18F FDG-PET/CT has poor diagnostic accuracy in diagnosing shoulder PJI.

PURPOSE: Chronic low-grade periprosthetic joint infection (PJI) of a shoulder replacement can be challenging to diagnose. 18F-FDG PET/CT is suggested as a modality to diagnose lower-limb PJI, but no studies on shoulder replacements exist. The aim of this study was therefore to determine the diagnostic accuracy of 18F-FDG PET/CT in diagnosing chronic PJI of the shoulder. METHODS: Patients evaluated for a failed shoulder replacement during a 3-year period were prospectively included in the study. All patients underwent pre-operative 18F-FDG PET/CT, and were evaluated for signs of infection by three independent reviewers using shoulder-specific criteria. Interrater-agreement was calculated between the reviewers. If the patient had revision surgery, biopsy specimens were obtained and cultured with bacterial growth in the cultures serving as gold standard of infection. RESULTS: A total of 86 patients were included in the study. Nine patients were 18F-FDG PET/CT positive for infection, with only three true positive. Using the gold standard, infection was diagnosed after revision surgery in 22 cases. All infections were chronic and caused by low-virulent microbes. The sensitivity of 18F-FDG PET/CT was 0.14 95% CI (0.03-0.36), specificity 0.91 95% CI (0.81-0.97), positive predictive value was 0.40 95% CI (0.15-0.71) and negative predictive value 0.71 95% CI (0.67-0.75). The inter-observer agreement was 0.56 (Fleiss' kappa), indicating moderate agreement of the visual FDG-PET evaluation using the shoulder-specific criteria. CONCLUSION: 18F-FDG PET/CT has poor diagnostic accuracy in diagnosing low-grade PJI of the shoulder. 18F-FDG PET/CT cannot be recommended as a part of the routine preoperative workup to diagnose low-grade infection of a shoulder replacement.

Influence of Cardiac CT based disease severity and clinical symptoms on the diagnostic performance of myocardial perfusion.

We aimed to identify factors influencing the sensitivity of perfusion imaging after an initial positive coronary computed tomography angiography (CCTA) using invasive coronary angiography (ICA) with conditional fractional flow reserve (FFR) as reference. Secondly we aimed to identify factors associated with revascularisation and to evaluate treatment outcome after ICA. We analysed 292 consecutive patients with suspected significant coronary artery disease (CAD) at CCTA, who underwent perfusion imaging with either cardiac magnetic resonance (CMR) or myocardial perfusion scintigraphy (MPS) followed by ICA with conditional FFR. Stratified analysis and uni- and multiple logistic regression analyses were performed to identify predictors of diagnostic agreement between perfusion scans and ICA and predictors of revascularisation. Myocardial ischemia evaluated with perfusion scans was present in 65/292 (22%) while 117/292 (40%) had obstructive CAD evaluated by ICA. Revascularisation rate was 90/292 (31%). The overall sensitivity for perfusion scans was 39% (30-48), specificity 89% (83-93), PPV 69% (57-80) and NPV 68% (62-74). Stratified analysis showed higher sensitivities in patients with multi-vessel disease at CCTA 49% (37-60) and typical chest pain 50% (37-60). Predictors of revascularisation were multi-vessel disease by CCTA (OR 3.51 [1.91-6.48]) and a positive perfusion scan (OR 4.69 [2.49-8.83]). The sensitivity for perfusion scans after CCTA was highest in patients with typical angina and multiple lesions at CCTA and predicted diagnostic agreement between perfusion scans and ICA. Abnormal perfusion and multi vessel disease at CCTA predicted revascularisation.

FDG-PET/CT in the management of lymphomas: current status and future directions.

