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. 1997 Aug 15;100(4):931–941. doi: 10.1172/JCI119609

Regulation of glucose homeostasis in humans with denervated livers.

G Perseghin 1, E Regalia 1, A Battezzati 1, S Vergani 1, A Pulvirenti 1, I Terruzzi 1, D Baratti 1, F Bozzetti 1, V Mazzaferro 1, L Luzi 1
PMCID: PMC508266  PMID: 9259593

Abstract

The liver plays a major role in regulating glucose metabolism, and since its function is influenced by sympathetic/ parasympathetic innervation, we used liver graft as a model of denervation to study the role of CNS in modulating hepatic glucose metabolism in humans. 22 liver transplant subjects were randomly studied by means of the hyperglycemic/ hyperinsulinemic (study 1), hyperglycemic/isoinsulinemic (study 2), euglycemic/hyperinsulinemic (study 3) as well as insulin-induced hypoglycemic (study 4) clamp, combined with bolus-continuous infusion of [3-3H]glucose and indirect calorimetry to determine the effect of different glycemic/insulinemic levels on endogenous glucose production and on peripheral glucose uptake. In addition, postabsorptive glucose homeostasis was cross-sectionally related to the transplant age (range = 40 d-35 mo) in 4 subgroups of patients 2, 6, 15, and 28 mo after transplantation. 22 subjects with chronic uveitis (CU) undergoing a similar immunosuppressive therapy and 35 normal healthy subjects served as controls. The results showed that successful transplantation was associated with fasting glucose concentration and endogenous glucose production in the lower physiological range within a few weeks after transplantation, and this pattern was maintained throughout the 28-mo follow-up period. Fasting glucose (4. 55+/-0.06 vs. 4.75+/-0.06 mM; P = 0.038) and endogenous glucose production (11.3+/-0.4 vs. 12.9+/-0.5 micromol/[kg.min]; P = 0.029) were lower when compared to CU and normal patients. At different combinations of glycemic/insulinemic levels, liver transplant (LTx) patients showed a comparable inhibition of endogenous glucose production. In contrast, in hypoglycemia, after a temporary fall endogenous glucose production rose to values comparable to those of the basal condition in CU and normal subjects (83+/-5 and 92+/-5% of basal), but it did not in LTx subjects (66+/-7%; P < 0.05 vs. CU and normal subjects). Fasting insulin and C-peptide levels were increased up to 6 mo after transplantation, indicating insulin resistance partially induced by prednisone. In addition, greater C-peptide but similar insulin levels during the hyperglycemic clamp (study 1) suggested an increased hepatic insulin clearance in LTx as compared to normal subjects. Fasting glucagon concentration was higher 6 mo after transplantation and thereafter. During euglycemia/hyperinsulinemia (study 3), the insulin-induced glucagon suppression detectable in CU and normal subjects was lacking in LTx subjects; furthermore, the counterregulatory response during hypoglycemia was blunted. In summary, liver transplant subjects have normal postabsorptive glucose metabolism, and glucose and insulin challenge elicit normal response at both hepatic and peripheral sites. Nevertheless, (a) minimal alteration of endogenous glucose production, (b) increased concentration of insulin and glucagon, and (c) defective counterregulation during hypoglycemia may reflect an alteration of the liver-CNS-islet circuit which is due to denervation of the transplanted graft.

