Tuula Tolvanen

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.

In Vivo Imaging of Prostate Cancer Using [68Ga]-Labeled Bombesin Analog BAY86-7548

Purpose: A novel [68Ga]-labeled DOTA-4-amino-1-carboxymethyl-piperidine-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2 peptide (BAY86-7548) having high affinity to bombesin receptor subtype II to detect primary and metastatic prostate carcinoma using positron emission tomography/computed tomography (PET/CT) was synthesized and evaluated for prostate cancer. Experimental Design: In this first human study with BAY86-7548, 14 men scheduled for radical prostatectomy (n = 11) or with biochemical recurrence after surgery or hormonal therapy (n = 3) were enrolled. The patients received an intravenous injection of BAY86-7548 followed by over 60-minute dynamic imaging of prostate gland (n = 10) and/or subsequent whole-body imaging (n = 14). The visual assessment of PET/CT images included evaluation of intraprostatic (12 subsextants) and pelvic nodal uptake of BAY86-7548 in 11 surgical patients and detection of potential metastatic foci in all patients. In patients with biochemical recurrence, results were compared with those of either [11C]-acetate (n = 2) or [18F]-fluoromethylcholine (n = 1) PET/CT. Results: We found a sensitivity, specificity, and accuracy of 88%, 81% and 83%, respectively, for detection of primary PCa and sensitivity of 70% for metastatic lymph nodes using histology as gold standard. BAY86-7548 correctly detected local recurrence in prostate bed and showed nodal relapse in accordance with [11C]-acetate PET/CT in 2 patients with biochemical relapse. In the third hormone refractory patient, BAY86-7548 failed to show multiple bone metastases evident on [18F]-fluoromethylcholine PET/CT. Conclusion: BAY86-7548 PET/CT is a promising molecular imaging technique for detecting intraprostatic prostate cancer. Clin Cancer Res; 19(19); 5434–43. ©2013 AACR.

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.

Plasma Pharmacokinetics, Whole-Body Distribution, Metabolism, and Radiation Dosimetry of 68Ga Bombesin Antagonist BAY 86-7548 in Healthy Men

This first-in-human study investigated the safety, tolerability, metabolism, pharmacokinetics, biodistribution, and radiation dosimetry of 68Ga-bombesin antagonist 68Ga-DOTA-4-amino-1-carboxymethylpiperidine-d-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2 (BAY 86-7548). Methods: Five healthy men underwent dynamic whole-body PET/CT after an intravenous injection of BAY 86-7548 (138 ± 5 MBq). Besides total radioactivity, plasma samples were analyzed by radio–high-performance liquid chromatography for metabolism of the tracer. Dosimetry was calculated using the OLINDA/EXM software. Results: Three radioactive plasma metabolites were detected. The proportion of unchanged BAY 86-7548 decreased from 92% ± 9% at 1 min after injection to 19% ± 2% at 65 min. The organs with the highest absorbed doses were the urinary bladder wall (0.62 mSv/MBq) and the pancreas (0.51 mSv/MBq). The mean effective dose was 0.051 mSv/MBq. BAY 86-7548 was well tolerated by all subjects. Conclusion: Intravenously injected BAY 86-7548 is safe, and rapid metabolism is demonstrated. A 150-MBq injection of BAY 86-7548 results in an effective dose of 7.7 mSv, which could be reduced to 5.7 mSv with frequent bladder voids.

64Cu- and 68Ga-labelled [Nle(14),Lys(40)(Ahx-NODAGA)NH2]-exendin-4 for pancreatic beta cell imaging in rats.

PURPOSE Glucagon-like peptide-1 receptor (GLP-1R) is a molecular target for imaging of pancreatic beta cells. We compared the ability of [Nle(14),Lys(40)(Ahx-NODAGA-(64)Cu)NH2]-exendin-4 ([(64)Cu]NODAGA-exendin-4) and [Nle(14),Lys(40)(Ahx-NODAGA-(68)Ga)NH2]-exendin-4 ([(68)Ga]NODAGA-exendin-4) to detect native pancreatic islets in rodents. PROCEDURES The stability, lipophilicity and affinity of the radiotracers to the GLP-1R were determined in vitro. The biodistribution of the tracers was assessed using autoradiography, ex vivo biodistribution and PET imaging. Estimates for human radiation dosimetry were calculated. RESULTS We found GLP-1R-specific labelling of pancreatic islets. However, the pancreas could not be visualised in PET images. The highest uptake of the tracers was observed in the kidneys. Effective dose estimates for [(64)Cu]NODAGA-exendin-4 and [(68)Ga]NODAGA-exendin-4 were 0.144 and 0.012 mSv/MBq, respectively. CONCLUSION [(64)Cu]NODAGA-exendin-4 might be more effective for labelling islets than [(68)Ga]NODAGA-exendin-4. This is probably due to the lower specific radioactivity of [(68)Ga]NODAGA-exendin-4 compared to [(64)Cu]NODAGA-exendin-4. The radiation dose in the kidneys may limit the use of [(64)Cu]NODAGA-exendin-4 as a clinical tracer.

