Increased Brain Monocarboxylic Acid Transport and Utilization in Type 1 Diabetes

• Published in: Diabetes (New York, N.Y.) Vol. 55; no. 4; pp. 929 - 934
• Main Authors: Mason, Graeme F., Petersen, Kitt F., Lebon, Vincent, Rothman, Douglas L., Shulman, Gerald I.
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.04.2006
• Subjects: Acetates - metabolism; Adult; Biological and medical sciences; Biological Transport; Brain - metabolism; Carboxylic acids; Diabetes; Diabetes Mellitus, Type 1 - blood; Diabetes Mellitus, Type 1 - metabolism; Diabetes research; Diabetes. Impaired glucose tolerance; Diagnosis; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Female; gamma-Aminobutyric Acid - metabolism; Genetic regulation; Glutamic Acid - metabolism; Humans; Insulin - blood; Kinetics; Male; Medical sciences; Reference Values; Risk factors; Type 1 diabetes; Endocrinopathy; Immunopathology; Type 1 diabetes; Biological transport; Central nervous system; Autoimmune disease; Encephalon
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/diabetes.55.04.06.db05-1325

Increased Brain Monocarboxylic Acid Transport and Utilization in Type 1 Diabetes Graeme F. Mason 1 2 , Kitt F. Petersen 3 , Vincent Lebon 4 , Douglas L. Rothman 2 5 and Gerald I. Shulman 3 6 1 Department of Psychiatry and Diagnostic Radiology, Yale School of Medicine, New Haven, Connecticut 2 Department of Diagnostic Radiology, Yale School of Medicine, New Haven, Connecticut 3 Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut 4 Groupe de Spectroscopie RMN, Unité d’Imagerie Isotopique Biochimique et Pharmacologique, Orsay Cedex, France 5 Department of Biomedical Engineering, Yale School of Medicine, New Haven, Connecticut 6 Department of Cellular and Molecular Physiology, Howard Hughes Medical Institute, Yale School of Medicine, New Haven, Connecticut Address correspondence and reprint requests to Dr. Gerald I. Shulman, Howard Hughes Medical Institute, Yale University School of Medicine, TAC S-269, P.O. Box 9812, New Haven, CT 06536-8012. E-mail: gerald.shulman{at}yale.edu Abstract We hypothesized that increased capacity for brain utilization of nonglucose substrates (monocarboxylic acids [MCAs]) by upregulation of the MCA transporters may contribute metabolic substrates during hypoglycemia. To test this hypothesis, we assessed brain acetate metabolism in five well-controlled type 1 diabetic subjects and six nondiabetic control subjects using 13 C magnetic resonance spectroscopy during infusions of [2- 13 C]acetate during hypoglycemia (∼55 mg/dl). Acetate is transported into the brain through MCA transporters that are also used for lactate and ketones. Brain acetate concentrations were over twofold higher in the subjects with diabetes than the control subjects ( P = 0.01). The fraction of oxidative metabolism from acetate ( P = 0.015) and the rate of MCA transport ( P = 0.01) were also approximately twofold higher in the diabetic subjects. We conclude that during hypoglycemia MCA transport in the brain was increased by appoximately twofold in patients with well-controlled type 1 diabetes, as reflected by higher brain acetate concentrations and rates of acetate oxidation. This upregulation would potentially allow a similar twofold increase in the transport of other MCAs, including lactate, during insulin-induced hypoglycemia. These data are consistent with the hypothesis that upregulation of MCA transport may contribute to the maintenance of brain energetics during hypoglycemia in patients with type 1 diabetes. MCA, monocarboxylic acid MRS, magnetic resonance spectroscopy PET, positron emission tomography TCA, tricarboxylic acid Footnotes The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted January 5, 2006. Received October 11, 2005. DIABETES