Biomedical subjects

Pirjo Nuutila

Publications and source records attributed to Pirjo Nuutila.

At least 19 recordsLinked to original sources

PubMed2007

Fluorine-18-L-dihydroxyphenylalanine (18F-DOPA) positron emission tomography as a tool to localize an insulinoma or beta-cell hyperplasia in adult patients.

CONTEXT AND OBJECTIVE: Fluorine-18-L-dihydroxyphenylalanine (18F-DOPA) positron emission tomography (PET) is a promising method in localizing neuroendocrine tumors. Recently, it has been shown to differentiate focal forms of congenital hyperinsulinism of infancy. The current study was set up to determine the potential of 18F-DOPA PET in identifying the insulin-secreting tumors or beta-cell hyperplasia of the pancreas in adults. PATIENTS AND METHODS: We prospectively studied 10 patients with confirmed hyperinsulinemic hypoglycemia and presumed insulin-secreting tumor using 18F-DOPA PET. Anatomical imaging was performed with computed tomography (CT) and magnetic resonance imaging (MRI). All patients were operated on, and histological verification was available in each case. Semiquantitative PET findings in the pancreas using standardized uptake values were compared to standardized uptake values of seven consecutive patients with nonpancreatic neuroendocrine tumors. RESULTS: By visual inspection of 18F-DOPA PET images, it was possible in nine of 10 patients to localize the pancreatic lesion, subsequently confirmed by histological analysis. 18F-DOPA uptake was enhanced in six of seven solid insulinomas and in the malignant insulinoma and its hepatic metastasis. Two patients with beta-cell hyperplasia showed increased focal uptake of 18F-DOPA in the affected areas. As compared to CT or MRI, 18F-DOPA PET was more sensitive in localizing diseased pancreatic tissue. CONCLUSION: 18F-DOPA PET was useful in most patients with insulinoma and negative CT, MRI, and ultrasound results. In agreement with previous findings in infants, preoperative 18F-DOPA imaging seems to be a method of choice for the detection of beta-cell hyperplasia in adults. It should be considered for the detection of insulinoma or beta-cell hyperplasia in patients with confirmed hyperinsulinemic hypoglycemias when other diagnostic work-up is negative.

Adult↗

PubMed2006

Free fatty acid depletion acutely decreases cardiac work and efficiency in cardiomyopathic heart failure.

BACKGROUND: Metabolic modulators that enhance myocardial glucose metabolism by inhibiting free fatty acid (FFA) metabolism may improve cardiac function in heart failure patients. We studied the effect of acute FFA withdrawal on cardiac function in patients with heart failure caused by idiopathic dilated cardiomyopathy (IDCM). METHODS AND RESULTS: Eighteen fasting nondiabetic patients with IDCM (14 men, 4 women, aged 58.8+/-8.0 years, ejection fraction 33+/-8.8%) and 8 matched healthy controls underwent examination of myocardial perfusion and oxidative and FFA metabolism, before and after acute reduction of serum FFA concentrations by acipimox, an inhibitor of lipolysis. Metabolism was monitored by positron emission tomography and [15O]H2O, [11C]acetate, and [11C]palmitate. Left ventricular function and myocardial work were echocardiographically measured, and efficiency of forward work was calculated. Acipimox decreased myocardial FFA uptake by >80% in both groups. Rate-pressure product and myocardial perfusion remained unchanged, whereas stroke volume decreased similarly in both groups. In the healthy controls, reduced cardiac work was accompanied by decreased oxidative metabolism (from 0.071+/-0.019 to 0.055+/-0.016 min(-1), P<0.01). In IDCM patients, cardiac work fell, whereas oxidative metabolism remained unchanged and efficiency fell (from 35.4+/-12.6 to 31.6+/-13.3 mm Hg x L x g(-1), P<0.05). CONCLUSIONS: Acutely decreased serum FFA depresses cardiac work. In healthy hearts, this is accompanied by parallel decrease in oxidative metabolism, and myocardial efficiency is preserved. In failing hearts, FFA depletion did not downregulate oxidative metabolism, and myocardial efficiency deteriorated. Thus, failing hearts are unexpectedly more dependent than healthy hearts on FFA availability. We propose that both glucose and fatty acid oxidation are required for optimal function of the failing heart.

Aged↗

PubMed2006

Simultaneous evaluation of myocardial blood flow, cardiac function and lung water content using [15O]H2O and positron emission tomography.

