The neuroendocrine control of glucose allocation

Summary

Here we propose that glucose metabolism can be understood on the basis of three concept-derived axioms: (I) A hierarchy exists among the glucose-utilizing organs with the brain served first, followed by muscle and fat. (II) Tissue-specific glucose transporters allocate glucose among organs in order to maintain brain glucose concentrations. (III) Exogenous carbohydrate supply compensates for glucose alterations that can temporarily occur in muscle and fat. Derived from the control theory, the simplest solution of allocating supply to 2 organs, e.g. brain and muscle, is a “fishbone”-structured model. We reviewed the literature, searching for neuroendocrine and metabolic mechanisms that can fulfill control functions in such a model: The tissue-specific glucose transporters are differentially regulated. GLUT 1, carrying glucose across the blood-brain-barrier, is independent of insulin. Instead, this trans-endothelial glucose transporter is rather dependent on potent regulators of blood vessel function like vascular endothelial growth factor - a pituitary counterregulatory hormone. GLUT 4, carrying glucose across the membranes of muscle and fat cells, depends on insulin. Thereby, insulin allocates glucose to muscle and fat. The hypothalamus-pituitary-adrenal (HPA) axis, the sympathetic nervous system (SNS), and vascular endothelial growth factor allocate glucose to the brain. Multiple “sensors” (some of which have only recently been identified as ATP sensitive potassium channels) measure glucose or glucose equivalents at various sites of the body: the ventromedial hypothalamus, the lateral hypothalamus, portal vein, pancreatic beta cell, renal tubule, muscle and adipose tissue. Feedback pathways both from the brain and from muscle and fat are involved in regulating glucose allocation and exogenous glucose supply. The main feedback signal from the brain is found to be glucose, that from muscle and fat appears to be leptin. In fact, the literature search revealed two or more biological mechanisms for the function of each component in the model, finding glucose regulation highly redundant. This review focuses on “brain glucose” control. The concept of glucose allocation presented here challenges the common opinion of “blood glucose” being the main parameter controlled. According to the latter opinion, hyperglycemia in the metabolic syndrome is due to a putative defect located within the closed loop including the beta cell, muscle and fat cells. That traditional view leaves some peculiarities of e.g. the metabolic syndrome unexplained. The concept of glucose allocation, however, would predict that weight gain - with abundance of glucose in muscle and fat - increases feedback to the brain (via hyperleptinemia) which in turn results in HPA-axis and SNS overdrive, impaired insulin secretion, and insulin resistance. HPA-axis overdrive would account for metabolic abnormalities such as central adiposity, hyperglycemia, dyslipidemia, and hypertension, that are well known clinical aspects the metabolic syndrome. This novel viewpoint of “brain glucose” control may shed new light on the pathogenesis of the metabolic syndrome and type 2 diabetes.

Key words:

Brain - Glucose - Blood-brain barrier - Metabolic syndrome - Mathematical model

References

• 1 Aguilar-Bryan L, Nichols C G, Wechsler S W, Clement J P, Boyd A E, Gonzalez G, Herrera-Sosa H, Nguy K, Bryan J, Nelson D A. Cloning of the beta cell high-affinity sulfonylurea receptor: a regulator of insulng secretion.  Science. 1995;  268 423-426
• 2 Ahima R S, Kelly J, Elmquist J K, Flier J S. Distinct physiologic and neuronal responses to decreased leptin and mild hyperleptinemia.  Endocrinology. 1999;  140 4923-4931
• 3 Amoroso S, Schmid-Antomarchi H, Fosset M, Lazdunski M. Glucose, sulfonylureas, and neurotransmitter release: role of ATP- sensitive K+ channels.  Science. 1990;  247 852-854
• 4 Anand B K, Brobeck J R. Hypothalamic control of food intake in rats and cats.  Yale J Biol Med. 1951;  24 123-146
• 5 Bado A, Levasseur S, Attoub S, Kermorgant S, Laigneua J P, Bortoluzzi M N, Moizo L, Lehy T, Guerre-Millo M, Le Marchand-Brustel Y, Lewin M J. The stomach is a source of leptin.  Nature. 1998;  394 790-793
• 6 Baron A D. Hemodynamic actions of insulin.  Am J Physiol. 1994;  267 E187-E202
• 7 Baron A D, Wallace P, Brechtel G. In vivo regulation of non-insulin-mediated and insulin-mediated glucose uptake by cortisol.  Diabetes. 1987a;  36 1230-1237
