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ABSTRACT: INTRODUCTION: Fabry disease is a rare lysosomal storage disorder leading to cellular accumulation of globotriaosylceramide, especially in blood vessels. It is associated with severe early onset cerebrovascular disease and kidney and heart failure. The purpose of this study was to reveal possible disturbances in white matter integrity in Fabry disease patients using voxelwise diffusion-tensor imaging (DTI) analysis. METHODS: Twelve Fabry disease patients, along with 13 healthy controls, underwent DTI and structural MRI. Voxel-based analysis of the DTI data was performed to assess possible differences in DTI parameters between Fabry disease patients and healthy controls. A selective region of interest analysis was performed for healthy volunteers and Fabry disease patients having a mild burden of T2-hyperintense lesions. We also measured normalised brain tissue volumes and performed a voxel-based volume analysis for grey matter. RESULTS: Voxel-based analysis of DTI data showed areas of significantly reduced fractional anisotropy and increased mean diffusivity in patients with Fabry disease. Eight patients had a mild burden of white matter lesions on their T2 scans. Region of interest analysis on areas showing reduced fractional anisotropy in voxelwise analysis also revealed reduced fractional anisotropy values in this patient group compared to eight healthy volunteers. The brain volume analyses did not reveal significant differences between the Fabry disease patients and the controls. CONCLUSION: These findings suggest a microstructural damage in brain white matter of Fabry disease patients, which can be revealed before excessive white matter lesions load is visible on conventional MR scans.
Neuroradiology 01/2013; · 2.82 Impact Factor
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ABSTRACT: Background/Aim: We tested the hypothesis that a persistent reduction in free fatty acid (FFA) levels improves cardiac function and systemic insulin sensitivity via a reduction in the myocardial and skeletal muscle adiposities and a modulation in adipokine release. Methods: Study subjects (body mass index 22-30 kg/m(2), 57 ± 3 yr old) underwent magnetic resonance imaging and spectroscopy to measure the cardiac function and the amounts of fat inside and around the myocardium and skeletal muscle, before (n = 10) and after acute (n = 8) and 1 wk (n = 7, one excluded from analysis) lowering of circulating FFA by acipimox. Circulating adipokines (leptin, adiponectin, resistin, TNFα, IL-6, IL-8, plasminogen activator inhibitor-I, macrophage chemoattractant protein-1) were measured. Results: The ejection fraction (62 ± 2 vs. 56 ± 1%, P = 0.0035), cardiac output (6.6 ± 0.3 vs. 5.5 ± 0.2 liters/min, P = 0.0018), and forward work (708 ± 49 vs. 539 ± 44 mm Hg × liters/min, P = 0.018) were significantly lower after 1 wk of FFA lowering. In the six subjects undergoing all sessions, the stroke and end-diastolic volumes were also reduced, insulin sensitivity was increased by 33%, and adiponectinemia was decreased (-26%, P = 0.03). No change in intracellular cardiac and skeletal muscle triglyceride levels was observed. Metabolic changes correlated with the lowering of FFA. The reduction in cardiac function was related with changes in glycemia and insulin sensitivity, whereas the deflection in left ventricular work was correlated with the decline in FFA, lipid, and blood pressure levels. Conclusions: A 1-wk FFA depletion suppressed cardiac function and improved insulin sensitivity. Intracellular triglyceride deposits in the heart and skeletal muscle played no role in the observed changes. Our data show that FFA participate in the physiological regulation of adipokine levels.
The Journal of clinical endocrinology and metabolism 07/2012; 97(9):3277-84. · 6.50 Impact Factor
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Ivan Jambor, Ronald Borra,
Jukka Kemppainen,
Virva Lepomäki,
Riitta Parkkola,
Kirsti Dean,
Kalle Alanen,
Eveliina Arponen,
Martti Nurmi,
Hannu J Aronen,
Heikki Minn
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ABSTRACT: We aimed to study the ability of contrast enhanced MRI at 1.5T and (11)C-acetate PET/CT, both individually and using fused data, to detect localized prostate cancer.
Thirty-six men with untreated prostate cancer and negative for metastatic disease on pelvic CT and bone scan were prospectively enrolled. A pelvic (11)C-acetate PET/CT scan was performed in all patients, and a contrast enhanced MRI scan in 33 patients (6 examinations using both endorectal coil and surface coils, and 27 examinations using surface coils only). After the imaging studies 10 patients underwent prostatectomy and 26 were treated by image guided external beam radiation treatment. Image fusion of co-registered PET and MRI data was performed based on anatomical landmarks visible on CT and MRI using an advanced in-house developed software package. PET/CT, MRI and fused PET/MRI data were evaluated visually and compared with biopsy findings on a lobar level, while a sextant approach was used for patients undergoing prostatectomy.
When using biopsy samples as method of reference, the sensitivity, specificity and accuracy for visual detection of prostate cancer on a lobar level by contrast enhanced MRI was 85%, 37%, 73% and that of (11)C-acetate PET/CT 88%, 41%, 74%, respectively. Fusion of PET with MRI data increased sensitivity, specificity and accuracy to 90%, 72% and 85%, respectively.
