Steady-state brain glucose concentrations during hypoglycemia in healthy humans and patients with type 1 diabetes

Kim C C van de Ven, Marinette van der Graaf, Cees J Tack, Arend Heerschap, Bastiaan E de Galan, Kim C C van de Ven, Marinette van der Graaf, Cees J Tack, Arend Heerschap, Bastiaan E de Galan

Abstract

The objective of this study was to investigate the relationship between plasma and brain glucose levels during euglycemia and hypoglycemia in healthy subjects and patients with type 1 diabetes mellitus (T1DM). Hyperinsulinemic euglycemic (5 mmol/L) and hypoglycemic (3 mmol/L) [1-(13)C]glucose clamps were performed in eight healthy subjects and nine patients with uncomplicated T1DM (HbA(1c) 7.7 ± 1.4%). Brain glucose levels were measured by (13)C magnetic resonance spectroscopy. Linear regression analysis was used to fit the relationship between plasma and brain glucose levels and calculate reversible Michaelis-Menten (MM) kinetic parameters. Brain glucose values during euglycemia (1.1 ± 0.4 μmol/g vs. 1.1 ± 0.3 μmol/g; P = 0.95) and hypoglycemia (0.5 ± 0.2 μmol/g vs. 0.6 ± 0.3 μmol/g; P = 0.52) were comparable between healthy subjects and T1DM patients. MM kinetic parameters of combined data were calculated to be maximum transport rate/cerebral metabolic rate of glucose (T(max)/CMR(glc)) = 2.25 ± 0.32 and substrate concentration at half maximal transport (K(t)) = 1.53 ± 0.88 mmol/L, which is in line with previously published data obtained under hyperglycemic conditions. In conclusion, the linear MM relationship between plasma and brain glucose can be extended to low plasma glucose levels. We found no evidence that the plasma to brain glucose relationship or the kinetics describing glucose transport over the blood-brain barrier differ between healthy subjects and patients with uncomplicated, reasonably well-controlled T1DM.

Figures

FIG. 1.
FIG. 1.
Representative spectra of two volunteers under euglycemia and hypoglycemia. A: Healthy subject. B: Patient with T1DM.
FIG. 2.
FIG. 2.
Data of healthy subjects (open squares) and patients with T1DM (closed circles) together with the best fit of the data and 95% CIs. R2 = 0.59; P < 0.001.

