The Role of Brain in Glucose Metabolism

  • Silvana ObiciEmail author
  • Paulo José Forcina MartinsEmail author
Reference work entry


The notion that the central nervous system (CNS) is crucial for the physiological control of glucose homeostasis is increasingly recognized. Hypothalamic neurons that regulate energy balance, glucose production, and utilization constantly sense fuel availability by receiving and integrating inputs from circulating nutrients and hormones such as insulin and leptin. In response to these peripheral signals, the hypothalamus sends out efferent impulses that restrain food intake and endogenous glucose production. This ensures the optimal regulation of energy homeostasis and keeps blood glucose levels in the normal range. Disruption of this intricate neural control is likely to occur in type 2 diabetes and obesity and may contribute to defects of glucose homeostasis and insulin resistance common to both diseases. This chapter will summarize recent evidence in support the role of the hypothalamus as crucial orchestrator of peripheral glucose metabolism.


Glucose homeostasis Hypothalamus Endogenous glucose production Insulin receptor Insulin receptor KATP channels Leptin Melanocortin a-MSH AgRP NPY Arcuate nucleus CNS 


  1. 1.
    Bernard C. Lecons sur les phenomenes de la vie. Cours de physiologies generale du Museum d’Histoir Naturelle. Paris: Librairie Delagrave; 1859.Google Scholar
  2. 2.
    Unger RH. The milieu interieur and the islets of Langerhans. Diabetologia. 1981;20:1–11.PubMedCrossRefGoogle Scholar
  3. 3.
    Shimazu T. The hypothalamus and metabolic control. In: Matsuyama, editors. Minatomachi.,Vol. 1st. Ehime:,Ehime University School of Medicine; 1998.Google Scholar
  4. 4.
    Schwartz MW, Porte Jr D. Diabetes, obesity, and the brain. Science. 2005;307:375–9.PubMedCrossRefGoogle Scholar
  5. 5.
    Davis SN, Colburn C, Dobbins R, Nadeau S, Neal D, Williams P, et al. Evidence that the brain of the conscious dog is insulin sensitive. J Clin Invest. 1995;95:593–602.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Schwartz MW, Sipols A, Kahn SE, Lattemann DF, Taborsky Jr GJ, Bergman RN, et al. Kinetics and specificity of insulin uptake from plasma into cerebrospinal fluid. Am J Physiol. 1990;259:E378–83.PubMedGoogle Scholar
  7. 7.
    Gerozissis K, Rouch C, Nicolaidis S, Orosco M. Brain insulin response to feeding in the rat is both macronutrient and area specific. Physiol Behav. 1998;65:271–5.PubMedCrossRefGoogle Scholar
  8. 8.
    Gerozissis K, Orosco M, Rouch C, Nicolaidis S. Insulin responses to a fat meal in hypothalamic microdialysates and plasma. Physiol Behav. 1997;62:767–72.PubMedCrossRefGoogle Scholar
  9. 9.
    Unger JW, Betz M. Insulin receptors and signal transduction proteins in the hypothalamo-hypophyseal system: a review on morphological findings and functional implications. Histol Histopathol. 1998;13:1215–24.PubMedGoogle Scholar
  10. 10.
    Marks JL, Porte Jr D, Stahl WL, Baskin DG. Localization of insulin receptor mRNA in rat brain by in situ hybridization. Endocrinology. 1990;127:3234–6.PubMedCrossRefGoogle Scholar
  11. 11.
    Baskin DG, Gierke EP, Wilcox BJ, Matsumoto AM, Schwartz MW. Food intake and estradiol effects on insulin binding in brain and liver. Physiol Behav. 1993;53:757–62.PubMedCrossRefGoogle Scholar
  12. 12.
    Richardson RD, Ramsay DS, Lernmark A, Scheurink AJ, Baskin DG, Woods SC. Weight loss in rats following intraventricular transplants of pancreatic islets. Am J Physiol. 1994;266:R59–64.PubMedGoogle Scholar
  13. 13.
    Woods SC, Lotter EC, McKay LD, Porte Jr D. Chronic intracerebroventricular infusion of insulin reduces food intake and body weight of baboons. Nature. 1979;282:503–5.PubMedCrossRefGoogle Scholar
  14. 14.
