Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1998 Oct 1;102(7):1403–1412. doi: 10.1172/JCI3030

Central nervous system nitric oxide synthase activity regulates insulin secretion and insulin action.

R Shankar 1, J S Zhu 1, B Ladd 1, D Henry 1, H Q Shen 1, A D Baron 1
PMCID: PMC508988  PMID: 9769333

Abstract

Systemic inhibition of nitric oxide synthase (NOS) with NG-monomethyl-L-arginine (L-NMMA) causes acute insulin resistance (IR), but the mechanism is unknown. We tested whether L-NMMA-induced IR occurs via NOS blockade in the central nervous system (CNS). Six groups of Sprague-Dawley rats were studied after chronic implantation of an intracerebroventricular (ICV) catheter into the lateral ventricle and catheters into the carotid artery and jugular vein. Animals were studied after overnight food deprivation, awake, unrestrained, and unstressed; all ICV infusion of L-NMMA or D-NMMA (control) were performed with artificial cerebrospinal fluid. ICV administration of L-NMMA resulted in a 30% rise in the basal glucose level after 2 h, while ICV D-NMMA had no effect on glucose levels. Insulin, epinephrine, and norepinephrine levels were unchanged from baseline in both groups. Tracer (3H-3-glucose)-determined glucose disposal rates during 2 h euglycemic hyperinsulinemic (300 microU/ml) clamps performed after ICV administration of L-NMMA were reduced by 22% compared with D-NMMA. Insulin secretory responses to a hyperglycemic clamp and to a superimposed arginine bolus were reduced by 28% in L-NMMA-infused rats compared with D-NMMA. In conclusion, ICV administration of L-NMMA causes hyperglycemia via the induction of defects in insulin secretion and insulin action, thus recapitulating abnormalities observed in type 2 diabetes. The data suggest the novel concept that central NOS-dependent pathways may control peripheral insulin action and secretion. This control is not likely to be mediated via adrenergic mechanisms and could occur via nonadrenergic, noncholinergic nitrergic neural and/or endocrine pathways. These data support previously published data suggesting that CNS mechanisms may be involved in the pathogenesis of some forms of insulin resistance and type 2 diabetes independent of adiposity.

Full Text

The Full Text of this article is available as a PDF (215.3 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Ahrén B., Taborsky G. J., Jr, Porte D., Jr Neuropeptidergic versus cholinergic and adrenergic regulation of islet hormone secretion. Diabetologia. 1986 Dec;29(12):827–836. doi: 10.1007/BF00870137. [DOI] [PubMed] [Google Scholar]
  2. Barbetti F. Pathophysiology of non-insulin-dependent diabetes and the search for candidate genes: dangerous liaisons? Acta Diabetol. 1996 Dec;33(4):257–262. [PubMed] [Google Scholar]
  3. Baron A. D., Brechtel G., Johnson A., Fineberg N., Henry D. P., Steinberg H. O. Interactions between insulin and norepinephrine on blood pressure and insulin sensitivity. Studies in lean and obese men. J Clin Invest. 1994 Jun;93(6):2453–2462. doi: 10.1172/JCI117254. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Baron A. D., Zhu J. S., Marshall S., Irsula O., Brechtel G., Keech C. Insulin resistance after hypertension induced by the nitric oxide synthesis inhibitor L-NMMA in rats. Am J Physiol. 1995 Oct;269(4 Pt 1):E709–E715. doi: 10.1152/ajpendo.1995.269.4.E709. [DOI] [PubMed] [Google Scholar]