• 8 Baron A D, Wallace P, Olefsky J M. In vivo regulation of non-insulin-mediated and insulin-mediated glucose uptake by epinephrine.  J Clin Endocrinol Metab. 1987b;  64 889-895
• 9 Baron A D, Zhu J S, Zhu J H, Weldon H, Maianu L, Garvey W T. Glucosamine induces insulin resistance in vivo by affecting GLUT 4 translocation in skeletal muscle. Implications for glucose toxicity.  J Clin Invest. 1995;  96 2792-2801
• 10 Baumann C A, Ribon V, Kanzaki M, Thurmond D C, Mora S, Shigematsu S, Bickel P E, Pessin J E, Saltiel A R. CAP defines a second signalling pathway required for insulin-stimulated glucose transport.  Nature. 2000;  407 202-207
• 11 Beck B, Richy S. Hypothalamic hypocretin/orexin and neuropeptide Y: divergent interaction with energy depletion and leptin.  Biochem Biophys Res Commun. 1999;  258 119-122
• 12 Bernardi H, De Weille J R, Epelbaum J, Mourre C, Amoroso S, Slama A, Fosset M, Lazdunski M. ATP-modulated K+ channels sensitive to antidiabetic sulfonylureas are present in adenohypophysis and are involved in growth hormone release.  Proc Natl Acad Sci USA. 1993;  90 1340-1344
• 13 Bernardis L L, Bellinger L L. The lateral hypothalamic area revisited: ingestive behavior.  Neurosci Biobehav Rev. 1996;  20 189-287
• 14 Blevins J E, Stanley B G, Reidelberger R D. Brain regions where cholecystokinin suppresses feeding in rats.  Brain Res. 2000;  860 1-10
• 15 Boden G, Chen X, DeSantis R, Kolaczynski J, Morris M. Evidence that suppression of insulin secretion by insulin itself is neurally mediated.  Metabolism. 1993;  42 786-789
• 16 Borg M A, Sherwin R S, Borg W P, Tamborlane W V, Shulman G I. Local ventromedial hypothalamus glucose perfusion blocks counterregulation during systemic hypoglycemia in awake rats.  J Clin Invest. 1997;  99 361-365
• 17 Borg W P, Sherwin R S, During M J, Borg M A, Shulman G I. Local ventromedial hypothalamus glucopenia triggers counterregulatory hormone release.  Diabetes. 1995;  44 180-184
• 18 Brobeck J R. Mechanisms of the development of obesity in animals with hypothalamic lesions.  Physiol Rev. 1946;  26 541-559
• 19 Bruning J C, Gautam D, Burks D J, Gilette J, Schubert M, Orban P C, Klein R, Krone W, Muller-Wieland D, Kahn C R. Role of Brain Insulin Receptor in Control of Body Weight and Reproduction.  Science. 2000;  289 2122-2125
• 20 Butler P C, Kryshak E J, Marsh M, Rizza R A. Effect of insulin on oxidation of intracellularly and extracellularly derived glucose in patients with NIDDM. Evidence for primary defect in glucose transport and/or phosphorylation but not oxidation.  Diabetes. 1990;  39 1373-1380
• 21 Byrne M M, Sturis J, Clement K, Vionnet N, Pueyo M E, Stoffel M, Takeda J, Passa P, Cohen D, Bell G I. Insulin secretory abnormalities in subjects with hyperglycemia due to glucokinase mutations.  J Clin Invest. 1994;  93 1120-1130
• 22 Cai X J, Widdowson P S, Harrold J, Wilson S, Buckingham R E, Arch J R, Tadayyon M, Clapham J C, Wilding J, Williams G. Hypothalamic orexin expression: modulation by blood glucose and feeding.  Diabetes. 1999;  48 2132-2137
• 23 Capaldo B, Napoli R, Guida R, Di Bonito P, Antoniello S, Auletta M, Pardo F, Rendina V, Sacca L. Forearm muscle insulin resistance during hypoglycemia: role of adrenergic mechanisms and hypoglycemia per se.  Am J Physiol. 1995;  268 E248-54
• 24 Caro J F, Kolaczynski J W, Nyce M R, Ohannesian J P, Opentanova I, Goldmann W H, Lynn R B, Zhang P L, Sinha M K, Considine R V. Decreased cerebrospinal-fluid/serum leptin ratio in obesity: a possible mechanism for leptin resistance.  Lancet. 1996;  348 159-161
• 25 Capaldo B, Chan S L, Dunne M J, Stillings M R, Morgan N G. The alpha 2-adrenoceptor antagonist efaroxan modulates K+ATP channels in insulin-secreting cells.  Eur J Pharmacol. 1991;  204 41-48
• 26 Chapman J C, McClenaghan N H, Cosgrove K E, Hashmi M N, Shepherd R M, Giesberts A N, White S J, Ammala C, Flatt P R, Dunne M J. ATP-sensitive potassium channels and efaroxan-induced insulin release in the electrofusion-derived BRIN-BD11 beta-cell line.  Diabetes. 1999;  48 2349-2357
• 27 Chen P, Li C, Haskell-Luevano C, Cone R D, Smith M S. Altered expression of agouti-related protein and its colocalization with neuropeptide Y in the arcuate nucleus of the hypothalamus during lactation.  Endocrinology. 1999;  140 2645-2650
• 28 Cline G W, Petersen K F, Krssak M, Shen J, Hundal R S, Trajanoski Z, Inzucchi S, Dresner A, Rothman D L, Shulman G I. Impaired glucose transport as a cause of decreased insulin-stimulated muscle glycogen synthesis in type 2 diabetes.  N Engl J Med. 1999;  341 240-246