    Sipols AJ, Baskin DG, Schwartz MW. Effect of intracerebroventricular insulin infusion on diabetic hyperphagia and hypothalamic neuropeptide gene expression. Diabetes. 1995;44:147–51.PubMedCrossRefGoogle Scholar
  15. 15.
    Schwartz MW, Sipols AJ, Marks JL, Sanacora G, White JD, Scheurink A, et al. Inhibition of hypothalamic neuropeptide Y gene expression by insulin. Endocrinology. 1992;130:3608–16.PubMedCrossRefGoogle Scholar
  16. 16.
    Sahu A, Dube MG, Phelps CP, Sninsky CA, Kalra PS, Kalra SP. Insulin and insulin-like growth factor II suppress neuropeptide Y release from the nerve terminals in the paraventricular nucleus: a putative hypothalamic site for energy homeostasis. Endocrinology. 1995;136:5718–24.PubMedCrossRefGoogle Scholar
  17. 17.
    Schwartz MW, Marks JL, Sipols AJ, Baskin DG, Woods SC, Kahn SE, et al. Central insulin administration reduces neuropeptide Y mRNA expression in the arcuate nucleus of food-deprived lean (Fa/Fa) but not obese (fa/fa) Zucker rats. Endocrinology. 1991;128:2645–7.PubMedCrossRefGoogle Scholar
  18. 18.
    Davis SN, Dunham B, Walmsley K, Shavers C, Neal D, Williams P, et al. Brain of the conscious dog is sensitive to physiological changes in circulating insulin. Am J Physiol. 1997;272:E567–75.PubMedGoogle Scholar
  19. 19.
    Liang C, Doherty JU, Faillace R, Maekawa K, Arnold S, Gavras H, et al. Insulin infusion in conscious dogs. Effects on systemic and coronary hemodynamics, regional blood flows, and plasma catecholamines. J Clin Invest. 1982;69:1321–36.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Rowe JW, YounG JB, Minaker KL, Stevens AL, Pallotta J, Landsberg L. Effect of insulin and glucose infusions on sympathetic nervous system activity in normal man. Diabetes. 1981;30:219–25.PubMedCrossRefGoogle Scholar
  21. 21.
    Bruning JC, Gautam D, Burks DJ, Gillette J, Schubert M, Orban PC, et al. Role of brain insulin receptor in control of body weight and reproduction. Science. 2000;289:2122–5.PubMedCrossRefGoogle Scholar
  22. 22.
    Okamoto H, Obici S, Accili D, Rossetti L. Restoration of liver insulin signaling in Insr knockout mice fails to normalize hepatic insulin action. J Clin Invest. 2005;115:1314–22.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Wolkow CA, Kimura KD, Lee MS, Ruvkun G. Regulation of C. Elegans life-span by insulinlike signaling in the nervous system. Science. 2000;290:147–50.PubMedCrossRefGoogle Scholar
  24. 24.
    Obici S, Zhang BB, Karkanias G, Rossetti L. Hypothalamic insulin signaling is required for inhibition of glucose production. Nat Med. 2002;8(12):1376–82.PubMedCrossRefGoogle Scholar
  25. 25.
    Karschin C, Ecke C, Ashcroft FM, Karschin A. Overlapping distribution of K(ATP) channel-forming Kir6.2 subunit and the sulfonylurea receptor SUR1 in rodent brain. FEBS Lett. 1997;401:59–64.PubMedCrossRefGoogle Scholar
  26. 26.
    Spanswick D, Smith MA, Mirshamsi S, Routh VH, Ashford ML. Insulin activates ATP-sensitive K+ channels in hypothalamic neurons of lean, but not obese rats. Nat Neuro sci. 2000;3:757–8.CrossRefGoogle Scholar
  27. 27.
    Pocai A, Lam TK, Gutierrez-Juarez R, Obici S, Schwartz GJ, Bryan J, et al. Hypothalamic K(ATP) channels control hepatic glucose production. Nature. 2005;434:1026–31.PubMedCrossRefGoogle Scholar
  28. 28.