  5. 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 Dec;96(6):2792–2801. doi: 10.1172/JCI118349. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Beard J. C., Weinberg C., Pfeifer M. A., Best J. D., Halter J. B., Porte D., Jr Modulation of arginine-induced glucagon release by epinephrine and glucose levels in man. J Clin Endocrinol Metab. 1983 Jun;56(6):1271–1277. doi: 10.1210/jcem-56-6-1271. [DOI] [PubMed] [Google Scholar]
  7. Berdeaux A. Nitric oxide: an ubiquitous messenger. Fundam Clin Pharmacol. 1993;7(8):401–411. doi: 10.1111/j.1472-8206.1993.tb01037.x. [DOI] [PubMed] [Google Scholar]
  8. Blasi C., Jeanrenaud B. Insulin resistance syndrome: defective GABA neuromodulation as a possible hereditary pathogenetic factor (the 'GABA hypothesis'). Med Hypotheses. 1993 Apr;40(4):197–206. doi: 10.1016/0306-9877(93)90041-n. [DOI] [PubMed] [Google Scholar]
  9. Boren D. R., Henry D. P., Selkurt E. E., Weinberger M. H. Renal modulation of urinary catecholamine excretion during volume expansion in the dog. Hypertension. 1980 Jul-Aug;2(4):383–389. doi: 10.1161/01.hyp.2.4.383. [DOI] [PubMed] [Google Scholar]
  10. Buchanan T. A., Sipos G. F., Madrilejo N., Liu C., Campese V. M. Hypertension without peripheral insulin resistance in spontaneously hypertensive rats. Am J Physiol. 1992 Jan;262(1 Pt 1):E14–E19. doi: 10.1152/ajpendo.1992.262.1.E14. [DOI] [PubMed] [Google Scholar]
  11. Buchanan T. A., Thawani H., Kades W., Modrall J. G., Weaver F. A., Laurel C., Poppiti R., Xiang A., Hsueh W. Angiotensin II increases glucose utilization during acute hyperinsulinemia via a hemodynamic mechanism. J Clin Invest. 1993 Aug;92(2):720–726. doi: 10.1172/JCI116642. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Chen H., Charlat O., Tartaglia L. A., Woolf E. A., Weng X., Ellis S. J., Lakey N. D., Culpepper J., Moore K. J., Breitbart R. E. Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice. Cell. 1996 Feb 9;84(3):491–495. doi: 10.1016/s0092-8674(00)81294-5. [DOI] [PubMed] [Google Scholar]
  13. DeFronzo R. A., Bonadonna R. C., Ferrannini E. Pathogenesis of NIDDM. A balanced overview. Diabetes Care. 1992 Mar;15(3):318–368. doi: 10.2337/diacare.15.3.318. [DOI] [PubMed] [Google Scholar]
  14. DeFronzo R. A. Lilly lecture 1987. The triumvirate: beta-cell, muscle, liver. A collusion responsible for NIDDM. Diabetes. 1988 Jun;37(6):667–687. doi: 10.2337/diab.37.6.667. [DOI] [PubMed] [Google Scholar]
  15. Frontoni S., Ohman L., Haywood J. R., Rossetti L. Increased insulin sensitivity in the high sodium one-kidney, one figure-8 hypertensive rat. Hypertension. 1992 Aug;20(2):192–198. doi: 10.1161/01.hyp.20.2.192. [DOI] [PubMed] [Google Scholar]
  16. Garvey W. T., Revers R. R., Kolterman O. G., Rubenstein A. H., Olefsky J. M. Modulation of insulin secretion by insulin and glucose in type II diabetes mellitus. J Clin Endocrinol Metab. 1985 Mar;60(3):559–568. doi: 10.1210/jcem-60-3-559. [DOI] [PubMed] [Google Scholar]
  17. Gerová M., Masánová C., Pavlásek J. Inhibition of NO synthase in the posterior hypothalamus increases blood pressure in the rat. Physiol Res. 1995;44(2):131–134. [PubMed] [Google Scholar]