Fusion of sequentially obtained PET/CT and MRI data for the localization of prostate cancer is feasible and superior to the performance of each individual modality alone.
European journal of radiology 02/2012; 81(11):2966-72. · 2.65 Impact Factor
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ABSTRACT: A switch from oxidative phosphorylation to glycolysis is frequently observed in cancer cells and is linked to tumor growth and invasion, but the underpinning molecular mechanisms controlling the switch are poorly understood. In this report we show that Notch signaling is a key regulator of cellular metabolism. Both hyper- and hypoactivated Notch induce a glycolytic phenotype in breast tumor cells, although by distinct mechanisms: hyperactivated Notch signaling leads to increased glycolysis through activation of the phosphatidylinositol 3-kinase/AKT serine/threonine kinase pathway, whereas hypoactivated Notch signaling attenuates mitochondrial activity and induces glycolysis in a p53-dependent manner. Despite the fact that cells with both hyper- and hypoactivated Notch signaling showed enhanced glycolysis, only cells with hyperactivated Notch promoted aggressive tumor growth in a xenograft mouse model. This phenomenon may be explained by that only Notch-hyperactivated, but not -hypoactivated, cells retained the capacity to switch back to oxidative phosphorylation. In conclusion, our data reveal a role for Notch in cellular energy homeostasis, and show that Notch signaling is required for metabolic flexibility.
Proceedings of the National Academy of Sciences 11/2011; 108(46):18814-9. · 9.68 Impact Factor
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Marco Bucci, Ronald Borra,
Kjell Någren,
Jussi P Pärkkä,
Silvia Del Ry,
Romina Maggio,
Helena Tuunanen,
Tapio Viljanen,
Manuela Cabiati,
Sara Rigazio,
Markku Taittonen,
Uberto Pagotto,
Riitta Parkkola,
Lionel H Opie,
Pirjo Nuutila,
Juhani Knuuti,
Patricia Iozzo
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ABSTRACT: Introduction: The metabolic modulator trimetazidine (TMZ) has been suggested to induce a metabolic shift from myocardial fatty acid oxidation (FAO) to glucose utilization, but this mechanism remains unproven in humans. The oxidation of plasma derived FA is commonly measured in humans, whereas the contribution of FA from triglycerides stored in the myocardium has been poorly characterized. Aims: To verify the hypothesis that TMZ induces a metabolic shift, we combined positron emission tomography (PET) and magnetic resonance spectroscopy ((1) H-MRS) to measure myocardial FAO from plasma and intracellular lipids, and myocardial glucose metabolism. Nine obese subjects were studied before and after 1 month of TMZ treatment. Myocardial glucose and FA metabolism were assessed by PET with (18) F-fluorodeoxyglucose and (11) C-palmitate. (1) H-MRS was used to measure myocardial lipids, the latter being integrated into the PET data analysis to quantify myocardial triglyceride turnover. Results: Myocardial FAO derived from intracellular lipids was at least equal to that of plasma FAs (P= NS). BMI and cardiac work were positively associated with the oxidation of plasma derived FA (P≤ 0.01). TMZ halved total and triglyceride-derived myocardial FAO (32.7 ± 8.0 to 19.6 ± 4.0 μmol/min and 23.7 ± 7.5 to 10.3 ± 2.7 μmol/min, respectively; P≤ 0.05). These changes were accompanied by increased cardiac efficiency since unchanged LV work (1.6 ± 0.2 to 1.6 ± 0.1 Watt/g × 10(2) , NS) was associated with decreased work energy from the intramyocardial triglyceride oxidation (1.6 ± 0.5 to 0.4 ± 0.1 Watt/g × 10(2) , P= 0.036). Conclusions: In obese subjects, we demonstrate that myocardial intracellular triglyceride oxidation significantly provides FA-derived energy for mechanical work. TMZ reduced the oxidation of triglyceride-derived myocardial FAs improving myocardial efficiency.
Cardiovascular Therapeutics 07/2011; · 2.35 Impact Factor
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ABSTRACT: We recently showed that patients with mitochondrial diabetes are insulin resistant in skeletal muscle before the decline in insulin secretion is observed. In this study, we further evaluate whether insulin resistance is associated with increased ectopic fat accumulation and altered adipose and hepatic tissue insulin sensitivity. We studied 15 nonobese patients with the m.3243A > G mutation. Five were without diabetes (group 1), three had newly diagnosed diabetes (group 2), and seven had previously diagnosed diabetes (group 3). Thirteen healthy volunteers of similar age and body mass index (BMI) served as controls. Insulin-stimulated glucose uptake was measured with positron emission tomography using 2- [(18)F]-fluoro-2-deoxyglucose during euglycemic hyperinsulinemia. Fat masses and liver fat content were measured with magnetic resonance imaging and spectroscopy. Compared with controls, insulin-stimulated glucose uptake in adipose tissue was decreased by ∼50% in all groups with the m.3243A > G mutation. In addition, fat masses were not different, but insulin-mediated suppression of lipolysis and adiponectin metabolism were blunted in patients with the m.3243A > G mutation. Hepatic fat content was normal (<5.6%) in 80% of patients and significantly elevated in one case only. Hepatic glucose metabolism in patients with m.3243A > G did not differ from that of controls. In conclusion, m.3243A > G mutation affects subcutaneous adipose tissue metabolism. This seems to occur before aberrant liver metabolism, if any, can be observed or before beta-cell failure results in mitochondrial diabetes.