FDG-PET/CT is the current state-of-the-art imaging in lymphoma and plays a central role in treatment decisions. At diagnosis, accurate staging is crucial for appropriate therapy selection: FDG-PET/CT can identify areas of lymphoma missed by CT alone and avoid under-treatment of patients with advanced disease stage who would have been misclassified as having limited stage disease by CT. Particularly in Hodgkin lymphoma, positive interim FDG-PET/CT scans are adversely prognostic for clinical outcomes and can inform PET-adapted treatment strategies, but such data are less consistent in diffuse large B-cell lymphoma. The use of quantitative FDG-PET/CT metrics using metabolic tumour volume, possibly in combination with other biomarkers, may better define prognostic subgroups and thus facilitate better treatment selection. After chemotherapy, FDG-PET/CT response is predictive of outcome and may identify a subgroup who benefit from consolidative radiotherapy. Novel therapies, in particular immunotherapies, exhibit different response patterns than conventional chemotherapy, which has led to modified response criteria that take into account the risk of transient pseudo-progression. In relapsed lymphoma, FDG-PET/CT after second-line therapy and prior to high-dose therapy is also strongly associated with outcome and may be used to guide intensity of salvage therapy in relapsed Hodgkin lymphoma. Currently, FDG-PET/CT has no role in the routine follow-up after complete metabolic response to therapy, but it remains a powerful tool for excluding relapse if patients develop clinical features suggestive of disease relapse. In conclusion, FDG-PET/CT plays major roles in the various phases of management of lymphoma and constitutes a step towards the pursuit of personalized treatment.

Diagnosing coronary artery disease after a positive coronary computed tomography angiography: the Dan-NICAD open label, parallel, head to head, randomized controlled diagnostic accuracy trial of cardiovascular magnetic resonance and myocardial perfusion scintigraphy.

Aims: Perfusion scans after coronary computed tomography angiography (CCTA) in patients with suspected coronary artery disease (CAD) may reduce unnecessary invasive coronary angiographies (ICAs). However, the diagnostic accuracy of perfusion scans after primary CCTA is unknown. The aim of this study was to determine the diagnostic accuracy of cardiac magnetic resonance (CMR) and myocardial perfusion scintigraphy (MPS) against ICA with fractional flow reserve (FFR) in patients suspected of CAD by CCTA. Methods and results: Included were consecutive patients (1675) referred to CCTA with symptoms of CAD and low/intermediate risk profile. Patients with suspected CAD based on CCTA were randomized 1:1 to CMR or MPS followed by ICA with FFR. Obstructive CAD was defined as FFR ≤ 0.80 or > 90% diameter stenosis by visual assessment. After initial CCTA, 392 patients (23%) were randomized; 197 to CMR and 195 to MPS. Perfusion scans and ICA were completed in 292 patients (CMR 148, MPS 144). Based on the ICA, 117/292 (40%) patients were classified with CAD. Sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) for CMR were 41%, 95% CI [28-54], 84% [75-91], 62% [45-78], and 68% [58-76], respectively. For the MPS group 36% [24-50], 94% [87-98], 81% [61-93], and 68% [59-76], respectively. Conclusion: Patients with low/intermediate CAD risk and a positive CCTA scan represent a challenge to perfusion techniques indicated by the low sensitivity of both CMR and MPS with FFR as a reference. The mechanisms underlying this discrepancy need further investigation.

Genetic Polymorphisms in Organic Cation Transporter 1 Attenuates Hepatic Metformin Exposure in Humans.

Metformin has been used successfully to treat type 2 diabetes for decades. However, the efficacy of the drug varies considerably from patient to patient and this may in part be due to its pharmacokinetic properties. The aim of this study was to examine if common polymorphisms in SLC22A1, encoding the transporter protein OCT1, affect the hepatic distribution of metformin in humans. We performed noninvasive 11 C-metformin positron emission tomography (PET)/computed tomography (CT) to determine hepatic exposure in 12 subjects genotyped for variants in SLC22A1. Hepatic distribution of metformin was significantly reduced after oral intake in carriers of M420del and R61C variants in SLC22A1 without being associated with changes in circulating levels of metformin. Our data show that genetic polymorphisms in transporter proteins cause variation in hepatic exposure to metformin, and it demonstrates the application of novel imaging techniques to investigate pharmacogenetic properties in humans.

Lipoprotein lipase activity does not predict very low-density lipoprotein-triglyceride fatty acid oxidation during exercise.