• 29 Cohen N, Rossetti L, Shlimovich P, Halberstam M, Hu M, Shamoon H. Counterregulation of hypoglycemia. Skeletal muscle glycogen metabolism during three hours of physiological hyperinsulinemia in humans.  Diabetes. 1995;  44 423-430
• 30 Collins A C, Pickup J C. Sample preparation and radioimmunoassay for circulating free and antibody-bound insulin concentrations in insulin-treated diabetics: a re-evaluation of methods.  Diabetes Med. 1985;  2 456-460
• 31 Commons K G, Kow L M, Milner T A, Pfaff D W. In the ventromedial nucleus of the rat hypothalamus, GABA-immunolabeled neurons are abundant and are innervated by both enkeph.  Brain Res. 1999;  816 58-67
• 32 Cone R D. The Central Melanocortin System and Energy Homeostasis.  Trends Endocrinol Metab. 1999;  10 211-216
• 33 Costa A, Poma A, Martignoni E, Nappi G, Ur E, Grossman A. Stimulation of corticotrophin-releasing hormone release by the obese (ob) gene product, leptin, from hypothalamic explants.  Neuroreport. 1997;  8 1131-1134
• 34 Cowley M A, Smart J L, Rubinstein M, Cerdan M G, Diano S, Horvath T L, Cone R D, Low M J. Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus.  Nature. 2001;  411 480-484
• 35 Dantz D, Beversdorf J, Fruehwald-Schultes B, Kern W, Jelkmann W, Born J, Fehm H L, Peters A. Vascular endothelial growth factor: a novel endocrine defensive response to hypoglycemia.  Journal of Clinical Endocrinology & Metabolism. 2002;  87 835-840
• 36 De Vivo D C, Trifiletti R R, Jacobson R I, Ronen G M, Behmand R A, Harik S I. Defective glucose transport across the blood-brain barrier as a cause of persistent hypoglycorrhachia, seizures, and developmental delay.  N Engl J Med. 1991;  325 703-709
• 37 Delaunay F, Khan A, Cintra A, Davani B, Ling Z C, Andersson A, Ostenson C G, Gustafsson J, Efendic S, Okret S. Pancreatic beta cells are important targets for the diabetogenic effects of glucocorticoids.  J Clin Invest. 1997;  100 2094-2098
• 38 DiStefano J J, Stubberud A R, William I J. Feedback and control systems, 2 edition. New York; McGraw-Hill 1990
• 39 Dryden S, Frankish H M, Wang Q, Williams G. Increased feeding and neuropeptide Y (NPY) but not NPY mRNA levels in the hypothalamus of the rat following central administration of the serotonin synthesis inhibitor p-chlorophenylalanine.  Brain Res. 1996;  724 232-237
• 40 Dunn Meynell A A, Rawson N E, Levin B E. Distribution and phenotype of neurons containing the ATP- sensitive K+ channel in rat brain.  Brain Res. 1998;  814 41-54
• 41 Dunning B E, Ahren B, Veith R C, Taborsky G J. Nonadrenergic sympathetic neural influences on basal pancreatic hormone secretion.  Am J Physiol. 1988;  255 E785-E792
• 42 Egawa M, Yoshimatsu H, Bray G A. Neuropeptide Y suppresses sympathetic activity to interscapular brown adipose tissue in rats.  Am J Physiol. 1991;  260 R328-R334
• 43 Delaunay F, El Haschimi K, Pierroz D D, Hileman S M, Bjorbaek C, Flier J S. Two defects contribute to hypothalamic leptin resistance in mice with diet-induced obesity.  J Clin Invest. 2000;  105 1827-1832
• 44 Elias C F, Aschkenasi C, Lee C, Kelly J, Ahima R S, Bjorbaek C, Flier J S, Saper C B, Elmquist J K. Leptin differentially regulates NPY and POMC neurons projecting to the lateral hypothalamic area.  Neuron. 1999;  23 775-786
• 45 Elias C F, Kelly J F, Lee C E, Ahima R S, Drucker D J, Saper C B, Elmquist J K. Chemical characterization of leptin-activated neurons in the rat brain.  J Comp Neurol. 2000;  423 261-281
• 46 Elias C F, Lee C, Kelly J, Aschkenasi C, Ahima R S, Couceyro P R, Kuhar M J, Saper C B, Elmquist J K. Leptin activates hypothalamic CART neurons projecting to the spinal cord.  Neuron. 1998;  21 1375-1385
• 47 Elmquist J K, Ahima R S, Maratos Flier E, Flier J S, Saper C B. Leptin activates neurons in ventrobasal hypothalamus and brainstem.  Endocrinology. 1997;  138 839-842
• 48 Emilsson V, Liu Y L, Cawthorne M A, Morton N M, Davenport M. Expression of the functional leptin receptor mRNA in pancreatic islets and direct inhibitory action of leptin on insulin secretion.  Diabetes. 1997;  46 313-316
• 49 Erickson J C, Clegg K E, Palmiter R D. Sensitivity to leptin and susceptibility to seizures of mice lacking neuropeptide Y.  Nature. 1996;  381 415-421
• 50 Fajans S S, Bell G I, Polonsky K S. Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young.  N Engl J Med. 2001;  345 971-980