Journal of Inherited Metabolic Disease 05/2011; 34(6):1205-12. · 3.58 Impact Factor
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Marco Bucci, Ronald Borra,
Kjell Någren,
Romina Maggio,
Helena Tuunanen,
Vesa Oikonen,
Silvia Del Ry,
Tapio Viljanen,
Markku Taittonen,
Sara Rigazio,
Daniela Giannessi,
Riitta Parkkola,
Juhani Knuuti,
Pirjo Nuutila,
Patricia Iozzo
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ABSTRACT: An impaired ability to store fatty acids (FA) in subcutaneous adipose tissue (SAT) may be implicated in the pathogenesis of obesity-related diseases via overexposure of lean tissues and production of free radicals from FA oxidation (FAO). We studied regional FA metabolism in skeletal muscle and adipose tissue in humans and investigated the long-term effects of the FAO inhibitor trimetazidine on glucose and FA metabolism. Positron emission tomography (PET) and [(11)C]palmitate were used to compare FA metabolism in SAT and skeletal muscle between eight obese and eight nonobese subjects (BMI ≥/< 30 kg/m(2)). A subgroup of nine subjects underwent a 1-mo trimetazidine administration. PET with [(11)C]palmitate and [(18)F]fluorodeoxyglucose, indirect calorimetry, and MRI before and after this period were performed to characterize glucose and FA metabolism, fat masses, skeletal muscle triglyceride, and creatine contents. Obesity was characterized by a 100% elevation in FAO and a defect in the FA esterification rate constant (P < 0.05) in skeletal muscle. FA esterification was reduced by ~70% in SAT (P < 0.001) in obese vs. control subjects. The degrees of obesity and insulin resistance were both negatively associated with esterification-related parameters and positively with FAO (P < 0.05). Trimetazidine increased skeletal muscle FA esterification (P < 0.01) and mildly upregulated glucose phosphorylation (P = 0.066). Our data suggest that human obesity is characterized by a defect in tissue FA storage capability, which is accompanied by a (potentially compensatory) elevation in skeletal muscle FAO; trimetazidine diverted FA from oxidative to nonoxidative pathways and provoked an initial activation of glucose metabolism in skeletal muscle.
AJP Endocrinology and Metabolism 04/2011; 301(1):E105-12. · 4.75 Impact Factor
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Jarna C Hannukainen, Ronald Borra,
Kaisa Linderborg,
Heikki Kallio,
Jan Kiss,
Virva Lepomäki,
Kari K Kalliokoski,
Urho M Kujala,
Jaakko Kaprio,
Olli J Heinonen,
Markku Komu,
Riitta Parkkola,
Markku Ahotupa,
Terho Lehtimäki,
Risto Huupponen,
Patricia Iozzo,
Pirjo Nuutila
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ABSTRACT: Ectopic fat in muscle and liver is linked to obesity and type 2 diabetes. Recently, pancreatic lipid accumulation has also been associated with β-cell dysfunction and reduced insulin production, leading to the development of type 2 diabetes. Physical exercise training has been shown to attenuate β-cell dysfunction in patients, but little is known about its effects on pancreatic and hepatic fat accumulation. In this study, we validated in-vivo proton magnetic resonance spectroscopy ((1)H MRS) in pancreatic fat measurement with biochemical measurements in a pig model. Thereafter, the effects of increased physical activity on the amounts of pancreatic and liver fat were studied in eight monozygotic twin pairs who have discordant physical activity and fitness.
Pancreatic fat content was studied in 15 pigs using (1)H MRS and/or biochemical analyses. In addition, liver and pancreatic fat were assessed using (1)H MRS in eight monozygotic male twin pairs with 18% mean difference in VO(2max) between the twin brothers.
Twins with higher physical fitness had 23% less liver fat (1.3±1.3% vs. 2.1±2.6%, p=0.022) but no such difference was observed in the pancreatic fat (8.2±9.3% vs. 9.8±8.5%, respectively, p=0.3). Hepatic fat content was inversely associated with VO(2max). A positive association was found between pancreatic and liver fat contents (β=5.18, p=0.012). Pancreatic fat content was also associated with insulin sensitivity indexes and plasma adiponectin and glutamyltransferase concentrations.
Pancreatic fat content is associated with insulin resistance and hepatic fat content. An active lifestyle seems to beneficially influence hepatic fat metabolism.
Journal of Hepatology 03/2011; 54(3):545-52. · 9.26 Impact Factor
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Ivan Jambor, Ronald Borra,
Jukka Kemppainen,
Virva Lepomäki,
Riitta Parkkola,
Kirsti Dean,
Kalle Alanen,
Eveliina Arponen,
Martti Nurmi,
Hannu J Aronen,
Heikki Minn
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ABSTRACT: We assessed the ability of (11)C-acetate PET/CT, MRI, and proton MR spectroscopy ((1)H-MRS) to image localized prostate cancer and detect its aggressiveness, using qualitative and quantitative approaches.
