[18F]Fluoride uptake in various bone types and soft tissues in rat.

BACKGROUND: In the development of new 18F-labelled tracers, it is important to assess the amount of released [18F]fluoride taken up in the bones of experimental animals because all 18F-labelled PET-tracers are prone, to lesser or higher degree, to undergo defluorination, with subsequent release of [18F]fluoride during scanning. However, the pharmacokinetics of [18F]fluoride in bones and other organs of healthy rats have not been well documented in a comprehensive manner. We aimed to study pharmacokinetics of [18F]NaF in rats in order to increase our understanding of the biodistribution of [18F]fluoride originating from defluorination of 18F-labelled tracers. We studied [18F]fluoride uptake in Sprague Dawley rat bones, including the epiphyseal parts of the tibia and radius, the mandible, ilium, lumbar vertebrae, costochondral joints, tibia, radius, and ribs, with 60-min in vivo PET/CT imaging. Kinetic parameters, K1, Ki, Ki/K1, and k3 were calculated with a three-compartment model. In addition, separate groups of male and female rats were studied with ex vivo bone and soft tissue harvesting and gamma counting over a 6-h period. RESULTS: [18F]fluoride perfusion and uptake varied among the different bones. [18F]fluoride uptake was higher in trabecular bones, due to high perfusion and osteoblastic activity, compared to cortical bones. In soft tissues, the organ-to-blood uptake ratios increased over time in the eyes, lungs, brain, testes, and ovaries during the 6 h study period. CONCLUSION: Understanding the pharmacokinetics of [18F]fluoride in various bones and soft tissues is highly useful for assessing 18F-labelled radiotracers that release [18F]fluoride.

Associations Between Brain Gray Matter Volumes and Adipose Tissue Metabolism in Healthy Adults.

OBJECTIVE: Gray matter (GM) volume in different brain loci has been shown to vary in obesity and diabetes, and elevated fasting plasma nonesterified fatty acid (NEFA) levels have been suggested as one potential mechanism. The hypothesis presented in this study is that brown adipose tissue (BAT) activity may correlate with GM volume in areas negatively associated with obesity and diabetes. METHODS: A total of 36 healthy patients (M/F: 12/24, age 39.7 ± 9.4 years, BMI 27.5 ± 5.6 kg/m2 ) were imaged with positron emission tomography using fatty acid analog [18 F]FTHA to measure NEFA uptake and with [15 O]H2 O to measure perfusion during cold exposure, at room temperature during fasting, or during a postprandial state. A 2-hour hyperinsulinemic euglycemic clamp was performed to measure whole-body insulin sensitivity (M value, mean 7.6 ± 3.9 mg/kg/min). T1-weighted magnetic resonance imaging at 1.5 T was performed on all patients. RESULTS: BAT NEFA uptake was associated directly with GM volume in anterior cerebellum and occipital lobe (P ≤ 0.04) when adjusted for age, gender, and intra-abdominal fat volume and with anterior cerebellum, limbic lobe, and temporal lobe GM volumes when adjusted for M value. CONCLUSIONS: BAT NEFA metabolism may participate in protection from cognitive degeneration associated with cardiometabolic risk factors, such as central obesity and insulin resistance. Potential causal relationships between BAT activity and GM volumes remain to be examined.

Changes in electrocardiogram parameters during acute nonshivering cold exposure and associations with brown adipose tissue activity, plasma catecholamine levels, and brachial blood pressure in healthy adults.