    Pocai A, Obici S, Schwartz GJ, Rossetti L. A brain-liver circuit regulates glucose homeostasis. Cell Metab. 2005;1:53–61. Available from:
  29. 29.
    Konner AC, Janoschek R, Plum L, Jordan SD, Rother E, Ma X, et al. Insulin action in AgRP-expressing neurons is required for suppression of hepatic glucose production. Cell Metab. 2007;5:438–49.PubMedCrossRefGoogle Scholar
  30. 30.
    Consoli A, Nurjhan N, Capani F, Gerich J. Predominant role of gluconeogenesis in increased hepatic glucose production in NIDDM. Diabetes. 1989;38:550–7.PubMedCrossRefGoogle Scholar
  31. 31.
    Ramnanan CJ, Kraft G, Smith MS, Farmer B, Neal D, Williams PE, et al. Interaction between the central and peripheral effects of insulin in controlling hepatic glucose metabolism in the conscious dog. Diabetes. 2013;62(1):74–84. Available from:
  32. 32.
    Ramnanan CJ, Saraswathi V, Smith MS, Donahue EP, Farmer B, Farmer TD, et al. Brain insulin action augments hepatic glycogen synthesis without suppressing glucose production or gluconeogenesis in dogs. J Clin Invest. 2011;121(9):3713–23. Available from:
  33. 33.
    Kishore P, Boucai L, Zhang K, Li W, Koppaka S, Kehlenbrink S, et al. Activation of K ATP channels suppresses glucose production in humans. J Clin Invest. 2011;121(12):4916–20.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Ott V, Lehnert H, Staub J, Wonne K, Born J, Hallschmid M. Central nervous insulin administration does not potentiate the acute glucoregulatory impact of concurrent mild hyperinsulinemia. Diabetes. 2015;64(3):760–5.PubMedCrossRefGoogle Scholar
  35. 35.
    Dash S, Xiao C, Morgantini C, Koulajian K, Lewis GF. Intranasal insulin suppresses endogenous glucose production in humans compared with placebo in the presence of similar venous insulin concentrations. Diabetes. 2015;64(3):766–74. Available from:
  36. 36.
    Heni M, Kullmann S, Preissl H, Fritsche A, Häring H-U. Impaired insulin action in the human brain: causes and metabolic consequences. Nat Rev Endocrinol. 2015;11(12):701–11. Available from:
  37. 37.
    Edgerton DS, Cherrington AD. Is brain insulin action relevant to the control of plasma glucose in humans? Diabetes. 2015;64(3):696–9. Available from:
  38. 38.
    Dash S, Xiao C, Morgantini C, Koulajian K, Lewis GF. Is insulin action in the brain relevant in regulating blood glucose in humans. J Clin Endocrinol Metab. 2015;100(7):2525–31.PubMedCrossRefGoogle Scholar
  39. 39.
    Heni M, Kullmann S, Preissl H, Fritsche A, Häring H-U. Impaired insulin action in the human brain: causes and metabolic consequences. Nat Rev Endocrinol. 2015;11(12):701–11. Available from:;
  40. 40.
    Rojas JM, Schwartz MW. Review article. Diabetes Obes Metab. 2014;24(2):285–305. Available from:
  41. 41.
    Friedman JM, Halaas JL. Leptin and the regulation of body weight in mammals. Nature. 1998;395:763–70.PubMedCrossRefGoogle Scholar
  42. 42.
    Schwartz MW, Woods SC, Porte Jr D, Seeley RJ, Baskin DG. Central nervous system control of food intake. Nature. 2000;404:661–71.PubMedGoogle Scholar
  43. 43.
    Cowley MA, Smart JL, Rubinstein M, Cerdan MG, Diano S, Horvath TL, et al. Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature. 2001;411:480–4.PubMedCrossRefGoogle Scholar
  44. 44.
    Cowley MA, Pronchuk N, Fan W, Dinulescu DM, Colmers WF, Cone RD. Integration of NPY, AGRP, and melanocortin signals in the hypothalamic paraventricular nucleus: evidence of a cellular basis for the adipostat. Neuron. 1999;24:155–63.PubMedCrossRefGoogle Scholar
  45. 45.