Twenty-one patients with untreated localized prostate cancer, diagnosed using transrectal ultrasound-guided biopsy, were prospectively enrolled. Cancer laterality was based on the percentage of cancer and the highest Gleason score determined from biopsies. In addition to PET/CT, 3-dimensional (1)H-MRS of the entire prostate volume using a quantitative approach was performed. The imaging and histologic findings of 8 patients undergoing subsequent prostatectomy were compared on a sextant level. For each lobe and sextant, standardized uptake values (SUVs) and (choline + creatine + polyamines)-to-citrate (CCP/C) ratios were obtained from (11)C-acetate PET/CT and (1)H-MRS, respectively. The visual and quantitative findings on PET/CT and MRI data were compared with cancer laterality and aggressiveness based on the Gleason score and with prostate-specific antigen (PSA) velocity and international risk group classification.
The sensitivity, specificity, and accuracy, on a lobar level using visual analysis, of (11)C-acetate PET/CT were 80%, 29%, 71%, respectively, and 89%, 29%, 79%, respectively, using contrast-enhanced MRI. The sensitivity and accuracy of (11)C-acetate PET/CT decreased to 64% and 63% and specificity increased to 62% when sextant analysis was performed. The agreement between prostate cancer laterality based on biopsy findings and visual interpretation of (11)C-acetate PET/CT and contrast-enhanced MRI was similar at 71%. The mean SUV maximum and CCP/C maximum for the dominant tumor lesion were 5.5 and 1.48, respectively, and did not differ significantly from values in the nondominant lobe. The dominant-lesion SUVs or CCP/C values were not associated with histologically determined prostate cancer aggressiveness, nor did PSA velocity correlate with the SUV or CCP/C values from the entire gland.
(11)C-acetate PET/CT, MRI, and (1)H-MRS enable detection of localized prostate cancer with comparable and limited accuracy but fail to provide information on cancer aggressiveness.
Journal of Nuclear Medicine 10/2010; 51(11):1676-83. · 6.38 Impact Factor
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Patricia Iozzo,
Marco Bucci,
Anne Roivainen,
Kjell Någren,
Mikko J Järvisalo,
Jan Kiss,
Letizia Guiducci,
Barbara Fielding,
Alexandru G Naum, Ronald Borra,
Kirsi Virtanen,
Timo Savunen,
Piero A Salvadori,
Ele Ferrannini,
Juhani Knuuti,
Pirjo Nuutila
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ABSTRACT: Hepatic lipotoxicity results from and contributes to obesity-related disorders. It is a challenge to study human metabolism of fatty acids (FAs) in the liver. We combined (11)C-palmitate imaging by positron emission tomography (PET) with compartmental modeling to determine rates of hepatic FA uptake, oxidation, and storage, as well as triglyceride release in pigs and human beings.
Anesthetized pigs underwent (11)C-palmitate PET imaging during fasting (n = 3) or euglycemic hyperinsulinemia (n = 3). Metabolic products of FAs were measured in arterial, portal, and hepatic venous blood. The imaging methodology then was tested in 15 human subjects (8 obese subjects); plasma (11)C-palmitate kinetic analyses were used to quantify systemic and visceral lipolysis.
In pigs, PET-derived and corresponding measured FA fluxes (FA uptake, esterification, and triglyceride FA release) did not differ and were correlated with each other. In human beings, obese subjects had increased hepatic FA oxidation compared with controls (mean +/- standard error of the mean, 0.16 +/- 0.01 vs 0.08 +/- 0.01 micromol/min/mL; P = .0007); FA uptake and esterification rates did not differ between obese subjects and controls. Liver FA oxidation correlated with plasma insulin levels (r = 0.61, P = .016), adipose tissue (r = 0.58, P = .024), and systemic insulin resistance (r = 0.62, P = .015). Hepatic FA esterification correlated with the systemic release of FA into plasma (r = 0.71, P = .003).
PET imaging can be used to measure FA metabolism in the liver. By using this technology, we found that obese individuals have increased hepatic oxidation of FA, in the context of adipose tissue insulin resistance, and increased FA flux from visceral fat. FA flux from visceral fat is proportional with the mass of the corresponding depot.
