- Christos Mantzoros, MD, DSc
Christos Mantzoros, MD, DSc
- Professor of Medicine
- Harvard Medical School
- Shanti Serdy, MD
Shanti Serdy, MD
- Instructor in Medicine
- Harvard Medical School
Insulin is a 51-amino acid peptide hormone that is synthesized and secreted by pancreatic beta cells (table 1). This topic will review the metabolic actions of insulin. The structure and function of the insulin receptor and details of insulin secretion are reviewed separately. (See "Structure and function of the insulin receptor" and "Pancreatic beta cell function".)
Insulin action begins with the binding of insulin to a heterotetrameric receptor on the cell membrane of the target cells. Insulin receptors are membrane glycoproteins composed of two separate insulin-binding (alpha-subunits) and two signal transduction (beta-subunits) domains. Binding of insulin to the receptor results in conformational change of the alpha-subunits that enables adenosine triphosphate (ATP) binding to the beta-subunit’s intracellular domain. ATP binding leads to activation of a tyrosine kinase in the beta-subunit that autophosphorylates the receptor. The phosphorylated receptor in turn phosphorylates other protein substrates beginning with insulin-receptor substrate (IRS) 1 and 2 [1-4]. The insulin signal is further propagated through a phosphorylation network involving other intracellular substances. The biochemistry of insulin action is reviewed in detail separately. (See "Structure and function of the insulin receptor".)
Through activation of these signaling pathways, insulin acts as a powerful regulator of metabolic function. Furthermore, insulin receptor-mediated activation of the mitogen-activated protein (MAP) kinase pathway has been implicated in insulin's effects on growth and proliferation .
Of clinical relevance, defects in insulin signaling have been demonstrated in several of the insulin resistance syndromes. (See "Insulin resistance: Definition and clinical spectrum".)
METABOLIC EFFECTS OF INSULIN
Insulin directly or indirectly affects the function of virtually every tissue in the body. However, in this brief overview we will focus on insulin's metabolic effects on the three tissues most responsible for energy storage: liver, muscle, and adipose tissue (table 2).
- Pessin JE, Saltiel AR. Signaling pathways in insulin action: molecular targets of insulin resistance. J Clin Invest 2000; 106:165.
- Previs SF, Withers DJ, Ren JM, et al. Contrasting effects of IRS-1 versus IRS-2 gene disruption on carbohydrate and lipid metabolism in vivo. J Biol Chem 2000; 275:38990.
- Samuel VT, Petersen KF, Shulman GI. Lipid-induced insulin resistance: unravelling the mechanism. Lancet 2010; 375:2267.
- Kido Y, Nakae J, Accili D. Clinical review 125: The insulin receptor and its cellular targets. J Clin Endocrinol Metab 2001; 86:972.
- Stumvoll M, Meyer C, Mitrakou A, et al. Renal glucose production and utilization: new aspects in humans. Diabetologia 1997; 40:749.
- Woerle HJ, Meyer C, Popa EM, et al. Renal compensation for impaired hepatic glucose release during hypoglycemia in type 2 diabetes: further evidence for hepatorenal reciprocity. Diabetes 2003; 52:1386.
- Ramnanan CJ, Edgerton DS, Rivera N, et al. Molecular characterization of insulin-mediated suppression of hepatic glucose production in vivo. Diabetes 2010; 59:1302.
- Philippe J. Insulin regulation of the glucagon gene is mediated by an insulin-responsive DNA element. Proc Natl Acad Sci U S A 1991; 88:7224.
- Sindelar DK, Balcom JH, Chu CA, et al. A comparison of the effects of selective increases in peripheral or portal insulin on hepatic glucose production in the conscious dog. Diabetes 1996; 45:1594.
- Edgerton DS, Lautz M, Scott M, et al. Insulin's direct effects on the liver dominate the control of hepatic glucose production. J Clin Invest 2006; 116:521.
- Girard J. Insulin's effect on the liver: "direct or indirect?" continues to be the question. J Clin Invest 2006; 116:302.
- Kahn BB. Lilly lecture 1995. Glucose transport: pivotal step in insulin action. Diabetes 1996; 45:1644.
- Burcelin R, Crivelli V, Perrin C, et al. GLUT4, AMP kinase, but not the insulin receptor, are required for hepatoportal glucose sensor-stimulated muscle glucose utilization. J Clin Invest 2003; 111:1555.
- Mandarino LJ, Printz RL, Cusi KA, et al. Regulation of hexokinase II and glycogen synthase mRNA, protein, and activity in human muscle. Am J Physiol 1995; 269:E701.
- Hue L, Rider MH. Role of fructose 2,6-bisphosphate in the control of glycolysis in mammalian tissues. Biochem J 1987; 245:313.
- Farese RV Jr, Yost TJ, Eckel RH. Tissue-specific regulation of lipoprotein lipase activity by insulin/glucose in normal-weight humans. Metabolism 1991; 40:214.
- Fielding BA, Frayn KN. Lipoprotein lipase and the disposition of dietary fatty acids. Br J Nutr 1998; 80:495.