Exercise lowers plasma triglyceride levels, but the physiological mechanisms remain not fully elucidated. Lipoprotein lipase (LPL) is a key enzyme in facilitating fatty acid uptake from lipoproteins. As exercise increases the efficiency of very low-density lipoprotein-triglyceride (VLDL-TG) oxidation, we hypothesized that muscle LPL activity would be a rate-limiting step and predict VLDL-TG Fatty acids oxidation during exercise. Sixteen healthy, lean subjects (eight men and eight women) were examined before and during an acute exercise bout (90 minutes at 50% of VO2-max). Heparin-releasable LPL activity was measured in muscle and adipose tissue biopsies. Breath 14 CO2 was measured after a primed-constant infusion of ex vivo labeled [14 C]-triolein VLDL-TG. Fractional VLDL-TG storage was measured in adipose tissue biopsies. Exercise did not affect muscle LPL activity (P=.30). No association was observed between muscle LPL activity and VLDL-TG oxidation, neither in the basal state (P=.17) nor during exercise (P=.83). Exercise did not affect upper body or lower body adipose tissue LPL activity (both P=.92). The basal adipose tissue fractional VLDL-TG storage (abdominal.13%±9%; femoral 17%±10% (P=.18)) was not associated with upper body (P=.56) or lower body (P=.44) subcutaneous adipose tissue LPL activity. Muscle LPL activity does not predict VLDL-TG oxidation during rest or exercise. In addition, adipose tissue LPL activity was not associated with VLDL-TG storage during rest. This suggests that LPL activity is present in excess of what is required to facilitate lipid uptake for oxidation during both rest and exercise.

Increased global arterial and subcutaneous adipose tissue inflammation in patients with moderate-to-severe psoriasis.

BACKGROUND: Psoriasis is associated with cardiovascular disease; it has been proposed that increased cardiovascular risk is caused by low-grade systemic inflammation involving organs and tissues other than the skin and joints. OBJECTIVES: To investigate signs of vascular inflammation in untreated patients with moderate-to-severe psoriasis assessed by 18 F-fluorodeoxyglucose (FDG) positron emission tomography-computed tomography. A secondary objective was to assess signs of subcutaneous adipose tissue inflammation. METHODS: This was an observational, controlled clinical study including patients with psoriasis (n = 12, mean ± SD age 61·4 ± 4·1 years, 83% men, mean ± SD Psoriasis Area Severity Index score 14·5 ± 4·3) and matched controls (n = 23, mean ± SD age 60·4 ± 4·5 years, 87% men). Vascular inflammation was measured using aortic maximal standardized uptake values (SUVmax ) and the target-to-background ratio (TBRmax ) of the whole vessel and aortic segments. Subcutaneous adipose tissue inflammation was assessed and compared with regard to SUVmax and TBRmax . RESULTS: Arterial inflammation was increased in patients with psoriasis vs. controls (mean ± SD whole vessel TBRmax 2·46 ± 0·31 vs. 2·09 ± 0·36; P = 0·005). In patients with psoriasis, higher FDG uptake values were observed for all aortic segments except the ascending aorta. Subcutaneous adipose tissue FDG uptake was increased in patients with psoriasis vs. controls (mean ± SD TBRmax 0·49 ± 0·18 vs. 0·31 ± 0·12; P = 0·002). Associations remained significant after adjusting for body mass index and age. CONCLUSIONS: Global arterial inflammation and subcutaneous inflammation were significantly increased in patients with moderate-to-severe psoriasis compared with controls.

Chronic adrenergic stimulation induces brown adipose tissue differentiation in visceral adipose tissue.

BACKGROUND: Recruitment of brown adipose tissue is a promising strategy to treat obesity and Type 2 diabetes, but the physiological effects of a large amount of metabolically active brown adipose tissue in humans are unknown. CASE REPORT: In the present paper, we report a case of massive brown adipose tissue infiltration of the visceral adipose tissue depot in a person with Type 2 diabetes with a catecholamine-secreting paraganglioma. The patient was evaluated with [18F]-fludeoxyglucose positron emission tomography/computed tomography on three occasions: pre-therapy, during α-blockade and postoperatively. During surgery, biopsies of visceral and subcutaneous adipose tissue were obtained and evaluated for brown adipose tissue. At diagnosis, brown adipose tissue glucose uptake, assessed by [18F]-fludeoxyglucose-positron emission tomography, was massively increased. [18F]-fludeoxyglucose uptake was confined to known locations for brown adipose tissue, with additional uptake in the visceral adipose tissue. As a result of increased thermogenesis, resting energy expenditure was doubled. After surgical removal of the tumour, antidiabetic medicine was no longer needed, despite an 8.2-kg weight gain. CONCLUSION: These results show that human visceral adipose tissue holds an unprecedented potential for brown adipogenic differentiation; however, a detrimental effect on glucose metabolism persisted despite massive brown adipose tissue activity, with a doubling of resting energy expenditure.