  18. Goldstein D. S., Eisenhofer G., Garty M., Folio C. J., Stull R., Brush J. E., Jr, Sax F. L., Keiser H. R., Kopin I. J. Implications of plasma levels of catechols in the evaluation of sympathoadrenomedullary function. Am J Hypertens. 1989 Mar;2(3 Pt 2):133S–139S. doi: 10.1093/ajh/2.3.133s. [DOI] [PubMed] [Google Scholar]
  19. Harada S., Tokunaga S., Momohara M., Masaki H., Tagawa T., Imaizumi T., Takeshita A. Inhibition of nitric oxide formation in the nucleus tractus solitarius increases renal sympathetic nerve activity in rabbits. Circ Res. 1993 Mar;72(3):511–516. doi: 10.1161/01.res.72.3.511. [DOI] [PubMed] [Google Scholar]
  20. Hirai T., Musch T. I., Morgan D. A., Kregel K. C., Claassen D. E., Pickar J. G., Lewis S. J., Kenney M. J. Differential sympathetic nerve responses to nitric oxide synthase inhibition in anesthetized rats. Am J Physiol. 1995 Oct;269(4 Pt 2):R807–R813. doi: 10.1152/ajpregu.1995.269.4.R807. [DOI] [PubMed] [Google Scholar]
  21. Horn T., Smith P. M., McLaughlin B. E., Bauce L., Marks G. S., Pittman Q. J., Ferguson A. V. Nitric oxide actions in paraventricular nucleus: cardiovascular and neurochemical implications. Am J Physiol. 1994 Jan;266(1 Pt 2):R306–R313. doi: 10.1152/ajpregu.1994.266.1.R306. [DOI] [PubMed] [Google Scholar]
  22. Huang P. L., Dawson T. M., Bredt D. S., Snyder S. H., Fishman M. C. Targeted disruption of the neuronal nitric oxide synthase gene. Cell. 1993 Dec 31;75(7):1273–1286. doi: 10.1016/0092-8674(93)90615-w. [DOI] [PubMed] [Google Scholar]
  23. Huang P. L., Huang Z., Mashimo H., Bloch K. D., Moskowitz M. A., Bevan J. A., Fishman M. C. Hypertension in mice lacking the gene for endothelial nitric oxide synthase. Nature. 1995 Sep 21;377(6546):239–242. doi: 10.1038/377239a0. [DOI] [PubMed] [Google Scholar]
  24. Ignarro L. J. Nitric oxide. A novel signal transduction mechanism for transcellular communication. Hypertension. 1990 Nov;16(5):477–483. doi: 10.1161/01.hyp.16.5.477. [DOI] [PubMed] [Google Scholar]
  25. Jeanrenaud B. Central nervous system and peripheral abnormalities: clues to the understanding of obesity and NIDDM. Diabetologia. 1994 Sep;37 (Suppl 2):S170–S178. [PubMed] [Google Scholar]
  26. Kahn C. R., Vicent D., Doria A. Genetics of non-insulin-dependent (type-II) diabetes mellitus. Annu Rev Med. 1996;47:509–531. doi: 10.1146/annurev.med.47.1.509. [DOI] [PubMed] [Google Scholar]
  27. Kamohara S., Burcelin R., Halaas J. L., Friedman J. M., Charron M. J. Acute stimulation of glucose metabolism in mice by leptin treatment. Nature. 1997 Sep 25;389(6649):374–377. doi: 10.1038/38717. [DOI] [PubMed] [Google Scholar]
  28. Kolterman O. G., Gray R. S., Griffin J., Burstein P., Insel J., Scarlett J. A., Olefsky J. M. Receptor and postreceptor defects contribute to the insulin resistance in noninsulin-dependent diabetes mellitus. J Clin Invest. 1981 Oct;68(4):957–969. doi: 10.1172/JCI110350. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Kolterman O. G., Gray R. S., Shapiro G., Scarlett J. A., Griffin J., Olefsky J. M. The acute and chronic effects of sulfonylurea therapy in type II diabetic subjects. Diabetes. 1984 Apr;33(4):346–354. doi: 10.2337/diab.33.4.346. [DOI] [PubMed] [Google Scholar]