BACKGROUND: Sympathetic activity causes changes in electrocardiogram (ECG) during cold exposure and the changes have been studied mostly during hypothermia and less during mild acute nonshivering cold exposure. Cold-induced sympathetic activity also activates brown adipose tissue (BAT) and increases arterial blood pressure (BP) and plasma catecholamine levels. We examined changes in ECG parameters during acute nonshivering cold exposure and their associations with markers of sympathetic activity during cold exposure: brachial blood pressure (BP), plasma catecholamine levels, and BAT activity measured by positron emission tomography (PET). METHODS AND RESULTS: Healthy subjects (M/F = 13/24, aged 20-55 years) were imaged with [15 O]H2 O (perfusion, N = 37) and [18 F]FTHA to measure plasma nonesterified fatty acid uptake (NEFA uptake, N = 37) during 2-h nonshivering cold exposure. 12-lead ECG (N = 37), plasma catecholamine levels (N = 17), and brachial BP (N = 31) were measured at rest in room temperature (RT) and re-measured after a 2-h nonshivering cold exposure. There were significant differences between RT and cold exposure in P axis (35.6 ± 26.4 vs. 50.8 ± 22.7 degrees, p = 0.005), PR interval (177.7 ± 24.6 ms vs.163.0 ± 28.7 ms, p = 0.001), QRS axis (42.1 ± 31.3 vs. 56.9 ± 24.1, p = 0.003), and QT (411.7 ± 25.5 ms vs. 434.5 ± 39.3 ms, p = 0.001). There was no significant change in HR, QRS duration, QTc, JTc, and T axis during cold exposure. Systolic BP (127.2 ± 15.7 vs. 131.8 ± 17.9 mmHg, p = 0.008), diastolic BP (81.7 ± 12.0 vs. 85.4 ± 13.0 mmHg, p = 0.02), and plasma noradrenaline level increased during cold exposure (1.97 ± 0.61 vs. 5.07 ± 1.32 µmol/L, p = 0.001). Cold-induced changes in ECG parameters did not correlate with changes in BAT activity, brachial BP, plasma catecholamines, or skin temperature. CONCLUSIONS: During short-term nonshivering cold exposure, there were increases in P axis, PR interval, QRS axis, and QT compared to RT in healthy adults. Cold-induced changes in ECG parameters did not correlate with BAT activity, brachial BP, or plasma catecholamine levels which were used as markers of cold-induced sympathetic activity.

Therapeutic Antibody Against Phosphorylcholine Preserves Coronary Function and Attenuates Vascular 18F-FDG Uptake in Atherosclerotic Mice.

This study showed that treatment with a therapeutic monoclonal immunoglobulin-G1 antibody against phosphorylcholine on oxidized phospholipids preserves coronary flow reserve and attenuates atherosclerotic inflammation as determined by the uptake of 18F-fluorodeoxyglucose in atherosclerotic mice. The noninvasive imaging techniques represent translational tools to assess the efficacy of phosphorylcholine-targeted therapy on coronary artery function and atherosclerosis in clinical studies.

High Brown Fat Activity Correlates With Cardiovascular Risk Factor Levels Cross-Sectionally and Subclinical Atherosclerosis at 5-Year Follow-Up.

OBJECTIVE: Brown adipose tissue (BAT) activity correlates negatively with obesity and insulin resistance, and BAT has been suggested to act as a protective factor against atherogenesis. We aimed to examine subclinical atherosclerosis and risk factor levels in a group of individuals who had 5 years earlier participated in positron-emission tomography studies with measurements of BAT activity. Approach and Results: Study cohort (males/females=5/26, baseline age 41.4±7.9 years; body mass index, 26.8±6.3 kg/m2) underwent positron-emission tomography imaging at baseline with [18F] FDG (glucose uptake) and [15O] H2O (perfusion) to measure BAT activity during cold exposure. At 5-year follow-up, ultrasound was performed to measure carotid intima-media thickness, carotid distensibility (a marker of arterial elasticity), and brachial flow-mediated dilation (an estimate of endothelial function). Fasting plasma lipids and hemoglobin A1c were measured from venous samples at baseline and at follow-up. Median values were used as cut points for high cold-induced BAT activity (BAT glucose uptake >2.40 µmoL/100 g per minute and perfusion >8.4 mL/100 g per minute). Baseline cold-induced BAT glucose uptake and perfusion correlated directly with carotid distensibility and inversely with mean bulbus intima-media thickness and maximum intima-media thickness (P always ≤0.02). Baseline body mass index, plasma triglycerides, and HbA1c correlated negatively with BAT glucose uptake and perfusion in cold (P always ≤0.048). Correlations between cold-induced BAT activity, cardiovascular risk factors, and atherosclerosis were attenuated with corrections for multiple comparisons. CONCLUSIONS: Cold-induced BAT activity at baseline seems to correlate with lower levels of conventional cardiovascular risk factors at baseline and with lower carotid intima-media thickness and higher carotid elasticity at 5-year follow-up.

Effects of short-term sprint interval and moderate-intensity continuous training on liver fat content, lipoprotein profile, and substrate uptake: a randomized trial.

