Merja Haaparanta

Glucose-free fatty acid cycle operates in human heart and skeletal muscle in vivo.

Positron emission tomography permits noninvasive measurement of regional glucose uptake in vivo in humans. We employed this technique to determine the effect of FFA on glucose uptake in leg, arm, and heart muscles. Six normal men were studied twice under euglycemic hyperinsulinemic (serum insulin approximately 500 pmol/liter) conditions, once during elevation of serum FFA by infusions of heparin and Intralipid (serum FFA 2.0 +/- 0.4 mmol/liter), and once during infusion of saline (serum FFA 0.1 +/- 0.01 mmol/liter). Regional glucose uptake rates were measured using positron emission tomography-derived 18F-fluoro-2-deoxy-D-glucose kinetics and the three-compartment model described by Sokoloff (Sokoloff, L., M. Reivich, C. Kennedy, M. C. Des Rosiers, C. S. Patlak, K. D. Pettigrew, O. Sakurada, and M. Shinohara. 1977. J. Neurochem. 28: 897-916). Elevation of plasma FFA decreased whole body glucose uptake by 31 +/- 2% (1,960 +/- 130 vs. 2,860 +/- 250 mumol/min, P less than 0.01, FFA vs. saline study). This decrease was due to inhibition of glucose uptake in the heart by 30 +/- 8% (150 +/- 33 vs. 200 +/- 28 mumol/min, P less than 0.02), and in skeletal muscles; both when measured in femoral (1,594 +/- 261 vs. 2,272 +/- 328 mumol/min, 25 +/- 13%) and arm muscles (1,617 +/- 411 to 2,305 +/- 517 mumol/min, P less than 0.02, 31 +/- 6%). Whole body glucose uptake correlated with glucose uptake in femoral (r = 0.75, P less than 0.005), and arm muscles (r = 0.69, P less than 0.05) but not with glucose uptake in the heart (r = 0.04, NS). These data demonstrate that the glucose-FFA cycle operates in vivo in both heart and skeletal muscles in humans.

Depressive symptoms and presynaptic dopamine function in neuroleptic-naive schizophrenia

We have previously reported aberrations in the striatal presynaptic dopamine function in neuroleptic-naive schizophrenic patients compared to healthy controls (Hietala, J., Syvälahti, E., Vuorio, K. et al., 1995. Lancet 346, 1130-1131). In this extended study we explore whether the altered presynaptic dopamine function correlates with the clinical symptomatology in schizophrenia. Striatal dopamine synthesis capacity (6-[18F]fluorodopa (FDOPA) uptake, Ki values) was studied with positron emission tomography in 10 neuroleptic-naive schizophrenic patients and 13 healthy controls. The clinical symptomatology was characterized with the Positive and Negative Symptom Scale (PANSS). The patients had an increased FDOPA uptake in striatum and lacked the asymmetry in caudate FDOPA uptake (p = 0.0005), confirming our earlier results. Left striatal FDOPA uptake (Ki) values correlated negatively with depressive symptoms in a highly significant manner. On the other hand, paranoid symptomatology correlated positively with right putamen FDOPA uptake at a trend level (rho = 0.73, p < 0.02). The lack of asymmetry in caudate Ki values did not associate with any dimension of psychopathology. The major finding in this study is that depressive symptoms in neuroleptic-naive first-admission schizophrenia are associated with low presynaptic dopamine function. This link appears to be hemisphere-related and may have drug-treatment implications, e.g., in prediction of response to D2 receptor blocking antipsychotic drugs. A possible connection between paranoid symptomatology and subcortical hyperdopaminergia is suggested, but this remains to be further verified.

Rate of progression in Parkinson's disease: A 6-[18F]fluoro-L-dopa PET study

The aim of this study was to investigate the rate of progression in Parkinsons disease (PD) with 6‐[18F]fluoro‐L‐dopa (FDOPA) positron emission tomography (PET). We investigated 21 patients with PD and eight healthy controls. Ten of the patients were de novo at the time of the first PET scan and antiparkinsonian medication was started thereafter, with a favourable response. A FDOPA PET scan was carried out twice at an approximately 5‐year interval. The regions of interest were drawn on individual magnetic resonance imaging (MRI) images, matched with the PET images.