  30. Krowicki Z. K., Sharkey K. A., Serron S. C., Nathan N. A., Hornby P. J. Distribution of nitric oxide synthase in rat dorsal vagal complex and effects of microinjection of nitric oxide compounds upon gastric motor function. J Comp Neurol. 1997 Jan 6;377(1):49–69. doi: 10.1002/(sici)1096-9861(19970106)377:1<49::aid-cne6>3.0.co;2-j. [DOI] [PubMed] [Google Scholar]
  31. Leahy J. L. Natural history of beta-cell dysfunction in NIDDM. Diabetes Care. 1990 Sep;13(9):992–1010. doi: 10.2337/diacare.13.9.992. [DOI] [PubMed] [Google Scholar]
  32. Lee G. H., Proenca R., Montez J. M., Carroll K. M., Darvishzadeh J. G., Lee J. I., Friedman J. M. Abnormal splicing of the leptin receptor in diabetic mice. Nature. 1996 Feb 15;379(6566):632–635. doi: 10.1038/379632a0. [DOI] [PubMed] [Google Scholar]
  33. Mancia G., Grassi G. Assessment of sympathetic cardiovascular influences in man: haemodynamic and humoral markers versus microneurography. Clin Auton Res. 1991 Sep;1(3):245–249. doi: 10.1007/BF01824995. [DOI] [PubMed] [Google Scholar]
  34. Moller D. E., Bjørbaek C., Vidal-Puig A. Candidate genes for insulin resistance. Diabetes Care. 1996 Apr;19(4):396–400. doi: 10.2337/diacare.19.4.396. [DOI] [PubMed] [Google Scholar]
  35. Moncada S., Palmer R. M., Higgs E. A. Biosynthesis of nitric oxide from L-arginine. A pathway for the regulation of cell function and communication. Biochem Pharmacol. 1989 Jun 1;38(11):1709–1715. doi: 10.1016/0006-2952(89)90403-6. [DOI] [PubMed] [Google Scholar]
  36. Nurminen M. L., Ylikorkala A., Vapaatalo H. Central inhibition of nitric oxide synthesis increases blood pressure and heart rate in anesthetized rats. Methods Find Exp Clin Pharmacol. 1997 Jan-Feb;19(1):35–41. [PubMed] [Google Scholar]
  37. Phillips M. S., Liu Q., Hammond H. A., Dugan V., Hey P. J., Caskey C. J., Hess J. F. Leptin receptor missense mutation in the fatty Zucker rat. Nat Genet. 1996 May;13(1):18–19. doi: 10.1038/ng0596-18. [DOI] [PubMed] [Google Scholar]
  38. Polonsky K. S., Sturis J., Bell G. I. Seminars in Medicine of the Beth Israel Hospital, Boston. Non-insulin-dependent diabetes mellitus - a genetically programmed failure of the beta cell to compensate for insulin resistance. N Engl J Med. 1996 Mar 21;334(12):777–783. doi: 10.1056/NEJM199603213341207. [DOI] [PubMed] [Google Scholar]
  39. Porte D., Jr, Robertson R. P. Control of insulin secretion by catecholamines, stress, and the sympathetic nervous system. Fed Proc. 1973 Jul;32(7):1792–1796. [PubMed] [Google Scholar]
  40. Possas O. S., Lewis S. J. NO-containing factors mediate hindlimb vasodilation produced by superior laryngeal nerve stimulation. Am J Physiol. 1997 Jul;273(1 Pt 2):H234–H243. doi: 10.1152/ajpheart.1997.273.1.H234. [DOI] [PubMed] [Google Scholar]
  41. Reaven G. M. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes. 1988 Dec;37(12):1595–1607. doi: 10.2337/diab.37.12.1595. [DOI] [PubMed] [Google Scholar]
  42. Revers R. R., Fink R., Griffin J., Olefsky J. M., Kolterman O. G. Influence of hyperglycemia on insulin's in vivo effects in type II diabetes. J Clin Invest. 1984 Mar;73(3):664–672. doi: 10.1172/JCI111258. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Rich S. S. Mapping genes in diabetes. Genetic epidemiological perspective. Diabetes. 1990 Nov;39(11):1315–1319. doi: 10.2337/diab.39.11.1315. [DOI] [PubMed] [Google Scholar]