Type 2 diabetes (T2D) and increased liver fat content (LFC) alter lipoprotein profile and composition and impair liver substrate uptake. Exercise training mitigates T2D and reduces LFC, but the benefits of different training intensities in terms of lipoprotein classes and liver substrate uptake are unclear. The aim of this study was to evaluate the effects of moderate-intensity continuous training (MICT) or sprint interval training (SIT) on LFC, liver substrate uptake, and lipoprotein profile in subjects with normoglycemia or prediabetes/T2D. We randomized 54 subjects (normoglycemic group, n = 28; group with prediabetes/T2D, n = 26; age = 40-55 yr) to perform either MICT or SIT for 2 wk and measured LFC with magnetic resonance spectroscopy, lipoprotein composition with NMR, and liver glucose uptake (GU) and fatty acid uptake (FAU) using PET. At baseline, the group with prediabetes/T2D had higher LFC, impaired lipoprotein profile, and lower whole body insulin sensitivity and aerobic capacity compared with the normoglycemic group. Both training modes improved aerobic capacity (P < 0.001) and lipoprotein profile (reduced LDL and increased large HDL subclasses; all P < 0.05) with no training regimen (SIT vs. MICT) or group effect (normoglycemia vs. prediabetes/T2D). LFC tended to be reduced in the group with prediabetes/T2D compared with the normoglycemic group posttraining (P = 0.051). When subjects were divided according to LFC (high LFC, >5.6%; low LFC, <5.6%), training reduced LFC in subjects with high LFC (P = 0.009), and only MICT increased insulin-stimulated liver GU (P = 0.03). Short-term SIT and MICT are effective in reducing LFC in subjects with fatty liver and in improving lipoprotein profile regardless of baseline glucose tolerance. Short-term MICT is more efficient in improving liver insulin sensitivity compared with SIT. NEW & NOTEWORTHY In the short term, both sprint interval training and moderate-intensity continuous training (MICT) reduce liver fat content and improve lipoprotein profile; however, MICT seems to be preferable in improving liver insulin sensitivity.

Influence of transport line material on the molar activity of cyclotron produced [18F]fluoride.

INTRODUCTION: Production of fluorine-18-labeled radiopharmaceuticals is always associated with the varying levels of the same compound containing stable fluorine-19. In practice, this affects the molar activity (Am), defined as amount of radioactivity divided by the molar quantity (Bq/mol). We have focused on studying how the material of the transport tubing connecting the cyclotron target chamber to the synthesis device affects the concentration of fluoride in the water arriving to the reaction vessel and subsequently the Am of the fluorine-18 labeled radiopharmaceuticals produced. METHODS: Batches of irradiated and non-irradiated water were analyzed for fluoride content after being transported via non-fluorinated (PEEK, PP) and fluorinated (PTFE, ETFE) tubing or using no tubing at all. Am for the [18F]fluoride was determined and compared with the Am of [18F]fluciclatide, synthesized from the same [18F]fluoride containing batches of water. RESULTS: Significantly higher concentrations of fluoride were seen in irradiated water that was transported in fluorinated tubing compared to non-irradiated water transported in tubing of the same material. This elevation of fluoride concentration is presumably caused by the interaction of ionizing radiation with the fluorinated tubing used between the target chamber and hot cell. Likewise, a significant difference was seen for PEEK tubing (non-fluorinated). This could be due to the fact that fluorine containing compounds are used in the manufacture of PEEK. When using fluorinated tubing for transport of the irradiated water, the resulting fluciclatide concentrations were significantly higher compared to when using non-fluorinated tubing. No significant difference was seen between fluciclatide concentrations when PTFE or ETFE tubing was compared to each other. Using no tubing resulted in lowest fluciclatide concentration. CONCLUSIONS: Fluorinated tubing is a source of stable fluoride, and Am can be increased by using non-fluorinated transport tubing. Of all the tubing materials studied PP is preferred.

Automated production of [18 F]FTHA according to GMP.