Gastroenterology 09/2010; 139(3):846-56, 856.e1-6. · 11.68 Impact Factor
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Ilkka H Heinonen,
Jukka Kemppainen,
Kimmo Kaskinoro,
Juha E Peltonen, Ronald Borra,
Markus Lindroos,
Vesa Oikonen,
Pirjo Nuutila,
Juhani Knuuti,
Robert Boushel,
Kari K Kalliokoski
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ABSTRACT: Although many effects of both acute and chronic hypoxia on the circulation are well characterized, the distribution and regulation of blood flow (BF) heterogeneity in skeletal muscle during systemic hypoxia is not well understood in humans. We measured muscle BF within the thigh muscles of nine healthy young men using positron emission tomography during one-leg dynamic knee extension exercise in normoxia and moderate physiological systemic hypoxia (14% O(2) corresponding to approximately 3,400 m of altitude) without and with local adenosine receptor inhibition with femoral artery infusion of aminophylline. Systemic hypoxia reduced oxygen extraction of the limb but increased muscle BF, and this flow increment was confined solely to the exercising quadriceps femoris muscle. Exercising muscle BF heterogeneity was reduced from rest (P = 0.055) but was not affected by hypoxia. Adenosine receptor inhibition had no effect on capillary BF during exercise in either normoxia or hypoxia. Finally, one-leg exercise increased muscle BF heterogeneity both in the resting posterior hamstring part of the exercising leg and in the resting contralateral leg, whereas mean BF was unchanged. In conclusion, the results show that increased BF during one-leg exercise in moderate hypoxia is confined only to the contracting muscles, and the working muscle hyperemia appears not to be directly mediated by adenosine. Increased flow heterogeneity in noncontracting muscles likely reflects sympathetic nervous constraints to curtail BF increments in areas other than working skeletal muscles, but this effect is not potentiated in moderate systemic hypoxia during small muscle mass exercise.
AJP Regulatory Integrative and Comparative Physiology 07/2010; 299(1):R72-9. · 3.34 Impact Factor
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Ilkka Heinonen,
Jukka Kemppainen,
Kimmo Kaskinoro,
Juha E Peltonen, Ronald Borra,
Markus M Lindroos,
Vesa Oikonen,
Pirjo Nuutila,
Juhani Knuuti,
Ylva Hellsten,
Robert Boushel,
Kari K Kalliokoski
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ABSTRACT: Adenosine is a widely used pharmacological agent to induce a "high-flow" control condition to study the mechanisms of exercise hyperemia, but it is not known how well an adenosine infusion depicts exercise-induced hyperemia, especially in terms of blood flow distribution at the capillary level in human muscle. Additionally, it remains to be determined what proportion of the adenosine-induced flow elevation is specifically directed to muscle only. In the present study, we measured thigh muscle capillary nutritive blood flow in nine healthy young men using PET at rest and during the femoral artery infusion of adenosine (1 mg min(-1) l thigh volume(-1)), which has previously been shown to induce a maximal whole thigh blood flow of approximately 8 l/min. This response was compared with the blood flow induced by moderate- to high-intensity one-leg dynamic knee extension exercise. Adenosine increased muscle blood flow on average to 40 +/- 7 ml x min(-1) x 100 g muscle(-1) with an aggregate value of 2.3 +/- 0.6 l/min for the whole thigh musculature. Adenosine also induced a substantial change in blood flow distribution within individuals. Muscle blood flow during the adenosine infusion was comparable with blood flow in moderate- to high-intensity exercise (36 +/- 9 ml x min(-1) x 100 g muscle(-1)), but flow heterogeneity was significantly higher during the adenosine infusion than during voluntary exercise. In conclusion, a substantial part of the flow increase in the whole limb blood flow induced by a high-dose adenosine infusion is conducted through the physiological non-nutritive shunt in muscle and/or also through tissues of the limb other than muscle. Additionally, an intra-arterial adenosine infusion does not mimic exercise hyperemia, especially in terms of muscle capillary flow heterogeneity, while the often-observed exercise-induced changes in capillary blood flow heterogeneity likely reflect true changes in nutritive flow linked to muscle fiber and vascular unit recruitment.
Journal of Applied Physiology 11/2009; 108(2):378-86. · 3.75 Impact Factor
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Patricia Iozzo,
Riikka Lautamaki, Ronald Borra,
Hanna-Riikka Lehto,
Marco Bucci,
Antti Viljanen,
Jussi Parkka,
Virva Lepomaki,
Romina Maggio,
Riitta Parkkola,
Juhani Knuuti,
Pirjo Nuutila
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ABSTRACT: To examine whether pericardial and myocardial fat depots may contribute to the association between diabetes and cardiovascular risk, including sex-related differences, and the role of adiponectin, we evaluated data in patients with obesity and without diabetes [nondiabetic (ND)] or with impaired glucose tolerance or type 2 diabetes and in lean ND controls.
Magnetic resonance imaging and spectroscopy were used to measure left ventricular (LV) function and abdominal sc and visceral fat areas to estimate respective masses, pericardial fat depots, and myocardial triglyceride content in 53 subjects (10 lean ND, 25 obese ND, six impaired-glucose-tolerance, and 12 type 2 diabetic patients with macrovascular disease); gender effects and adiponectin levels were evaluated in the available subset of subjects.
Myocardial and pericardial fat increased progressively across study groups. They were lower in obese women than men (P = 0.002), but cardiac steatosis caught up in hyperglycemic women (+81% vs. ND, P = 0.01). Adiponectin was inversely related with both fat depots (P < 0.01) and LV mass (P = 0.003) and positively with LV function (P = 0.03). In multiple regression analysis, myocardial and pericardial fat were independently related with plasma glucose levels, only pericardial fat mass was associated with visceral adiposity and myocardial fat with cardiac output and work.
We conclude that glycemia, gender, adiponectin, and cardiac workload are associated with, and hyperglycemia and male gender are independent positive predictors of, heart adiposity. Once glucose tolerance becomes impaired, the evolution of cardiac steatosis is more pronounced in women.