References

    1. Cryer PE. The barrier of hypoglycemia in diabetes. Diabetes 2008;57:3169–3176
    1. Pardridge WM, Boado RJ, Farrell CR. Brain-type glucose transporter (GLUT-1) is selectively localized to the blood-brain barrier. Studies with quantitative western blotting and in situ hybridization. J Biol Chem 1990;265:18035–18040
    1. Gruetter R, Ugurbil K, Seaquist ER. Steady-state cerebral glucose concentrations and transport in the human brain. J Neurochem 1998;70:397–408
    1. de Graaf RA, Pan JW, Telang F, et al. . Differentiation of glucose transport in human brain gray and white matter. J Cereb Blood Flow Metab 2001;21:483–492
    1. Choi IY, Lee SP, Kim SG, Gruetter R. In vivo measurements of brain glucose transport using the reversible Michaelis-Menten model and simultaneous measurements of cerebral blood flow changes during hypoglycemia. J Cereb Blood Flow Metab 2001;21:653–663
    1. Seaquist ER, Damberg GS, Tkac I, Gruetter R. The effect of insulin on in vivo cerebral glucose concentrations and rates of glucose transport/metabolism in humans. Diabetes 2001;50:2203–2209
    1. van de Ven KC, van der Graaf M, Tack CJ, Klomp DW, Heerschap A, de Galan BE. Optimized [1-(13)C]glucose infusion protocol for 13C magnetic resonance spectroscopy at 3T of human brain glucose metabolism under euglycemic and hypoglycemic conditions. J Neurosci Methods 2010;186:68–71
    1. van de Ven KC, de Galan BE, van der Graaf M, et al. . Effect of acute hypoglycemia on human cerebral glucose metabolism measured by ¹³C magnetic resonance spectroscopy. Diabetes 2011;60:1467–1473
    1. Clarke WL, Cox DJ, Gonder-Frederick LA, Julian D, Schlundt D, Polonsky W. Reduced awareness of hypoglycemia in adults with IDDM. A prospective study of hypoglycemic frequency and associated symptoms. Diabetes Care 1995;18:517–522
    1. De Galan BE, De Mol P, Wennekes L, Schouwenberg BJ, Smits P. Preserved sensitivity to beta2-adrenergic receptor agonists in patients with type 1 diabetes mellitus and hypoglycemia unawareness. J Clin Endocrinol Metab 2006;91:2878–2881
    1. Van Den Bergh AJ, Tack CJ, Van Den Boogert HJ, Vervoort G, Smits P, Heerschap A. Assessment of human muscle glycogen synthesis and total glucose content by in vivo 13C MRS. Eur J Clin Invest 2000;30:122–128
    1. Serlie MJ, de Haan JH, Tack CJ, et al. . Glycogen synthesis in human gastrocnemius muscle is not representative of whole-body muscle glycogen synthesis. Diabetes 2005;54:1277–1282
    1. Klomp DW, Renema WK, van der Graaf M, de Galan BE, Kentgens AP, Heerschap A. Sensitivity-enhanced 13C MR spectroscopy of the human brain at 3 Tesla. Magn Reson Med 2006;55:271–278
    1. Klomp DW, Kentgens AP, Heerschap A. Polarization transfer for sensitivity-enhanced MRS using a single radio frequency transmit channel. NMR Biomed 2008;21:444–452
    1. Vanhamme L, van den Boogaart A, Van Huffel S. Improved method for accurate and efficient quantification of MRS data with use of prior knowledge. J Magn Reson 1997;129:35–43
    1. Naressi A, Couturier C, Devos JM, et al. . Java-based graphical user interface for the MRUI quantitation package. MAGMA 2001;12:141–152
    1. Ross B, Lin A, Harris K, Bhattacharya P, Schweinsburg B. Clinical experience with 13C MRS in vivo. NMR Biomed 2003;16:358–369
    1. Reyngoudt H, Claeys T, Vlerick L, et al. . Age-related differences in metabolites in the posterior cingulate cortex and hippocampus of normal ageing brain: A (1)H-MRS study. Eur J Radiol 2012;81:e223–e231
    1. Gjedde A, Diemer NH. Autoradiographic determination of regional brain glucose content. J Cereb Blood Flow Metab 1983;3:303–310
    1. Seaquist ER, Tkac I, Damberg G, Thomas W, Gruetter R. Brain glucose concentrations in poorly controlled diabetes mellitus as measured by high-field magnetic resonance spectroscopy. Metabolism 2005;54:1008–1013
    1. Fanelli CG, Dence CS, Markham J, et al. . Blood-to-brain glucose transport and cerebral glucose metabolism are not reduced in poorly controlled type 1 diabetes. Diabetes 1998;47:1444–1450
    1. Heikkilä O, Lundbom N, Timonen M, Groop PH, Heikkinen S, Mäkimattila S. Hyperglycaemia is associated with changes in the regional concentrations of glucose and myo-inositol within the brain. Diabetologia 2009;52:534–540
    1. Kreis R, Ross BD. Cerebral metabolic disturbances in patients with subacute and chronic diabetes mellitus: detection with proton MR spectroscopy. Radiology 1992;184:123–130
    1. Criego AB, Tkac I, Kumar A, Thomas W, Gruetter R, Seaquist ER. Brain glucose concentrations in patients with type 1 diabetes and hypoglycemia unawareness. J Neurosci Res 2005;79:42–47
    1. Bingham EM, Dunn JT, Smith D, et al. . Differential changes in brain glucose metabolism during hypoglycaemia accompany loss of hypoglycaemia awareness in men with type 1 diabetes mellitus. An [11C]-3-O-methyl-D-glucose PET study. Diabetologia 2005;48:2080–2089

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