Gender and Insulin Sensitivity in the Heart and in Skeletal Muscles: Studies Using Positron Emission Tomography

Good insulin sensitivity is independently associated with a low risk for coronary heart disease, but it is unclear whether this risk factor differs between men and women. We compared insulin sensitivity of glucose uptake directly in muscle and heart tissues between healthy women (age 29 ± 2 years, body mass index [BMI] 22 ± 1 kg/m2, VO2max 39 ± 4 ml · kg−1 · min−1) and men matched for age (31 ± 2 years), BMI (23 ± 1 kg/m2), and VO2max (44 ± 3 ml · kg−1 · min−1) using [18F]fluoro-2-deoxy-D-glucose and positron emission tomography under hyperinsulinemic (insulin infusion rate 1 mU · kg−1 · min−1) normoglycemic conditions. Whole body insulin sensitivity was 41% greater in women (52 ± 6 μmol · kg body wt−1 · min−1) than in men (37 ± 3 μmol · kg body wt−1 · min−1, P < 0.05). This difference was explained by a 47% greater rate of glucose uptake by femoral muscles (113 ± 10 vs. 77 ± 7 μmol · kg muscle−1 · min−1, women vs. men, P < 0.01). Insulin-stimulated glucose uptake rates in the heart were similar in women (738 ± 58) and men (749 ± 62 μmol · kg muscle−1 · min−1). Femoral muscle insulin sensitivity was closely correlated with whole body insulin sensitivity (r = 0.84, P < 0.001). Gender and VO2max together explained 68% of the variation in femoral muscle glucose uptake. We conclude that women are more sensitive to insulin than equally fit men because of enhanced muscle but not heart insulin sensitivity.

Glucose Uptake in the Chronically Dysfunctional but Viable Myocardium

BACKGROUND The regulation of glucose uptake in the dysfunctional but viable myocardium has not been studied previously in humans. METHODS AND RESULTS Seven patients with an occluded major coronary artery but no previous infarction were studied twice with 2-[(18)F]fluoro-2-deoxy-D-glucose positron emission tomography, once in the fasting state and once during hyperinsulinemic euglycemic clamping. Myocardial blood flow was measured with [(15)O]H2O. The myocardial region beyond an occluded artery that showed stable wall-motion abnormality represented chronically dysfunctional but viable tissue. Six of the patients were later revascularized, and wall-motion recovery was detected in the corresponding regions, which confirmed viability. A slightly reduced myocardial blood flow was detected in the dysfunctional than in the remote myocardial regions (0.81 +/- 0.27 versus 1.02 +/- 0.23 mL x g(-1) x min(-1),P=.036). In the fasting state, glucose uptake was slightly increased in the dysfunctional regions compared with normal myocardium (15 +/- 10 versus 11 +/- 10 micromol/100 g per minute, P=.038). During insulin clamping, a striking increase in glucose uptake by insulin was obtained in both the dysfunctional and the normal regions (72 +/- 22 and 79 +/- 21 micromol/100 g per minute, respectively; P<.001, fasting versus clamping). CONCLUSIONS Contrary to previous suggestions, glucose uptake can be increased strikingly by insulin in chronically dysfunctional but viable myocardium. This demonstrates that insulin control over glucose uptake is preserved in the dysfunctional myocardium and provides a rational basis for metabolic intervention.

Sex differences in striatal presynaptic dopamine synthesis capacity in healthy subjects

BACKGROUND There are sex differences in the clinical features of several neuropsychiatric illnesses associated with dopamine dysfunction. The effects of sex on brain dopaminergic function have been sparsely studied in human subjects using modern imaging techniques. We have previously reported that the apparent affinity of [(11)C]raclopride for striatal D(2) dopamine receptors in vivo is lower in women than in men, whereas D(2) receptor density is not different. This finding indirectly suggests that women have a higher synaptic concentration of dopamine in the striatum. We explored further the basis of this phenomenon in an independent study and hypothesized that striatal presynaptic dopamine synthesis capacity would also be elevated in women. METHODS A total of 23 healthy men and 12 healthy women (age range 20-60 years) were studied using positron emission tomography and [(18)F]fluorodopa. RESULTS Women had significantly higher striatal [(18)F]fluorodopa uptake (Ki values) than men. The difference was more marked in the caudate (+26%) than in the putamen (+12%). In addition, there was a negative correlation between striatal [(18)F]fluorodopa Ki values and age in men but not in women. CONCLUSIONS The results further substantiate sex differences in striatal dopaminergic function in humans. This finding may be associated with sex differences in vulnerability and clinical course of neuropsychiatric disorders with dopaminergic dysregulation, e.g., schizophrenia, alcohol dependence, and Parkinsons disease.

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.