The Effects of Bariatric Surgery on Pancreatic Lipid Metabolism and Blood Flow

CONTEXT Bariatric surgery leads to a rapid and sustained weight loss often accompanied with improvement in glucose homeostasis. OBJECTIVE The objective of this study was to investigate the effects of bariatric surgery on pancreatic lipid metabolism, blood flow, and glycemic control. DESIGN This was a longitudinal study. SETTING The study was conducted in a clinical research center. PARTICIPANTS This study included 27 morbidly obese and 15 healthy control subjects. INTERVENTIONS Measurements were performed using positron emission tomography with the palmitate analog 14(R,S)-[(18)F]fluoro-6-thia-heptadecanoic acid and radiowater ([(15)O]H2O) and computed tomography. In morbidly obese subjects, positron emission tomography/computed tomography imaging studies were performed before and 6 months after bariatric surgery (either Roux-en-Y gastric bypass or sleeve gastrectomy). MAIN OUTCOME MEASURES Pancreatic fat and fat-free volume, fatty acid uptake and blood flow were measured as well as parameters of β-cell function, glucose tolerance, and insulin sensitivity. RESULTS Six months after bariatric surgery, 23% excess weight loss was observed (P < .0001), and diabetes remission was seen in 7 of 10 patients. When compared with preoperative values, after surgery, notable decreases in pancreatic fat volume (P < .01), fatty acid uptake, and blood flow (both P < .05) were seen, whereas no change was seen in pancreatic fat-free volume. The decrease in pancreatic fat volume and the preservation of blood flow were associated with favorable glucose homeostasis and β-cell function. CONCLUSIONS Bariatric surgery elicits marked alterations in pancreatic lipid metabolism and blood flow, which may contribute to the observed improvement in glucose homeostasis and remission of type 2 diabetes.

Evaluation of 68Ga-labeled tracers for PET imaging of myocardial perfusion in pigs☆

PURPOSE We evaluated four potential gallium-68 (68Ga)-labeled tracers for positron emission tomography (PET) imaging of myocardial perfusion in comparison with oxygen-15-labeled water ([15O]water) in healthy pigs. Four hexadentate salicylaldimine ligands derived from bis(3-aminopropyl)ethylenediamine (BAPEN) that showed promise in previous rat experiments were selected for this study. METHODS Following an evaluation of myocardial blood flow with [15O]water PET, the pigs (total n=14) underwent a dynamic 90-min PET study with one of four 68Ga-labeled BAPEN derivatives (n=3-5 per tracer) either at rest or under adenosine stress. Serial arterial blood samples were collected during the imaging for the measurements of total radioactivity, radiometabolites, plasma protein binding and blood-to-plasma ratio for the 68Ga chelates. Time-activity curves of the left ventricular blood pool and myocardium were derived from PET images, and metabolite-corrected arterial input function was used for kinetic modeling. Also, ex vivo biodistribution of 68Ga radioactivity was analyzed. RESULTS All four 68Ga tracers showed undesirably slow myocardial accumulation over time, but their in vivo stability, clearance from blood and the kinetics of the myocardium uptake varied. [68Ga][Ga-(sal)2BAPDMEN]1+ showed the highest myocardial uptake in PET images and tissue samples (myocardium-to-blood ratio 7.63±1.89, myocardium-to-lung ratio 3.03±0.33 and myocardium-to-liver ratio 1.80±0.82). However, there was no correlation between the myocardial perfusion measured with [15O]water and the net uptake rates or K1 values of the 68Ga chelates. CONCLUSION Our results revealed that myocardial accumulation of the 68Ga chelates proposed for myocardial perfusion imaging with PET was slow and not determined by myocardial perfusion in a large animal model. These findings suggest that the studied tracers are not suitable for clinical imaging of myocardial perfusion.

