Integrated Roles of Glucoregulatory Hormones during Postprandial, Postabsorptive, and Stress States of Metabolism: A Review
This review describes the roles of the regulatory and counter-regulatory hormones that are involved in the physiological regulation of blood glucose. Dysfunction in the regulatory processes of blood glucose underlies the fundamental pathology seen in both type 1 and type 2 diabetes mellitus, the major cause of heart disease and stroke in the world and an estimated total medical cost of $245 billion annually. Previous studies that have reviewed the physiology of glucose homeostasis have not detailed the interplay between the regulatory hormones and their roles in stimulating or inhibiting the key metabolic enzymes during the various stages of metabolism, including the prandial, post-absorptive, prolonged fasting, and stress states. In addition, previous studies have not described the roles of additional hormones that are recently understood to be essential to blood glucose regulation, including the hormones amylin and irisin. This review describes the sequelae of hormonal changes, their enzymatic regulation, and subsequent metabolic changes that function to either increase or decrease blood glucose levels to ultimately restore euglycemia during these various stages of metabolism. Moreover, many of the hormones detailed in this review, as well as the metabolic enzymes and processes they regulate, are emerging targets for pharmaceutical intervention in patients with both type 1 and type 2 diabetes mellitus. In order to further the understanding of the pathophysiology underlying diabetes mellitus as well as potential future targets for pharmaceutical therapy, the extensive and integrated roles of glucoregulatory hormones that dominate the postprandial, post-absorptive, and stress states of metabolism are examined.
Cryer PE. Glucose counterregulation in man. Diabetes. 1981;30(3):261-264.
Dinneen S, Alzaid A, Turk D, Rizza R. Failure of glucagon suppression contributes to postprandial hyperglycaemia in IDDM. Diabetologia. 1995;38(3):337-343.
Kruger DF, Gatcomb PM, Owen SK. Clinical implications of amylin and amylin deficiency. Diabetes Educ. 1999;25(3):389-97.
Lugari R, Dei Cas A, Ugolotti D, et al. Evidence for early impairment of glucagon-like peptide 1-induced insulin secretion in human type 2 (non insulin-dependent) diabetes. Horm Metab Res. 2002;34(3):150-154.
Centers for Disease Control and Prevention. Diabetes At a Glance 2016. https://www.cdc.gov/chronicdisease/resources/publications/aag/diabetes.htm. Accessed September 26, 2017.
Centers for Disease Control and Prevention. Leading Causes of Death. https://www.cdc.gov/nchs/fastats/leading-causes-of-death.htm. Accessed September 26, 2017.
American Diabetes Association. Economic costs of diabetes in the U.S. in 2012. Diabetes Care. 2013;36(4):1033-1046.
Gerich JE. Physiology of glucose homeostasis. Diabetes Obes Metab. 2000;2(6):345-350.
Kuo T, McQueen A, Chen TC, Wang JC. Regulation of glucose homeostasis by glucocorticoids. Adv Exp Med Biol. 2015;872:99-126.
Roder PV, Wu B, Liu Y, Han W. Pancreatic regulation of glucose homeostasis. Exp Mol Med. 2016;48:e219.
Suh SH, Paik IY, Jacobs K. Regulation of blood glucose homeostasis during prolonged exercise. Mol Cells. 2007;23(3):272-279.
Consoli A, Kennedy F, Miles J, Gerich J. Determination of krebs cycle metabolic carbon exchange in vivo and its use to estimate the individual contributions of gluconeogenesis and glycogenolysis to overall glucose output in man. J Clin Invest. 1987;80(5):1303-1310.
Rizza RA, Gerich JE, Haymond MW, et al. Control of blood sugar in insulin-dependent diabetes: Comparison of an artificial endocrine pancreas, continuous subcutaneous insulin infusion, and intensified conventional insulin therapy. N Engl J Med. 1980;303(23):1313-1318.
Wahren J, Felig P, Hagenfeldt L. Physical exercise and fuel homeostasis in diabetes mellitus. Diabetologia. 1978;14(4):213-222.
Gerich JE. Lilly lecture 1988. glucose counterregulation and its impact on diabetes mellitus. Diabetes. 1988;37(12):1608-1617.
Gerich JE. Control of glycaemia. Baillieres Clin Endocrinol Metab. 1993;7(3):551-586.
Perriello G, Jorde R, Nurjhan N, et al. Estimation of glucose-alanine-lactate-glutamine cycles in postabsorptive humans: Role of skeletal muscle. Am J Physiol. 1995;269(3 Pt 1):E443-50.