- Vaughan M, Steinberg D. Glyceride biosynthesis, glyceride breakdown, and glycogen breakdown in adipose tissue: Mechanism and regulation. In: Handbook of physiology: Adipose tissue, Renold AE, Cahill GF (Eds), American Physiological Society, Washington, DC 1965. Vol 24, p.239.
- Strålfors P, Björgell P, Belfrage P. Hormonal regulation of hormone-sensitive lipase in intact adipocytes: identification of phosphorylated sites and effects on the phosphorylation by lipolytic hormones and insulin. Proc Natl Acad Sci U S A 1984; 81:3317.
- Zimmermann R, Lass A, Haemmerle G, Zechner R. Fate of fat: the role of adipose triglyceride lipase in lipolysis. Biochim Biophys Acta 2009; 1791:494.
- Lass A, Zimmermann R, Oberer M, Zechner R. Lipolysis - a highly regulated multi-enzyme complex mediates the catabolism of cellular fat stores. Prog Lipid Res 2011; 50:14.
- Enoksson S, Degerman E, Hagström-Toft E, et al. Various phosphodiesterase subtypes mediate the in vivo antilipolytic effect of insulin on adipose tissue and skeletal muscle in man. Diabetologia 1998; 41:560.
- Strålfors P, Honnor RC. Insulin-induced dephosphorylation of hormone-sensitive lipase. Correlation with lipolysis and cAMP-dependent protein kinase activity. Eur J Biochem 1989; 182:379.
- Duncan RE, Ahmadian M, Jaworski K, et al. Regulation of lipolysis in adipocytes. Annu Rev Nutr 2007; 27:79.
- Kitabchi AE, Umpierrez GE, Miles JM, Fisher JN. Hyperglycemic crises in adult patients with diabetes. Diabetes Care 2009; 32:1335.
- Keller U, Gerber PP, Stauffacher W. Fatty acid-independent inhibition of hepatic ketone body production by insulin in humans. Am J Physiol 1988; 254:E694.
- Keller U, Lustenberger M, Stauffacher W. Effect of insulin on ketone body clearance studied by a ketone body "clamp" technique in normal man. Diabetologia 1988; 31:24.
- Jefferson LS. Lilly Lecture 1979: role of insulin in the regulation of protein synthesis. Diabetes 1980; 29:487.
- Flakoll PJ, Kulaylat M, Frexes-Steed M, et al. Amino acids augment insulin's suppression of whole body proteolysis. Am J Physiol 1989; 257:E839.
- Rosenfield RL, Barnes RB, Cara JF, Lucky AW. Dysregulation of cytochrome P450c 17 alpha as the cause of polycystic ovarian syndrome. Fertil Steril 1990; 53:785.
- Adashi EY, Hsueh AJ, Yen SS. Insulin enhancement of luteinizing hormone and follicle-stimulating hormone release by cultured pituitary cells. Endocrinology 1981; 108:1441.
- Adashi EY, Resnick CE, D'Ercole AJ, et al. Insulin-like growth factors as intraovarian regulators of granulosa cell growth and function. Endocr Rev 1985; 6:400.
- Veldhuis JD, Zhang G, Garmey JC. Troglitazone, an insulin-sensitizing thiazolidinedione, represses combined stimulation by LH and insulin of de novo androgen biosynthesis by thecal cells in vitro. J Clin Endocrinol Metab 2002; 87:1129.
- Arslanian SA, Lewy V, Danadian K, Saad R. Metformin therapy in obese adolescents with polycystic ovary syndrome and impaired glucose tolerance: amelioration of exaggerated adrenal response to adrenocorticotropin with reduction of insulinemia/insulin resistance. J Clin Endocrinol Metab 2002; 87:1555.
- Book CB, Dunaif A. Selective insulin resistance in the polycystic ovary syndrome. J Clin Endocrinol Metab 1999; 84:3110.
- Goodarzi MO, Dumesic DA, Chazenbalk G, Azziz R. Polycystic ovary syndrome: etiology, pathogenesis and diagnosis. Nat Rev Endocrinol 2011; 7:219.
- Abrahamson, DI, Schkloven, et al. Influence of massive doses of insulin on peripheral blood flow in man. Am J Physiol 1939; 128:124.
- Steinberg HO, Brechtel G, Johnson A, et al. Insulin-mediated skeletal muscle vasodilation is nitric oxide dependent. A novel action of insulin to increase nitric oxide release. J Clin Invest 1994; 94:1172.
- Hartell NA, Archer HE, Bailey CJ. Insulin-stimulated endothelial nitric oxide release is calcium independent and mediated via protein kinase B. Biochem Pharmacol 2005; 69:781.
- Tabit CE, Chung WB, Hamburg NM, Vita JA. Endothelial dysfunction in diabetes mellitus: molecular mechanisms and clinical implications. Rev Endocr Metab Disord 2010; 11:61.
- Johnstone MT, Creager SJ, Scales KM, et al. Impaired endothelium-dependent vasodilation in patients with insulin-dependent diabetes mellitus. Circulation 1993; 88:2510.
- Calver A, Collier J, Vallance P. Inhibition and stimulation of nitric oxide synthesis in the human forearm arterial bed of patients with insulin-dependent diabetes. J Clin Invest 1992; 90:2548.