PURPOSE: This study sought to evaluate an imaging approach using [15O]H2O and positron emission tomography (PET) for simultaneous assessment of myocardial perfusion, cardiac function and lung water content as a potential indicator of pulmonary oedema. METHODS: Twenty-six subjects divided into two groups (group I, 13 patients with idiopathic dilated cardiomyopathy; group II, 13 healthy volunteers) underwent dynamic PET scanning after intravenous infusion of approximately 995 MBq [15O]H2O. In both groups, echocardiograms were performed after the PET studies. From the dynamic [15O]H2O data, lung water content (LWC) at equilibrium, myocardial blood flow (MBF), cardiac output (CO), stroke volume (SV) and stroke volume indexes (SVI) using the indicator dilution principle were determined. RESULTS: LWC was 18% (p = 0.038) higher in patients than in controls. Global MBF did not differ significantly between the groups, but regional MBF values were significantly lower (p < 0.05) in the anterior and septal walls in the patient group. The results of the Passing-Bablok regression indicated the absence of a systematic difference between the two techniques. Bland-Altman analysis performed for each group (patients vs healthy controls) showed a non-significant bias (p > 0.1) of -0.02 +/- 0.82 vs -0.05 +/- 0.54 l/min (CO), -1.44 +/- 14.31 vs 1.70 +/- 10.56 ml/beat (SV) and 0.47 +/- 6.21 vs 0.30 +/- 5.02 ml/beat/m2 (SVI). The 95% limits of agreement were -1.62 to 1.59 vs -1.11 to 1.01 l/min (CO), -26.61 to 29.49 vs -22.39 to 18.99 ml/beat (SV) and -11.69 to 12.88 vs -9.53 to 10.14 ml/beat/m2 (SVI). Right ventricular CO was increased by 33% (p = 0.014) in the patient group as compared with normal controls. CONCLUSION: Our results demonstrate that additional analysis of cardiac function and lung water content are feasible from the dynamic cardiac [15O]H2O PET studies acquired for myocardial perfusion. The parameters appear to work as expected. Further studies are warranted to elucidate the clinical value of these new parameters.

Body Water↗

PubMed2006

Increased physical activity decreases hepatic free fatty acid uptake: a study in human monozygotic twins.

Exercise is considered to be beneficial for free fatty acid (FFA) metabolism, although reports of the effects of increased physical activity on FFA uptake and oxidation in different tissues in vivo in humans have been inconsistent. To investigate the heredity-independent effects of physical activity and fitness on FFA uptake in skeletal muscle, the myocardium, and liver we used positron emission tomography (PET) in nine healthy young male monozygotic twin pairs discordant for physical activity and fitness. The cotwins with higher physical activity constituting the more active group had a similar body mass index but less body fat and 18 +/- 10% higher (P < 0.001) compared to the less active brothers with lower physical activity. Low-intensity knee-extension exercise increased skeletal muscle FFA and oxygen uptake six to 10 times compared to resting values but no differences were observed between the groups at rest or during exercise. At rest the more active group had lower hepatic FFA uptake compared to the less active group (5.5 +/- 4.3 versus 9.0 +/- 6.1 micromol (100 ml)(-1) min(-1), P = 0.04). Hepatic FFA uptake associated significantly with body fat percentage (P = 0.05). Myocardial FFA uptake was similar between the groups. In conclusion, in the absence of the confounding effects of genetic factors, moderately increased physical activity and aerobic fitness decrease body adiposity even in normal-weighted healthy young adult men. Further, increased physical activity together with decreased intra-abdominal adiposity seems to decrease hepatic FFA uptake but has no effects on skeletal muscle or myocardial FFA uptake.

Adipose Tissue↗

PubMed2006

Myocardial triglyceride content and epicardial fat mass in human obesity: relationship to left ventricular function and serum free fatty acid levels.