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Selected References

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  1. Barbara L., Benzi G., Gaiani S., Fusconi F., Zironi G., Siringo S., Rigamonti A., Barbara C., Grigioni W., Mazziotti A. Natural history of small untreated hepatocellular carcinoma in cirrhosis: a multivariate analysis of prognostic factors of tumor growth rate and patient survival. Hepatology. 1992 Jul;16(1):132–137. doi: 10.1002/hep.1840160122. [DOI] [PubMed] [Google Scholar]
  2. Battezzati A., Luzi L., Perseghin G., Bianchi E., Spotti D., Secchi A., Vergani S., Di Carlo V., Pozza G. Persistence of counter-regulatory abnormalities in insulin-dependent diabetes mellitus after pancreas transplantation. Eur J Clin Invest. 1994 Nov;24(11):751–758. doi: 10.1111/j.1365-2362.1994.tb01072.x. [DOI] [PubMed] [Google Scholar]
  3. Benzo C. A. Minireview. The hypothalamus and blood glucose regulation. Life Sci. 1983 May 30;32(22):2509–2515. doi: 10.1016/0024-3205(83)90231-x. [DOI] [PubMed] [Google Scholar]
  4. Boon A. P., Hubscher S. G., Lee J. A., Hines J. E., Burt A. D. Hepatic reinnervation following orthotopic liver transplantation in man. J Pathol. 1992 Jun;167(2):217–222. doi: 10.1002/path.1711670210. [DOI] [PubMed] [Google Scholar]
  5. Carobi C., Magni F. The afferent innervation of the liver: a horseradish peroxidase study in the rat. Neurosci Lett. 1981 May 29;23(3):269–274. doi: 10.1016/0304-3940(81)90009-4. [DOI] [PubMed] [Google Scholar]
  6. Cavallo-Perin P., Cassader M., Bozzo C., Bruno A., Nuccio P., Dall'Omo A. M., Marucci M., Pagano G. Mechanism of insulin resistance in human liver cirrhosis. Evidence of a combined receptor and postreceptor defect. J Clin Invest. 1985 May;75(5):1659–1665. doi: 10.1172/JCI111873. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Chiasson J. L., Liljenquist J. E., Sinclair-Smith B. C., Lacy W. W. Gluconeogenesis from alanine in normal postabsorptive man. Intrahepatic stimulatory effect of glucagon. Diabetes. 1975 Jun;24(6):574–584. doi: 10.2337/diab.24.6.574. [DOI] [PubMed] [Google Scholar]
  8. Cuneo R. C., Hickman P. E., Wallace J. D., Teh B. T., Ward G., Veldhuis J. D., Waters M. J. Altered endogenous growth hormone secretory kinetics and diurnal GH-binding protein profiles in adults with chronic liver disease. Clin Endocrinol (Oxf) 1995 Sep;43(3):265–275. doi: 10.1111/j.1365-2265.1995.tb02031.x. [DOI] [PubMed] [Google Scholar]
  9. DeFronzo R. A., Ferrannini E., Hendler R., Felig P., Wahren J. Regulation of splanchnic and peripheral glucose uptake by insulin and hyperglycemia in man. Diabetes. 1983 Jan;32(1):35–45. doi: 10.2337/diab.32.1.35. [DOI] [PubMed] [Google Scholar]
  10. DeFronzo R. A., Ferrannini E. Regulation of hepatic glucose metabolism in humans. Diabetes Metab Rev. 1987 Apr;3(2):415–459. doi: 10.1002/dmr.5610030204. [DOI] [PubMed] [Google Scholar]
  11. DeFronzo R. A., Tobin J. D., Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol. 1979 Sep;237(3):E214–E223. doi: 10.1152/ajpendo.1979.237.3.E214. [DOI] [PubMed] [Google Scholar]
  12. Donovan C. M., Hamilton-Wessler M., Halter J. B., Bergman R. N. Primacy of liver glucosensors in the sympathetic response to progressive hypoglycemia. Proc Natl Acad Sci U S A. 1994 Mar 29;91(7):2863–2867. doi: 10.1073/pnas.91.7.2863. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Frayn K. N. Calculation of substrate oxidation rates in vivo from gaseous exchange. J Appl Physiol Respir Environ Exerc Physiol. 1983 Aug;55(2):628–634. doi: 10.1152/jappl.1983.55.2.628. [DOI] [PubMed] [Google Scholar]
