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Effects of Insulin on Brain Glucose Metabolism (Printer

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Effects of Insulin on Brain Glucose Metabolism (printer-friendly) http://www.medscape.com/viewarticle/736579_print www.medscape.com Authors and Disclosures Jussi Hirvonen,1,2 Kirsi A. Virtanen,1 Lauri Nummenmaa,1,3,4 Jarna C. Hannukainen,1 Miikka-Juhani Honka,1 Marco Bucci,1 Sergey V. Nesterov,1,5 Riitta Parkkola,2 Juha Rinne,1 Patricia Iozzo,1,6 and Pirjo Nuutila1 Turku PET Centre, University of Turku and Turku University Hospital, Turku, Finland; 2Department of Radiology, University of Turk
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  www.medscape.com   FromDiabetes Abstract and Introduction Abstract Objective —Insulin stimulates brain glucose metabolism, but this effect of insulin is already maximal at fasting concentrationsin healthy subjects. It is not known whether insulin is able to stimulate glucose metabolism above fasting concentrations inpatients with impaired glucose tolerance. Research Design And Methods —We studied the effects of insulin on brain glucose metabolism and cerebral blood flow in13 patients with impaired glucose tolerance and nine healthy subjects using positron emission tomography (PET). All subjectsunderwent PET with both [ 18 F]fluorodeoxyglucose (for brain glucose metabolism) and [ 15 O]H 2 O (for cerebral blood flow) intwo separate conditions (in the fasting state and during a euglycemic-hyperinsulinemic clamp). Arterial blood samples wereacquired during the PET scans to allow fully quantitative modeling. Results —The hyperinsulinemic clamp increased brain glucose metabolism only in patients with impaired glucose tolerance(whole brain: +18%, P  = 0.001) but not in healthy subjects (whole brain: +3.9%, P  = 0.373). The hyperinsulinemic clamp didnot alter cerebral blood flow in either group. Conclusions —We found that insulin stimulates brain glucose metabolism at physiological postprandial levels in patients withimpaired glucose tolerance but not in healthy subjects. These results suggest that insulin stimulation of brain glucosemetabolism is maximal at fasting concentrations in healthy subjects but not in patients with impaired glucose tolerance. Introduction Peripheral insulin resistance is a hallmark of metabolic syndrome and type 2 diabetes, but it is unclear if the brain also showsinsulin resistance. Peripheral insulin crosses the blood-brain barrier via an active transport mechanism and binds to insulinreceptors on neurons and glial cells. Insulin has a catabolic effect; in addition, it influences memory functions by modulatingneurotransmitter release and synaptic plasticity. [1–4] Therefore, determining whether insulin resistance also occurs in the brainin metabolic syndrome is important. [5] Obese individuals have a decreased cerebrospinal fluid–to–plasma insulin ratio, [6] diminished catabolic responses to intranasal insulin, [7] and decreased cortical brain activity after insulin, [8] suggesting braininsulin resistance. [1,5] However, these indirect studies do not establish the relationship between insulin and brain glucosemetabolism, which is important given the role of the brain in glucose sensing. [9] Direct evidence on the effects of insulin on the brain may be obtained with positron emission tomography (PET) and Authors and Disclosures Jussi Hirvonen, 1,2 Kirsi A. Virtanen, 1 Lauri Nummenmaa, 1,3,4 Jarna C. Hannukainen, 1 Miikka-Juhani Honka, 1 MarcoBucci, 1 Sergey V. Nesterov, 1,5 Riitta Parkkola, 2 Juha Rinne, 1 Patricia Iozzo, 1,6 and Pirjo Nuutila 1 1 Turku PET Centre, University of Turku and Turku University Hospital, Turku, Finland; 2 Department of Radiology, University of Turku, Turku, Finland; 3 Brain Research Unit, Low Temperature Laboratory, Aalto University School of Science andTechnology, Helsinki, Finland; 4 Department of Biomedical Engineering and Computational Science, Aalto University School of Science and Technology, Helsinki, Finland; 5 I.M. Sechenov Institute of Evolutionary Physiology and Biochemistry, RAS, St.Petersburg, Russia; 6 Institute of Clinical Physiology, National Research Council, Pisa, Italy Corresponding author  Jussi Hirvonen, jueshi@utu.fi. Effects of Insulin on Brain Glucose Metabolism in Impaired GlucoseTolerance Jussi Hirvonen; Kirsi A. Virtanen; Lauri Nummenmaa; Jarna C. Hannukainen; Miikka-Juhani Honka; Marco Bucci; Sergey V.Nesterov; Riitta Parkkola; Juha Rinne; Patricia Iozzo; Pirjo NuutilaPosted: 02/03/2011; Diabetes. 