NMR IN BIOMEDICINE NMR Biomed. 2004;17:405–410 Published online in Wiley InterScience (www.interscience.wiley.com). DOI:10.1002/nbm.896 Metabolic profile of the hippocampus of Zucker Diabetic Fatty rats assessed by in vivo 1 H magnetic resonance spectroscopy Marinette van der Graaf, 1 Susan W. J. Janssen, 2,3y Jack J. A. van Asten, 1 Ad R. M. M. Hermus, 3 C. G. J. (Fred) Sweep, 4 Jeroen A. Pikkemaat, 1z Gerard J. M. Martens 2 and Arend Heerschap 1 * 1 Department of Radiology, University Medical, Centre Nijmegen, The Netherlands 2 Department of Molecular Animal Physiology, Faculty of Science, University of Nijmegen, Nijmegen The Netherlands 3 Department of Endocrinology, University Medical Centre, Nijmegen, The Netherlands 4 Department of Chemical Endocrinology, University Medical Centre, Nijmegen, The Netherlands Received 22 April 2004; Revised 7 June 2004; Accepted 10 June 2004 ABSTRACT: Localized in vivo 1 H magnetic resonance spectroscopy (MRS) was used to investigate metabolite levels in the brain of adult Zucker Diabetic Fatty (ZDF) rats, an animal model for type 2 diabetes mellitus. This study focussed on the hippocampus, assumed to be one of the main brain areas affected by this disease. Together with an almost 5-fold increase in blood glucose concentration measured by glucose oxidation, significant increases were found in the hippocampal concentrations of glucose (4.93 vs 1.66 mM p < 0.001), myo-inositol (6.52 vs 4.30 mM; p < 0.05), and total creatine (12.71 vs 10.50 mM; p < 0.05) in ZDF rats (n ¼ 5) compared with littermates (n ¼ 5). Although no obvious alterations were detected in the hippocampal levels of other metabolites, including NAA þ NAAG and choline-containing compounds in the ZDF rats, the increase in Glc and Ins levels is in line with elevated brain tissue contents of these metabolites in patients with diabetes mellitus. Copyright # 2004 John Wiley & Sons, Ltd. KEYWORDS: 1 H MRS; diabetes mellitus; brain metabolites; ZDF rat; glucose, myo-inositol; creatine INTRODUCTION Diabetes mellitus is a complex metabolic disorder char- acterised by chronic hyperglycaemia, 1 which may lead to long-term complications in both the peripheral and the central nervous system. 2–4 Studies on diabetic neuropa- thy have focussed primarily on the peripheral nervous system. Compared with the complications of diabetes in the peripheral nervous system the diabetic complications in the central nervous system are less obvious. However, especially in older type 2 diabetic patients, cognitive deficits can be observed. 5 In diabetic rats, central nervous system damage is characterized by impairment of learn- ing and memory, changes in synaptic plasticity and neurophysiologic alterations. 6,7 Thus far, little is known about the pathogenesis of these cerebral manifestations of diabetes. Possibly, a decreased cerebral blood supply and an aberrant glucose metabolism, which both play a role in the pathogenesis of peripheral diabetic neuropathy, are involved. 8,9 The hippocampus is a brain structure involved in learning and memory. 10 During chronic stress, structural and functional changes have been observed in the rat hippocampus. 11 In rats with streptozotocin-induced dia- betes, the hippocampus seems to be extremely suscepti- ble to stressful events, which can lead to changes in hippocampal synaptic plasticity 12 and even irreversible hippocampal damage. 13 The present study focuses on possible metabolic changes in the hippocampus of adult Zucker Diabetic Fatty (ZDF) rats. The ZDF rat is a widely used animal model for type 2 diabetes mellitus (type 2 DM), and originates from a non-inbred colony of Zucker Fatty rats containing a number of obese rats that spontaneously developed overt diabetes mellitus. 14 Be- tween 7 and 10 weeks of age homozygous male ZDF rats become mildly hyperglycaemic and thereafter develop overt diabetes. 14,15 In a previous study on pancreatic tissue of ZDF rats, severe histopathological changes Copyright # 2004 John Wiley & Sons, Ltd. NMR Biomed. 2004;17:405–410 *Correspondence to: A. Heerschap, Department of Radiology, University Medical Centre, Nijmegen, PO Box 9101, 6500 HB Nijmegen, The Netherlands. E-mail: A.Heerschap@rad.umcn.nl y Present address: Center for Biological Medicines and Medical Technology, National Institute for Public Health and Environment, Bilthoven, The Netherlands. z Present address: Philips Research, Eindhoven, The Netherlands. Contract/grant sponsor: Dutch Diabetes Foundation; contract grant number: 95.116. Abbreviations used: Ala, alanine; Asp, aspartate; Cho, choline; GABA, -aminobutyrate; Glc, glucose; Glu, glutamate; Gln, glutamine; GPC, glycerophosphorylcholine; GSH, glutathione; Ins, myo-inositol; Lac, lactate; NAA, N-acetylaspartate; NAAG, N-acetylaspartylglutamate; PCho, phosphocholine; PE, phosphory- lethanolamine; Scyllo, scyllo-inositol; Tau, taurine; tCr, total creati- ne ¼ phosphocreatine þ creatine; ZDF, Zucker Diabetic Fatty.