  14. Groen A. K., Vervoorn R. C., Van der Meer R., Tager J. M. Control of gluconeogenesis in rat liver cells. I. Kinetics of the individual enzymes and the effect of glucagon. J Biol Chem. 1983 Dec 10;258(23):14346–14353. [PubMed] [Google Scholar]
  15. Grunstein H. S., James D. E., Storlien L. H., Smythe G. A., Kraegen E. W. Hyperinsulinemia suppresses glucose utilization in specific brain regions: in vivo studies using the euglycemic clamp in the rat. Endocrinology. 1985 Feb;116(2):604–610. doi: 10.1210/endo-116-2-604. [DOI] [PubMed] [Google Scholar]
  16. Hansen C. P., Boesby S., Kirkegaard P. Glucose homeostasis after orthotopic liver transplantation in the pig. Transplantation. 1991 Mar;51(3):587–589. doi: 10.1097/00007890-199103000-00009. [DOI] [PubMed] [Google Scholar]
  17. Havel P. J., Taborsky G. J., Jr The contribution of the autonomic nervous system to changes of glucagon and insulin secretion during hypoglycemic stress. Endocr Rev. 1989 Aug;10(3):332–350. doi: 10.1210/edrv-10-3-332. [DOI] [PubMed] [Google Scholar]
  18. Iwatsuki S., Starzl T. E., Sheahan D. G., Yokoyama I., Demetris A. J., Todo S., Tzakis A. G., Van Thiel D. H., Carr B., Selby R. Hepatic resection versus transplantation for hepatocellular carcinoma. Ann Surg. 1991 Sep;214(3):221–229. doi: 10.1097/00000658-199109000-00005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Järhult J., Falck B., Ingemansson S., Nobin A. The functional importance of sympathetic nerves to the liver and endocrine pancreas. Ann Surg. 1979 Jan;189(1):96–100. doi: 10.1097/00000658-197901000-00018. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Kjaer M., Jurlander J., Keiding S., Galbo H., Kirkegaard P., Hage E. No reinnervation of hepatic sympathetic nerves after liver transplantation in human subjects. J Hepatol. 1994 Jan;20(1):97–100. doi: 10.1016/s0168-8278(05)80473-8. [DOI] [PubMed] [Google Scholar]
  21. Krentz A. J., Dousset B., Mayer D., McMaster P., Buckels J., Cramb R., Smith J. M., Nattrass M. Metabolic effects of cyclosporin A and FK 506 in liver transplant recipients. Diabetes. 1993 Dec;42(12):1753–1759. doi: 10.2337/diab.42.12.1753. [DOI] [PubMed] [Google Scholar]
  22. Lamarche L., Yamaguchi N., Péronnet F. Hepatic denervation reduces adrenal catecholamine secretion during insulin-induced hypoglycemia. Am J Physiol. 1995 Jan;268(1 Pt 2):R50–R57. doi: 10.1152/ajpregu.1995.268.1.R50. [DOI] [PubMed] [Google Scholar]
  23. Lautt W. W. Afferent and efferent neural roles in liver function. Prog Neurobiol. 1983;21(4):323–348. doi: 10.1016/0301-0082(83)90016-3. [DOI] [PubMed] [Google Scholar]
  24. Lindfeldt J., Ahrén B., Holmin T. Glucose homeostasis after peri-arterial hepatic denervation in partially hepatectomized rats. Res Exp Med (Berl) 1993;193(6):397–405. doi: 10.1007/BF02576248. [DOI] [PubMed] [Google Scholar]
  25. Luzi L., Battezzati A., Perseghin G., Bianchi E., Vergani S., Secchi A., La Rocca E., Staudacher C., Spotti D., Ferrari G. Lack of feedback inhibition of insulin secretion in denervated human pancreas. Diabetes. 1992 Dec;41(12):1632–1639. doi: 10.2337/diab.41.12.1632. [DOI] [PubMed] [Google Scholar]