14-(R,S)-[18 F]fluoro-6-thia-heptadecanoic acid is a tracer for fatty acid imaging by positron emission tomography. High demand for this tracer required us to replace semiautomatic synthesis with a fully automated procedure. An automated synthesis device was constructed in-house for multistep nucleophilic 18 F-fluorination and a control system was developed. The synthesis device was combined with a sterile filtration unit and both were qualified. 14-(R,S)-[18 F]fluoro-6-thia-heptadecanoic acid was produced according to good manufacturing practice guidelines set by the European Union. The synthesis includes an initial nucleophilic labelling reaction, deprotection, preparative HPLC separation, purification of the final product, and formulation for injection. The duration and temperature of the reaction and hydrolysis were optimized, and the radiochemical stability of the formulated product was determined. The rotary evaporator used to evaporate the solvent after HPLC purification was replaced with solid phase extraction purification. We also replaced the human serum albumin used in the earlier procedure with a phosphate buffer-ascorbic acid mixture in the final formulation solution. From 2011 to 2016, we performed 219 synthesis procedures, 94% of which were successful. The radiochemical yield of 14-(R,S)-[18 F]fluoro-6-thia-heptadecanoic acid, decay-corrected to the end of bombardment, was 13% ± 6.3%. The total amount of formulated end product was 1.7 ± 0.8 GBq at end of synthesis.

Effects of atorvastatin and diet interventions on atherosclerotic plaque inflammation and [18F]FDG uptake in Ldlr-/-Apob100/100 mice.

BACKGROUND AND AIMS: Uptake of the positron emission tomography (PET) tracer 2-deoxy-2-[18F]-fluoro-d- glucose ([18F]FDG) into macrophages is a sensitive marker of inflammation in atherosclerosis. To assess the anti-inflammatory effects of statins, we studied whether atorvastatin therapy reduces aortic [18F]FDG uptake in hypercholesterolemic mice deficient in low-density lipoprotein receptor (Ldlr), and expressing only apolipoprotein B-100 (Ldlr-/-Apob100/100). METHODS: Thirty-six Ldlr-/-Apob100/100 mice were fed a high-fat diet (HFD) for 12 weeks and then allocated to receive a HFD (n = 13), chow diet (Chow, n = 12), or HFD with added atorvastatin (HFD + A, n = 11), for another 12 weeks. In addition to aortic histopathology, [18F]FDG uptake was studied in vivo using PET/computed tomography (CT), and ex vivo by gamma counting of excised aorta. RESULTS: Total cholesterol levels were lower in the Chow and HFD + A groups than in the HFD group (10 ± 3.2, 23 ± 4.9 and 34 ± 9.2 mmol/l, respectively), with the Chow group also showing a lower plaque burden and lower numbers of macrophages in the lesions. Compared to the HFD group, [18F]FDG uptake in the aorta (normalized for blood) was lower in the Chow group in both in vivo (2.1 ± 0.21 vs. 1.7 ± 0.25, p = 0.018) and ex vivo (5.2 ± 2.3 vs. 2.8 ± 0.87, p = 0.011) analyses, whereas atorvastatin had no effect on uptake (2.1 ± 0.42 in vivo and 3.9 ± 1.8 ex vivo). [18F]FDG uptake correlated with plasma total cholesterol levels. CONCLUSIONS: Atorvastatin therapy did not show cholesterol-independent effects on inflammation in atherosclerotic lesions in Ldlr-/-Apob100/100 mice, as determined by histology and [18F]FDG PET, whereas a cholesterol-lowering diet intervention was effective.

Two weeks of moderate-intensity continuous training, but not high-intensity interval training, increases insulin-stimulated intestinal glucose uptake.

Similar to muscles, the intestine is also insulin resistant in obese subjects and subjects with impaired glucose tolerance. Exercise training improves muscle insulin sensitivity, but its effects on intestinal metabolism are not known. We studied the effects of high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) on intestinal glucose and free fatty acid uptake from circulation in humans. Twenty-eight healthy, middle-aged, sedentary men were randomized for 2 wk of HIIT or MICT. Intestinal insulin-stimulated glucose uptake and fasting free fatty acid uptake from circulation were measured using positron emission tomography and [18F]FDG and [18F]FTHA. In addition, effects of HIIT and MICT on intestinal GLUT2 and CD36 protein expression were studied in rats. Training improved aerobic capacity (P = 0.001) and whole body insulin sensitivity (P = 0.04), but not differently between HIIT and MICT. Insulin-stimulated glucose uptake increased only after the MICT in the colon (HIIT = 0%; MICT = 37%) (P = 0.02 for time × training) and tended to increase in the jejunum (HIIT = -4%; MICT = 13%) (P = 0.08 for time × training). Fasting free fatty acid uptake decreased in the duodenum in both groups (HIIT = -6%; MICT = -48%) (P = 0.001 time) and tended to decrease in the colon in the MICT group (HIIT = 0%; MICT = -38%) (P = 0.08 for time × training). In rats, both training groups had higher GLUT2 and CD36 expression compared with control animals. This study shows that already 2 wk of MICT enhances insulin-stimulated glucose uptake, while both training modes reduce fasting free fatty acid uptake in the intestine in healthy, middle-aged men, providing an additional mechanism by which exercise training can improve whole body metabolism.NEW & NOTEWORTHY This is the first study where the effects of exercise training on the intestinal substrate uptake have been investigated using the most advanced techniques available. We also show the importance of exercise intensity in inducing these changes.