• 51 Fan W, Dinulescu D M, Butler A A, Zhou J, Marks D L, Cone R D. The central melanocortin system can directly regulate serum insulin levels.  Endocrinology. 2000;  141 3072-3079
• 52 Ferrara N, Henzel W J. Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells.  Biochem Biophys Res Commun. 1989;  161 851-858
• 53 Ferrara N, Houck K, Jakeman L, Leung D W. Molecular and biological properties of the vascular endothelial growth factor family of proteins.  Endocr Rev. 1992;  13 18-32
• 54 Fink R I, Wallace P, Brechtel G, Olefsky J M. Evidence that glucose transport is rate-limiting for in vivo glucose uptake.  Metabolism. 1992;  41 897-902
• 55 Friedman J M, Halaas J L. Leptin and the regulation of body weight in mammals.  Nature. 1998;  395 763-770
• 56 Froguel P, Zouali H, Vionnet N, Velho G, Vaxillaire M, Sun F, Lesage S, Stoffel M, Takeda J, Passa P. Familial hyperglycemia due to mutations in glucokinase. Definition of a subtype of diabetes mellitus.  N Engl J Med. 1993;  328 697-702
• 57 Fruehwald-Schultes B, Kern W, Born J, Fehm H L, Peters A. Comparison of the inhibitory effect of insulin and hypoglycemia on insulin secretion in humans.  Metabolism. 2000a;  49 950-953
• 58 Fruehwald-Schultes B, Kern W, Dantz D, Born J, Fehm H L, Peters A. Preserved hypothermic response to hypoglycemia after antecedent hypoglycemia.  Metabolism. 2000b;  49 794-798
• 59 Frühwald-Schultes B, Kern W, Bong W, Wellhöner P, Kerner W, Born J, Fehm H L, Peters A. Supraphysiological hyperinsulinemia acutely increases hypothalamic-pituitary-adrenal secretory activity in humans.  J Clin Endocrinol Metab. 1999a;  84 3041-3046
• 60 Frühwald-Schultes B, Kern W, Deininger E, Wellhöner P, Kerner W, Born J, Fehm H L, Peters A. Protective effects of insulin against hypoglycemia-associated counterregulatory failure.  J Clin Endocrinol Metab. 1999b;  84 1551-1557
• 61 Gardner J D, Rothwell N J, Luheshi G N. Leptin affects food intake via CRF-receptor-mediated pathways.  Nat Neurosci. 1998;  1 103
• 62 Gerendai I, Halasz B. Central nervous system structures connected with the endocrine glands. Findings obtained with the viral transneuronal tracing technique.  Exp Clin Endocrinol Diabetes. 2000;  108 389-395
• 63 Gjedde A. Blood-barrier glucose transfer. In: Bradbury, W.B. (Ed.), Physiology and pharmacology of the blood-brain barrier. Berlin; Springer 1992: 65-115
• 64 Gloddek J, Pagotto U, Paez P M, Arzt E, Stalla G K, Renner U. Pituitary adenylate cyclase-activating polypeptide, interleukin-6 and glucocorticoids regulate the release of vascular endothelial growth factor in pituitary folliculostellate cells.  J Endocrinol. 1999;  160 483-490
• 65 Gray R S, Cowan P, di Mario U, Elton R A, Clarke B F, Duncan L J. Influence of insulin antibodies on pharmacokinetics and bioavailability of recombinant human and highly purified beef insulins in insulin dependent diabetics.  Br Med J. 1985;  290 1687-1691
• 66 Green A, Carroll R M, Dobias S B. Desensitization of beta-adrenergic receptors in adipocytes causes increased insulin sensitivity of glucose transport.  Am J Physiol. 1996;  271 E271-E276
• 67 Guillam M T, Dupraz P, Thorens B. Glucose uptake, utilization, and signaling in GLUT 2-null islets.  Diabetes. 2000;  49 1485-1491
• 68 Guillaume-Gentil C, Assimacopoulos-Jeannet F, Jeanrenaud B. Involvement of non-esterified fatty acid oxidation in glucocorticoid- induced peripheral insulin resistance in vivo in rats.  Diabetologia. 1993;  36 899-906
• 69 Hahn T M, Breininger J F, Baskin D G, Schwartz M W. Coexpression of Agrp and NPY in fasting-activated hypothalamic neurons.  Nat Neurosci. 1998a;  1 271-272
• 70 Hahn T M, Breininger J F, Baskin D G, Schwartz M W. Coexpression of Agrp and NPY in fasting-activated hypothalamic neurons.  Nat Neurosci. 1998b;  1 271-272
• 71 Hakansson M L, Meister B. Transcription factor STAT3 in leptin target neurons of the rat hypothalamus.  Neuroendocrinology. 1998;  68 420-427
• 72 Hannibal J, Jessop D S, Fahrenkrug J, Harbuz M S, Larsen P J. PACAP gene expression in neurons of the rat hypothalamo-pituitary- adrenocortical axis is induced by endotoxin and interleukin-1beta.  Neuroendocrinology. 1999;  70 73-82
• 73 Hannibal J, Mikkelsen J D, Fahrenkrug J, Larsen P J. Pituitary adenylate cyclase-activating peptide gene expression in corticotropin-releasing factor-containing parvicellular neurons of the rat hypothalamic paraventricular nucleus is induced by colchicine, but not by adrenalectomy, acute osmotic, ether, or restraint stress.  Endocrinology. 1995;  136 4116-4124