Insulin resistance characterizes glucose uptake in skeletal muscle but not in the heart in NIDDM

Summary Skeletal muscle insulin resistance and coronary heart disease (CHD) often precede non-insulin-dependent diabetes mellitus (NIDDM). A recent study showed the myocardium of patients with CHD to be insulin resistant, independent of blood flow. We determined whether myocardial insulin resistance is a feature of NIDDM patients with no CHD. Skeletal muscle and myocardial glucose uptake were determined in 10 patients with NIDDM and 9 age- and weight-matched normal men of similar age and body mass index men using [18F]-2-fluoro-2-deoxy-d-glucose and positron emission tomography under normoglycaemic hyperinsulinaemic conditions. Whole body glucose uptake, as determined by the euglycaemic clamp technique, was significantly lower in the patients with NIDDM (35 ± 3 μmol/kg body weight · min) than the normal subjects (45 ± 3 μmol/kg body weight · min, p < 0.02). Insulin-stimulated femoral muscle glucose uptake was significantly lower in the patients with NIDDM (71 ± 6 μmol/kg muscle · min) than in the normal subjects (96 ± 5 μmol/kg muscle · min, p < 0.01). Whole body glucose uptake was correlated with femoral muscle glucose uptake in the entire group (r = 0.76, p < 0.001), in patients with NIDDM and in normal subjects. Rates of insulin-stimulated myocardial glucose uptake were comparable between the patients with NIDDM (814 ± 76 μmol/kg muscle · min) and the normal subjects (731 ± 63 μmol/kg muscle · min, p > 0.4). Whole body or femoral muscle, and myocardial glucose uptake were not correlated in all subjects, patients with NIDDM or normal subjects. We conclude that insulin resistance of the myocardium is not a feature of uncomplicated NIDDM. [Diabetologia (1998) 41: 555-559]

Progression in Parkinson's disease: A positron emission tomography study with a dopamine transporter ligand [18F]CFT

We studied the rate of progression of striatal dopamine transporter function in Parkinsons disease (PD). Eight patients with early PD without antiparkinsonian medication and 7 healthy volunteers were investigated with [18F]CFT positron emission tomography (PET). The PET scan was carried out twice at an approximate 2‐year interval. The uptake of [18F]CFT was calculated as a region‐cerebellum:cerebellum ratio at 180 to 210 minutes after injection. At the first PET scan, the [18F]CFT uptake in PD patients in the putamen was 1.45 ± 0.45 (mean ± SD) (42% of the control mean) and 2.43 ± 0.59 in the caudate nucleus (76% of the control mean). The ratios declined by the time of the second PET scan, and the rate of annual decline of the baseline mean in PD patients was 13.1% in the putamen and 12.5% in the caudate nucleus. In controls, the corresponding figures were 2.1% for the putamen and 2.9% for the caudate nucleus. The decline in [18F]CFT uptake was significantly higher in PD patients than in controls. Thus, dopamine transporter ligands such as [18F]CFT seem to be sensitive markers for the rate of progression in PD. Ann Neurol 2000;47:804–808

The A1 allele of the human D2 dopamine receptor gene is associated with increased activity of striatal L-amino acid decarboxylase in healthy subjects.

The A1 allele of the TaqI restriction fragment length polymorphism (RFLP) of the human dopamine D2 receptor gene (DRD2) is associated with a low density of D2 dopamine receptors in the striatum. Because of the important role of D2 autoreceptors in regulating dopamine synthesis, we aimed to examine whether subjects with the A1 allele have altered presynaptic dopamine function in the brain. We also studied the effects of two other DRD2 polymorphisms, C957 T and −141C Ins/Del, which have been suggested to affect D2 receptor levels in brain. The relationships between the TaqIA RFLP, C957 T and −141C Ins/Del polymorphisms and striatal dopamine synthesis in 33 healthy Finnish volunteers were studied using positron emission tomography and [18F]fluorodopa ([18F]FDOPA), a radiolabelled analog of the dopamine precursor L-DOPA. Heterozygous carriers of the A1 allele (A1/A2; 10 subjects) had significantly higher (18%) [18F]FDOPA uptake in the putamen than subjects without the A1 allele (A2/A2; 23 subjects). C957 T and −141C Ins/Del polymorphisms did not significantly affect [18F]FDOPA Ki values. These results demonstrate that the A1 allele of DRD2 gene is associated with increased striatal activity of aromatic L-amino acid decarboxylase, the final enzyme in the biosynthesis of dopamine and the rate-limiting enzyme for trace amine (e.g. &bgr;-phenylethylamine) synthesis. The finding can be explained by lower D2 receptor expression leading to decreased autoreceptor function, and suggests that dopamine and/or trace amine synthesis rate is increased in the brains of A1 allele carriers.