18-kDa translocator protein ligand 18F-FEMPA: Biodistribution and uptake into atherosclerotic plaques in mice.

BACKGROUND: Radioligands of 18-kDa translocator protein (TSPO) expressed on activated macrophages are a potential approach for imaging of inflammation in atherosclerosis. We evaluated a novel TSPO-targeted tracer 18F-FEMPA for the detection of atherosclerotic plaque inflammation in mice. METHODS AND RESULTS: The distribution kinetics of 18F-FEMPA was evaluated by in vivo PET/CT imaging. 18F-FEMPA uptake was compared in atherosclerotic (LDLR-/-ApoB100/100, n = 10) and healthy mice (C57BL/6 N, n = 7) ex vivo at twenty minutes post-injection. Biodistribution was analyzed from harvested tissue samples, and aortas were sectioned for autoradiography. Aortas of LDLR-/-ApoB100/100 mice showed large, macrophage-rich atherosclerotic plaques. In vivo, 18F-FEMPA showed rapid blood clearance but no difference in aortic uptake between atherosclerotic and healthy mice. In the mice studied ex vivo at 20 minutes post-injection, quantification of radioactivity in the whole aorta showed 1.3-fold higher 18F-FEMPA accumulation in atherosclerotic than healthy mice (P = .028). Autoradiography showed higher tracer uptake in plaque areas with high macrophage content as compared with areas of no macrophages (count densities 190 ± 54 vs 40 ± 13 PSL/mm2, P < .001), but the uptake in the plaques was not higher than in the normal vessel wall (230 ± 78 PSL/mm2). In vitro blocking showed specific accumulation in mouse and human atherosclerotic plaques. Immunohistochemistry confirmed co-localization of TSPO and macrophages. CONCLUSIONS: 18F-FEMPA shows rapid blood clearance and uptake in the mouse aorta. Uptake in atherosclerotic plaques correlated with the amount of macrophages, but did not exceed that in the normal vessel wall.

Parametric Binding Images of the TSPO Ligand 18F-DPA-714.

18F-labeled N,N-diethyl-2-(2-[4-(2-fluoroethoxy)phenyl]-5,7-dimethylpyrazolo[1,5-α]pyrimidine-3-yl)acetamide (DPA-714) is a radioligand for the 18-kDa translocator protein. The purpose of the present study was to identify the best method for generating quantitative parametric images of 18F-DPA-714 binding. METHODS: Ninety-minute dynamic 18F-DPA-714 PET scans with full arterial sampling from 6 healthy subjects and 9 Alzheimer disease (AD) patients were used. Plasma-input-based Logan graphical analysis and spectral analysis were used to generate parametric volume of distribution (VT) images. Five versions of Ichise, reference Logan, and 2 basis function implementations (receptor parametric mapping and simplified reference tissue model 2 [SRTM2]) of SRTM, all using gray matter cerebellum as the reference region, were applied to generate nondisplaceable binding potential (BPND) images. RESULTS: Plasma-input Logan analysis (r2 = 0.99; slope, 0.88) and spectral analysis (r2 = 0.99, slope, 0.93) generated estimates of VT that correlated well with values obtained using nonlinear regression. BPND values generated using SRTM2 (r2 = 0.83; slope, 0.95) and reference Logan analysis (r2 = 0.88; slope, 1.01) correlated well with nonlinear regression-based estimates. CONCLUSION: Both Logan analysis and spectral analysis can be used to obtain quantitatively accurate VT images of 18F-DPA-714. In addition, SRTM2 and reference Logan analysis can provide accurate BPND images. These parametric images could be used for voxel-based comparisons.