Woerle HJ, Meyer C, Dostou JM, et al. Pathways for glucose disposal after meal ingestion in humans. Am J Physiol Endocrinol Metab. 2003;284(4):E716-25.
Wright EM, Hirayama BA, Loo DF. Active sugar transport in health and disease. J Intern Med. 2007;261(1):32-43.
Meyer C, Dostou J, Nadkarni V, Gerich J. Effects of physiological hyperinsulinemia on systemic, renal, and hepatic substrate metabolism. Am J Physiol. 1998;275(6 Pt 2):F915-21.
Meyer C, Nadkarni V, Stumvoll M, Gerich J. Human kidney free fatty acid and glucose uptake: Evidence for a renal glucose-fatty acid cycle. Am J Physiol. 1997;273(3 Pt 1):E650-4.
Uldry M, Thorens B. The SLC2 family of facilitated hexose and polyol transporters. Pflugers Arch. 2004;447(5):480-489.
Bouche C, Serdy S, Kahn CR, Goldfine AB. The cellular fate of glucose and its relevance in type 2 diabetes. Endocr Rev. 2004;25(5):807-830.
Jhun BH, Rampal AL, Liu H, Lachaal M, Jung CY. Effects of insulin on steady state kinetics of GLUT4 subcellular distribution in rat adipocytes. evidence of constitutive GLUT4 recycling. J Biol Chem. 1992;267(25):17710-17715.
Rodnick KJ, Piper RC, Slot JW, James DE. Interaction of insulin and exercise on glucose transport in muscle. Diabetes Care. 1992;15(11):1679-1689.
Fanelli C, Calderone S, Epifano L, et al. Demonstration of a critical role for free fatty acids in mediating counterregulatory stimulation of gluconeogenesis and suppression of glucose utilization in humans. J Clin Invest. 1993;92(4):1617-1622.
Nauck MA, Heimesaat MM, Behle K, et al. Effects of glucagon-like peptide 1 on counterregulatory hormone responses, cognitive functions, and insulin secretion during hyperinsulinemic, stepped hypoglycemic clamp experiments in healthy volunteers. J Clin Endocrinol Metab. 2002;87(3):1239-1246.
Gosmanov NR, Szoke E, Israelian Z, et al. Role of the decrement in intraislet insulin for the glucagon response to hypoglycemia in humans. Diabetes Care. 2005;28(5):1124-1131.
Baggio LL, Drucker DJ. Biology of incretins: GLP-1 and GIP. Gastroenterology. 2007;132(6):2131-2157.
Koda JE, Fineman M, Rink TJ, Dailey GE, Muchmore DB, Linarelli LG. Amylin concentrations and glucose control. Lancet. 1992;339(8802):1179-1180.
Martin C. The physiology of amylin and insulin: Maintaining the balance between glucose secretion and glucose uptake. Diabetes Educ. 2006;32 Suppl 3:101S-104S.
Woods SC, Lutz TA, Geary N, Langhans W. Pancreatic signals controlling food intake; insulin, glucagon and amylin. Philos Trans R Soc Lond B Biol Sci. 2006;361(1471):1219-1235.
Asmar M, Bache M, Knop FK, Madsbad S, Holst JJ. Do the actions of glucagon-like peptide-1 on gastric emptying, appetite, and food intake involve release of amylin in humans? J Clin Endocrinol Metab. 2010;95(5):2367-2375.
Qi D, Cai K, Wang O, et al. Fatty acids induce amylin expression and secretion by pancreatic beta-cells. Am J Physiol Endocrinol Metab. 2010;298(1):E99-E107.
Westermark P, Andersson A, Westermark GT. Islet amyloid polypeptide, islet amyloid, and diabetes mellitus. Physiol Rev. 2011;91(3):795-826.
Lutz TA. Control of energy homeostasis by amylin. Cell Mol Life Sci. 2012;69(12):1947-1965.
Sexton PM, Paxinos G, Kenney MA, Wookey PJ, Beaumont K. In vitro autoradiographic localization of amylin binding sites in rat brain. Neuroscience. 1994;62(2):553-567.
Lutz TA. The role of amylin in the control of energy homeostasis. Am J Physiol Regul Integr Comp Physiol. 2010;298(6):R1475-84.
Fang J, Landersdorfer CB, Cirincione B, Jusko WJ. Study reanalysis using a mechanism-based pharmacokinetic/pharmacodynamic model of pramlintide in subjects with type 1 diabetes. AAPS J. 2013;15(1):15-29.
Gromada J, Franklin I, Wollheim CB. Alpha-cells of the endocrine pancreas: 35 years of research but the enigma remains. Endocr Rev. 2007;28(1):84-116.