- Williams SB, Cusco JA, Roddy MA, et al. Impaired nitric oxide-mediated vasodilation in patients with non-insulin-dependent diabetes mellitus. J Am Coll Cardiol 1996; 27:567.
- McVeigh GE, Brennan GM, Johnston GD, et al. Impaired endothelium-dependent and independent vasodilation in patients with type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia 1992; 35:771.
- Williams SB, Goldfine AB, Timimi FK, et al. Acute hyperglycemia attenuates endothelium-dependent vasodilation in humans in vivo. Circulation 1998; 97:1695.
- Davidson JA, Parkin CG. Is hyperglycemia a causal factor in cardiovascular disease? Does proving this relationship really matter? Yes. Diabetes Care 2009; 32 Suppl 2:S331.
- Banskota NK, Taub R, Zellner K, King GL. Insulin, insulin-like growth factor I and platelet-derived growth factor interact additively in the induction of the protooncogene c-myc and cellular proliferation in cultured bovine aortic smooth muscle cells. Mol Endocrinol 1989; 3:1183.
- Juhan-Vague I, Alessi MC, Vague P. Thrombogenic and fibrinolytic factors and cardiovascular risk in non-insulin-dependent diabetes mellitus. Ann Med 1996; 28:371.
- Schneider DJ, Nordt TK, Sobel BE. Attenuated fibrinolysis and accelerated atherogenesis in type II diabetic patients. Diabetes 1993; 42:1.
- Nordt TK, Sawa H, Fujii S, Sobel BE. Induction of plasminogen activator inhibitor type-1 (PAI-1) by proinsulin and insulin in vivo. Circulation 1995; 91:764.
- Calles-Escandon J, Mirza SA, Sobel BE, Schneider DJ. Induction of hyperinsulinemia combined with hyperglycemia and hypertriglyceridemia increases plasminogen activator inhibitor 1 in blood in normal human subjects. Diabetes 1998; 47:290.
- Del Giudice ME, Fantus IG, Ezzat S, et al. Insulin and related factors in premenopausal breast cancer risk. Breast Cancer Res Treat 1998; 47:111.
- Gunter MJ, Hoover DR, Yu H, et al. Insulin, insulin-like growth factor-I, and risk of breast cancer in postmenopausal women. J Natl Cancer Inst 2009; 101:48.
- Goodwin PJ, Ennis M, Pritchard KI, et al. Fasting insulin and outcome in early-stage breast cancer: results of a prospective cohort study. J Clin Oncol 2002; 20:42.
- Kaaks R, Toniolo P, Akhmedkhanov A, et al. Serum C-peptide, insulin-like growth factor (IGF)-I, IGF-binding proteins, and colorectal cancer risk in women. J Natl Cancer Inst 2000; 92:1592.
- Schoen RE, Tangen CM, Kuller LH, et al. Increased blood glucose and insulin, body size, and incident colorectal cancer. J Natl Cancer Inst 1999; 91:1147.
- Koohestani N, Tran TT, Lee W, et al. Insulin resistance and promotion of aberrant crypt foci in the colons of rats on a high-fat diet. Nutr Cancer 1997; 29:69.
- Watkins LF, Lewis LR, Levine AE. Characterization of the synergistic effect of insulin and transferrin and the regulation of their receptors on a human colon carcinoma cell line. Int J Cancer 1990; 45:372.
- Sandhu MS, Dunger DB, Giovannucci EL. Insulin, insulin-like growth factor-I (IGF-I), IGF binding proteins, their biologic interactions, and colorectal cancer. J Natl Cancer Inst 2002; 94:972.
- Moschos SJ, Mantzoros CS. The role of the IGF system in cancer: from basic to clinical studies and clinical applications. Oncology 2002; 63:317.
- Petridou E, Mantzoros C, Dessypris N, et al. Plasma adiponectin concentrations in relation to endometrial cancer: a case-control study in Greece. J Clin Endocrinol Metab 2003; 88:993.
- Mantzoros C, Petridou E, Dessypris N, et al. Adiponectin and breast cancer risk. J Clin Endocrinol Metab 2004; 89:1102.
- Dal Maso L, Augustin LS, Karalis A, et al. Circulating adiponectin and endometrial cancer risk. J Clin Endocrinol Metab 2004; 89:1160.
- Wei EK, Giovannucci E, Fuchs CS, et al. Low plasma adiponectin levels and risk of colorectal cancer in men: a prospective study. J Natl Cancer Inst 2005; 97:1688.
- Dalamaga M, Diakopoulos KN, Mantzoros CS. The role of adiponectin in cancer: a review of current evidence. Endocr Rev 2012; 33:547.
- INSULIN SIGNALING
- METABOLIC EFFECTS OF INSULIN
- Insulin and glucose metabolism
- - Glucose production
- - Glucose utilization
- Insulin and fat metabolism
- Insulin and ketone body metabolism
- Insulin and protein metabolism
- PARACRINE EFFECTS OF INSULIN
- OTHER ACTIONS OF INSULIN
- Vascular function
- Growth and cancer