Human brown adipose tissue [(15)O]O2 PET imaging in the presence and absence of cold stimulus.

PURPOSE: Brown adipose tissue (BAT) is considered a potential target for combatting obesity, as it produces heat instead of ATP in cellular respiration due to uncoupling protein-1 (UCP-1) in mitochondria. However, BAT-specific thermogenic capacity, in comparison to whole-body thermogenesis during cold stimulus, is still controversial. In our present study, we aimed to determine human BAT oxygen consumption with [(15)O]O2 positron emission tomography (PET) imaging. Further, we explored whether BAT-specific energy expenditure (EE) is associated with BAT blood flow, non-esterified fatty acid (NEFA) uptake, and whole-body EE. METHODS: Seven healthy study subjects were studied at two different scanning sessions, 1) at room temperature (RT) and 2) with acute cold exposure. Radiotracers [(15)O]O2, [(15)O]H2O, and [(18)F]FTHA were given for the measurements of BAT oxygen consumption, blood flow, and NEFA uptake, respectively, with PET-CT. Indirect calorimetry was performed to assess differences in whole-body EE between RT and cold. RESULTS: BAT-specific EE and oxygen consumption was higher during cold stimulus (approx. 50 %); similarly, whole-body EE was higher during cold stimulus (range 2-47 %). However, there was no association in BAT-specific EE and whole-body EE. BAT-specific EE was found to be a minor contributor in cold induced whole-body thermogenesis (almost 1 % of total whole-body elevation in EE). Certain deep muscles in the cervico-thoracic region made a major contribution to this cold-induced thermogenesis (CIT) without any visual signs or individual perception of shivering. Moreover, BAT-specific EE associated with BAT blood flow and NEFA uptake both at RT and during cold stimulus. CONCLUSION: Our study suggests that BAT is a minor and deep muscles are a major contributor to CIT. In BAT, both in RT and during cold, cellular respiration is linked with circulatory NEFA uptake.

Resistance training enhances insulin suppression of endogenous glucose production in elderly women.

An altered prenatal environment during maternal obesity predisposes offspring to insulin resistance, obesity, and their consequent comorbidities, type 2 diabetes and cardiovascular disease. Telomere shortening and frailty are additional risk factors for these conditions. The aim of this study was to evaluate the effects of resistance training on hepatic metabolism and ectopic fat accumulation. Thirty-five frail elderly women, whose mothers' body mass index (BMI) was known, participated in a 4-mo resistance training program. Endogenous glucose production (EGP) and hepatic and visceral fat glucose uptake were measured during euglycemic hyperinsulinemia with [(18)F]fluorodeoxyglucose and positron emission tomography. Ectopic fat was measured using magnetic resonance spectroscopy and imaging. We found that the training intervention reduced EGP during insulin stimulation [from 5.4 (interquartile range 3.0, 7.0) to 3.9 (-0.4, 6.1) µmol·kg body wt(-1)·min(-1), P = 0.042] in the whole study group. Importantly, the reduction was higher among those whose EGP was more insulin resistant at baseline (higher than the median) [-5.6 (7.1) vs. 0.1 (5.4) µmol·kg body wt(-1)·min(-1), P = 0.015]. Furthermore, the decrease in EGP was associated with telomere elongation (r = -0.620, P = 0.001). The resistance training intervention did not change either hepatic or visceral fat glucose uptake or the amounts of ectopic fat. Maternal obesity did not influence the studied measures. In conclusion, resistance training improves suppression of EGP in elderly women. The finding of improved insulin sensitivity of EGP with associated telomere lengthening implies that elderly women can reduce their risk for type 2 diabetes and cardiovascular disease with resistance training.

Effect of Bariatric Surgery on Adipose Tissue Glucose Metabolism in Different Depots in Patients With or Without Type 2 Diabetes.