Schuit FC, Derde MP, Pipeleers DG. Sensitivity of rat pancreatic A and B cells to somatostatin. Diabetologia. 1989;32(3):207-212.
Bostrom P, Wu J, Jedrychowski MP, et al. A PGC1-alpha-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature. 2012;481(7382):463-468.
Roca-Rivada A, Castelao C, Senin LL, et al. FNDC5/irisin is not only a myokine but also an adipokine. PLoS One. 2013;8(4):e60563.
Orava J, Nuutila P, Lidell ME, et al. Different metabolic responses of human brown adipose tissue to activation by cold and insulin. Cell Metab. 2011;14(2):272-279.
Huh JY, Dincer F, Mesfum E, Mantzoros CS. Irisin stimulates muscle growth-related genes and regulates adipocyte differentiation and metabolism in humans. Int J Obes (Lond). 2014;38(12):1538-1544.
Lee HJ, Lee JO, Kim N, et al. Irisin, a novel myokine, regulates glucose uptake in skeletal muscle cells via AMPK. Mol Endocrinol. 2015;29(6):873-881.
Liu TY, Shi CX, Gao R, et al. Irisin inhibits hepatic gluconeogenesis and increases glycogen synthesis via the PI3K/Akt pathway in type 2 diabetic mice and hepatocytes. Clin Sci (Lond). 2015;129(10):839-850.
Lecavalier L, Bolli G, Cryer P, Gerich J. Contributions of gluconeogenesis and glycogenolysis during glucose counterregulation in normal humans. Am J Physiol. 1989;256(6 Pt 1):E844-51.
Gerich JE. Physiology of glucagon. Int Rev Physiol. 1981;24:243-275.
Magnusson I, Rothman DL, Gerard DP, Katz LD, Shulman GI. Contribution of hepatic glycogenolysis to glucose production in humans in response to a physiological increase in plasma glucagon concentration. Diabetes. 1995;44(2):185-189.
Gerich J, Cryer P, Rizza R. Hormonal mechanisms in acute glucose counterregulation: The relative roles of glucagon, epinephrine, norepinephrine, growth hormone, and cortisol. Metabolism. 1980;29(11 Suppl 1):1164-1175.
Lager I. The insulin-antagonistic effect of the counterregulatory hormones. J Intern Med Suppl. 1991;735:41-47.
Rizza RA, Cryer PE, Haymond MW, Gerich JE. Adrenergic mechanisms of catecholamine action on glucose homeostasis in man. Metabolism. 1980;29(11 Suppl 1):1155-1163.
Rizza RA, Mandarino LJ, Gerich JE. Effects of growth hormone on insulin action in man. mechanisms of insulin resistance, impaired suppression of glucose production, and impaired stimulation of glucose utilization. Diabetes. 1982;31(8 Pt 1):663-669.
Fluck DC. Catecholamines. Br Heart J. 1972;34(9):869-873.
Bolli GB, Gottesman IS, Cryer PE, Gerich JE. Glucose counterregulation during prolonged hypoglycemia in normal humans. Am J Physiol. 1984;247(2 Pt 1):E206-14.
De Feo P, Perriello G, Torlone E, et al. Contribution of adrenergic mechanisms to glucose counterregulation in humans. Am J Physiol. 1991;261(6 Pt 1):E725-36.
Bidlingmaier M, Strasburger CJ. Growth hormone. Handb Exp Pharmacol. 2010;(195):187-200. doi(195):187-200.
De Feo P, Perriello G, Torlone E, et al. Demonstration of a role for growth hormone in glucose counterregulation. Am J Physiol. 1989;256(6 Pt 1):E835-43.
De Feo P, Perriello G, Torlone E, et al. Contribution of cortisol to glucose counterregulation in humans. Am J Physiol. 1989;257(1 Pt 1):E35-42.
Rizza RA, Mandarino LJ, Gerich JE. Cortisol-induced insulin resistance in man: Impaired suppression of glucose production and stimulation of glucose utilization due to a postreceptor detect of insulin action. J Clin Endocrinol Metab. 1982;54(1):131-138.
Stumvoll M, Meyer C, Mitrakou A, Nadkarni V, Gerich JE. Renal glucose production and utilization: New aspects in humans. Diabetologia. 1997;40(7):749-757.
Cersosimo E, Garlick P, Ferretti J. Insulin regulation of renal glucose metabolism in humans. Am J Physiol. 1999;276(1 Pt 1):E78-84.
- Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution - Non-Commercial 4.0 International License that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.
- Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgement of its initial publication in the Medical Student Press Journal.
- Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work (See The Effect of Open Access).