CONTEXT AND OBJECTIVE: Ectopic fat accumulation within and around the myocardial wall has been implicated in the pathogenesis of heart disease in obesity. We evaluated myocardial and epicardial fat, left ventricular (LV) function, and metabolic risk factors in nine (five lean, four moderately obese) men. METHODS: Myocardial fat percent was quantified in the septum by proton magnetic resonance spectroscopy. Reproducibility was assessed by triplicate systolic and diastolic measurements. LV parameters and epicardial fat were determined by magnetic resonance imaging. Waist-to-hip ratio and liver enzymes (alanine transaminase) were used as surrogate markers of visceral and liver fat contents. RESULTS: Myocardial fat (2.1 +/- 0.5 vs. 0.8 +/- 0.1, P = 0.03) and epicardial fat (120 +/- 33 vs. 55 +/- 12 g, P = 0.08) were higher in obese than lean subjects. Individuals with above-median alanine transaminase values had a 4-fold elevation in myocardial fat. The coefficient of variation of repeated myocardial fat percent determinations was 17 +/- 3 and 23 +/- 3% in systole and diastole, respectively. Myocardial fat was correlated with free fatty acid (FFA) levels (r = 0.76; P = 0.017), epicardial fat (r = 0.69; P = 0.042), and waist-to-hip ratio (r = 0.70; P = 0.035), and it showed a tendency to associate positively with LV work. Epicardial fat was associated with peripheral vascular resistance (positively) and the cardiac index (negatively). FFA levels were significantly correlated with LV mass (r = 0.72; P = 0.030) and forward work (r = 0.74; P = 0.023). CONCLUSIONS/INTERPRETATION: The accumulation of triglyceride in and around the myocardium of moderately obese individuals is significant, and it is related to FFA exposure, generalized ectopic fat excess, and peripheral vascular resistance. These changes precede LV overload and hypertrophy.

Adipose Tissue↗

PubMed2006

Structural and functional changes in peripheral vasculature of Fabry patients.

OBJECTIVE: Fabry disease is a lysosomal storage disorder due to deficient alpha-galactosidase A activity, which leads to glycosphingolipid accumulation especially in vascular smooth-muscle and endothelial cells. Little is known about the effects of Fabry disease on peripheral artery function and structure. Therefore, we aimed to further characterize the peripheral vascular structural and functional changes in Fabry disease. METHODS AND RESULTS: We measured structural and functional vascular parameters, including intima-media thickness (IMT) of brachial and carotid arteries and abdominal aorta, carotid and aortic compliance, and brachial artery flow-mediated dilatation (FMD) in 17 Fabry patients and 34 healthy controls matched for age, sex and smoking. Carotid IMT (0.64 +/- 0.15 vs 0.57 +/- 0.12 mm), brachial IMT (1.02 +/- 0.25 vs 0.74 +/- 0.18 mm), and aortic IMT (0.31 +/- 0.09 vs 0.26 +/- 0.04 mm) were significantly increased, and brachial FMD was significantly impaired (6.3 +/- 5.0 vs 9.7 +/- 3.9%) in Fabry patients compared to healthy controls (p < 0.05 in all comparisons after adjustments for age, LDL-cholesterol, and systolic blood pressure). No differences were observed in arterial compliance between the groups. CONCLUSIONS: These data suggest that Fabry disease affects arterial function and structure by disturbing peripheral endothelial function and promoting intima-media thickening.

Adult↗

PubMed2006

Relationship between local perfusion and FFA uptake in human skeletal muscle-no effect of increased physical activity and aerobic fitness.

We investigated heredity-independent effects of increased physical activity and aerobic fitness on skeletal muscle free fatty acid (FFA) uptake, perfusion, and their heterogeneity at rest and during exercise. Also, the relationship between local skeletal muscle FFA uptake and perfusion was studied. Nine young adult male monozygotic twin pairs with significant difference in physical activity [229 min (SD 156) average time spent for conditioning exercise per week in more and 98 min (SD 71) in less active twins, P = 0.013] and aerobic fitness [18% (SD 10) difference in maximum O2 uptake] between brothers were studied using positron emission tomography. Submaximal knee-extension exercise increased perfusion, FFA uptake, and oxygen uptake in quadriceps femoris muscles 6-10 times compared with resting values (P < 0.001). More active twins tended to utilize more oxygen, while no differences were found in muscle perfusion or FFA uptake between groups. Mean perfusion and FFA uptake correlated strongly at a whole muscle level, both at rest (r = 0.97, P = 0.03 in more and r = 0.98, P = 0.02 in less active twins) and during exercise (r = 0.99, P = 0.01 and r = 0.94, P = 0.06), but at the voxel level (87 mm3) correlation was only moderate during exercise [r = 0.73 (SD 0.08) vs. r = 0.74 (SD 0.10), P = 0.92] and weak at rest [r = 0.28 (SD 0.13) vs. r = 0.33 (SD 0.21), P = 0.58]. Exercise decreased both perfusion and FFA uptake heterogeneity within the muscles (P < 0.001) similarly in both groups. In conclusion, long-term history of moderately increased physical activity tends to enhance muscle oxidative metabolism, but it does not have any significant influence on the FFA uptake or perfusion rates or their heterogeneity in skeletal muscle. Submaximal knee-extension exercise decreases heterogeneity of muscle FFA uptake and perfusion and improves matching between local muscle perfusion and FFA uptake. Thus it seems that the genetic influence is more important to determine the heterogeneity of perfusion and FFA uptake in skeletal muscle than exercise training.