1-11C-Methyl-4-Piperidinyl-N-Butyrate Radiation Dosimetry in Humans by Dynamic Organ-Specific Evaluation

Deficits of cholinergic neurotransmission contribute to various neurologic and psychiatric conditions. The neurotransmitter acetylcholine is hydrolyzed in the synaptic clefts by 2 enzymes, acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). 1-[11C]-Methyl-4-piperidinyl-N-butyrate (11C-MP4B) is a radioligand for the assessment study of BuChE activity in human brain with PET. In the present study the radiation-absorbed doses of the 11C-MP4B were estimated in humans according to the guidelines of the International Commission on Radiological Protection. Two different data acquisition protocols—dynamic organ-specific evaluation (DOSE) and whole-body scanning—were compared. Both methods are widely used for evaluation of radiation burden of 11C-labeled PET tracers. Methods: Fixed-bed PET on the upper neck, thorax, abdomen, or pelvic region was performed on 7 healthy subjects after injection of 707 ± 34 MBq (mean ± SD) of 11C-MP4B. Brain input was derived from our previous studies on 18 healthy control subjects and 10 patients with Alzheimers disease. Regions of interest were drawn on transverse images of all visible organs. Radiation dose estimates were calculated from organ residence times using the MIRDOSE3 software. Urine samples were collected after imaging to estimate tracer extraction. To compare the estimates for absorbed doses between the whole-body scan approach and the DOSE method, we simulated whole-body data acquisition methods used in 11C dosimetry studies with our fixed-bed data. Results: The organs with the highest radiation-absorbed doses were the liver, urinary bladder, kidneys (renal cortex), upper large intestine, trabecular bone, salivary glands, and heart wall. Up to 60% of the injected dose was excreted via the urinary pathway, and the clearance was relatively rapid, as 30% of the radioactivity was excreted within 60 min after injection. With a 2-h voiding interval the effective dose was 4.2 μSv/MBq. Conclusion: 11C-MP4B causes less radiation burden than previously studied 11C-labeled PET tracers. No intolerably high absorbed doses were observed in critical organs. With 740 MBq of injected radioactivity, the radiation burden is equivalent to 3.11 mSv. This would allow multiple PET examinations per year to be performed on the same subject. The DOSE method and the simulated whole-body imaging approach produced similar results.

68Ga-Chloride PET Reveals Human Pancreatic Adenocarcinoma Xenografts in Rats—Comparison with FDG

PurposeThe aim of the study was to compare 68Ga-chloride with 2-[18F]fluoro-2-deoxy-d-glucose (FDG) for the imaging of pancreatic xenografts.ProceduresRats with subcutaneous human pancreatic adenocarcinoma xenografts were evaluated in vivo by dynamic positron emission tomography (PET) and ex vivo by measuring radioactivity of excised tissues and by digital autoradiography of tumor cryosections.ResultsBoth tracers were capable of delineating all subcutaneous tumors from surrounding tissues by PET. The standardized uptake values of tumors by PET were 0.9 ± 0.3 (mean ± SD) for 68Ga-chloride (n = 13) and 1.8 ± 1.2 for FDG (n = 11). Ex vivo studies showed tumor-to-muscle ratio of 4.0 ± 0.3 for 68Ga-chloride (n = 4) and 7.9 ± 3.2 for FDG (n = 4).Conclusions68Ga-chloride delineated subcutaneously implanted pancreatic adenocarcinoma xenografts by PET, but the uptake was lower than FDG. Further studies to clarify the value of 68Ga-chloride for PET imaging of tumors are warranted.

Cardiac remodeling in a new pig model of chronic heart failure: Assessment of left ventricular functional, metabolic, and structural changes using PET, CT, and echocardiography

AimsLarge animal models are needed to study disease mechanisms in heart failure (HF). In the present study we characterized the functional, metabolic, and structural changes of myocardium in a novel pig model of chronic myocardial infarction (MI) by using multimodality imaging and histology.Methods and ResultsMale farm pigs underwent a two-step occlusion of the left anterior descending coronary artery with concurrent distal ligation and implantation of a proximal ameroid constrictor (HF group), or sham operation (control group). Three months after the operation, cardiac output and wall stress were measured by echocardiography. Left ventricle (LV) volumes and mass were measured by computed tomography (CT). Myocardial perfusion was evaluated by [15O]water and oxygen consumption using [11C]acetate positron emission tomography, and the efficiency of myocardial work was calculated. Histological examinations were conducted to detect MI, hypertrophy, and fibrosis. Animals in the HF group had a large anterior MI scar. CT showed larger LV diastolic volume and lower ejection fraction in HF pigs than in controls. Perfusion and oxygen consumption in the remote non-infarcted myocardium were preserved in HF pigs as compared to controls. Global LV work and efficiency were significantly lower in HF than control pigs and was associated with increased wall stress. Histology showed myocyte hypertrophy but not increased interstitial fibrosis in the remote segments in HF pigs.ConclusionsThe chronic post-infarction model of HF is suitable for studies aimed to evaluate LV remodeling and changes in oxidative metabolism and can be useful for testing new therapies for HF.