2011;60(2):443-447. © 2011 American Diabetes Association, Inc. Effects of Insulin on Brain Glucose Metabolism (printer-friendly)http://www.medscape.com/viewarticle/736579_print1 de 907-02-2011 12:19  18 F-labeled fluorodeoxyglucose ([ 18 F]FDG). Studies in healthy subjects have shown that brain glucose metabolism does notincrease after increasing plasma insulin concentrations above physiological fasting levels [10,11] but decreases after decreasing plasma insulin concentration below physiological fasting levels, [12,13] suggesting that the insulin effect is alreadysaturated at fasting concentrations in healthy subjects. In contrast, Anthony et al. [12] recently demonstrated that reducingplasma insulin does not reduce brain glucose metabolism in patients with impaired glucose tolerance. However, it is not knownwhether insulin stimulates brain glucose metabolism above fasting levels in these patients or whether this effect is alreadysaturated at fasting levels, as in healthy subjects. [12,13] To characterize the dose-response relationship of plasma insulin and brain glucose metabolism in patients with impairedglucose tolerance, we used [ 18 F]FDG PET to measure brain glucose metabolism in two conditions (in the fasting state andduring a euglycemic-hyperinsulinemic clamp) in both healthy subjects and patients with impaired glucose tolerance. [ 18 F]FDGis a glucose analog that is taken up in the brain and trapped after phosphorylation; thus, the measured signal approximatesuptake of glucose. The euglycemic-hyperinsulinemic clamp allows close monitoring and adjustment of plasma glucose whileinducing a constant insulin stimulation. In a subset of subjects, we also measured the effects of insulin on cerebral blood flowwith [ 15 O]H 2 O PET. Research Design and Methods Twenty-two subjects (Table 1), classified either as healthy or as having impaired glucose tolerance, [14] were recruited toparticipate in two PET studies performed during the fasting state and euglycemic-hyperinsulinemia in separate days inrandomized order. The PET studies measured brain glucose metabolism with [ 18 F]FDG (13 patients, nine healthy) and bloodflow with [ 15 O]H 2 O (six patients, eight healthy). All subjects were not studied with [ 15 O]H 2 O because this scan was omittedfrom the study based on interim results. All subjects gave their written informed consent after the study had been approved bythe ethics committee of the hospital district of southwestern Finland. Table 1. Demographic and metabolic characteristics of the study groups CharacteristicsHealthysubjectsImpaired glucosetolerance P  n 913Baseline dataSex (female/male)4/58/50.6Age (years)38 ± 1249 ± 80.04Weight (kg)75 ± 10112 ± 20<0.001BMI (kg/m 2 )24 ± 238 ± 8<0.001Fat (bioimpedance) (%)28 ± 444 ± 9<0.001Waist circumference (cm)85 ± 10119 ± 14<0.001Fasting plasma glucose (mmol/L)5.3 ± 0.55.9 ± 0.50.012-h oral glucose tolerance test (plasma glucose) (mmol/L)5.1 ± 1.08.6 ± 1.0<0.001During PET: fasting statePlasma glucose (mmol/L)5.4 ± 0.45.8 ± 0.60.06Serum insulin (mU/L)4 ± 311 ± 4<0.001During PET: hyperinsulinemiaPlasma glucose (mmol/L)5.1 ± 0.34.8 ± 0.80.2Serum insulin (steady state) (mU/L)58 ± 573 ± 190.02 Effects of Insulin on Brain Glucose Metabolism (printer-friendly)http://www.medscape.com/viewarticle/736579_print2 de 907-02-2011 12:19  Euglycemic-hyperinsulinemic Clamp The euglycemic-hyperinsulinemic clamp (1 mU · kg −1 · min −1 ) technique was used during the PET scan, as previouslydescribed. [15,16] PET Acquisition The PET studies were performed after a 12-h fast using the General Electric Advance PET camera (General Electric MedicalSystems, Milwaukee, WI). [16] The [ 15 O]H 2 O PET scan started at 45 min and the [ 18 F]FDG scan at 60 min after the position tothe scanner or the start of euglycemic-hyperinsulinemic clamp. The synthesis [17,18] and image acquisition [16,19] of [ 15 O]H 2 Oand [ 18 F]FDG were performed as previously described. Quantification of Brain Glucose Metabolism Glucose metabolism (CMRglu; μmol · 100 g −1 · min −1 ) was calculated for each voxel separately using the linear Gjedde-Patlak plot with the arterial plasma input function (linear start time 10 min) as previously described. [20] CMRglu images werenormalized into standard space as previously described [21] using SPM5 (www.fil.ion.ucl.ac.uk/spm/) running on Matlab for Windows (version 7.3.0.267; Math Works, Natick, MA). Regions of interest (frontal cortex, temporal cortex, parietal cortex,occipital cortex, mesial temporal cortex, insula, striatum, cerebellum, and thalamus) were applied in standard space usingImadeus software (version 