Sustained AS160 and TBC1D1 phosphorylations in human skeletal muscle 30 min after a single bout of exercise.

BACKGROUND: phosphorylation of AS160 and TBC1D1 plays an important role for GLUT4 mobilization to the cell surface. The phosphorylation of AS160 and TBC1D1 in humans in response to acute exercise is not fully characterized. OBJECTIVE: to study AS160 and TBC1D1 phosphorylation in human skeletal muscle after aerobic exercise followed by a hyperinsulinemic euglycemic clamp. DESIGN: eight healthy men were studied on two occasions: 1) in the resting state and 2) in the hours after a 1-h bout of ergometer cycling. A hyperinsulinemic euglycemic clamp was initiated 240 min after exercise and in a time-matched nonexercised control condition. We obtained muscle biopsies 30 min after exercise and in a time-matched nonexercised control condition (t = 30) and after 30 min of insulin stimulation (t = 270) and investigated site-specific phosphorylation of AS160 and TBC1D1. RESULTS: phosphorylation on AS160 and TBC1D1 was increased 30 min after the exercise bout, whereas phosphorylation of the putative upstream kinases, Akt and AMPK, was unchanged compared with resting control condition. Exercise augmented insulin-stimulated phosphorylation on AS160 at Ser(341) and Ser(704) 270 min after exercise. No additional exercise effects were observed on insulin-stimulated phosphorylation of Thr(642) and Ser(588) on AS160 or Ser(237) and Thr(596) on TBC1D1. CONCLUSIONS: AS160 and TBC1D1 phosphorylations were evident 30 min after exercise without simultaneously increased Akt and AMPK phosphorylation. Unlike TBC1D1, insulin-stimulated site-specific AS160 phosphorylation is modified by prior exercise, but these sites do not include Thr(642) and Ser(588). Together, these data provide new insights into phosphorylation of key regulators of glucose transport in human skeletal muscle.

Postprandial VLDL-triacylglycerol secretion is not suppressed in obese type 2 diabetic men.

AIMS/HYPOTHESIS: Type 2 diabetes is characterised by insulin resistance and increased post-absorptive secretion of VLDL-triacylglycerol (VLDL-TAG). Whether postprandial suppression of endogenous VLDL-TAG secretion is abnormal--a finding that would link hyperlipidaemia and type 2 diabetes--remains unclear. METHODS: Eight type 2 diabetic men and eight healthy men were studied before and after a fat-free test meal (40% of resting energy expenditure). VLDL-TAG kinetics were assessed using a primed-constant infusion of ex vivo labelled [1-(14)C]triolein VLDL-TAG using non-steady-state calculations. RESULTS: Type 2 diabetic men had a higher basal VLDL-TAG secretion rate and concentration than healthy men (mean ± SD secretion rate 137 ± 61 vs 78 ± 30 µmol/min, respectively [p = 0.03]; median concentration 1.03 [range 0.58-1.75] vs 0.33 [0.13-1.14] mmol/l, respectively [p < 0.01]). Postprandially, the VLDL-TAG secretion rate decreased in healthy men (p < 0.01), but remained unchanged in diabetic men (p = 0.47). The VLDL-TAG concentration increased in diabetic men and decreased in healthy men postprandially (p < 0.05). The difference in VLDL-TAG secretion rate between the two groups approached significance (p = 0.06) and the relative change in VLDL-TAG secretion rate was significantly different (p = 0.01) between the two groups. Basal VLDL-TAG clearance was significantly lower in diabetic men (diabetic men 133 [49-390] ml/min; healthy controls 215 [137-933] ml/min [p < 0.05]). After meal ingestion, clearance decreased in healthy men (p = 0.03), but was unchanged in diabetic men (p = 0.58). CONCLUSIONS/INTERPRETATION: Obese type 2 diabetic men have impaired postprandial suppression of VLDL-TAG secretion compared with lean healthy men, contributing to their postprandial lipaemia and hypertriacylglycerolaemia.