  44. Robertson R. P. Defective insulin secretion in NIDDM: integral part of a multiplier hypothesis. J Cell Biochem. 1992 Mar;48(3):227–233. doi: 10.1002/jcb.240480302. [DOI] [PubMed] [Google Scholar]
  45. Shapoval L. N., Sagach V. F., Pobegailo L. S. Nitric oxide influences ventrolateral medullary mechanisms of vasomotor control in the cat. Neurosci Lett. 1991 Oct 28;132(1):47–50. doi: 10.1016/0304-3940(91)90430-2. [DOI] [PubMed] [Google Scholar]
  46. Sivitz W. I., Walsh S. A., Morgan D. A., Thomas M. J., Haynes W. G. Effects of leptin on insulin sensitivity in normal rats. Endocrinology. 1997 Aug;138(8):3395–3401. doi: 10.1210/endo.138.8.5327. [DOI] [PubMed] [Google Scholar]
  47. Smith D., Rossetti L., Ferrannini E., Johnson C. M., Cobelli C., Toffolo G., Katz L. D., DeFronzo R. A. In vivo glucose metabolism in the awake rat: tracer and insulin clamp studies. Metabolism. 1987 Dec;36(12):1167–1174. doi: 10.1016/0026-0495(87)90244-7. [DOI] [PubMed] [Google Scholar]
  48. Takaya K., Ogawa Y., Isse N., Okazaki T., Satoh N., Masuzaki H., Mori K., Tamura N., Hosoda K., Nakao K. Molecular cloning of rat leptin receptor isoform complementary DNAs--identification of a missense mutation in Zucker fatty (fa/fa) rats. Biochem Biophys Res Commun. 1996 Aug 5;225(1):75–83. doi: 10.1006/bbrc.1996.1133. [DOI] [PubMed] [Google Scholar]
  49. Thomas J., Fouad F. M., Tarazi R. C., Bravo E. L. Evaluation of plasma catecholamines in humans. Correlation of resting levels with cardiac responses to beta-blocking and sympatholytic drugs. Hypertension. 1983 Nov-Dec;5(6):858–863. doi: 10.1161/01.hyp.5.6.858. [DOI] [PubMed] [Google Scholar]
  50. Uemura K., Tamagawa T., Chen Y., Maeda N., Yoshioka S., Itoh K., Miura H., Iguchi A., Hotta N. NG-methyl-L-arginine, an inhibitor of nitric oxide synthase, affects the central nervous system to produce peripheral hyperglycemia in conscious rats. Neuroendocrinology. 1997 Aug;66(2):136–144. doi: 10.1159/000127231. [DOI] [PubMed] [Google Scholar]
  51. Vettor R., Cusin I., Ganten D., Rohner-Jeanrenaud F., Ferrannini E., Jeanrenaud B. Insulin resistance and hypertension: studies in transgenic hypertensive TGR(mREN-2)27 rats. Am J Physiol. 1994 Dec;267(6 Pt 2):R1503–R1509. doi: 10.1152/ajpregu.1994.267.6.R1503. [DOI] [PubMed] [Google Scholar]
  52. Woods S. C., Porte D., Jr Neural control of the endocrine pancreas. Physiol Rev. 1974 Jul;54(3):596–619. doi: 10.1152/physrev.1974.54.3.596. [DOI] [PubMed] [Google Scholar]
  53. Wörl J., Wiesand M., Mayer B., Greskötter K. R., Neuhuber W. L. Neuronal and endothelial nitric oxide synthase immunoreactivity and NADPH-diaphorase staining in rat and human pancreas: influence of fixation. Histochemistry. 1994 Nov;102(5):353–364. doi: 10.1007/BF00268906. [DOI] [PubMed] [Google Scholar]
  54. Yki-Järvinen H. Pathogenesis of non-insulin-dependent diabetes mellitus. Lancet. 1994 Jan 8;343(8889):91–95. doi: 10.1016/s0140-6736(94)90821-4. [DOI] [PubMed] [Google Scholar]
  55. 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 Dec 1;372(6505):425–432. doi: 10.1038/372425a0. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES