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01-06-2015 | Review Article

Insulin and GH–IGF-I axis: endocrine pacer or endocrine disruptor?

Authors: Andrea Giustina, R. Berardelli, C. Gazzaruso, G. Mazziotti

Published in: Acta Diabetologica | Issue 3/2015

Abstract

Growth hormone/insulin-like growth factor (IGF) axis may play a role in maintaining glucose homeostasis in synergism with insulin. IGF-1 can directly stimulate glucose transport into the muscle through either IGF-1 or insulin/IGF-1 hybrid receptors. In severely decompensated diabetes including diabetic ketoacidosis, plasma levels of IGF-1 are low and insulin delivery into the portal system is required to normalize IGF-1 synthesis and bioavailability. Normalization of serum IGF-1 correlated with the improvement of glucose homeostasis during insulin therapy providing evidence for the use of IGF-1 as biomarker of metabolic control in diabetes. Taking apart the inherent mitogenic discussion, diabetes treatment using insulins with high affinity for the IGF-1 receptor may act as an endocrine pacer exerting a cardioprotective effect by restoring the right level of IGF-1 in bloodstream and target tissues, whereas insulins with low affinity for the IGF-1 receptor may lack this positive effect. An excessive and indirect stimulation of IGF-1 receptor due to sustained and chronic hyperinsulinemia over the therapeutic level required to overtake acute/chronic insulin resistance may act as endocrine disruptor as it may possibly increase the cardiovascular risk in the short and medium term and mitogenic/proliferative action in the long term. In conclusion, normal IGF-1 may be hypothesized to be a good marker of appropriate insulin treatment of the subject with diabetes and may integrate and make more robust the message coming from HbA1c in terms of prediction of cardiovascular risk.

WHO Consultation (1999) Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus. Geneva: World Health Organization; Report no. 99.2. http://whqlibdoc.who.int/hq/1999/who_ncd_ncs_99.2.pdf

ESC (2013) Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J 34:3035–3087

International Diabetes Federation (2011) Global burden: prevalence and projections, 2011 and 2030. http://www.diabetesatlas.org/content/diabetes-and-impairedglucose-tolerance

Bergman M (2013) Inadequacies of current approaches to prediabetes and diabetes prevention. Endocrine 44:623–633PubMed

Bergman M (2013) Pathophysiology of prediabetes and treatment implications for the prevention of type 2 diabetes mellitus. Endocrine 43:504–513PubMed

American Diabetes Association (2013) Economic costs of diabetes in the U.S. in 2012. Diabetes Care 36:1033–1046PubMedCentral

Esposito K, Giugliano D (2014) Healthy lifestyle for metabolic health: no more excuse! Endocrine 46:176–178PubMed

Maddaloni E, Pozzilli P (2014) SMART diabetes: the way to go (safe and multifactorial approach to reduce the risk for therapy in diabetes). Endocrine 46:3–5PubMed

Esposito K, Maiorino MI, Bellastella G, Giugliano D (2014) New guidelines for metabolic targets in diabetes: clinician’s opinion does matter. Endocrine. doi:10.1007/s12020-014-0205-2

10.

Giustina A, Veldhuis JD (1998) Pathophysiology of the neuroregulation of growth hormone secretion in experimental animals and the human. Endocr Rev 19:717–797PubMed

11.

Kamenický P, Mazziotti G, Lombès M, Giustina A, Chanson P (2014) Growth hormone, insulin-like growth factor-1, and the kidney: pathophysiological and clinical implications. Endocr Rev 35:234–281PubMed

12.

Rajpathak SN, Gunter MJ, Wylie-Rosett J, Ho GY, Kaplan RC, Muzumdar R, Rohan TE, Strickler HD (2009) The role of insulin-like growth factor-I and its binding proteins in glucose homeostasis and type 2 diabetes. Diabetes Metab Res Rev 25:3–12PubMedCentralPubMed

13.

Woods SC, Porte D Jr (1977) Relationship between plasma and cerebrospinal fluid insulin levels of dogs. Am J Physiol 233:331–334

14.

Banks WB (2004) The source of cerebral insulin. Eur J Pharmacol 490:5–12PubMed

15.