Blood Flow Velocity↗

PubMed2006

Human radiation dosimetry of [11C]MeAIB, a new tracer for imaging of system A amino acid transport.

PURPOSE: [N-methyl-11C]alpha-methylaminoisobutyric acid ([11C]MeAIB) is a promising positron emission tomography (PET) tracer for imaging hormonally regulated system A amino acid transport. Uptake of [11C]MeAIB is totally specific for amino acid transport since [11C]MeAIB is metabolically stable both extra- and intracellularly. The aim of this study was to measure cumulated radioactivity in different organs and estimate the absorbed radiation doses to humans with the Medical Internal Radiation Dosimetry (MIRD) method. METHODS: Radiation absorbed doses were calculated from PET images for 25 volunteers. Dynamic acquisition data were obtained for the thoracic, abdominal, femoral and head and neck regions. The median dose of intravenously injected [11C]MeAIB was 422+/-35 MBq, with a range of 295-493 MBq. After PET imaging the radioactivity in voided urine was measured. Experimental human data were used for residence time estimates. Radiation doses were calculated with commonly used software. RESULTS: The effective dose for a 70-kg adult was 0.004 mSv/MBq, corresponding to a 1.72 mSv effective dose from the PET study with injection of 430 MBq [11C]MeAIB. The highest absorbed doses were in the pancreas (0.018 mGy/MBq), kidneys (0.017 mGy/MBq), intestine (0.014 mGy/MBq), liver (0.008 mGy/MBq) and stomach (0.005 mGy/MBq). Only 0.57% of injected activity was excreted to urine within 1 h after injection. CONCLUSION: Biodistribution of [11C]MeAIB in the abdominal region reflected the high activity of the transportation of amino acids via system A and these organs also had the highest radiation doses. An effective dose of 0.004 mSv/MBq is fully justified when [11C]MeAIB PET is performed to study system A activity in vivo.

Amino Acid Transport System A↗

PubMed2006

[11C]palmitate kinetics across the splanchnic bed in arterial, portal and hepatic venous plasma during fasting and euglycemic hyperinsulinemia.

PURPOSE: The liver is fundamental in regulating lipid metabolism, and it supplies fatty acids (FA) to the rest of the body in the form of triglycerides (TG); the time-related relevance of this process is incompletely defined. The aim of the study was to investigate the appearance of labeled TG in the hepatic vascular bed after [11C]palmitate injection during fasting and insulin stimulation. METHODS: Plasma [11C]palmitate kinetics in arterial, portal and hepatic venous lipid fractions was studied in eight anesthetized pigs during fasting or euglycemic hyperinsulinemia. Plasma analyses were conducted at 10 and 40 min after tracer injection. Corresponding liver positron emission tomography (PET) images were acquired for the semiquantitative determination of hepatic FA uptake. RESULTS: At 10 min, plasma levels of unchanged [11C]palmitate were lower in hyperinsulinemic than in fasting experiments in the artery and in the portal vein (P< or=.03), suggesting faster clearance. Levels of unmetabolized [11C]palmitate did not differ between portal and arterial plasma. In the fasting state, a tendency to a positive arterial and portal vs. hepatic venous gradient was observed, indicative of net hepatic [11C]palmitate extraction. Labeled TG were already detectable at 10 min (fasting vs. hyperinsulinemia, ns) and were higher in fasting than in hyperinsulinemic animals at 40 min (92+/-1% and 82+/-6% of arterial plasma radioactivity). Higher proportions of labeled TG were recovered in portal vein plasma, suggesting release by the gut. The portal and the arterial-portal vs. hepatic venous TG gradient tended to be positive. Accordingly, hepatic FA uptake was higher, but declined more rapidly during fasting than during hyperinsulinemia. CONCLUSION: The study indicates that the redistribution of [11C]palmitate between different lipid pools occurs within the short time interval of most PET experiments and is strongly influenced by insulin. Labeled TG constitute an additional [11C]palmitate source in the modeling of PET data.