The Journal of clinical endocrinology and metabolism 10/2009; 94(11):4472-82. · 6.50 Impact Factor
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Saila P Kauhanen,
Gaber Komar,
Marko P Seppänen,
Kirsti I Dean,
Heikki R Minn,
Sami A Kajander,
Irina Rinta-Kiikka,
Kalle Alanen, Ronald J Borra,
Pauli A Puolakkainen,
Pirjo Nuutila,
Jari T Ovaska
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ABSTRACT: To prospectively compare the accuracy of combined positron emission tomography/computed tomography using F-fluorodeoxyglucose (FDG-PET/CT), multidetector row computed tomography (MDCT), and magnetic resonance imaging (MRI) in the evaluation of patients with suspected pancreatic malignancy.
FDG-PET/CT imaging is increasingly used for staging of pancreatic cancer. Preliminary data suggest a significant influence of FDG-PET/CT on treatment planning, although its role is still evolving.
Thirty-eight consecutive patients with suspicion of pancreatic malignancy were enrolled. Patients underwent a protocol including FDG-PET/CT, MDCT, and MRI combined with magnetic resonance cholangiopancreatography, all of which were blindly evaluated. The findings were confirmed macroscopically at operation and/or by histopathologic analysis (n = 29) or follow-up (n = 9). Results of TNM classification of different imaging methods were compared with clinical TNM classification.
Pancreatic adenocarcinoma was diagnosed in 17 patients, neuroendocrine tumor in 3, mass-forming pancreatitis in 4, cystic lesion in 6, and fibrosis in 2. Six patients had a finding of a normal pancreas. The diagnostic accuracy of FDG-PET/CT for pancreatic malignancy was 89%, compared with 76% and 79% for MDCT and MRI, respectively. In the differential diagnosis of suspected malignant biliary stricture at endoscopic retrograde cholangiopancreaticography (n = 21), FDG-PET/CT had a positive predictive value of 92%. In 17 patients with advanced pancreatic adenocarcinoma, FDG-PET/CT had a sensitivity of 30% for N- and 88% for M-staging. Both MDCT and MRI had sensitivities of 30% for N- and 38% for M-staging. Furthermore, the clinical management of 10 patients (26%) was altered after FDG-PET/CT.
FDG-PET/CT was more sensitive than conventional imaging in the diagnosis of both primary pancreatic adenocarcinoma and associated distant metastases. In contrast, the sensitivity of FDG-PET/CT was poor in detecting local lymph node metastasis, which would have been important for an assessment of resectability. We recommend the use of FDG-PET/CT in the evaluation of diagnostically challenging cases, especially in patients with biliary strictures without evidence of malignancy in conventional imaging.
Annals of surgery 09/2009; 250(6):957-63. · 7.90 Impact Factor
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Antti P M Viljanen,
Anna Karmi, Ronald Borra,
Jussi P Pärkkä,
Virva Lepomäki,
Riitta Parkkola,
Riikka Lautamäki,
Mikko Järvisalo,
Markku Taittonen,
Tapani Rönnemaa,
Patricia Iozzo,
Juhani Knuuti,
Pirjo Nuutila,
Olli T Raitakari
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ABSTRACT: Obesity is associated with increased fatty acid uptake in the myocardium, and this may have deleterious effects on cardiac function. The aim of this study was to evaluate how weight loss influences myocardial metabolism and cardiac work in obese adults. Thirty-four obese (mean body mass index 33.7 +/- 0.7 kg/m(2)) but otherwise healthy subjects consumed a very low calorie diet for 6 weeks. Cardiac substrate metabolism and work were measured before and after the diet. Myocardial fatty acid uptake was measured in 18 subjects using fluorine-18-fluoro-6-thia-heptadecanoic acid and positron emission tomography, and myocardial glucose uptake was measured in 16 subjects using fluorine-18-2-fluoro-2-deoxyglucose. Myocardial structure and cardiac function were measured using magnetic resonance imaging. Consumption of the very low calorie diet decreased weight (-11.2 +/- 0.6 kg, p <0.0001). Myocardial fatty acid uptake decreased from 4.2 +/- 0.4 to 2.9 +/- 0.2 micromol/100 g/min (p <0.0001). Myocardial mass decreased by 7% (p <0.005), and cardiac work decreased by 26% (p <0.0001). Whole-body insulin sensitivity increased by 33% (p <0.01), but insulin-stimulated myocardial glucose uptake remained unchanged (p = 0.90). Myocardial triglyceride content decreased by 31% (n = 8, p = 0.076). In conclusion, weight reduction decreases myocardial fatty acid uptake in parallel with myocardial mass and cardiac work. These results show that the increased fatty acid uptake found in the hearts of obese patients can be reversed by weight loss.