• 74 Hasselbach S G, Knudsen G M, Videbaek C, Pinborg L H, Schmidt J F, Holm S, Paulson O B. No effect of insulin on glucose blood-brain barrier transport and cerebral metabolism in humans.  Diabetes. 1999;  48 1915-1921
• 75 Havel P J, Hahn T M, Sindelar D K, Baskin D G, Dallman M F, Weigle D S, Schwartz M W. Effects of streptozotocin-induced diabetes and insulin treatment on the hypothalamic melanocortin system and muscle uncoupling protein 3 expression in rats.  Diabetes. 2000;  49 244-252
• 76 Havel P J, Taborsky G J. The contribution of the autonomic nervous system to changes of glucagon and insulin secretion during hypoglycemic stress.  Endocr Rev. 1989;  10 332-350
• 77 Haynes W G, Morgan D A, Walsh S A, Mark A L, Sivitz W I. Receptor-mediated regional sympathetic nerve activation by leptin.  J Clin Invest. 1997;  100 270-278
• 78 Heiman M L, Ahima R S, Craft L S, Schoner B, Stephens T W, Flier J S. Leptin inhibition of the hypothalamic-pituitary-adrenal axis in response to stress.  Endocrinology. 1997;  138 3859-3863
• 79 Hevener A L, Bergman R N, Donovan C M. Novel glucosensor for hypoglycemic detection localized to the portal vein.  Diabetes. 1997;  46 1521-1525
• 80 Hevener A L, Bergman R N, Donovan C M. Portal vein affernets are critical for the sympathoadrenal response to hypoglycemia.  Diabetes. 2000;  49 8-12
• 81 Hotamisligil G S. The role of TNFalpha and TNF receptors in obesity and insulin resistance.  J Intern Med. 1999;  245 621-625
• 82 Jabbour H N, Boddy S C, Lincoln G A. Pattern and localisation of expression of vascular endothelial growth factor and its receptor flt-1 in the ovine pituitary gland: expression is independent of hypothalamic control.  Mol Cell Endocrinol. 1997;  134 91-100
• 83 Jakeman L B, Winer J, Bennett G L, Altar C A, Ferrara N. Binding sites for vascular endothelial growth factor are localized on endothelial cells in adult rat tissues.  J Clin Invest. 1992;  89 244-253
• 84 Jansen A S, Hoffman J L, Loewy A D. CNS sites involved in sympathetic and parasympathetic control of the pancreas: a viral tracing study.  Brain Res. 1997;  766 29-38
• 85 Kalra S P, Dube M G, Pu S, Xu B, Hovath T L, Kalra P S. Interacting appetite-regulating pathways in the hypothalamic regulation of body weight.  Endocr Rev. 1999;  20 68-100
• 86 Kanai Y, Lee W S, You G, Brown D, Hediger M A. The human kidney low affinity Na+/glucose cotransporter SGLT2. Delineation of the major renal reabsorptive mechanism for D-glucose.  J Clin Invest. 1994;  93 397-404
• 87 Kieffer T J, Habener J F. The adipoinsular axis: effects of leptin on pancreatic beta-cells.  Am J Physiol Endocrinol Metab. 2000;  278 E1-E14
• 88 Kieffer T J, Heller R S, Leech C A, Holz G G, Habener J F. Leptin suppression of insulin secretion by the activation of ATP- sensitive K+ channels in pancreatic beta-cells.  Diabetes. 1997;  46 1087-1093
• 89 Kim M S, Rossi M, Abusnana S, Sunter D, Morgan D G, Small C J, Edwards C M, Heath M M, Stanley S A, Seal L J, Bhatti J R, Smith D M, Ghatei M A, Bloom S R. Hypothalamic localization of the feeding effect of agouti-related peptide and alpha-melanocyte-stimulating hormone.  Diabetes. 2000;  49 177-182
• 90 Klein J, Fasshauer M, Ito M, Lowell B B, Benito M, Kahn C R. beta(3)-adrenergic stimulation differentially inhibits insulin signaling and decreases insulin-induced glucose uptake in brown adipocytes.  J Biol Chem. 1999;  274 34795-34802
• 91 Kleinzeller A, McAvoy E M. Glucose transport and metabolism in rat renal proximal tubules: multicomponent effects of insulin.  Biochim Biophys Acta. 1986;  856 545-555
• 92 Korzon Burakowska A, Hopkins D, Matyka K, Lomas J, Pernet A, Macdonald I, Amiel S. Effects of glycemic control on protective responses against hypoglycemia in type 2 diabetes.  Diabetes Care. 1998;  21 283-290
• 93 Kow L M, Pfaff D W. The effects of the TRH metabolite cyclo(His-Pro) and its analogs on feeding.  Pharmacol Biochem Behav. 1991;  38 359-364
• 94 Kristensen P, Judge M E, Thim L, Ribel U, Christjansen K N, Wulff B S, Clausen J T, Jensen P B, Madsen O D, Vrang N, Larsen P J, Hastrup S. Hypothalamic CART is a new anorectic peptide regulated by leptin.  Nature. 1998;  393 72-76
• 95 Kulkarni R N, Bruning J C, Winnay J N, Postic C, Magnuson M A, Kahn C R. Tissue-specific knockout of the insulin receptor in pancreatic beta cells creates an insulin secretory defect similar to that in type 2 diabetes.  Cell. 1999;  96 329-339