Animals↗

PubMed2006

Liver steatosis coexists with myocardial insulin resistance and coronary dysfunction in patients with type 2 diabetes.

Nonalcoholic fatty liver (NAFL) is a common comorbidity in patients with type 2 diabetes and links to the risk of coronary syndromes. The aim was to determine the manifestations of metabolic syndrome in different organs in patients with liver steatosis. We studied 55 type 2 diabetic patients with coronary artery disease using positron emission tomography. Myocardial perfusion was measured with [15O]H2O and myocardial and skeletal muscle glucose uptake with 2-deoxy-2-[18F]fluoro-D-glucose during hyperinsulinemic euglycemia. Liver fat content was determined by magnetic resonance proton spectroscopy. Patients were divided on the basis of their median (8%) into two groups with low (4.6 +/- 2.0%) and high (17.4 +/- 8.0%) liver fat content. The groups were well matched for age, BMI, and fasting plasma glucose. In addition to insulin resistance at the whole body level (P = 0.012) and muscle (P = 0.002), the high liver fat group had lower insulin-stimulated myocardial glucose uptake (P = 0.040) and glucose extraction rate (P = 0.0006) compared with the low liver fat group. In multiple regression analysis, liver fat content was the most significant explanatory variable for myocardial insulin resistance. In addition, the high liver fat group had increased concentrations of high sensitivity C-reactive protein, soluble forms of E-selectin, vascular adhesion protein-1, and intercellular adhesion molecule-1 (P < 0.05) and lower coronary flow reserve (P = 0.02) compared with the low liver fat group. In conclusion, in patients with type 2 diabetes and coronary artery disease, liver fat content is a novel independent indicator of myocardial insulin resistance and reduced coronary functional capacity. Further studies will reveal the effect of hepatic fat reduction on myocardial metabolism and coronary function.

Biomarkers↗

PubMed2006

Decreased myocardial free fatty acid uptake in patients with idiopathic dilated cardiomyopathy: evidence of relationship with insulin resistance and left ventricular dysfunction.

BACKGROUND: Results on myocardial substrate metabolism in the failing heart have been contradictory. Insulin resistance, a common comorbidity in heart failure patients, and medical therapy may modify myocardial metabolism in complex fashions. Therefore, we characterized myocardial oxidative and free fatty acid (FFA) metabolism in patients with idiopathic dilated cardiomyopathy (IDCM) and investigated the contributions of insulin resistance and beta-blocker therapy. METHODS AND RESULTS: Nineteen patients with IDCM (age 58 +/- 8 years, ejection fraction 33 +/- 8.8%) and 15 healthy controls underwent examination of myocardial blood perfusion, oxidative and FFA metabolism using positron emission tomography and [(15)O]H(2)O, [(11)C]acetate and [(11)C]palmitate, respectively. Echocardiography was used to assess myocardial function, work, and efficiency of forward work. Insulin resistance was calculated using the homeostasis model assessment index (HOMA index) and the degree of beta-blockade was estimated with a beta-adrenoceptor occupancy test. IDCM patients were characterized by decreased cardiac efficiency (35 +/- 2 versus 57 +/- 12 mm Hg.L.g(-1), P < .0001) and reduced myocardial FFA uptake (5.5 +/- 2.0 versus 6.4 +/- 1.2 mumol.100 g(-1).min(-1), P < .05), but the FFA beta-oxidation rate constant was not changed. In the patients, myocardial FFA uptake was inversely associated with left ventricular (LV) ejection fraction (r = -0.63, P < .01), indicating that further depression of LV function induces an opposite switch to greater FFA uptake. The FFA beta-oxidation rate constant correlated positively with the HOMA index (r = 0.53, P < .05). In patients on beta-1 selective beta-blockers, beta-1 adrenoceptor occupancy correlated inversely with LV work, oxidative metabolism, and FFA uptake; similar relationships were not found in patients on nonselective beta-blocker. CONCLUSIONS: Myocardial FFA metabolism is reduced in patients with IDCM. However, when LV function is further depressed and insulin resistance manifested, myocardial FFA uptake and oxidation are, in turn, upregulated. These findings may partly explain the discrepancies between previous studies about cardiac metabolism in heart failure.

