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Hypothalamic insulin signaling is required for inhibition of glucose production

Abstract

Circulating insulin inhibits endogenous glucose production. Here we report that bidirectional changes in hypothalamic insulin signaling affect glucose production. The infusion of either insulin or a small-molecule insulin mimetic in the third cerebral ventricle suppressed glucose production independent of circulating levels of insulin and of other glucoregulatory hormones. Conversely, central antagonism of insulin signaling impaired the ability of circulating insulin to inhibit glucose production. Finally, third-cerebral-ventricle administration of inhibitors of ATP-sensitive potassium channels, but not of antagonists of the central melanocortin receptors, also blunted the effect of hyperinsulinemia on glucose production. These results reveal a new site of action of insulin on glucose production and suggest that hypothalamic insulin resistance can contribute to hyperglycemia in type 2 diabetes mellitus.

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Figure 1: Effect of ICV administration of insulin and insulin mimetic on glucose uptake and production.
Figure 2: Antagonism of hypothalamic insulin action in the presence of peripheral hyperinsulinemia.
Figure 3: Effect of ICV administration of insulin antagonists on peripheral and hepatic insulin action.
Figure 4: Effect of hypothalamic KATP channels or melanocortin receptors blockade on peripheral and hepatic insulin action.

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References

  1. Taylor, S.I. Deconstructing type 2 diabetes. Cell 97, 9–12 (1999).

    Article  CAS  PubMed  Google Scholar 

  2. Sindelar, D.K. et al. Basal hepatic glucose production is regulated by the portal vein insulin concentration. Diabetes 47, 523–529 (1998).

    Article  CAS  PubMed  Google Scholar 

  3. Boden, G., Chen, X., Ruiz, J., White, J.V. & Rossetti, L. Mechanisms of fatty acids induced inhibition of glucose uptake. J. Clin. Invest. 93, 438–446 (1994).

    Article  Google Scholar 

  4. Lewis, G.F., Vranic, M., Harley, P. & Giacca, A. Fatty acids mediate the acute extrahepatic effects of insulin on hepatic glucose production in humans. Diabetes 46, 111–119 (1997).

    Article  Google Scholar 

  5. Rebrin, K., Steil, G.M., Getty, L. & Bergman, R.N. Free fatty acid as a link in the regulation of hepatic glucose output by peripheral insulin. Diabetes 44, 1038–1045 (1995).

    Article  CAS  PubMed  Google Scholar 

  6. Rebrin, K., Steil, G.M., Mittelman, S.D. & Bergman, R.N. Causal linkage between insulin suppression of lipolysis and suppression of liver glucose output in dogs. J. Clin. Invest. 98, 741–749 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Sindelar, D.K. et al. The role of fatty acids in mediating the effects of peripheral insulin on hepatic glucose production in the conscious dog. Diabetes 46, 187–196 (1997).

    Article  CAS  PubMed  Google Scholar 

  8. Woods, S.C., Lotter, E.C. & Porte, D. Jr. Chronic intracerebroventricular infusion of insulin reduces food intake and body weight of baboons. Nature 282, 503–505 (1979).

    Article  CAS  PubMed  Google Scholar 

  9. Woods, S.C., Seeley, R.J., Porte, D.J. & Schwartz, M.W. Signals that regulate food intake and energy homeostasis. Science 280, 1378–1383 (1998).

    Article  CAS  PubMed  Google Scholar 

  10. Davies, S.N. et al. Evidence that the brain of the conscious dog is insulin sensitive. J. Clin. Invest. 95, 593–602 (1995).

    Article  Google Scholar 

  11. Williams, P. & Cherrington, A.D. Brain of the conscious dog is sensitive to physiological changes in circulating insulin. Am. J. Physiol. 272, E567–575 (1997).

    PubMed  Google Scholar 

  12. Sipols, A.J., Baskin, D.G. & Schwartz, M.W. Effect of intracerebroventricular insulin infusion on diabetic hyperphagia and hypothalamic neuropeptide gene expression. Diabetes 44, 147–151 (1995).