• 96 Kumagai A K, Kang Y S, Boado R J, Pardridge W M. Upregulation of blood-brain barrier GLUT 1 glucose transporter protein and mRNA in experimental chronic hypoglycemia.  Diabetes. 1995;  44 1399-1404
• 97 Lazdunski M. ATP-sensitive potassium channels: an overview.  J Cardiovasc Pharmacol. 24 ((Suppl 4)) 1994;  S1-S5
• 98 Lee A D, Hansen P A, Schluter J, Gulve E A, Gao J, Holloszy J O. Effects of epinephrine on insulin-stimulated glucose uptake and GLUT 4 phosphorylation in muscle.  Am J Physiol. 1997;  273 C1082-C1087
• 99 Levin B E, Dunn-Meynell A, Routh V H. Brain glucose sensing and body energy homoestasis: role in obesity and diabetes.  Am J Physiol. 1999;  276 R1223-R1231
• 100 Liu X H, Morris R, Spiller D, White M, Williams G. Orexin a preferentially excites glucose-sensitive neurons in the lateral hypothalamus of the rat in vitro.  Diabetes. 2001;  50 2431-2437
• 101 Looker H C, Knowler W C, Hanson R L. Changes in BMI and Weight Before and After the Development of Type 2 Diabetes.  Diabetes Care. 2001;  24 1917-1922
• 102 Lowell B B, Spiegelman B M. Towards a molecular understanding of adaptive thermogenesis.  Nature. 2000;  404 652-660
• 103 Luheshi G N, Gardner J D, Rushforth D A, Loudon A S, Rothwell N J. Leptin actions on food intake and body temperature are mediated by IL-1.  Proc Natl Acad Sci U S A. 1999;  96 7047-7052
• 104 Luiten P G, ter Horst G J, Steffens A B. The hypothalamus, intrinsic connections and outflow pathways to the endocrine system in relation to the control of feeding and metabolism.  Prog Neurobiol. 1987;  28 1-54
• 105 Masuzaki H, Ogawa Y, Sagawa N, Hosoda K, Matsumoto T, Mise H, Nishimura H, Yoshimasa Y, Tanaka I, Mori T, Nakao K. Nonadipose tissue production of leptin: leptin as a novel placenta- derived hormone in humans.  Nat Med. 1997;  3 1029-1033
• 106 McCall A L, Fixman L B, Fleming N, Tornheim K, Chick W, Ruderman N B. Chronic hypoglycemia increases brain glucose transport.  Am J Physiol. 1986;  251 E442-7
• 107 Miki T, Liss B, Minami K, Shiuchi T, Saraya A, Kashima Y, Horiuchi M, Ashcroft F, Minokoshi Y, Roeper J, Seino S. ATP-sensitive K+ channels in the hypothalamus are essential for the maintenance of glucose homeostasis.  Nat Neurosci. 2001;  4 507-512
• 108 Miki T, Nagashima K, Seino S. The structure and function of the ATP-sensitive K+ channel in insulin- secreting pancreatic beta-cells.  J Mol Endocrinol. 1999;  22 113-123
• 109 Mizuno A, Murakami T, Otani S, Kuwajima M, Shima K. Leptin affects pancreatic endocrine functions through the sympathetic nervous system.  Endocrinology. 1998;  139 3863-3870
• 110 Mizuno T M, Bergen H, Funabashi T, Kleopoulos S P, Zhong Y G, Bauman W A, Mobbs C V. Obese gene expression: reduction by fasting and stimulation by insulin and glucose in lean mice, and persistent elevation in acquired (diet- induced) and genetic (yellow agouti) obesity.  Proc Natl Acad Sci U S A. 1996;  93 3434-3438
• 111 Mueller W M, Gregoire F M, Stanhope K L, Mobbs C V, Mizuno T M, Warden C H, Stern J S, Havel P J. Evidence that glucose metabolism regulates leptin secretion from cultured rat adipocytes.  Endocrinology. 1998;  139 551-558
• 112 Ohsaka Y, Tokumitsu Y, Nomura Y. Suppression of insulin-stimulated phosphatidylinositol 3-kinase activity by the beta3-adrenoceptor agonist CL316243 in rat adipocytes.  FEBS Lett. 1997;  402 246-250
• 113 Okamoto S, Irie Y, Ishikawa I, Kimura K, Masayuki S. Central leptin suppresses splenic lymphocyte functions through activation of the corticotropin-releasing hormone-sympathetic nervous system.  Brain Res. 2000;  855 192-197
• 114 Oltmanns K M, Fruehwald-Schultes B, Klein H H, Raspe H H, Born J, Fehm H L, Peters A. Evidence of cortisol-related symptom complex (CRSC) in type 2 diabetes. A population based study.  Exp Clin Endocrinol Diabetes. 2001;  109 A16
• 115 Oomura Y, Ooyama H, Sugimori M, Nakamura T, Yamada Y. Glucose inhibition of the glucose-sensitive neurone in the rat lateral hypothalamus.  Nature. 1974;  247 284-286
• 116 Orsini J C, Armstrong D L, Wayner M J. Responses of lateral hypothalamic neurons recorded in vitro to moderate changes in glucose concentration.  Brain Res Bull. 1992;  29 503-505
• 117 Paulmyer-Lacroix O, Anglade G, Grino M. Insulin-induced hypoglycaemia increases colocalization of corticotrophin-releasing factor and arginine vasopressin mRNAs in the rat hypothalamic paraventricular nucleus.  J Mol Endocrinol. 1994;  13 313-320
• 118 Pekala P, Marlow M, Heuvelman D, Connolly D. Regulation of hexose transport in aortic endothelial cells by vascular permeability factor and tumor necrosis factor-alpha, but not by insulin.  J Biol Chem. 1990;  265 18051-18054