Adrenergic beta-Antagonists↗

PubMed2006

The association between muscle EMG and perfusion in knee extensor muscles.

The relationships between electromyographic (EMG) activity and force as well as muscle blood flow and work have been well established. However, the association between muscle blood flow and EMG activity remains unsolved. Thus, to test the hypothesis that muscle EMG activity relates to muscle perfusion in different compartments of the quadriceps femoris (QF) muscle, 12 healthy male subjects were studied. During two very submaximal exercise bouts, at different exercise intensities, oxygen labelled radiowater and positron emission tomography were used to measure muscle perfusion. In addition, produced force of knee extensors and muscle EMG activity in the vastus lateralis (VL), vastus medialis (VM) and rectus femoris (RF) muscles were recorded during both exercise bouts. Although the exercise intensity and average force production was higher during the second exercise bout (38 +/- 15 versus 51 +/- 17 N; P = 0.007), the mean EMG activity was lower (RF; P<0.001) or unchanged (VL; P = 0.722 and VM; P = 0.640). During the second exercise period, perfusion also remained unchanged in the entire QF muscle (P = 0.223) and in its separate muscles (VL, P = 0.703; VM, P = 0.141; RF, P = 0.113) in a group level. However, the individual changes in muscle perfusion were tightly related to changes in muscle EMG activity in VL (r = 0.84; P = 0.002) and VM (r = 0.68; P = 0.015) but poorly in the RF muscle (r = 0.40; P = 0.257). In conclusion, the different associations between muscle perfusion and EMG activity in different QF muscles suggests specific functional role of the vasti muscles and the RF muscle.

Adult↗

PubMed2006

Insulin improves myocardial blood flow in patients with type 2 diabetes and coronary artery disease.

Insulin infusion improves myocardial blood flow (MBF) in healthy subjects. Until now, the effect of insulin on myocardial perfusion in type 2 diabetic subjects with coronary artery disease (CAD) has been unknown. We studied the effects of insulin on MBF in ischemic regions evaluated by single-photon emission-computed tomography and coronary angiography and in nonischemic regions in 43 subjects (ages 63 +/- 7 years) with type 2 diabetes (HbA(1c) 7.1 +/- 0.9%). MBF was measured at fasting and during a euglycemic-hyperinsulinemic clamp at rest (n = 43) and during adenosine-induced (140 mug . kg(-1) . min(-1) for 7 min) hyperemia (n = 26) using positron emission tomography and (15)O-labeled water. MBF was significantly attenuated in ischemic regions as compared with in nonischemic regions (P < 0.0001) and was increased by insulin as compared with in the fasting state (P < 0.0001). At rest, insulin infusion increased MBF by 13% in ischemic regions (P = 0.043) and 22% in nonischemic regions (P = 0.003). During adenosine infusion, insulin enhanced MBF by 20% (P = 0.018) in ischemic regions and 18% (P = 0.045) in nonischemic regions. In conclusion, insulin infusion improved MBF similarly in ischemic and nonischemic regions in type 2 diabetic subjects with CAD. Consequently, in addition to its metabolic effects, insulin infusion may improve endothelial function and thus increase the threshold for ischemia and partly contribute to the beneficial effects found in clinical trials in these subjects.

Aged↗

PubMed2006

Noninvasive diagnosis of focal hyperinsulinism of infancy with [18F]-DOPA positron emission tomography.

Congenital hyperinsulinism of infancy (CHI) is characterized by severe hypoglycemia due to dysregulated insulin secretion, associated with either focal or diffuse pathology of the endocrine pancreas. The focal condition is caused by a paternally inherited mutation in one of the genes encoding the subunits of the beta-cell ATP-sensitive potassium channel (SUR1/ABCC8 or Kir6.2/KCNJ11) and somatic loss of maternal 11p15 alleles within the affected area. Until now, preoperative diagnostics have relied on technically demanding and invasive catheterization techniques. We evaluated the utility of fluorine-18 l-3,4-dihydroxyphenylalanine ([(18)F]-DOPA) positron emission tomography (PET) to identify focal pancreatic lesions in 14 CHI patients, 11 of which carried mutations in the ABCC8 gene (age 1-42 months). To reduce bias in PET image interpretation, quantitative means for evaluation of pancreatic [(18)F]-DOPA uptake were established. Five patients had a visually apparent focal accumulation of [(18)F]-DOPA and standardized uptake value (SUV) >50% higher (mean 1.8-fold) than the maximum SUV of the unaffected part of the pancreas. When these patients were operated on, a focus of 4-5 x 5-8 mm matching with the PET scan was found, and all were normoglycemic after resection of the focus. The remaining nine patients had diffuse accumulation of [(18)F]-DOPA in the pancreas (SUV ratio <1.5). Diffuse histology was verified in four of these, and pancreatic catheterization was consistent with diffuse pathology in four cases. In conclusion, [(18)F]-DOPA PET is a promising noninvasive method for the identification and localization of the focal form of CHI.