1.2.; Forima, Turku, Finland) to obtain glucose metabolism values. Hypothalamus was not includedbecause it is too small to be reliably quantified. Quantification of Cerebral Blood Flow Cerebral blood flow (mL · 100 g −1 · min −1 ) was calculated for each voxel separately based on a one-tissue compartmentalmodel using the arterial radioactivity concentration as the input function as previously described. [19] Image analysis for cerebral blood images was done as described above for images of glucose metabolism. Voxel-based Mapping Analysis Voxel-based mapping analysis was done using SPM5. Spatially normalized glucose metabolism images were smoothed with12-mm full width at half-maximum Gaussian kernel. Voxel maps of clamp effects were created by subtracting fasting imagesfrom clamp images. These subtraction images were compared between groups using T-contrasts, with and without age ascovariate, with voxel-level uncorrected P  < 0.05 and cluster-level corrected P  < 0.05. Statistical Analyses of Volume of Interest Data Statistical analyses of volume-of-interest data were done using SPSS version 17.0 for Windows (SPSS, Chicago, IL). Datawere analyzed using repeated-measures ANOVA with region, hemisphere, and condition as within-subject factors; groupstatus as the between-subject factor; and sex as a covariate. We also ran the same model with age as a covariate. We alsoused paired t  tests within groups and independent-samples t  tests between groups. Data are mean ± SD. Results Brain Glucose Metabolism In the fasting condition, brain glucose metabolism was similar between patients with impaired glucose metabolism (wholebrain: 15.6 μmol · 100 g −1 · min −1 ) and healthy subjects (whole brain: 15.0 μmol · 100 g −1 · min −1 ; +0.5%, P  = 0.896). Across all subjects, the hyperinsulinemic clamp increased whole-brain glucose metabolism by ~12% (main effect of thecondition: F  = 7.11, P  = 0.015). However, groups were different in terms of the treatment effects (group × condition interaction: Whole-body glucose uptake ( M  value) (μmol · kg −1 ·min −1 )30.3 ± 6.011.9 ± 4.2<0.001 Data are means ± SD. Effects of Insulin on Brain Glucose Metabolism (printer-friendly)http://www.medscape.com/viewarticle/736579_print3 de 907-02-2011 12:19  F  = 8.59, P  = 0.009). The hyperinsulinemic clamp increased brain glucose metabolism only in patients with impaired glucosetolerance (whole brain: +18%, P  = 0.001) but not in healthy subjects (whole brain: +3.9%, P  = 0.373) (Fig. 1; Table 2). Thisfinding was confirmed by the voxel-based mapping analysis, which showed a large significant cluster throughout the brain, withthe largest increase in glucose metabolism in the right posterior insula (Fig. 2). Although plasma insulin was higher in patientsthan in healthy subjects, fasting ( r  = 0.35, P  = 0.114) or clamp ( r  = 0.05, P  = 0.842) insulin, or the change from fasting to clamp( r  = −0.06, P  = 0.792) insulin, did not correlate with change in brain glucose metabolism. Table 2. Regional brain glucose metabolism values in the fasting and clamp conditions in healthysubjects and in patients with impairedglucose tolerance RegionHealthy subjects ( n = 9)Impaired glucose tolerance ( n = 13)Group × conditioninteraction P  Brain glucose metabolism(μmol · 100 g −1 · min −1 )ChangeBrain glucose metabolism(μmol · 100 g −1 · min −1 )ChangeFastClamp% P  FastClamp% P  FRO15.9 ± 1.216.4 ± 1.53.30.50615.8 ± 2.118.6 ± 2.518.0 <0.0010.009 LTEMP16.5 ± 1.217.2 ± 1.74.20.36416.0 ± 1.818.8 ± 2.218.2 <0.0010.010 PAR14.0 ± 0.814.6 ± 1.64.50.28314.7 ± 1.917.2 ± 2.517.7 <0.0010.009 OCC16.7 ± 0.917.6 ± 2.25.50.23117.8 ± 2.220.7 ± 2.917.1 <0.0010.015 MTEMP12.8 ± 0.612.9 ± 1.11.20.77813.0 ± 1.615.3 ± 1.918.3 <0.0010.003 INS17.5 ± 1.217.7 ± 1.71.60.77716.3 ± 1.919.0 ± 2.017.5 <0.0010.003 STR16.9 ± 0.917.5 ± 1.63.80.34016.2 ± 2.319.2 ± 2.220.2 <0.0010.013 CER10.6 ± 1.210.9 ± 1.53.40.52910.7 ± 1.912.2 ± 2.016.5 0.035 0.150THA16.4 ± 1.617.1 ± 2.35.00.32716.2 ± 2.919.5 ± 2.622.9 <0.0010.020 P  values are from paired samples t  tests except for the last column, where P  values are from thegroup × condition interaction in repeated-measures ANOVA. P  values denoting statistical significance( P  < 0.05) appear in boldface. CER, cerebellum; FRO, frontal cortex; INS, insula; LTEMP, lateraltemporal cortex; MTEMP, mesialtemporal cortex; OCC, occipital cortex; PAR, parietal cortex; STR,striatum; THA, thalamus. Effects of Insulin on Brain Glucose Metabolism (printer-friendly)http://www.medscape.com/viewarticle/736579_print4 de 907-02-2011 12:19
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