Ghasemi R, Haeri A, Dargahi L, Mohamed Z, Ahmadiani A (2013) Insulin in the brain: sources, localization and functions. Mol Neurobiol 47:145–171PubMed

16.

Havrankova J, Schmechel D, Roth J, Brownstein M (1978) Identification of insulin in rat brain. Proc Natl Acad Sci USA 75:5737–5741PubMedCentralPubMed

17.

Duarte AI, Moreira PI, Oliveira CR (2012) Insulin in central nervous system: more than just a peripheral hormone. J Aging Res 2012:384017PubMedCentralPubMed

18.

LeRoith D, Lowe WL Jr, Shemer J, Raizada MK, Ota A (1988) Development of brain insulin receptors. Int J Biochem 20:225–230PubMed

19.

Schlessinger J (2000) Cell signaling by receptor tyrosine kinases. Cell 103:211–225PubMed

20.

Wada A, Yokoo H, Yanagita T, Kobayashi H (2005) New twist on neuronal insulin receptor signaling in health, disease, and therapeutics. J Pharmacol Sci 99:128–143PubMed

21.

Brummer T, Schmitz-Peiffer C, Daly RJ (2010) Docking proteins. FEBS J 277:4356–4369PubMed

22.

Boura-Halfon S, Zick Y (2009) Chapter 12 serine kinases of insulin receptor substrate proteins. In: Gerald L (ed) Vitamins and hormones, vol 80. Academic, London, pp 313–349

23.

Banks WA, Kastin AJ (1988) Differential permeability of the blood-brain barrier to two pancreatic peptides: insulin and amylin. Peptides 19:883–889

24.

Clarke DW, Mudd L, Boyd FT Jr (1986) Insulin is released from rat brain neuronal cells in culture. J Neurochem 47:831–836PubMed

25.

Hoyer S (2003) Memory function and brain glucose metabolism. Pharmacopsychiatry 36:S62–S67PubMed

26.

Zhao W, Chen H, Xu H, Moore E, Meiri N, Quon MJ, Alkon DL (1999) Brain insulin receptors and spatial memory. Correlated changes in gene expression, tyrosine phosphorylation, and signaling molecules in the hippocampus of water maze trained rats. J Biol Chem 274:34893–34902PubMed

27.

Bingham EM, Hopkins D, Smith D, Pernet A, Hallett W, Reed L, Marsden PK, Amiel SA (2002) The role of insulin in human brain glucose metabolism: an 18fluoro-deoxyglucose positron emission tomography study. Diabetes 51:3384–3390PubMed

28.

Schulingkamp RJ, Pagano TC, Hung D, Raffa RB (2000) Insulin receptors and insulin action in the brain: review and clinical implications. Neurosci Biobehav Rev 24:855–872PubMed

29.

McCall AL (2004) Cerebral glucose metabolism in diabetes mellitus. Eur J Pharmacol 490:147–158PubMed

30.

Ghosh A, Yuk YC, Mansfield BC, Chou JY (2005) Brain contains a functional glucose-6-phosphatase complex capable of endogenous glucose production. J Biol Chem 280:11114–11119PubMed

31.

Giustina A, Braunstein G (2014) Hypothalamic syndromes. In: Jameson L, De Groot L (eds) Endocrinology: adult and pediatric, 7th edn. Elsevier, Philadelphia (in press)

32.

Plum L, Belgardt BF, Brüning JC (2006) Central insulin action in energy and glucose homeostasis. J Clin Invest 116:1761–1766PubMedCentralPubMed

33.

Levin BE (2006) Metabolic sensing neurons and the control of energy homeostasis. Physiol Behav 89:486–489PubMed

34.

Morton GJ, Cummings DE, Baskin DG, Barsh GS, Schwartz MW (2006) Central nervous system control of food intake and body weight. Nature 443:289–295PubMed

35.

Havel PJ (2001) Peripheral signals conveying metabolic information to the brain: short-term and long-term regulation of food intake and energy homeostasis. Exp Biol Med 226(11):963–977

36.