  26. Luzi L., Perseghin G., Regalia E., Sereni L. P., Battezzati A., Baratti D., Bianchi E., Terruzzi I., Hilden H., Groop L. C. Metabolic effects of liver transplantation in cirrhotic patients. J Clin Invest. 1997 Feb 15;99(4):692–700. doi: 10.1172/JCI119213. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Luzi L., Secchi A., Facchini F., Battezzati A., Staudacher C., Spotti D., Castoldi R., Ferrari G., Di Carlo V., Pozza G. Reduction of insulin resistance by combined kidney-pancreas transplantation in type 1 (insulin-dependent) diabetic patients. Diabetologia. 1990 Sep;33(9):549–556. doi: 10.1007/BF00404143. [DOI] [PubMed] [Google Scholar]
  28. Mazzaferro V., Regalia E., Doci R., Andreola S., Pulvirenti A., Bozzetti F., Montalto F., Ammatuna M., Morabito A., Gennari L. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med. 1996 Mar 14;334(11):693–699. doi: 10.1056/NEJM199603143341104. [DOI] [PubMed] [Google Scholar]
  29. Miller R. E. Pancreatic neuroendocrinology: peripheral neural mechanisms in the regulation of the Islets of Langerhans. Endocr Rev. 1981 Fall;2(4):471–494. doi: 10.1210/edrv-2-4-471. [DOI] [PubMed] [Google Scholar]
  30. Navasa M., Feu F., García-Pagán J. C., Jiménez W., Llach J., Rimola A., Bosch J., Rodés J. Hemodynamic and humoral changes after liver transplantation in patients with cirrhosis. Hepatology. 1993 Mar;17(3):355–360. [PubMed] [Google Scholar]
  31. Nielsen J. H., Mandrup-Poulsen T., Nerup J. Direct effects of cyclosporin A on human pancreatic beta-cells. Diabetes. 1986 Sep;35(9):1049–1052. doi: 10.2337/diab.35.9.1049. [DOI] [PubMed] [Google Scholar]
  32. Niijima A. Visceral afferents and metabolic function. Diabetologia. 1981 Mar;20 (Suppl):325–330. [PubMed] [Google Scholar]
  33. Novin D., VanderWeele D. A., Rezek M. Infusion of 2-deoxy-D-glucose into the hepatic-portal system causes eating: evidence for peripheral glucoreceptors. Science. 1973 Aug 31;181(4102):858–860. doi: 10.1126/science.181.4102.858. [DOI] [PubMed] [Google Scholar]
  34. Okazaki H., Tanaka K., Nagase H., Inoue S. Modulation of insulin secretion by hepatic vagotomy in cirrhotic rats. Physiol Behav. 1993 Mar;53(3):521–525. doi: 10.1016/0031-9384(93)90147-8. [DOI] [PubMed] [Google Scholar]
  35. Pagano G., Cavallo-Perin P., Cassader M., Bruno A., Ozzello A., Masciola P., Dall'omo A. M., Imbimbo B. An in vivo and in vitro study of the mechanism of prednisone-induced insulin resistance in healthy subjects. J Clin Invest. 1983 Nov;72(5):1814–1820. doi: 10.1172/JCI111141. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Petrides A. S., DeFronzo R. A. Glucose metabolism in cirrhosis: a review with some perspectives for the future. Diabetes Metab Rev. 1989 Dec;5(8):691–709. doi: 10.1002/dmr.5610050805. [DOI] [PubMed] [Google Scholar]
  37. RUSSEK M. Participation of hepatic glucoreceptors in the control of intake of food. Nature. 1963 Jan 5;197:79–80. doi: 10.1038/197079b0. [DOI] [PubMed] [Google Scholar]
  38. Ringe B., Pichlmayr R., Wittekind C., Tusch G. Surgical treatment of hepatocellular carcinoma: experience with liver resection and transplantation in 198 patients. World J Surg. 1991 Mar-Apr;15(2):270–285. doi: 10.1007/BF01659064. [DOI] [PubMed] [Google Scholar]
  39. Rizza R. A., Mandarino L. J., Gerich J. E. Dose-response characteristics for effects of insulin on production and utilization of glucose in man. Am J Physiol. 1981 Jun;240(6):E630–E639. doi: 10.1152/ajpendo.1981.240.6.E630. [DOI] [PubMed] [Google Scholar]