Body composition determines direct FFA storage pattern in overweight women.

Direct FFA storage in adipose tissue is a recently appreciated pathway for postabsorptive lipid storage. We evaluated the effect of body fat distribution on direct FFA storage in women with different obesity phenotypes. Twenty-eight women [10 upper body overweight/obese (UBO; WHR >0.85, BMI >28 kg/m(2)), 11 lower body overweight/obese (LBO; WHR <0.80, BMI >28 kg/m(2)), and 7 lean (BMI <25 kg/m(2))] received an intravenous bolus dose of [9,10-(3)H]palmitate- and [1-(14)C]triolein-labeled VLDL tracer followed by upper body subcutaneous (UBSQ) and lower body subcutaneous (LBSQ) fat biopsies. Regional fat mass was assessed by combining DEXA and CT scanning. We report greater fractional storage of FFA in UBSQ fat in UBO women compared with lean women (P < 0.01). The LBO women had greater storage per 10(6) fat cells in LBSQ adipocytes compared with UBSQ adipocytes (P = 0.04), whereas the other groups had comparable storage in UBSQ and LBSQ adipocytes. Fractional FFA storage was significantly associated with fractional VLDL-TG storage in both UBSQ (P < 0.01) and LBSQ (P = 0.03) adipose tissue. In conclusion, UBO women store a greater proportion of FFA in the UBSQ depot compared with lean women. In addition, LBO women store FFA more efficiently in LBSQ fat cells compared with UBSQ fat cells, which may play a role in development of their LBO phenotype. Finally, direct FFA storage and VLDL-TG fatty acid storage are correlated, indicating they may share a common rate-limiting pathway for fatty acid storage in adipose tissue.

Time-course effects of physiological free fatty acid surges on insulin sensitivity in humans.

AIM: Physiological elevations of free fatty acids (FFAs) occur in bell-shaped surges lasting some hours, observed nocturnally, during exercise and inflammation. The time-course effects of such FFA surges on insulin sensitivity are unknown. We therefore aimed to define the effects of a graded 4-h FFA elevation intended to mimick physiological excursions. METHODS: Eight lean, healthy men were studied on two occasions: (1) control (saline) and (2) 4 h graded infusion of intralipid (20%)/heparin. Insulin sensitivity was continuously assessed by isotope dilution (3H-glucose) during an 8 h hyperinsulinemic-euglycaemic clamp (0.5 mU kg(-1) min(-1) ). Phosphorylation of Akt and ERK1/2 was measured in muscle biopsies taken at 0 and 120 min. Inflammatory cytokines were assessed with a Luminex Suspension Array System. RESULTS: Infusion of intralipid caused a bell-shaped increase in FFA levels reaching peak levels ~1.9 mmol L(-1) and markedly impairing insulin sensitivity. Impairment of insulin sensitivity was apparent (P>0.05) 120 min after initiation of FFA infusion, significant after 270 min (P < 0.001) and peaked after 360 min. FFA induced insulin resistance prevailed 210 min after cessation of FFA infusion. No effect was observed on Akt and ERK1/2 phosphorylation. CONCLUSIONS: (1) Physiological FFA elevations require at least 120 min to induce insulin resistance, (2) that insulin resistance peaks 360 min after initiation of FFA exposure and (3) ceases 210 min after termination of the FFA infusion. These observations add to our understanding of FFA induced insulin resistance in relation to circadian variations, exercise, generalized inflammation and exposure to stress hormones such as growth hormone.

Safety and efficacy of ghrelin agonist TZP-101 in relieving symptoms in patients with diabetic gastroparesis: a randomized, placebo-controlled study.