    Butler AA, Cone RD. Knockout studies defining different roles for melanocortin receptors in energy homeostasis. AnnN YAcad Sci. 2003;994:240–5.CrossRefGoogle Scholar
  46. 46.
    Butler AA, Kesterson RA, Khong K, Cullen MJ, Pelleymounter MA, Dekoning J, et al. A unique metabolic syndrome causes obesity in the melanocortin-3 receptor-deficient mouse. Endocrinology. 2000;141:3518–21.PubMedCrossRefGoogle Scholar
  47. 47.
    Huszar D, Lynch CA, Fairchild-Huntress V, Dunmore JH, Fang Q, Berkemeier LR, et al. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell. 1997;88:131–41.PubMedCrossRefGoogle Scholar
  48. 48.
    Halaas JL, Gajiwala KS, Maffei M, Cohen SL, Chait BT, Rabinowitz D, et al. Weight-reducing effects of the plasma protein encoded by the obese gene. Science. 1995;269:543–6.PubMedCrossRefGoogle Scholar
  49. 49.
    Halaas JL, Boozer C, Blair-West J, Fidahusein N, Denton DA, Friedman JM. Physiological response to long-term peripheral and central leptin infusion in lean and obese mice. Proc Natl Acad Sci USA. 1997;94:8878–83.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Pelleymounter MA, Cullen MJ, Baker MB, Hecht R, Winters D, Boone T, et al. Effects of the obese gene product on body weight regulation in ob/ob mice. Science. 1995;269:540–3.PubMedCrossRefGoogle Scholar
  51. 51.
    Liu L, Karkanias GB, Morales JC, Hawkins M, Barzilai N, Wang J, et al. Intracerebroventricular leptin regulates hepatic but not peripheral glucose fluxes. J Biol Chem. 1998;273:31160–7.PubMedCrossRefGoogle Scholar
  52. 52.
    Schwartz MW, Baskin DG, Bukowski TR, Kuijper JL, Foster D, Lasser G, et al. Specificity of leptin action on elevated blood glucose levels and hypothalamic neuropeptide Y gene expression in ob/ob mice. Diabetes. 1996;45:531–5.PubMedCrossRefGoogle Scholar
  53. 53.
    Rossetti L, Massillon D, Barzilai N, Vuguin P, Chen W, Hawkins M, et al. Short term effects of leptin on hepatic gluconeogenesis and in vivo insulin action. J Biol Chem. 1997;272:27758–63.PubMedCrossRefGoogle Scholar
  54. 54.
    Barzilai N, Wang J, Massilon D, Vuguin P, Hawkins M, Rossetti L. Leptin selectively decreases visceral adiposity and enhances insulin action. J Clin Invest. 1997;100:3105–10.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Muoio DM, Dohm GL, Fiedorek Jr FT, Tapscott EB, Coleman RA, Dohn GL. Leptin directly alters lipid partitioning in skeletal muscle. Diabetes. 1997;46:1360–3.PubMedCrossRefGoogle Scholar
  56. 56.
    Muoio DM, Dohm GL, Tapscott EB, Coleman RA. Leptin opposes insulin’s effects on fatty acid partitioning in muscles isolated from obese ob/ob mice. Am J Physiol. 1999;276:E913–21.PubMedGoogle Scholar
  57. 57.
    Minokoshi Y, Kim YB, Peroni OD, Fryer LG, Muller C, Carling D, et al. Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase. Nature. 2002;415:339–43.PubMedCrossRefGoogle Scholar
  58. 58.
    Grill HJ, Schwartz MW, Kaplan JM, Foxhall JS, Breininger J, Baskin DG. Evidence that the caudal brainstem is a target for the inhibitory effect of leptin on food intake. Endocrinology. 2002;143:239–46.PubMedCrossRefGoogle Scholar
  59. 59.
    Obici S, Feng Z, Tan J, Liu L, Karkanias G. Central melanocortin receptors regulate insulin action. Commentary. 2001;108(7):963–4.Google Scholar
  60. 60.
    Barzilai N, She L, Liu L, Wang J, Hu M, Vuguin P, et al. Decreased visceral adiposity accounts for leptin effect on hepatic but not peripheral insulin action. Am J Physiol. 1999;277:E291–8.PubMedGoogle Scholar
  61. 61.
    Balthasar N, Coppari R, McMinn J, Liu SM, Lee CE, Tang V, et al. Leptin receptor signaling in POMC neurons is required for normal body weight homeostasis. Neuron. 2004;42:983–91.PubMedCrossRefGoogle Scholar
  62. 62.
    Haynes WG, Morgan DA, Djalali A, Sivitz WI, Mark AL. Interactions between the melanocortin system and leptin in control of sympathetic nerve traffic. Hypertension. 1999;33:542–7.PubMedCrossRefGoogle Scholar
  63. 63.
    Gutierrez-Juarez R, Obici S, Rossetti L. Melanocortin-independent effects of leptin on hepatic glucose fluxes. J Biol Chem. 2004;279:49704–15.PubMedCrossRefGoogle Scholar
  64. 64.
    Chhabra KH, Adams JM, Fagel B, Lam DD, Qi N, Rubinstein M, et al. Hypothalamic POMC deficiency improves glucose tolerance despite insulin resistance by increasing glycosuria. Diabetes. 2016;65(3):660–72. Available from:
  65. 65.
    Berglund ED, Liu T, Kong X, Sohn J-W, Vong L, Deng Z, et al. Melanocortin 4 receptors in autonomic neurons regulate thermogenesis and glycemia. Nat Neurosci. 2014;7(7):911–3. Available from:
  66. 66.
    Chinookoswong N, Wang JL, Shi ZQ. Leptin restores euglycemia and normalizes glucose turnover in insulin-deficient diabetes in the rat. Diabetes. 1999;48:1487–92.PubMedCrossRefGoogle Scholar
  67. 67.
    Yu X, Park BH, Wang MY, Wang ZV, Unger RH. Making insulin-deficient type 1 diabetic rodents thrive without insulin. Proc Natl Acad Sci U S A. 2008;105(37):14070–5.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    German JP, Thaler JP, Wisse BE, Oh-I S, Sarruf DA, Matsen ME, et al. Leptin activates a novel CNS mechanism for insulin-independent normalization of severe diabetic hyperglycemia. Endocrinology. 2011;152(2):394–404. Available from:
  69. 69.
    Niswender KD, Morton GJ, Stearns WH, Rhodes CJ, Myers Jr MG, Schwartz MW. Intracellular signalling. Key enzyme in leptin-induced anorexia. Nature. 2001;413:794–5.PubMedCrossRefGoogle Scholar
  70. 70.
    Niswender KD, Morrison CD, Clegg DJ, Olson R, Baskin DG, Myers Jr MG, et al. Insulin activation of phosphatidylinositol 3-kinase in the hypothalamic arcuate nucleus: a key mediator of insulin-induced anorexia. Diabetes. 2003;52:227–31.PubMedCrossRefGoogle Scholar
  71. 71.
    Menendez JA, Mcgregor IS, Healey PA, Atrens DM, Leibowitz SF. Metabolic effects of neuropeptide-y injections into the paraventricular nucleus of the hypothalamus. Brain Res. 1990;516(1):8–14.PubMedCrossRefGoogle Scholar
  72. 72.
    Billington CJ, Briggs JE, Grace M, Levine AS. Effects of intracerebroventricular injection of neuropeptide-y on energy-metabolism. Am J Physiol. 1991;260(2):R321–7.PubMedGoogle Scholar
  73. 73.
    Marks JL, Waite K. Intracerebroventricular neuropeptide Y acutely influences glucose metabolism and insulin sensitivity in the rat. J Neuro endocr. 1997;9:99–103.Google Scholar
  74. 74.
    van den Hoek AM, van Heijningen C, der Elst JPSV, Ouwens DM, Havekes LM, Romijn JA, et al. Intracerebroventricular administration of neuropeptide Y induces hepatic insulin resistance via sympathetic innervation. Diabetes. 2008;57(9):2304–10.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Baskin DG, Figlewicz LD, Seeley RJ, Woods SC, Porte Jr D, Schwartz MW. Insulin and leptin: dual adiposity signals to the brain for the regulation of food intake and body weight. Brain Res. 1999;848:114–23.PubMedCrossRefGoogle Scholar
  76. 76.