Fulop T, Larbi A, Douziech N (2003) Insulin receptor and ageing. Pathol Biol 51:574–580PubMed

37.

Duarte AI, Santos MS, Oliveira CR, Rego AC (2005) Insulin neuroprotection against oxidative stress in cortical neurons—involvement of uric acid and glutathione antioxidant defenses. Free Rad Biol Med 39:876–889PubMed

38.

Craft S (2005) Insulin resistance syndrome and Alzheimer’s disease: age- and obesity-related effects on memory, amyloid, and inflammation. Neurobiol Aging 26:S65–S69

39.

Ristow M (2004) Neurodegenerative disorders associated with diabetes mellitus. J Mol Med 82:510–529PubMed

40.

Watson GS, Craft S (2004) Modulation of memory by insulin and glucose: neuropsychological observations in Alzheimer’s disease. Eur J Pharmacol 490:97–113PubMed

41.

Piroli GG, Grillo CA, Charron MJ, McEwen BS, Reagan LP (2004) Biphasic effects of stress upon GLUT8 glucose transporter expression and trafficking in the diabetic rat hippocampus. Brain Res 1006:28–35PubMed

42.

Mayer G, Nitsch R, Hoyer S (1990) Effects of changes in peripheral and cerebral glucose metabolism on locomotor activity, learning and memory in adult male rats. Brain Res 532:95–100PubMed

43.

Saltiel AR, Pessin JE (2002) Insulin signaling pathways in time and space. Trends Cell Biol 12:65–71PubMed

44.

Medema RH, de Vries-Smits AM, van der Zon GC, Maassen JA, Bos JL (1993) Ras activation by insulin and epidermal growth factor through enhanced exchange of guanine nucleotides on p21ras. Mol Cell Biol 13:155–162PubMedCentralPubMed

45.

Goalstone M, Carel K, Leitner JW, Draznin B (1997) Insulin stimulates the phosphorylation and activity of farnesyltransferase via the Ras-mitogen-activated protein kinase pathway. Endocrinology 138:5119–5124PubMed

46.

Shulman GI (2000) Cellular mechanisms of insulin resistance. J Clin Invest 106:171–176PubMedCentralPubMed

47.

Draznin B (2010) Mitogenic action of insulin: friend, foe or ‘frenemy’? Diabetologia 53:229–233PubMed

48.

Tsatsoulis A, Mantzaris MD, Bellou S, Andrikoula M (2013) Insulin resistance: an adaptive mechanism becomes maladaptive in the current environment—an evolutionary perspective. Metabolism 62:622–633PubMed

49.

Schenk S, Saberi M, Olefsky JM (2008) Insulin sensitivity: modulation by nutrients and inflammation. J Clin Invest 118:2992–3002PubMedCentralPubMed

50.

Hotamisligil GS (2006) Inflammation and metabolic disorders. Nature 444:860–867PubMed

51.

Savage DB, Petersen KF, Shulman GI (2007) Disordered lipid metabolism and the pathogenesis of insulin resistance. Physiol Rev 87:507–520PubMedCentralPubMed

52.

Unger RH, Scherer PE (2010) Gluttony, sloth and the metabolic syndrome: a roadmap to lipotoxicity. Trends Endocrinol Metab 21:345–352PubMedCentralPubMed

53.

Sims EA, Danforth E Jr, Horton ES, Bray GA, Glennon JA, Salans LB (1973) Endocrine and metabolic effects of experimental obesity in man. Recent Prog Horm Res 29:457–496PubMed

54.

Garg A, Misra A (2004) Lipodystrophies: rare disorders causing metabolic syndrome. Endocrinol Metab Clin N Am 33:305–331

55.

Heilbronn LK, Gan SK, Turner N, Campbell LV, Chisholm DJ (2007) Markers of mitochondrial biogenesis and metabolism are lower in overweight and obese insulin-resistant subjects. J Clin Endocrinol Metab 92:1467–1473PubMed

56.

Giustina A, Licini M, Schettino M, Doga M, Pizzocolo G, Negro-Vilar A (1994) Physiological role of galanin in the regulation of anterior pituitary function in humans. Am J Physiol 266:E57–E61PubMed

57.