The American journal of cardiology 06/2009; 103(12):1721-6. · 3.58 Impact Factor
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ABSTRACT: The objective of this research was to study (1) the mutual relationship between liver fat content (LFC) and hepatic glucose uptake (HGU) in patients with type 2 diabetes mellitus and (2) the relationship between changes in LFC and HGU uptake induced by rosiglitazone in these patients. Liver fat was measured with proton magnetic resonance spectroscopy and insulin-stimulated HGU with [(18)F]-labeled 2-fluoro-2-deoxyglucose positron emission tomography in 54 patients with type 2 diabetes mellitus and 8 healthy subjects. Measurements were repeated in diabetic patients after a 16-week intervention period with rosiglitazone (n = 27) or placebo (n = 27). Patients with diabetes had lower HGU (24.5 +/- 14.2 vs 35.6 +/- 9.7 micromol/[kg min], P < .01) and higher LFC (10.9% +/- 9.2% vs 2.5% +/- 1.4%, P < .001) compared with healthy subjects. Liver fat was inversely associated with HGU (r = -0.31, P < .05), but more strongly with whole-body insulin sensitivity and adiponectin levels. Rosiglitazone treatment reduced liver fat by 24.8% (P = .01 vs placebo) and increased HGU by 29.2% (P = .013 vs placebo). This decrease in LFC was best explained by the increment in suppression of nonesterified fatty acid levels during hyperinsulinemia (P < .001) and improved glycemic control (P = .034), but not by changes in HGU. A significant inverse relationship between LFC and HGU was observed, but changes were not related. This suggests that the beneficial effects of rosiglitazone on liver metabolism are indirect and can be partly explained by increased suppression of nonesterified fatty acid levels, leading to reduced liver fat.
Metabolism: clinical and experimental 11/2008; 57(10):1445-51. · 2.59 Impact Factor
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Antti P M Viljanen,
Patricia Iozzo, Ronald Borra,
Mikko Kankaanpää,
Anna Karmi,
Riikka Lautamäki,
Mikko Järvisalo,
Riitta Parkkola,
Tapani Rönnemaa,
Letizia Guiducci,
Terho Lehtimäki,
Olli T Raitakari,
Andrea Mari,
Pirjo Nuutila
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ABSTRACT: Weight loss has been shown to decrease liver fat content and whole-body insulin resistance. The current study was conducted to investigate the simultaneous effects of rapid weight reduction with a very-low-calorie diet on liver glucose and fatty acid metabolism and liver adiposity.
We hypothesized that liver insulin resistance and free fatty acid uptake would decrease after weight loss and that they are associated with reduction of liver fat content.
Thirty-four healthy obese subjects (body mass index, 33.7 +/- 8.0 kg/m(2)) were studied before and after a very-low-calorie diet for 6 wk. Hepatic glucose uptake and endogenous glucose production were measured with [(18)F]fluorodeoxyglucose during hyperinsulinemic euglycemia and fasting hepatic fatty acid uptake with [(18)F]fluoro-6-thia-heptadecanoic acid and positron emission tomography. Liver volume and fat content were measured using magnetic resonance imaging and spectroscopy.
Subjects lost weight (11.2 +/- 2.9 kg; P < 0.0001). Liver volume decreased by 11% (P < 0.002), which was partly explained by decreased liver fat content (P < 0.0001). Liver free fatty acid uptake was 26% lower after weight loss (P < 0.003) and correlated with the decrement in liver fat content (r = 0.54; P < 0.03). Hepatic glucose uptake during insulin stimulation was unchanged, but the endogenous glucose production decreased by 40% (P < 0.04), and hepatic insulin resistance by 40% (P < 0.05).
The liver responds to a 6-wk period of calorie restriction with a parallel reduction in lipid uptake and storage, accompanied by enhancement of hepatic insulin sensitivity and clearance.
Journal of Clinical Endocrinology & Metabolism 10/2008; 94(1):50-5. · 6.50 Impact Factor
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Lotfi Slimani,
Nobuyuki Kudomi,
Vesa Oikonen,
M Jarvisalo,
Jan Kiss,
Alexandru Naum, Ronald Borra,
Antti Viljanen,
Hannu Sipila,
Ele Ferrannini,
Timo Savunen,
Pirjo Nuutila,
Patricia Iozzo
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ABSTRACT: Hepatic perfusion plays an important role in liver physiology and disease. This study was undertaken to (a) validate the use of Positron Emission Tomography (PET) and oxygen-15-labeled water ([(15)O]H(2)O) to quantify hepatic and portal perfusion, and (b) examine relationships between portal perfusion and liver glucose and lipid metabolism.
Liver [(15)O]H(2)O-PET images were obtained in 14 pigs during fasting or hyperinsulinemia. Carotid arterial and portal venous blood were sampled for [(15)O]H(2)O activity; Doppler ultrasonography was used invasively as the reference method. A single arterial input compartment model was developed to estimate portal tracer kinetics and liver perfusion. Endogenous glucose production (EGP) and insulin-mediated whole body glucose uptake (wbGU) were determined by standard methods.
Hepatic arterial and portal venous perfusions were 0.15+/-0.07 and 1.11+/-0.34 ml/min/ml of tissue, respectively. The agreement between ultrasonography and [(15)O]H(2)O-PET was good for total and portal liver perfusion, and poor for arterial perfusion. Portal perfusion was correlated with EGP (r=or+0.62, p=0.03), triglyceride (r=or+0.66, p=0.01), free fatty acid levels (r=or+0.76, p=0.003), and plasma lactate levels (r=or-0.81, p=0.0009).