    Obici S, Feng Z, Morgan K, Stein D, Karkanias G, Rossetti L. Central administration of oleic acid inhibits glucose production and food intake. Diabetes. 2002;51:271–5.PubMedCrossRefGoogle Scholar
  77. 77.
    Levin BE, Dunn-Meynell AA, Routh VH. Brain glucose sensing and body energy homeostasis: role in obesity and diabetes. Am J Physiol. 1999;276:R1223–31.PubMedGoogle Scholar
  78. 78.
    Miller JC, Gnaedinger JM, Rapaport SI. Utilization of plasma fatty acids in rat brain: distribution of 14C-Palmitate between oxidative and synthetic pathways. J Neuro chem. 1987;49:1507–14.Google Scholar
  79. 79.
    Loftus TM, Jaworsky DE, Frehywot GL, Townsend CA, Ronnett GV, Lane MD, et al. Reduced food intake and body weight in mice treated with fatty acid synthase inhibitors. Science. 2000;288:2379–81.PubMedCrossRefGoogle Scholar
  80. 80.
    McGarry JD, Mannaerts GP, Foster DW. A possible role for malonyl-CoA in the regulation of hepatic fatty acid oxidation and ketogenesis. J Clin Invest. 1977;60:265–70.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    McGarry JD, Takabayashi Y, Foster DW. The role of malonyl-coa in the coordination of fatty acid synthesis and oxidation in isolated rat hepatocytes. J Biol Chem. 1978;253:8294–300.PubMedGoogle Scholar
  82. 82.
    Obici S, Rossetti L. Minireview: nutrient sensing and the regulation of insulin action and energy balance. Endocrinology. 2003;144:5172–8. Available from:
  83. 83.
    Hu Z, Dai Y, Prentki M, Chohnan S, Lane MD. A role for hypothalamic malonyl-CoA in the control of food intake. J Biol Chem. 2005;280:39681–3.PubMedCrossRefGoogle Scholar
  84. 84.
    He W, Lam TKT, Obici S, Rossetti L. Molecular disruption of hypothalamic nutrient sensing induces obesity. Nat Neurosci. 2006;9(2):227–33. Available from:
  85. 85.
    Obici S, Feng Z, Arduini A, Conti R, Rossetti L. Inhibition of hypothalamic carnitine palmitoyltransferase-1 decreases food intake and glucose production. Nat Med. 2003;9:756–61.PubMedCrossRefGoogle Scholar
  86. 86.
    Wolfgang MJ, Lane MD. The role of hypothalamic malonyl-CoA in energy homeostasis. J Biol Chem. 2006;281:37265–9.PubMedCrossRefGoogle Scholar
  87. 87.
    Lam TK, van de Werve G, Giacca A. Free fatty acids increase basal hepatic glucose production and induce hepatic insulin resistance at different sites. Am J Physiol Endocrinol Metab. 2003;284:E281–90.PubMedCrossRefGoogle Scholar
  88. 88.
    Lam TK, Carpentier A, Lewis GF, van de Werve G, Fantus IG, Giacca A. Mechanisms of the free fatty acid-induced increase in hepatic glucose production. Am J Physiol Endocrinol Metab. 2003;284:E863–73.PubMedCrossRefGoogle Scholar
  89. 89.
    Lam TK, Pocai A, Gutierrez-Juarez R, Obici S, Bryan J, Aguilar-Bryan L, et al. Hypothalamic sensing of circulating fatty acids is required for glucose homeostasis. Nat Med. 2005;11:320–7.PubMedCrossRefGoogle Scholar
  90. 90.
    Chen X, Iqbal N, Boden G. The effects of free fatty acids on gluconeogenesis and glycogenolysis in normal subjects. J Clin Invest. 1999;103:365–72.PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Mayer J. Glucostatic mechanism of regulation of food intake. N Engl J Med. 1953;249:13–6.PubMedCrossRefGoogle Scholar
  92. 92.
    Lam TK, Gutierrez-Juarez R, Pocai A, Rossetti L. Regulation of blood glucose by hypothalamic pyruvate metabolism. Science. 2005;309:943–7.PubMedCrossRefGoogle Scholar
  93. 93.
    Moore MC, Connolly CC, Cherrington AD. Autoregulation of hepatic glucose production. Eur J Endocrinol. 1998;138:240–8.PubMedCrossRefGoogle Scholar
  94. 94.
    Cota D, Proulx K, Smith KA, Kozma SC, Thomas G, Woods SC, et al. Hypothalamic mTOR signaling regulates food intake. Science. 2006;312:927–30.PubMedCrossRefGoogle Scholar
  95. 95.
    Arrieta-Cruz I, Su Y, Gutiérrez-Juárez R. Suppression of endogenous glucose production by isoleucine and valine and impact of diet composition. Nutrients. 2016;8(2):79. Available from:
  96. 96.
    Su Y, Lam TKT, He W, Pocai A, Bryan J, Aguilar-Bryan L, et al. Hypothalamic leucine metabolism regulates liver glucose production. Diabetes. 2012;61(1):85–93. Available from:
  97. 97.
    Holst JJ, Gromada J. Role of incretin hormones in the regulation of insulin secretion in diabetic and nondiabetic humans. Am J Physiol Metab. 2004;287(2):E199–206.Google Scholar
  98. 98.
    Schirra J, Nicolaus M, Roggel R, Katschinski M, Storr M, Woerle HJ, et al. Endogenous glucagon-like peptide 1 controls endocrine pancreatic secretion and antro-pyloro-duodenal motility in humans. Gut. 2006;55(2):243–51.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Willms B, Werner J, Holst JJ, Orskov C, Creutzfeldt W, Nauck MA. Gastric emptying glucose responses, and insulin secretion after a liquid test meal: effects of exogenous glucagon-like peptide-1 (GLP-1)-(7–36) amide in type 2 (noninsulin-dependent) diabetic patients. J Clin Endocrinol Metab. 1996;81(1):327–32.PubMedGoogle Scholar
  100. 100.
    Zander M, Madsbad S, Madsen JL, Holst JJ. Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and beta-cell function in type 2 diabetes: a parallel-group study. Lancet. 2002;359:824–30.PubMedCrossRefGoogle Scholar
  101. 101.
    Sandoval D. CNS GLP-1 regulation of peripheral glucose homeostasis. Physiol Behav. 2008;94:670–4.PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Knauf C, Cani PD, Perrin C, Iglesias MA, Maury JF, Bernard E, et al. Brain glucagon-like peptide-1 increases insulin secretion and muscle insulin resistance to favor hepatic glycogen storage. J Clin Invest. 2005;115:3554–63.PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Sandoval DA, Bagnol D, Woods SC, D’Alessio DA, Seeley RJ. Arcuate glucagon-like peptide 1 receptors regulate glucose homeostasis but not food intake. Diabetes. 2008;57:2046–54.PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Beenken A, Mohammadi M. The FGF family: biology, pathophysiology and therapy. Nat Rev Drug Discov. 2009;8(3):235–53.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Fu L, John LM, Adams SH, Yu XX, Tomlinson E, Renz M, et al. Fibroblast growth factor 19 increases metabolic rate and reverses dietary and leptin-deficient diabetes. Endocrinology. 2004;145(6):2594–603.PubMedCrossRefGoogle Scholar
  106. 106.
    Morton GJ, Matsen ME, Bracy DP, Meek TH, Nguyen HT, Stefanovski D, et al. FGF19 action in the brain induces insulin-independent glucose lowering. J Clin Invest. 2013;123(11): 4799–808. Available from:
  107. 107.
    Mojiminiyi OA, Abdella NA. Associations of resistin with inflammation and insulin resistance in patients with type 2 diabetes mellitus. Scand J Clin Lab Invest. 2007;67(2):215–25.PubMedCrossRefGoogle Scholar
  108. 108.
    Rangwala SM, Rich AS, Rhoades B, Shapiro JS, Obici S, Rossetti L, et al. Abnormal glucose homeostasis due to chronic hyperresistinemia. Diabetes. 2004;53(8):1937–41.Google Scholar
  109. 109.
    Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, et al. The hormone resistin links obesity to diabetes. Nature. 2001;409:307–12.PubMedCrossRefGoogle Scholar
  110. 110.