Giustina A, Girelli A, Alberti D, Bossoni S, Buzi F, Doga M, Schettino M, Wehrenberg WB (1991) Effects of pyridostigmine on spontaneous and growth hormone-releasing hormone stimulated growth hormone secretion in children on daily glucocorticoid therapy after liver transplantation. Clin Endocrinol 35:491–498

58.

Giustina A, Bossoni S, Bodini C, Girelli A, Balestrieri GP, Pizzocolo G, Wehrenberg WB (1992) Arginine normalizes the growth hormone (GH) response to GH-releasing hormone in adult patients receiving chronic daily immunosuppressive glucocorticoid therapy. J Clin Endocrinol Metab 74:1301–1305PubMed

59.

Giustina A, Wehrenberg WB (1995) Influence of thyroid hormones on the regulation of growth hormone secretion. Eur J Endocrinol 133:646–653PubMed

60.

Wehrenberg WB, Giustina A (1992) Basic counterpoint: mechanisms and pathways of gonadal steroid modulation of growth hormone secretion. Endocr Rev 13:299–308PubMed

61.

Mazziotti G, Giustina A (2013) Glucocorticoids and the regulation of growth hormone secretion. Nat Rev Endocrinol 9:265–276PubMed

62.

Rinderknecht E, Humbel RE (1978) The amino acid sequence of human insulin-like growth factor I and its structural homology with proinsulin. J Biol Chem 253:2769–2776PubMed

63.

Böni-Schnetzler M, Schmid C, Meier PJ, Froesch ER (1991) Insulin regulates insulin-like growth factor I mRNA in rat hepatocytes. Am J Physiol 260:E846–E851PubMed

64.

Giustina A, Mazziotti G, Canalis E (2008) Growth hormone, insulin-like growth factors, and the skeleton. Endocr Rev 29:535–559PubMedCentralPubMed

65.

Juul A (2003) Serum levels of insulin-like growth factor I and its binding proteins in health and disease. Growth Horm IGF Res 13:113–170PubMed

66.

Janssen JA, Lamberts SW (1999) Is the measurement of free IGF-I more indicative than that of total IGF-I in the evaluation of the biological activity of the GH/IGF-I axis? J Endocrinol Invest 22:313–315PubMed

67.

Ullrich A, Gray A, Tam AW et al (1986) Insulin-like growth factor I receptor primary structure: comparison with insulin receptor suggests structural determinants that define functional specificity. EMBO J 5:2503–2512PubMedCentralPubMed

68.

Clemmons D (2012) Metabolic actions of insulin-like growth factor-I in normal physiology and diabetes. Endocrinol Metab Clin N Am 41:425–443

69.

Kim JJ, Accili D (2002) Signalling through IGF-I and insulin receptors: where is the specificity? Growth Horm IGF Res 12:84–90PubMed

70.

Zapf J, Schmid C, Froesch ER (1984) Biological and immunological properties of insulin-like growth factors (IGF) I and II. Clin Endocrinol Metab 13:3–30PubMed

71.

Soos MA, Whittaker J, Lammers R, Ullrich A, Siddle K (1990) Receptors for insulin and insulin-like growth factor-I can form hybrid dimers. characterisation of hybrid receptors in transfected cells. Biochem J 270:383–390PubMedCentralPubMed

72.

Kasuya J, Paz IB, Maddux BA, Goldfine ID, Hefta SA, Fujita-Yamaguchi Y (1993) Characterization of human placental insulin-like growth factor-I/insulin hybrid receptors by protein microsequencing and purification. Biochemistry 32:13531–13536PubMed

73.

Seely BL, Reichart DR, Takata Y, Yip C, Olefsky JM (1995) A functional assessment of insulin/insulin-like growth factor-I hybrid receptors. Endocrinology 136:1635–1641PubMed

74.

Bailyes EM, Nave BT, Soos MA, Orr SR, Hayward AC, Siddle K (1997) Insulin receptor/IGF-I receptor hybrids are widely distributed in mammalian tissues: quantification of individual receptor species by selective immunoprecipitation and immunoblotting. Biochem J 327:209–215PubMedCentralPubMed

75.