Child, Preschool↗

PubMed2006

18F-FDG assessment of glucose disposal and production rates during fasting and insulin stimulation: a validation study.

UNLABELLED: The glucose analog (18)F-FDG is commonly used to quantify regional glucose uptake in vivo. The aim of this study was to test whether the analysis of plasma (18)F-FDG kinetics could be used to estimate endogenous glucose production (EGP) and the total rate of appearance (Ra), total rate of disappearance (Rd), and the metabolic clearance rate (MCR) of glucose. METHODS: Fourteen pigs were coinjected with (18)F-FDG and 6,6-(2)H-glucose ((2)H-G) during fasting (n = 6) and during physiologic (1.0 mU.kg(-1).min(-1), n = 4) and supraphysiologic (5.0 mU.kg(-1).min(-1), n = 4) euglycemic hyperinsulinemia. Arterial plasma was sampled for 180 min to quantify the parameters for the 2 tracers. RESULTS: Fasting Rd((2))(H-G) and Rd(FDG) were 12.3 +/- 2.1 and 13.3 +/- 1.3 micromol.kg(-1).min(-1) (difference not statistically significant [NS]). M values were more than doubled between the 2 clamp studies (P < 0.0001). Rd((2))(H-G) and Rd(FDG) were dose-dependently higher during the hyperinsulinemic state (19.8 +/- 3.7 vs. 18.9 +/- 1.1 and 31.4 +/- 4.1 vs. 31.9 +/- 2.3 in 1.0 and 5.0 mU.kg(-1).min(-1) studies, respectively; difference between tracers NS) than during the fasting state, with a parallel suppression of EGP((2))(H-G) and EGP(FDG). Parameters estimated by (18)F-FDG and (2)H-G were equivalent in all groups; their agreement was confirmed by Bland-Altman examination. Total Rd(FDG) correlated with Rd((2))(H-G) (r = 0.74; P = 0.003), M (r = 0.92; P = 0.001), MCR((2))(H-G) (r = 0.52; P = 0.037), and EGP((2))(H-G) (r = -0.71; P = 0.004). EGP(FDG) correlated with EGP((2))(H-G) (r = 0.62; P = 0.018), Rd((2))(H-G) (r = -0.78; P = 0.001), and MCR((2))(H-G) (r = -0.67; P = 0.008). The (18)F-FDG mean transit time correlated inversely with the M and Rd values and positively with EGP. CONCLUSION: The glucose analog (18)F-FDG can be used in the simultaneous estimation of whole-body glucose turnover and production and regional (18)F-FDG PET measurements under both fasting and insulin-stimulated conditions.

Animals↗

PubMed2005

The influence of hepatic lipase C-480T polymorphism on coronary flow reserve in young men is independent of the plasma cholesterol level.

BACKGROUND: The hepatic lipase (HL) gene C-480T promoter polymorphism affects gene transcription and enzyme activity and leads to CC, CT, and TT genotypes. Recently, HL expression was detected in macrophages. It has been postulated that HL might have a direct role in the pathogenesis of atherosclerosis without changes in the plasma profile. We hypothesized that the difference of plasma cholesterol level may not influence the effect of HL genotype on coronary reactivity. METHODS: A total of 108 young men (aged 34+/-5 years) were genotyped and divided into three groups. These groups contained 45, 49 and 14 men having either normal (4.9+/-1.2 mmol/L), mildly (5.5+/-0.8 mmol/L) or severely (7.8+/-1.9 mmol/L, subjects with familial hypercholesterolemia) elevated mean plasma cholesterol level, respectively. Myocardial blood flow (MBF) was measured at rest and during adenosine or dipyridamole-induced hyperemia with positron emission tomography using [(15)O] H(2)O. RESULTS: The effect of HL genotype on the indices of MBF was parallel within all cholesterol groups and therefore they were combined. In all subjects, basal flow did not differ between the genotypes. However, men with CC genotype had a significantly higher hyperemic blood flow (3.86+/-1.26 mLg(-1)min(-1) versus 3.20+/-1.38 mLg(-1)min(-1), p=0.007), higher coronary flow reserve (CFR, 4.80+/-1.77 versus 3.77+/-1.43, p=0.001) and lower coronary resistance during hyperemia (25.63+/-9.98 mmHg min g mL(-1) versus 35.00+/-23.95 mmHg min g mL(-1), p=0.003) than T allele carriers. In multivariate regression analysis, after adjustment for age, body mass index, serum lipids, blood pressure, adenosine or dipyridamole administration, and study group, HL polymorphism was an independent predictor of blood flow during hyperemia (p=0.016), coronary resistance (p=0.014), and CFR (p=0.005), respectively. CONCLUSIONS: The HL C-480 T polymorphism is associated with CFR, which is an early indicator of atherosclerosis, independently of the level of plasma cholesterol in young men.