• 119 Peraldi P, Spiegelman B. TNF-alpha and insulin resistance: summary and future prospects.  Mol Cell Biochem. 1998;  182 169-175
• 120 Polonsky K S, Given B D, Hirsch L J, Tillil H, Shapiro E T, Beebe C, Frank B H, Galloway J A, Van Cauter E. Abnormal patterns of insulin secretion in non-insulin-dependent diabetes mellitus.  N Engl J Med. 1988;  318 1231-1239
• 121 Qu D, Ludwig D S, Gammeltoft S, Piper M, Pelleymounter M A, Cullen M J, Mathes W F, Przypek R, Kanarek R, Maratos-Flier E. A role for melanin-concentrating hormone in the central regulation of feeding behaviour.  Nature. 1996;  380 243-247
• 122 Reaven G M, Laws A. Insulin resistance - The metabolic syndrome X. Totowa, New Jersey; Humana Press 1999
• 123 Rorsman P, Berggren P O, Bokvist K, Ericson H, Mohler H, Ostenson C G, Smith P A. Glucose-inhibition of glucagon secretion involves activation of GABAA- receptor chloride channels.  Nature. 1989;  341 233-236
• 124 Saad M F, Khan A, Sharma A, Michael R, Riad-Gabriel M G, Boyadjian R, Jinagouda S D, Steil G M, Kamdar V. Physiological insulinemia acutely modulates plasma leptin.  Diabetes. 1998;  47 544-549
• 125 Satoh N, Ogawa Y, Katsuura G, Numata Y, Tsuji T, Hayase M, Ebihara K, Masuzaki H, Hosoda K, Yoshimasa Y, Nakao K. Sympathetic activation of leptin via the ventromedial hypothalamus: leptin-induced increase in catecholamine secretion.  Diabetes. 1999;  48 1787-1793
• 126 Schoeller D A, Cella L K, Sinha M K, Caro J F. Entrainment of the diurnal rhythm of plasma leptin to meal timing.  J Clin Invest. 1997;  100 1882-1887
• 127 Schuit F C, Huypens P, Heimberg H, Pipeleers D G. Glucose sensing in pancreatic beta-cells: a model for the study of other glucose-regulated cells in gut, pancreas, and hypothalamus.  Diabetes. 2001;  50 1-11
• 128 Schwartz M W, Figlewicz D P, Baskin D G, Woods S, Porte D J. Insulin in the brain: A hormonal regulator of energy balance.  Endocr Rev. 1992;  13 387-414
• 129 Schwartz M W, Seeley R J, Campfield L A, Burn P, Baskin D G. Identification of targets of leptin action in rat hypothalamus.  J Clin Invest. 1996;  98 1101-1106
• 130 Schwartz M W, Woods S C, Porte D J, Seeley R J, Baskin D G. Central nervous system control of food intake.  Nature. 2000;  404 661-671
• 131 Seaquist E R, Damberg G S, 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
• 132 Seidner G, Alvarez M G, Yeh J I, O‘Driscoll K R, Klepper J, Stump T S, Wang D, Spinner N B, Birnbaum M J, De Vivo D C. GLUT 1 deficiency syndrome caused by haploinsufficiency of the blood-brain barrier hexose carrier.  Nat Genet. 1998;  18 188-191
• 133 Seino S, Iwanaga T, Nagashima K, Miki T. Diverse roles of K(ATP) channels learned from Kir6.2 genetically engineered mice.  Diabetes. 2000;  49 311-318
• 134 Shamoon H, Friedman S, Canton C, Zacharowicz L, Hu M, Rossetti L. Increased epinephrine and skeletal muscle responses to hypoglycemia in non-insulin-dependent diabetes mellitus.  J Clin Invest. 1994;  93 2562-2571
• 135 Shapiro E T, Cooper M, Chen C T, Given B D, Polonsky K S. Change in hexose distribution volume and fractional utilization of [18F]-2-deoxy-2-fluoro-D-glucose in brain during acute hypoglycemia in humans.  Diabetes. 1990;  39 175-180
• 136 Shepherd P R, Kahn B B. Glucose transporters and insulin action-implications for insulin resistance and diabetes mellitus.  N Engl J Med. 1999;  341 248-257
• 137 Shimada M, Tritos N A, Lowell B B, Flier J S, Maratos-Flier E. Mice lacking melanin-concentrating hormone are hypophagic and lean.  Nature. 1998;  396 670-674
• 138 Silver I A, Erecinska M. Glucose-induced intracellular ion changes in sugar-sensitive hypothalamic neurons.  J Neurophysiol. 1998;  79 1733-1745
• 139 Simpson I A, Appel N M, Hokari M, Oki J, Holman G D, Maher F, Koehler-Stec E M, Vannucci S J, Smith Q R. Blood-brain barrier glucose transporter: effects of hypo- and hyperglycemia revisited.  J Neucrochem. 1999;  72 238-247
• 140 Sone H, Deo B K, Kumagai A K. Enhancement of glucose transport by vascular endothelial growth factor in retinal endothelial cells.  Invest Ophthalmol Vis Sci. 2000;  41 1876-1884
• 141 Spanswick D, Smith M A, Groppi V E, Logan S D, Ashford M L. Leptin inhibits hypothalamic neurons by activation of ATP-sensitive potassium channels.  Nature. 1997;  390 521-525
• 142 Spanswick D, Smith M A, Mirshamsi S, Routh V H, Ashford M L. Insulin activates ATP-sensitive K+ channels in hypothalamic neurons of lean, but not obese rats.  Nat Neurosci. 2000;  3 757-758