BACKGROUND: Gastroparesis, a chronic disorder of abnormal gastric motility, is common in patients with diabetes mellitus. A synthetic, selective ghrelin receptor agonist, TZP-101, is in clinical development for treatment of gastroparesis. This double-blind, randomized, placebo-controlled study evaluated the safety and efficacy of multiple TZP-101 doses in patients with moderate to severe symptomatic diabetic gastroparesis. METHODS: Patients were admitted to the hospital and adaptively randomized to receive a single 30-min intravenous infusion of 20, 40, 80, 160, 320, or 600 µg kg(-1) TZP-101, (n = 57) or placebo, (n = 19) for four consecutive days. Symptoms were evaluated daily with the patient-rated Gastroparesis Cardinal Symptom Index (GCSI) and Gastroparesis Symptom Assessment (GSA). Clinicians rated gastroparesis symptoms on treatment day 4. KEY RESULTS: The 80 µg kg(-1) dose was identified as the most effective dose. On day 4, there was statistically significant improvement compared with placebo in the severity of GCSI Loss of Appetite and Vomiting scores for that dose group (P = 0.034 and P = 0.006). In addition, at the 80 µg kg(-1) dose, the proportion of patients with at least 50% improvement in vomiting score was significantly different (P = 0.019) compared with placebo. Meal-related GSA scores for Postprandial fullness were significantly improved in the 80 µg kg(-1) TZP-101 group compared with placebo (P = 0.012). Clinicians rated the 80 µg kg(-1) group better improved than placebo for overall symptom assessment (P = 0.047). Safety profiles were similar in the placebo and TZP-101 groups and all doses were well-tolerated. CONCLUSIONS & INFERENCES: TZP-101 appears to be safe, well-tolerated, and effective at acutely addressing several gastroparesis symptoms.

Forearm and leg amino acid metabolism in the basal state and during combined insulin and amino acid stimulation after a 3-day fast.

AIM: Fasting is characterized by a progressive loss of protein, but data on protein kinetics are unclear and few have studied the effects of re-feeding. The present study was designed to test the hypothesis that a combined infusion of insulin and amino acids after fasting would induce compensatory increases in protein synthesis and reductions in protein breakdown at the whole body level and in muscle. METHODS: We included 10 healthy male volunteers and studied them twice: (1) in the post-absorptive state and (2) after 72 h of fasting. Amino acid kinetics was measured using labelled phenylalanine and tyrosine, whole body energy expenditure was assessed and urea nitrogen synthesis rates were calculated. RESULTS: After fasting we observed an increase in arterial blood concentration of branched chain amino acids and a decrease in gluconeogenic amino acids (P < 0.05). Isotopically determined whole body, forearm and leg phenylalanine fluxes were unaltered apart from a 30% decrease in phenylalanine-to-tyrosine conversion (2.0 vs. 1.4 mumol kg(-1) h(-1), P < 0.01). During infusion of insulin and amino acids, amino acid concentrations increased. CONCLUSION: Our data indicate that after a 72-h fast basal and insulin/amino acid-stimulated regional phenylalanine fluxes in leg and forearm muscle are unaltered. During fasting concentrations of gluconeogenic amino acids decrease and hepatic and/or renal phenylalanine-to-tyrosine conversion decreases. Thus, as opposed to glucose and lipid metabolism, fasting does not induce insulin resistance as regards amino acid metabolism.

Ghrelin receptor agonist (TZP-101) accelerates gastric emptying in adults with diabetes and symptomatic gastroparesis.

BACKGROUND: TZP-101 is a synthetic, selective ghrelin agonist in development for gastroparesis. AIM: To assess safety and effects of TZP-101 in diabetes patients with symptomatic gastroparesis. METHODS: Adults with type 1 or type 2 diabetes mellitus received placebo and TZP-101 (80, 160, 320 or 600 microg/kg) infusions in a cross-over manner following a radiolabelled meal. Blood glucose levels were stabilized using a hyperinsulinemic-euglycemic clamp. Primary endpoints were gastric half emptying and latency times. Secondary measures included assessment of gastroparesis symptoms and endocrine responses. RESULTS: Ten patients with type 1 (n = 7) or 2 (n = 3) diabetes, moderate-to-severe gastroparesis symptoms and > or =29% retention 4 h after a radiolabelled solid meal were enrolled. TZP-101 produced significant reductions in solid meal half-emptying (20%, P = 0.043) and latency (34%, P = 0.037) times vs. placebo. Reductions in overall postmeal symptom intensity (24%) and postprandial fullness (37%) following TZP-101 infusion were not statistically significant. Most adverse events were mild and self-limiting and there were no identifiable differences in numbers or types of adverse events between TZP-101 and placebo. CONCLUSIONS: This proof-of-concept study demonstrates that the ghrelin agonist TZP-101 is well-tolerated in diabetes patients with moderate-to-severe chronic gastroparesis and shows statistically significant improvements in gastric emptying.