Estimates of liver perfusion by [(15)O]H(2)O-PET compared well with those by ultrasonography. The method allowed to predict portal tracer concentrations which is essential in human studies. Portal perfusion may affect liver nutrient handling.
Journal of Hepatology 07/2008; 48(6):974-82. · 9.26 Impact Factor
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Sara Rigazio,
Hanna-Riikka Lehto,
Helena Tuunanen,
Kjell Någren,
Mikko Kankaanpaa,
Claudia Simi, Ronald Borra,
Alexandru G Naum,
Riitta Parkkola,
Juhani Knuuti,
Pirjo Nuutila,
Patricia Iozzo
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ABSTRACT: Lipolysis may regulate liver free fatty acid (FFA) uptake and triglyceride accumulation; both are potential causes of insulin resistance and liver damage. We evaluated whether 1) systemic FFA release is the major determinant of liver FFA uptake in fasting humans in vivo and 2) the beneficial metabolic effects of FFA lowering can be explained by a reduction in liver triglyceride content. Sixteen healthy subjects were subdivided in two groups of similar characteristics to undergo positron emission tomography with [(11)C]acetate and [(11)C]palmitate to quantify liver FFA metabolism (n = 8), or magnetic resonance spectroscopy (MRS) to measure hepatic fat content (n = 8), before and after the acute lowering of circulating FFAs by using the antilipolytic agent acipimox. MRS was again repeated after a 1-wk treatment period. Acipimox suppressed FFA levels while stimulating hepatic fractional extraction of FFAs (P < 0.05). As a result, fasting liver FFA uptake was decreased by 79% (P = 0.0002) in tight association with lipolysis (r = 0.996, P < 0.0001). The 1-wk treatment induced a significant improvement in systemic (+30%) and liver (+70%) insulin sensitivity (P < 0.05) and decreased circulating triglycerides (-20%, P = 0.06) and liver enzymes (ALT -20%, P = 0.03). No change in liver fat content was observed after either acute or sustained FFA suppression. We conclude that acute and sustained inhibitions of lipolysis and liver FFA uptake fail to deplete liver fat in healthy human subjects. Liver FFA uptake was decreased in proportion to FFA delivery. As a consequence, liver and systemic insulin sensitivity were improved, together with liver function, independently of changes in hepatic triglyceride accumulation.
AJP Endocrinology and Metabolism 05/2008; 295(2):E413-9. · 4.75 Impact Factor
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Patricia Iozzo,
Mikko J Jarvisalo,
Jan Kiss, Ronald Borra,
Gratian A Naum,
Antti Viljanen,
Tapio Viljanen,
Amalia Gastaldelli,
Emma Buzzigoli,
Letizia Guiducci,
Elisabetta Barsotti,
Timo Savunen,
Juhani Knuuti,
Merja Haaparanta-Solin,
Ele Ferrannini,
Pirjo Nuutila
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ABSTRACT: The liver is inaccessible to organ balance measurements in humans. To validate [(18)F]fluorodeoxyglucose ([(18)F]FDG) positron emission tomography (PET) in the quantification of hepatic glucose uptake (HGU), we determined [(18)F]FDG modeling parameters, lumped constant (LC), and input functions (single arterial versus dual).
Anesthetized pigs were studied during fasting (n = 6), physiologic (n = 4), and supraphysiologic (n = 4) hyperinsulinemia. PET was performed with C(15)O (blood pool) and [(18)F]FDG (glucose uptake). 6,6-Deuterated glucose ([(2)H]G) was coinjected with [(18)F]FDG and blood collected from the carotid artery and portal and hepatic veins to compute LC as ratio between tracers fractional extraction. HGU was estimated from PET images and ex vivo from high-performance liquid chromatography measurements of liver [(18)F]FDG versus [(18)F]FDG-6-phosphate and [(18)F]-glycogen. Endogenous glucose production was measured with [(2)H]G and hepatic blood flow by flowmeters.
HGU was increased in hyperinsulinemia versus fasting (P < .05). Fractional extraction of [(18)F]FDG and [(2)H]G was similar (not significant), intercorrelated (r = 0.98, P < .0001), and equally higher during hyperinsulinemia than fasting (P <or= .05), with an LC of 0.98 +/- 0.10 and 1.18 +/- 0.26, respectively. [(18)F]FDG-PET modeling provided HGU values that did not differ from, and were correlated with, those from ex vivo measurements (r = 0.61, P <or= .02); proportional estimates of liver perfusion and endogenous glucose production were also obtained. Single and dual input functions produced strongly intercorrelated results (r > 0.95, P < .0001), with a modest underestimation of HGU by the former.
[(18)F]FDG-PET-derived parameters provide accurate quantification of HGU and estimates of liver perfusion and glucose production. In the liver, LC of [(18)F]FDG is nearly unitary. Using a single arterial input introduces only a small error in estimation of HGU.
Gastroenterology 02/2007; 132(2):531-42. · 11.68 Impact Factor