• 143 Spina M, Merlo-Pich E, Chan R K, Basso A M, Rivier J, Vale W, Koob G F. Appetite-suppressing effects of urocortin, a CRF-related neuropeptide.  Science. 1996;  273 1561-1564
• 144 Spyer G, Hattersley A T, Macdonald I A, Amiel S, MacLeod K M. Hypoglycaemic counter-regulation at normal blood glucose concentrations in patients with well controlled type-2 diabetes.  Lancet. 2000;  356 1970-1974
• 145 Steffens A B. Influence of reversible obesity on eating behavior, blood glucose, and insulin in the rat.  Am J Physiol. 1975;  228 1738-1744
• 146 Steppan C M, Bailey S T, Bhat S, Brown E J, Banerjee R R, Wright C M, Patel H R, Ahima R S, Lazar M A. The hormone resistin links obesity to diabetes.  Nature. 2001;  409 307-312
• 147 Stumvoll M, Meyer C, Mitrakou A, Gerich J E. Important role of the kidney in human carbohydrate metabolism.  Med Hypotheses. 1999;  52 363-366
• 148 Tack C J, Smits P, Willemsen J J, Lenders J W, Thien T, Lutterman J A. Effects of insulin on vascular tone and sympathetic nervous system in NIDDM.  Diabetes. 1996;  45 15-22
• 149 Tartaglia L A. The leptin receptor.  J Biol Chem. 1997;  272 6093-6096
• 150 Thomas P M, Cote G J, Wohllk N, Haddad B, Mathew P M, Rabl W, Agular-Bryan L, Gagel R F, Bryan J. Mutations in the sulfonylurea receptor gene in familial persistent hyperinsulinemic hypoglycemia of infancy.  Science. 1995;  268 426-429
• 151 Uehara Y, Shimizu H, Ohtani K, Sato N, Mori M. Hypothalamic corticotropin-releasing hormone is a mediator of the anorexigenic effect of leptin.  Diabetes. 1998;  47 890-893
• 152 Vaisse C, Clement K, Durand E, Hercberg S, Guy-Grand B, Froguel P. Melanocortin-4 receptor mutations are a frequent and heterogeneous cause of morbid obesity.  J Clin Invest. 2000;  106 253-262
• 153 Van Cauter E, Polonsky K S, Scheen A J. Roles of circadian rhythmicity and sleep in human glucose regulation.  Endocr Rev. 1997;  18 716-738
• 154 Van Dijk G, de Groote C, Chavez M, van der W Y, Steffens A B, Strubbe J H. Insulin in the arcuate nucleus of the hypothalamus reduces fat consumption in rats.  Brain Res. 1997;  777 147-152
• 155 Van Haeften T W, Heiling V J, Gerich J E. Adverse effects of insulin antibodies on postprandial plasma glucose and insulin profiles in diabetic patients without immune insulin resistance. Implications for intensive insulin regimens.  Diabetes. 1987;  36 305-309
• 156 Veneman T, Mitrakou A, Mokan M, Cryer P E, Gerich J. Effect of hyperketonemia and hyperlacticacidemia on symptoms, cognitive dysfunction, and counterregulatory hormone responses during hypoglycemia in normal humans.  Diabetes. 1994;  43 1311-1317
• 157 Wang J, Liu R, Hawkins M, Barzilai N, Rossetti L. A nutrient-sensing pathway regulates leptin gene expression in muscle and fat.  Nature. 1998;  393 684-688
• 158 Wellhöner P, Frühwald-Schultes B, Kern W, Dantz D, Born J, Fehm H L, Peters A. Glucose metabolism rather than insulin is a main determinant of leptin secretion in humans.  J Clin Endocr Metab. 2000;  85 1267-1271
• 159 Yamada K, Ji J J, Yuan H, Miki T, Sato S, Horimoto N, Shimizu T, Seino S, Inagaki N. Protective role of ATP-sensitive potassium channels in hypoxia-induced generalized seizure.  Science. 2001;  292 1543-1546
• 160 Yang X, Kow L M, Funabashi T, Mobbs C V. Hypothalamic glucose sensor.  Diabetes. 1999;  48 1763-1772
• 161 Yki-Jarvinen H, Sahlin K, Ren J M, Koivisto V A. Localization of rate-limiting defect for glucose disposal in skeletal muscle of insulin-resistant type I diabetic patients.  Diabetes. 1990;  39 157-167
• 162 Yki-Jarvinen H, Young A A, Lamkin C, Foley J E. Kinetics of glucose disposal in whole body and across the forearm in man.  J Clin Invest. 1987;  79 1713-1719
• 163 Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman J M. Positional cloning of the mouse obese gene and its human homologue.  Nature. 1994;  372 425-432
• 164 Zhao A Z, Bornfeldt K E, Beavo J A. Leptin inhibits insulin secretion by activation of phosphodiesterase 3B.  J Clin Invest. 1998;  102 869-873
• 165 Zisman A, Peroni O D, Abel E D, Michael M D, Mauvais-Jarvis F, Lowell B B, Wojtaszewski J F, Hirshman M F, Virkamaki A, Goodyear L J, Kahn B B. Targeted disruption of the glucose transporter 4 selectively in muscle causes insulin resistance and glucose intolerance.  Nat Med. 2000;  6 924-928

1 ¹ In this article, glucose that has been carried by GLUT 1 across the luminal membrane of BBB endothelial cells is referred to as “brain glucose”.