Adenosine↗

PubMed2005

Positive family history of coronary artery disease is associated with reduced myocardial vasoreactivity in healthy men.

OBJECTIVE: Positive family history as a risk factor for coronary artery disease seems to be most important in subjects who otherwise are at low risk. We examined the association between family history of coronary artery disease and myocardial vasoreactivity in healthy men. METHODS: 35 non-smoking healthy men (age 35+/-7 years) were studied: 16 had positive family history of coronary artery disease and 19 had negative family history. The myocardial blood flow measurements were performed basally and during adenosine infusion (140 mug/kg/min) with and without simultaneous physiological hyperinsulinemia (insulin infusion at a rate of 1 mU/kg/min) using positron emission tomography and O-15-water. RESULTS: Basal myocardial blood flow was similar between the subjects with positive and negative family history of coronary artery disease (0.79+/-0.19 and 0.79+/-0.21 mL g(-1) min(-1), NS). Adenosine stimulated flow was significantly reduced in subjects with positive family history (3.0+/-0.5 vs 4.0+/-1.2 mL g(-1) min(-1), respectively, p=0.003). During physiological hyperinsulinemia adenosine stimulated flow was further enhanced in both groups but significantly blunted in subjects with positive family history (3.7+/-0.9 vs 5.2+/-1.5 mL g(-1) min(-1), respectively, p=0.001). These differences remained significant after simultaneous controlling for age, BMI, HbA1c, LDL-cholesterol, HDL-cholesterol and blood pressure (p=0.002). CONCLUSIONS: Healthy non-smoking men with positive family history of coronary artery disease are characterized by impaired myocardial vasoreactivity.

Adult↗

PubMed2005

Rosiglitazone treatment increases subcutaneous adipose tissue glucose uptake in parallel with perfusion in patients with type 2 diabetes: a double-blind, randomized study with metformin.

CONTEXT: We have shown that rosiglitazone increases whole-body and adipose tissue insulin sensitivity in humans. OBJECTIVE: The aim of this study was to further examine whether possible changes in adipose perfusion could explain increased adipose tissue glucose uptake (GU). PATIENTS: Thirty-seven patients with newly diagnosed type 2 diabetes were included. INTERVENTION: Patients were randomized into treatment with rosiglitazone, metformin, or placebo for 26 wk in a double-blinded trial. DESIGN: Femoral adipose flow and GU were measured with [15O]H2O, [18F]fluorodeoxyglucose and positron emission tomography during euglycemic hyperinsulinemia. Adipose masses were measured using magnetic resonance imaging. RESULTS: Metformin and rosiglitazone treatment improved glycemic control, but only rosiglitazone increased whole-body insulin sensitivity. Rosiglitazone treatment increased flow by 72% (P < 0.01) and GU by 23% (P < 0.05) and thereby decreased adipose tissue glucose extraction by 18% (P < 0.05); no changes were observed in the metformin or placebo-treated groups. When the adipose masses were taken into account, rosiglitazone treatment increased flow by 73% (P < 0.01) and GU by 24% (P < 0.05). During hyperinsulinemia, flow correlated with GU (r = 0.63; P < 0.01). CONCLUSIONS: In conclusion, s.c. GU is associated with flow in patients with type 2 diabetes. Rosiglitazone treatment enhances GU and flow but decreases glucose extraction, suggesting that perfusion may contribute to adipose tissue insulin sensitization by rosiglitazone.

Adipose Tissue↗