glucose uptake in human obesity. Eight obese (age 26+/-1 yr, body mass index 37+/-1 kg/m2) and seven nonobese males (25+/-2 yr, 23+/-1 kg/m2) received an infusion of bradykinin into the femoral artery of one leg under intravenously maintained normoglycemic hyperinsulinemic conditions. Blood flow was measured simultaneously in the bradykinin and insulin- and the insulin-infused leg before and during hyperinsulinemia using [15O]-labeled water ([15O]H2O) and positron emission tomography (PET). Glucose uptake was quantitated immediately thereafter in both legs using [18F]- fluoro-deoxy-glucose ([18F]FDG) and PET. Whole body insulin-stimulated glucose uptake was lower in the obese (507+/-47 mumol/m2 . min) than the nonobese (1205+/-97 micromol/m2 . min, P < 0.001) subjects. Muscle glucose uptake in the insulin-infused leg was 66% lower in the obese (19+/-4 micromol/kg muscle . min) than in the nonobese (56+/-9 micromol/kg muscle . min, P < 0.005) subjects. Bradykinin increased blood flow during hyperinsulinemia in the obese subjects by 75% from 16+/-1 to 28+/-4 ml/kg muscle . min (P < 0.05), and in the normal subjects by 65% from 23+/-3 to 38+/-9 ml/kg muscle . min (P < 0.05). However, this flow increase required twice as much bradykinin in the obese (51+/-3 microg over 100 min) than in the normal (25+/-1 mug, P < 0.001) subjects. In the obese subjects, blood flow in the bradykinin and insulin-infused leg (28+/-4 ml/kg muscle . min) was comparable to that in the insulin-infused leg in the normal subjects during hyperinsulinemia (24+/-5 ml/kg muscle . min). Despite this, insulin-stimulated glucose uptake remained unchanged in the bradykinin and insulin-infused leg (18+/-4 mumol/kg . min) compared with the insulin-infused leg (19+/-4 micromol/kg muscle . min) in the obese subjects. Insulin-stimulated glucose uptake also was unaffected by bradykinin in the normal subjects (58+/-10 vs. 56+/-9 micromol/kg . min, bradykinin and insulin versus insulin leg). These data demonstrate that obesity is characterized by two distinct defects in skeletal muscle: insulin resistance of cellular glucose extraction and impaired endothelium-dependent vasodilatation. Since a 75% increase in blood flow does not alter glucose uptake, insulin resistance in obesity cannot be overcome by normalizing muscle blood flow.

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.

Intact insulin stimulation of skeletal muscle blood flow, its heterogeneity and redistribution, but not of glucose uptake in non-insulin-dependent diabetes mellitus.

We tested the hypothesis that defects in insulin stimulation of skeletal muscle blood flow, flow dispersion, and coupling between flow and glucose uptake contribute to insulin resistance of glucose uptake in non-insulin-dependent diabetes mellitus (NIDDM). We used positron emission tomography combined with [15O]H2O and [18F]-2-deoxy--glucose and a Bayesian iterative reconstruction algorithm to quantitate mean muscle blood flow, flow heterogeneity, and their relationship to glucose uptake under normoglycemic hyperinsulinemic conditions in 10 men with NIDDM (HbA1c 8.1+/-0.5%, age 43+/-2 yr, BMI 27.3+/-0.7 kg/m2) and in 7 matched normal men. In patients with NIDDM, rates of whole body (35+/-3 vs. 44+/-3 micromol/kg body weight.min, P < 0.05) and femoral muscle (71+/-6 vs. 96+/-7 micromol/kg muscle.min, P < 0.02) glucose uptake were significantly decreased. Insulin increased mean muscle blood flow similarly in both groups, from 1.9+/-0.3 to 2.8+/-0.4 ml/100 g muscle.min in the patients with NIDDM, P < 0.01, and from 2.3+/-0.3 to 3.0+/-0.3 ml/100 g muscle.min in the normal subjects, P < 0.02. Pixel-by-pixel analysis of flow images revealed marked spatial heterogeneity of blood flow. In both groups, insulin increased absolute but not relative dispersion of flow, and insulin-stimulated but not basal blood flow colocalized with glucose uptake. These data provide the first evidence for physiological flow heterogeneity in human skeletal muscle, and demonstrate that insulin increases absolute but not relative dispersion of flow. Furthermore, insulin redirects flow to areas where it stimulates glucose uptake. In patients with NIDDM, these novel actions of insulin are intact, implying that muscle insulin resistance can be attributed to impaired cellular glucose uptake.

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.

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.