    Article  CAS  PubMed  Google Scholar 

  13. Richardson, R.D. et al. Weight loss in rats following intraventricular transplant of pancreatic islets. Am. J. Physiol. 266, R59–64 (1994).

    CAS  PubMed  Google Scholar 

  14. Wang, J. & Leibowitz, K.L. Central insulin inhibits hypothalamic galanin and neuropeptide Y gene expression and peptide release in intact rats. Brain Res. 777, 231–236 (1997).

    Article  CAS  PubMed  Google Scholar 

  15. Schwartz, M.W. et al. Inhibition of hypothalamic neuropeptide Y gene expression by insulin. Endocrinology 130, 3608–3616 (1992).

    Article  CAS  PubMed  Google Scholar 

  16. Sahu, A. et al. 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 136, 5718–5724 (1995).

    Article  CAS  PubMed  Google Scholar 

  17. Liang, C.S.J. et al. Insulin infusion in conscious dogs: Effects on systemic and coronary hemodynamics, regional blood flows, and plasma catecholamines. J. Clin. Invest. 69, 1321–1336 (1982).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Rowe, J.W., Young, J.B. & Minaker, K.L. Effect of insulin and glucose infusions on sympathetic nervous system activity in normal men. Diabetes 30, 219–225 (1981).

    Article  CAS  PubMed  Google Scholar 

  19. Schwartz, M.W., Figlewicz, D.P., Baskin, D.G., Woods, S.C. & Porte, D.J. Insulin in the brain: A hormonal regulator of energy balance. Endocr. Rev. 13, 387–414 (1992).

    CAS  PubMed  Google Scholar 

  20. Air, E.L. et al. Small molecule insulin mimetics reduce food intake and body weight and prevent development of obesity. Nature Med. 8, 179–183 (2002).

    Article  CAS  PubMed  Google Scholar 

  21. McGowan, M.K., Andrews, K.M. & Grossman, S.P. Chronic intrahypothalamic infusions of insulin or insulin antibodies alter body weight and food intake in the rat. Physiol. Behav. 51, 753–766 (1992).

    Article  CAS  PubMed  Google Scholar 

  22. Bruning, J.C. et al. Role of brain insulin receptor in control of body weight and reproduction. Science 289, 2122–2125 (2000).

    Article  CAS  PubMed  Google Scholar 

  23. Obici, S., Feng, Z., Karkanias, G., Baskin, D.G. & Rossetti, L. Selective attenuation of hypothalamic insulin receptor expression induces hyperphagia and insulin resistance. Nature Neurosci. 5, 566–572 (2002).

    Article  CAS  PubMed  Google Scholar 

  24. Liu, L. et al. Intracerebroventricular leptin regulates hepatic but not peripheral glucose fluxes. J. Biol. Chem. 273, 31160–31167 (1998).

    Article  CAS  PubMed  Google Scholar 

  25. Obici, S. et al. Central melanocortin receptors regulate insulin action. J. Clin. Invest. 108, 1079–1085 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Zhang, B.G. et al. Discovery of a small molecule insulin mimetic with antidiabetic activity in mice. Science 284, 974–977 (1999).

    Article  CAS  PubMed  Google Scholar 

  27. Rossetti, L., Smith, D., Shulman, G.I., Papachristou, D. & DeFronzo, R.A. Corection of hyperglycemia with phlorizin normalizes tissue sensitivity to insulin in diabetic rats. J. Clin. Invest. 79, 1510–1515 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Rossetti, L. & Giaccari, A. Relative contribution of glycogen synthesis and glycolysis to insulin-mediated glucose uptake. A dose-response euglycemic clamp study in normal and diabetic rats. J. Clin. Invest. 85, 1785–1792 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Spanswick, D., Smith, M.A., Mirshamsi, S., Routh, V.H. & Ashford, M.L.J. Insulin activates ATP-sensitive K+ channels in hypothalamic neurons of lean, but not obese rats. Nature Neurosci. 3, 757–762 (2000).