Visceral fat mass is a strong predictor of circulating ghrelin levels in premenopausal women.

OBJECTIVE: A well known inverse relationship exists between obesity and circulating ghrelin concentrations. However, obesity is a heterogeneous disease entity and upper-body obesity (UBO) is associated with more profound metabolic disturbances than lower-body obesity (LBO). We therefore aimed to investigate the impact of body composition on circulating ghrelin levels in women spanning a wide range of body composition phenotypes. SUBJECTS AND METHODS: Ten (UBO; waist-to-hip ratio (WHR) >0.85, body mass index (BMI) >28 kg/m(2)), ten LBO (WHR <0.80, BMI >28 kg/m(2)) and ten lean women (BMI<25 kg/m(2)) were studied. Total ghrelin levels were measured under basal and hyperinsulinemic (0.6 mU/kg per min) conditions. Body fat distribution was determined by dual X-ray absorptiometry in combination with computed tomography at the L2-L3 level. RESULTS: As expected, an inverse correlation existed between basal ghrelin concentration and BMI (r=-0.40, P=0.03) and total fat mass (r=-0.39, P=0.04). Visceral fat mass was a strong predictor (r=-0.56, P=0.003) of circulating ghrelin levels, even when adjusted for BMI (P=0.02) or body composition group (P=0.04). The suppressive effect of insulin on ghrelin concentration was significantly diminished in the UBO compared with the lean controls (P=0.012) and a highly significant inverse correlation existed with visceral fat mass (r=-0.52, P=0.004). CONCLUSIONS: Visceral fat mass is a strong predictor of basal ghrelin concentrations and also attenuates the suppressive effect of insulin on ghrelin concentrations. These data provide further evidence that the UBO phenotype is associated with more profound metabolic abnormalities than obesity per se.

Dose-response effects of free fatty acids on amino acid metabolism and ureagenesis.

AIM: Free fatty acids (FFAs) are important fuels and have vital protein-sparing effects, particularly during conditions of metabolic stress and fasting. However, it is uncertain whether these beneficial effects are evident throughout the physiological range or only occur at very high FFA concentrations. It is also unclear whether secondary alterations in hormone levels and ketogenesis play a role. We therefore aimed at describing dose-response relationships between amino acid metabolism and circulating FFA concentrations at clamped hormone levels. METHODS: Eight healthy men were studied on four occasions (6 h basal, 2 h glucose clamp). Endogenous lipolysis was blocked with acipimox and Intralipid was infused at varying rates (0, 3, 6 or 12 microL kg(-1) min(-1)) to obtain four different levels of circulating FFAs. Endogenous growth hormone, insulin and glucagon secretion was blocked by somatostatin (300 microg h(-1)) and replaced exogenously. 15N-phenylalanine, 2H4-tyrosine and 13C-urea were infused continuously to assess protein turnover and ureagenesis. RESULTS: We obtained four distinct levels of FFA concentrations ranging from 0.03 to 2.1 mmol L(-1) and 3-hydroxybutyrate concentrations from 10 to 360 micromol L(-1). Whole-body phenylalanine turnover and phenylalanine-to-tyrosine degradation decreased with increasing FFA levels as did insulin-stimulated forearm fluxes of phenylalanine. Phenylalanine, tyrosine and urea concentrations also decreased progressively, whereas urea turnover was unperturbed. CONCLUSION: Circulating FFAs decrease amino acid concentrations and inhibit whole-body phenylalanine fluxes and phenylalanine-to-tyrosine conversion. Our data cover FFA concentrations from 0 to 2 mmol L(-1) and indicate that FFAs exert their protein conserving effects in the upper physiological range (>1.5 mmol L(-1)).