  40. Roden M., Perseghin G., Petersen K. F., Hwang J. H., Cline G. W., Gerow K., Rothman D. L., Shulman G. I. The roles of insulin and glucagon in the regulation of hepatic glycogen synthesis and turnover in humans. J Clin Invest. 1996 Feb 1;97(3):642–648. doi: 10.1172/JCI118460. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Rossetti L., Smith D., Shulman G. I., Papachristou D., DeFronzo R. A. Correction of hyperglycemia with phlorizin normalizes tissue sensitivity to insulin in diabetic rats. J Clin Invest. 1987 May;79(5):1510–1515. doi: 10.1172/JCI112981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. STEELE R. Influences of glucose loading and of injected insulin on hepatic glucose output. Ann N Y Acad Sci. 1959 Sep 25;82:420–430. doi: 10.1111/j.1749-6632.1959.tb44923.x. [DOI] [PubMed] [Google Scholar]
  43. Schmitt M. Influences of hepatic portal receptors on hypothalamic feeding and satiety centers. Am J Physiol. 1973 Nov;225(5):1089–1095. doi: 10.1152/ajplegacy.1973.225.5.1089. [DOI] [PubMed] [Google Scholar]
  44. Schwartz M. W., Figlewicz D. P., Baskin D. G., Woods S. C., Porte D., Jr Insulin in the brain: a hormonal regulator of energy balance. Endocr Rev. 1992 Aug;13(3):387–414. doi: 10.1210/edrv-13-3-387. [DOI] [PubMed] [Google Scholar]
  45. Selberg O., Burchert W., vd Hoff J., Meyer G. J., Hundeshagen H., Radoch E., Balks H. J., Müller M. J. Insulin resistance in liver cirrhosis. Positron-emission tomography scan analysis of skeletal muscle glucose metabolism. J Clin Invest. 1993 May;91(5):1897–1902. doi: 10.1172/JCI116407. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Shimazu T. Reciprocal innervation of the liver: its significance in metabolic control. Adv Metab Disord. 1983;10:355–384. doi: 10.1016/b978-0-12-027310-2.50019-0. [DOI] [PubMed] [Google Scholar]
  47. Smith G. P., Gibbs J., Strohmayer A. J., Root A. W., Stokes P. E. Effect of 2-deoxy-D-glucose on insulin response to glucose in intact and adrenalectomized monkeys. Endocrinology. 1973 Mar;92(3):750–754. doi: 10.1210/endo-92-3-750. [DOI] [PubMed] [Google Scholar]
  48. Stevenson R. W., Steiner K. E., Davis M. A., Hendrick G. K., Williams P. E., Lacy W. W., Brown L., Donahue P., Lacy D. B., Cherrington A. D. Similar dose responsiveness of hepatic glycogenolysis and gluconeogenesis to glucagon in vivo. Diabetes. 1987 Mar;36(3):382–389. doi: 10.2337/diab.36.3.382. [DOI] [PubMed] [Google Scholar]
  49. Tanaka K., Inoue S., Saito S., Nagase H., Takamura Y. Hepatic vagal amino acid sensors modulate amino acid induced insulin and glucagon secretion in the rat. J Auton Nerv Syst. 1993 Mar;42(3):225–231. doi: 10.1016/0165-1838(93)90367-4. [DOI] [PubMed] [Google Scholar]
  50. Wada M., Connolly C. C., Tarumi C., Neal D. W., Cherrington A. D. Hepatic denervation does not significantly change the response of the liver to glucagon in conscious dogs. Am J Physiol. 1995 Feb;268(2 Pt 1):E194–E203. doi: 10.1152/ajpendo.1995.268.2.E194. [DOI] [PubMed] [Google Scholar]
  51. Woods S. C., Porte D., Jr Relationship between plasma and cerebrospinal fluid insulin levels of dogs. Am J Physiol. 1977 Oct;233(4):E331–E334. doi: 10.1152/ajpendo.1977.233.4.E331. [DOI] [PubMed] [Google Scholar]

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