    Article  CAS  PubMed  Google Scholar 

  30. Spanswick, D., Smith, M.A., Groppi, V.E., Logan, S.D. & Ashford, M.L.J. Leptin inhibits hypothalamic neurons by activation of ATP-sensitive potassium channels. Nature 390, 521–525 (1997).

    Article  CAS  PubMed  Google Scholar 

  31. Harvey, J. et al. Essential role of phosphoinositide 3-kinase in leptin-induced KATP channel activation in the rat CRI-G1 insulinoma cell line. J. Biol. Chem. 275, 4660–4669 (2000).

    Article  CAS  PubMed  Google Scholar 

  32. Miki, T. et al. ATP-sensitive K+ channels in the hypothalamus are essential for the maintenance of glucose homeostasis. Nature Neurosci. 4, 507–512 (2001).

    Article  CAS  PubMed  Google Scholar 

  33. Obici, S., Feng, Z., Morgan, K., Stein, D., Karkanias, G. & Rossetti, L. Central administration of oleic acid inhibits glucose production and food intake. Diabetes 51, 271–275 (2002).

    Article  CAS  PubMed  Google Scholar 

  34. Unger, J.W. & Betz, M. Insulin receptors and signal transduction proteins in the hypothalamo-hypophyseal system: A review on morphological findings and functional implications. Histol. Histopathol. 13, 1215–1224 (1998).

    CAS  PubMed  Google Scholar 

  35. Marks, J.L., Porte, D.J., Stahl, W.L. & Baskin, D.J. Localization of insulin receptor mRNA in rat brain by in situ hybridization. Endocrinology 127, 3234–3236 (1990).

    Article  CAS  PubMed  Google Scholar 

  36. Baskin, D.G., Sipols, A.J., Schwartz, M.W. & White, M.F. Immunocytochemical detection of insulin receptor substrate-1 (IRS-1) in rat brain: Colocalization with phosphotyrosine. Regul. Pep. 48, 257–266 (1993).

    Article  CAS  Google Scholar 

  37. Numan, S. & Russell, D.S. Discrete expression of insulin receptor substrate-4 mRNA in adult rat brain. Brain Res. 72, 97–102 (1999).

    CAS  Google Scholar 

  38. Hopkins, D.F. & Williams, G. Insulin receptors are widely distributed in human brain and bind human and porcine insulin with equal affinity. Diabet. Med. 14, 1044–1050 (1997).

    Article  CAS  PubMed  Google Scholar 

  39. Gerozissis, K., Rouch, C., Nicolaidis, S. & Orosco, M. Brain insulin response to feeding in the rat is both macronutrient and area specific. Physiol. Behav. 66, 271–275 (1999).

    Article  CAS  PubMed  Google Scholar 

  40. Fan, W., Boston, B.A., Kesterson, R.A., Hruby, V.J. & Cone, R.D. Role of melanocortinergic neurons in feeding and the agouti obesity syndrome. Nature 385, 165–168 (1997).

    Article  CAS  PubMed  Google Scholar 

  41. Seeley, R.J. et al. Melanocortin receptors in leptin effects. Nature 385, 390–349 (1997).

    Article  Google Scholar 

  42. Palkovits, M. Isolated removal of hypothalamic or other brain nuclei of the rat. Brain Res. 59, 449–450 (1973).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by grants from the National Institutes of Health (to L.R., DK 48321 and DK 45024) and the AECOM Diabetes Research & Training Center (DK 20541). S.O. was the recipient of a post-doctoral fellowship and a Junior Faculty Award from the American Diabetes Association.

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Correspondence to Luciano Rossetti.

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B.B.Z. is employed by the Merck Research Laboratories, and Cpd1 was originally reported by their group. L.R. has a consultation agreement (in unrelated areas) with Merck Research Laboratories.

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Obici, S., Zhang, B., Karkanias, G. et al. Hypothalamic insulin signaling is required for inhibition of glucose production. Nat Med 8, 1376–1382 (2002). https://doi.org/10.1038/nm1202-798

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