Pandini G, Frasca F, Mineo R, Sciacca L, Vigneri R, Belfiore A (2002) Insulin/insulin-like growth factor I hybrid receptors have different biological characteristics depending on the insulin receptor isoform involved. J Biol Chem 277:39684–39695PubMed

76.

LeRoith D, Werner H, Beitner-Johnson D, Roberts CT Jr (1995) Molecular and cellular aspects of the insulin-like growth factor I receptor. Endocr Rev 16:143–163PubMed

77.

Alexandrides T, Moses AC, Smith RJ (1989) Developmental expression of receptors for insulin, insulin-like growth factor I (IGF-I), and IGF-II in rat skeletal muscle. Endocrinology 124:1064–1076PubMed

78.

Russell-Jones DL, Bates AT, Umpleby AM et al (1995) A comparison of the effects of IGF-I and insulin on glucose metabolism, fat metabolism and the cardiovascular system in normal human volunteers. Eur J Clin Invest 25:403–411PubMed

79.

Boulware SD, Tamborlane WV, Rennert NJ, Gesundheit N, Sherwin RS (1994) Comparison of the metabolic effects of recombinant human insulin-like growth factor-I and insulin. Dose-response relationships in healthy young and middle-aged. J Clin Invest 93:1131–1139PubMedCentralPubMed

80.

Elahi D, McAloon-Dyke M, Fukagawa NK et al (1993) Effects of recombinant human IGF-I on glucose and leucine kinetics in men. Am J Physiol 265:E831–E838PubMed

81.

Laager R, Ninnis R, Keller U (1993) Comparison of the effects of recombinant human insulin-like growth factor-I and insulin on glucose and leucine kinetics in humans. J Clin Invest 92:1903–1909PubMedCentralPubMed

82.

Guler HP, Zapf J, Froesch ER (1987) Short-term metabolic effects of recombinant human insulin-like growth factor I in healthy adults. N Engl J Med 317:137–140PubMed

83.

Frystyk J, Grofte T, Skjaerbaek C, Orskov H (1997) The effect of oral glucose on serum free insulin-like growth factor-I and -II in health adults. J Clin Endocrinol Metab 82:3124–3127PubMed

84.

Furling D, Marette A, Puymirat J (1999) Insulin-like growth factor I circumvents defective insulin action in human myotonic dystrophy skeletal cells. Endocrinology 140:4244–4250PubMed

85.

Henry RR, Abrams L, Nikoulina S, Ciaraldi TP (1995) Insulin action and glucose metabolism in nondiabetic control and NIDDM subjects. Diabetes 44:936–946PubMed

86.

DiGirolamo M, Eden S, Enberg O, Isaksson O, Lönnroth P, Hall K, Smith U (1986) Specific binding of human growth hormone but not insulin-like growth factors by human adipocytes. FEBS Lett 205:15–19PubMed

87.

Giustina A, Bossoni S, Cimino A, Pizzocolo G, Romanelli G, Wehrenberg WB (1990) Impaired growth hormone (GH) response to pyridostigmine in type 1 diabetic patients with exaggerated GH-releasing hormone-stimulated GH secretion. J Clin Endocrinol Metab 71:1486–1490PubMed

88.

Giustina A, Bossoni S, Bodini C, Cimino A, Pizzocolo G, Schettino M, Wehrenberg WB (1991) Effects of exogenous growth hormone pretreatment on the pituitary growth hormone response to growth hormone-releasing hormone alone or in combination with pyridostigmine in type I diabetic patients. Acta Endocrinol 125:510–517PubMed

89.

Giustina A, Desenzani P, Perini P, Deghenghi R, Bugari G, Wehrenberg WB, Giustina G (1996) Hypothalamic control of growth hormone (GH) secretion in type I diabetic men: effect of the combined administration of GH-releasing hormone and hexarelin, a novel GHRP-6 analog. Endocr Res 22:159–174PubMed

90.

Giustina A, Desenzani P, Perini P, Bazzigaluppi E, Bodini C, Bossoni S, Poiesi C, Wehrenberg WB, Bosi E (1997) Glutamate decarboxylase autoimmunity and growth hormone secretion in type I diabetes mellitus. Metabolism 46:382–387PubMed

91.