OBJECTIVE: We investigated fat distribution and tissue-specific insulin-stimulated glucose uptake (GU) in seven fat compartments (visceral and subcutaneous) and skeletal muscle in morbidly obese patients with (T2D) and without (ND) type 2 diabetes before and 6 months after bariatric surgery. RESEARCH DESIGN AND METHODS: A total of 23 obese patients (BMI 43.0 ± 3.6 kg/m(2); 9 T2D and 14 ND) were recruited from a larger, randomized multicenter SLEEVEPASS study. MRI (for fat distribution) and [(18)F]-fluorodeoxyglucose PET (for GU) studies were performed for the obese patients before and 6 months postsurgery; 10 lean subjects served as control subjects and were studied once. RESULTS: At baseline, visceral fat GU was 30 ± 7% of muscle GU in control subjects and 57 ± 5% in obese patients. Visceral and deep subcutaneous fat were more abundant (despite same total fat mass) and less insulin sensitive in T2D than ND; in both, GU was impaired compared with control subjects. Postsurgery, visceral fat mass decreased (∼40%) more than subcutaneous fat (7%). Tissue-specific GU was improved, but not normalized, at all sites in T2D and ND alike. The contribution of visceral fat to whole-body GU was greater in T2D than ND but decreased similarly with surgery. Subcutaneous fat made a fourfold greater contribution to whole-body GU in obese versus lean subjects (15% vs. 4%) both before and after surgery. CONCLUSIONS: Bariatric surgery leads to sustained weight loss and improves tissue-specific glucose metabolism in morbidly obese patients. We conclude that 1) enhanced visceral fat accumulation is a feature of T2D, 2) severe obesity compromises muscle insulin sensitivity more than fat insulin sensitivity, and 3) fat mass expansion is a sink for plasma glucose.

Resistance training improves skeletal muscle insulin sensitivity in elderly offspring of overweight and obese mothers.

AIMS/HYPOTHESIS: Maternal obesity predisposes offspring to adulthood morbidities, including type 2 diabetes. Type 2 diabetes and insulin resistance have been associated with shortened telomere length. First, we aimed to investigate whether or not maternal obesity influences insulin sensitivity and its relationship with leucocyte telomere length (LTL) in elderly women. Second, we tested whether or not resistance exercise training improves insulin sensitivity in elderly frail women. METHODS: Forty-six elderly women, of whom 20 were frail offspring of lean/normal weight mothers (OLM, BMI ≤26.3 kg/m2) and 17 were frail offspring of overweight/obese mothers (OOM,BMI ≥28.1 kg/m2), were studied before and after a 4 month resistance training (RT) intervention. Muscle insulin sensitivity of glucose uptake was measured using 18F-fluoro-2-deoxyglucose and positron emission tomography with computed tomography during a hyperinsulinaemic­euglycaemic clamp. Muscle mass and lipid content were measured using magnetic resonance and LTL was measured using real-time PCR. RESULTS: The OOM group had lower thigh muscle insulin sensitivity compared with the OLM group (p=0.048) but similar whole body insulin sensitivity. RT improved whole body and skeletal muscle insulin sensitivity in the OOM group only (p=0.004 and p=0.013, respectively), and increased muscle mass in both groups (p <0 .01). In addition, in the OOM group, LTL correlated with different thigh muscle groups insulin sensitivity (ρ ≥ 0.53; p ≤ 0.05). Individuals with shorter LTL showed a higher increase in skeletal muscle insulin sensitivity after training (ρ ≥ −0.61; p ≤ 0.05). CONCLUSIONS/INTERPRETATION: Maternal obesity and having telomere shortening were associated with insulin resistance in adult offspring. A resistance exercise training programme may reverse this disadvantage among offspring of obese mothers. Trial registration: ClinicalTrials.gov NCT01931540.

68Ga-DOTA-Siglec-9--a new imaging tool to detect synovitis.

INTRODUCTION: Vascular adhesion protein-1 (VAP-1) is an adhesion molecule, which upon inflammation is rapidly translocated from intracellular sources to the endothelial cell surface. We have recently discovered that sialic acid- binding immunoglobulin-like lectin 9 (Siglec-9) is a leukocyte ligand of VAP-1 and that 68Ga-labeled Siglec-9 motif peptide facilitates in vivo imaging of inflammation. This study evaluated the feasibility of 68Ga-DOTA-Siglec-9 positron emission tomography (PET) for the assessment of synovitis. METHODS: Rabbits with synovial inflammation were injected with 18F-FDG or 68Ga-DOTA-Siglec-9 and studied by gamma counting and autoradiography. Certain rabbits were also examined with magnetic resonance imaging (MRI). After PET imaging, rabbits were intravenously administered with anti-VAP-1 antibody to evaluate luminal expression of VAP-1 by immunohistochemistry. Finally, binding of Siglec-9 peptide and VAP-1 positive vessels were evaluated by double staining of rheumatoid arthritis synovium. RESULTS: Intra-articular injection of hemagglutinin induced mild synovial inflammation in rabbit knee with luminal expression of VAP-1. Synovitis was clearly visualized by 68Ga-DOTA-Siglec-9 PET in addition to 18F-FDG-PET and MRI. Compared with the 18F-FDG, the ex vivo inflamed-to-control synovium ratio of 68Ga-DOTA-Siglec-9 was similar (1.7 ± 0.4 vs. 1.5 ± 0.2, P = 0.32). Double staining revealed that Siglec-9 peptide binds to VAP-1 positive vessels in human rheumatoid synovium. CONCLUSION: Ga-DOTA-Siglec-9 PET tracer detected VAP-1 positive vasculature in the mild synovitis of rabbits comparable with 18F-FDG, suggesting its potential for in vivo imaging of synovial inflammation in patients with rheumatic diseases.

