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Science 5 August 2005:
Vol. 309. no. 5736, pp. 943 - 947
DOI: 10.1126/science.1112085
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Reports

Regulation of Blood Glucose by Hypothalamic Pyruvate Metabolism

Tony K. T. Lam, Roger Gutierrez-Juarez, Alessandro Pocai, Luciano Rossetti*

The brain keenly depends on glucose for energy, and mammalians have redundant systems to control glucose production. An increase in circulating glucose inhibits glucose production in the liver, but this negative feedback is impaired in type 2 diabetes. Here we report that a primary increase in hypothalamic glucose levels lowers blood glucose through inhibition of glucose production in rats. The effect of glucose requires its conversion to lactate followed by stimulation of pyruvate metabolism, which leads to activation of adenosine triphosphate (ATP)–sensitive potassium channels. Thus, interventions designed to enhance the hypothalamic sensing of glucose may improve glucose homeostasis in diabetes.

Departments of Medicine and Molecular Pharmacology, Diabetes Research Center, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.

* To whom correspondence should be addressed. E-mail: rossetti{at}aecom.yu.edu

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THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
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J. Neurosci. 28, 4888-4896
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Involvement of lactate in glucose metabolism and glucosensing function in selected tissues of rainbow trout.
S. Polakof and J. L. Soengas (2008)
J. Exp. Biol. 211, 1075-1086
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Activation of Central Lactate Metabolism Lowers Glucose Production in Uncontrolled Diabetes and Diet-Induced Insulin Resistance.
M. Chari, C. K.L. Lam, P. Y.T. Wang, and T. K.T. Lam (2008)
Diabetes 57, 836-840
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In vitro evidences for glucosensing capacity and mechanisms in hypothalamus, hindbrain, and Brockmann bodies of rainbow trout.
S. Polakof, J. M. Miguez, and J. L. Soengas (2007)
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Brain Glucose Sensing, Counterregulation, and Energy Homeostasis.
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Physiology 22, 241-251
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Orchestration of Glucose Homeostasis: From a Small Acorn to the California Oak.
R. N. Bergman (2007)
Diabetes 56, 1489-1501
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Glucose sensing by hypothalamic neurones and pancreatic islet cells: AMPle evidence for common mechanisms?.
P. D. Mountjoy and G. A. Rutter (2007)
Exp Physiol 92, 311-319
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{alpha}-Cells of the Endocrine Pancreas: 35 Years of Research but the Enigma Remains.
J. Gromada, I. Franklin, and C. B. Wollheim (2007)
Endocr. Rev. 28, 84-116
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Role of malonyl-CoA in heart disease and the hypothalamic control of obesity.
C. D.L. Folmes and G. D. Lopaschuk (2007)
Cardiovasc Res 73, 278-287
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Transforming growth factor-beta in the brain regulates fat metabolism during endurance exercise.
T. Ishikawa, W. Mizunoya, T. Shibakusa, K. Inoue, and T. Fushiki (2006)
Am J Physiol Endocrinol Metab 291, E1151-E1159
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Long-range negative correlation of glucose dynamics in humans and its breakdown in diabetes mellitus.
H. Ogata, K. Tokuyama, S. Nagasaka, A. Ando, I. Kusaka, N. Sato, A. Goto, S. Ishibashi, K. Kiyono, Z. R. Struzik, et al. (2006)
Am J Physiol Regulatory Integrative Comp Physiol 291, R1638-R1643
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The Brain-Gut-Islet Connection.
S. C. Woods, S. C. Benoit, and D. J. Clegg (2006)
Diabetes 55, S114-S121
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Reduction in the Number of Astrocytes and Their Projections Is Associated with Increased Synaptic Protein Density in the Hypothalamus of Poorly Controlled Diabetic Rats.
A. M. Lechuga-Sancho, A. I. Arroba, L. M. Frago, C. Garcia-Caceres, A. D.-R. de Celix, J. Argente, and J. A. Chowen (2006)
Endocrinology 147, 5314-5324
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Minireview: The Brain as a Molecular Target for Diabetic Therapy.
E. Prodi and S. Obici (2006)
Endocrinology 147, 2664-2669
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Papers of Note.
(2005)
Sci. Aging Knowl. Environ. 2005, nw30
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Science. ISSN 0036-8075 (print), 1095-9203 (online)