    Muse ED, Lam TK, Scherer PE, Rossetti L. Hypothalamic resistin induces hepatic insulin resistance. J Clin Invest. 2007;117:1670–8.PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Singhal NS, Lazar MA, Ahima RS. Central resistin induces hepatic insulin resistance via neuropeptide Y. J Neurosci. 2007;27:12924–32.PubMedCrossRefGoogle Scholar
  112. 112.
    Meguid MM, Fetissov SO, Varma M, Sato T, Zhang L, Laviano A, et al. Hypothalamic dopamine and serotonin in the regulation of food intake. Nutrition. 2000;16:843–57.PubMedCrossRefGoogle Scholar
  113. 113.
    Murzi E, Contreras Q, Teneud L, Valecillos B, Parada MA, De Parada MP, et al. Diabetes decreases limbic extracellular dopamine in rats. Neurosci Lett. 1996;202:141–4.PubMedCrossRefGoogle Scholar
  114. 114.
    Pijl H. Reduced dopaminergic tone in hypothalamic neural circuits: expression of a “thrifty” genotype underlying the metabolic syndrome? Eur J Pharmacol. 2003;480:125–31.PubMedCrossRefGoogle Scholar
  115. 115.
    Nonogaki K, Strack AM, Dallman MF, Tecott LH. Leptin-independent hyperphagia and type 2 diabetes in mice with a mutated serotonin 5-HT2C receptor gene. Nat Med. 1998;4:1152–6.PubMedCrossRefGoogle Scholar
  116. 116.
    Zhou L, Sutton GM, Rochford JJ, Semple RK, Lam DD, Oksanen LJ, et al. Serotonin 2C receptor agonists improve type 2 diabetes via melanocortin-4 receptor signaling pathways. Cell Metab. 2007;6:398–405.PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Ader M, Kim SP, Catalano KJ, Ionut V, Hucking K, Richey JM, et al. Metabolic dysregulation with atypical antipsychotics occurs in the absence of underlying disease: a placebo-controlled study of olanzapine and risperidone in dogs. Diabetes. 2005;54:862–71.PubMedCrossRefGoogle Scholar
  118. 118.
    Houseknecht KL, Robertson AS, Zavadoski W, Gibbs EM, Johnson DE, Rollema H. Acute effects of atypical antipsychotics on whole-body insulin resistance in rats: implications for adverse metabolic effects. Neuropsychopharmacology. 2007;32:289–97.PubMedCrossRefGoogle Scholar
  119. 119.
    Chintoh AF, Mann SW, Lam L, Lam C, Cohn TA, Fletcher PJ, et al. Insulin resistance and decreased glucose-stimulated insulin secretion after acute olanzapine administration. J Clin Psychopharmacol. 2008;28:494–9.PubMedCrossRefGoogle Scholar
  120. 120.
    Martins PJF, Haas M, Obici S. Central nervous system delivery of the antipsychotic olanzapine induces hepatic insulin resistance. Diabetes. 2010; 59: 2418–25. Available from:
  121. 121.
    Rother E, Konner AC, Bruning JC. Neurocircuits integrating hormone and nutrient signaling in control of glucose metabolism. Am J Physiol Endocrinol Metab. 2008;294:E810–6.PubMedCrossRefGoogle Scholar
  122. 122.
    Levin BE, Dunn-Meynell AA, Routh VH. Brain glucosensing and the K(ATP) channel. Nat Neurosci. 2001;4:459–60.PubMedGoogle Scholar
  123. 123.
    Parton LE, Ye CP, Coppari R, Enriori PJ, Choi B, Zhang CY, et al. Glucose sensing by POMC neurons regulates glucose homeostasis and is impaired in obesity. Nature. 2007;449:228–32.PubMedCrossRefGoogle Scholar
  124. 124.
    Ross R, Wang PY, Chari M, Lam CK, Caspi L, Ono H, et al. Hypothalamic protein kinase C regulates glucose production. Diabetes. 2008;57:2061–5.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Department of Medicine, Division of EndocrinologyUniversity of CincinnatiCincinnatiUSA

Personalised recommendations