[18F]FDG Accumulation in Early Coronary Atherosclerotic Lesions in Pigs.

OBJECTIVE: Inflammation is an important contributor to atherosclerosis progression. A glucose analogue 18F-fluorodeoxyglucose ([18F]FDG) has been used to detect atherosclerotic inflammation. However, it is not known to what extent [18F]FDG is taken up in different stages of atherosclerosis. We aimed to study the uptake of [18F]FDG to various stages of coronary plaques in a pig model. METHODS: First, diabetes was caused by streptozotocin injections (50 mg/kg for 3 days) in farm pigs (n = 10). After 6 months on high-fat diet, pigs underwent dual-gated cardiac PET/CT to measure [18F]FDG uptake in coronary arteries. Coronary segments (n = 33) were harvested for ex vivo measurement of radioactivity and autoradiography (ARG). RESULTS: Intimal thickening was observed in 16 segments and atheroma type plaques in 10 segments. Compared with the normal vessel wall, ARG showed 1.7±0.7 times higher [18F]FDG accumulation in the intimal thickening and 4.1±2.3 times higher in the atheromas (P = 0.004 and P = 0.003, respectively). Ex vivo mean vessel-to-blood ratio was higher in segments with atheroma than those without atherosclerosis (2.6±1.2 vs. 1.3±0.7, P = 0.04). In vivo PET imaging showed the highest target-to-background ratio (TBR) of 2.7. However, maximum TBR was not significantly different in segments without atherosclerosis (1.1±0.5) and either intimal thickening (1.2±0.4, P = 1.0) or atheroma (1.6±0.6, P = 0.4). CONCLUSIONS: We found increased uptake of [18F]FDG in coronary atherosclerotic lesions in a pig model. However, uptake in these early stage lesions was not detectable with in vivo PET imaging. Further studies are needed to clarify whether visible [18F]FDG uptake in coronary arteries represents more advanced, highly inflamed plaques.

Quantification of [18F]DPA-714 binding in the human brain: initial studies in healthy controls and Alzheimer's disease patients.

Fluorine-18 labelled N,N-diethyl-2-(2-[4-(2-fluoroethoxy)phenyl]-5,7-dimethylpyrazolo[1,5-α]pyrimidine-3-yl)acetamide ([(18)F]DPA-714) binds to the 18-kDa translocator protein (TSPO) with high affinity. The aim of this initial methodological study was to develop a plasma input tracer kinetic model for quantification of [(18)F]DPA-714 binding in healthy subjects and Alzheimer's disease (AD) patients, and to provide a preliminary assessment whether there is a disease-related signal. Ten AD patients and six healthy subjects underwent a dynamic positron emission tomography (PET) study along with arterial sampling and a scan protocol of 150 minutes after administration of 250 ± 10 MBq [(18)F]DPA-714. The model that provided the best fits to tissue time activity curves (TACs) was selected based on Akaike Information Criterion and F-test. The reversible two tissue compartment plasma input model with blood volume parameter was the preferred model for quantification of [(18)F]DPA-714 kinetics, irrespective of scan duration, volume of interest, and underlying volume of distribution (VT). Simplified reference tissue model (SRTM)-derived binding potential (BPND) using cerebellar gray matter as reference tissue correlated well with plasma input-based distribution volume ratio (DVR). These data suggest that [(18)F]DPA-714 cannot be used for separating individual AD patients from healthy subjects, but further studies including TSPO binding status are needed to substantiate these findings.