Giustina A, Lorusso R, Borghetti V, Bugari G, Misitano V, Alfieri O (1996) Impaired spontaneous growth hormone secretion in severe dilated cardiomyopathy. Am Heart J 131:620–622PubMed

92.

Bereket A, Lang CH, Wilson TA (1999) Alterations in the growth hormone-insulin-like growth factor axis in insulin dependent diabetes mellitus. Horm Metab Res 31:172–181PubMed

93.

Giustina A, Wehrenberg WB (1994) Growth hormone neuroregulation in diabetes mellitus. Trends Endocrinol Metab 5:73–78PubMed

94.

Giustina A, Bresciani E, Tassi C, Girelli A, Valentini U (1994) Effect of pyridostigmine on the growth hormone response to growth hormone-releasing hormone in lean and obese type II diabetic patients. Metabolism 43:893–898PubMed

95.

Friedrich N, Thuesen B, Jørgensen T, Juul A, Spielhagen C, Wallaschofksi H, Linneberg A (2012) The association between IGF-I and insulin resistance: a general population study in Danish adults. Diabetes Care 35:768–773PubMedCentralPubMed

96.

Singh A, Donnino R, Weintraub H, Schwartzbard A (2013) Effect of strict glycemic control in patients with diabetes mellitus on frequency of macrovascular events. Am J Cardiol 112:1033–1038PubMed

97.

Bianchi C, Miccoli R, Del Prato S (2013) Hyperglycemia and vascular metabolic memory: truth or fiction? Curr Diab Rep 13:403–410PubMed

98.

Johnson EL (2012) Glycemic variability in type 2 diabetes mellitus: oxidative stress and macrovascular complications. Adv Exp Med Biol 771:139–154PubMed

99.

Sesti G, Sciacqua A, Cardellini M, Marini MA, Maio R, Vatrano M, Succurro E, Lauro R, Federici M, Perticone F (2005) Plasma concentration of IGF-I is independently associated with insulin sensitivity in subjects with different degrees of glucose tolerance. Diabetes Care 28:120–125PubMed

100.

Yakar S, Liu JL, Fernandez AM, Wu Y, Schally AV, Frystyk J, Chernausek SD, Mejia W, Le Roith D (2001) Liver-specific IGF-1 gene deletion leads to muscle insulin insensitivity. Diabetes 50:1110–1118PubMed

101.

Arnqvist HJ (2008) The role of IGF-system in vascular insulin resistance. Horm Metab Res 40:588–592PubMed

102.

Chantelau E, Kimmerle R, Meyer-Schwickerath R (2008) Insulin, insulin analogues and diabetic retinopathy. Arch Physiol Biochem 114:54–62PubMed

103.

Smith LEH (2005) IGF-1 and retinopathy of prematurity in the preterm infant. Biol Neonate 88:237–244PubMed

104.

Hammes HP (2005) Pericytes and the pathogenesis of diabetic retinopathy. Horm Metab Res 37:39–43PubMed

105.

Bornfeldt KAH (1993) Actions of insulin-like growth factor I and insulin in vascular smooth muscle: receptor interaction and growth-promoting effects. In: Flyvbjerg HOKAA, Orskov H, Alberti KGGM (eds) Growth hormone and insulin-like growth factor-I. Wiley, Chichester

106.

Bennett MR, Evan GI, Schwartz SM (1995) Apoptosis of human vascular smooth muscle cells derived from normal vessels and coronary atherosclerotic plaques. J Clin Invest 95:2266–2274PubMedCentralPubMed

107.

Du J, Delafontaine P (1995) Inhibition of vascular smooth muscle cell growth through antisense transcription of a rat insulin-like growth factor I receptor cDNA. Circ Res 76:963–972PubMed

108.

Ezzat VA, Duncan ER, Wheatcroft SB, Kearney MT (2008) The role of IGF-I and its binding proteins in the development of type 2 diabetes and cardiovascular disease. Diabetes Obes Metab 10:198–211PubMed

109.

Izhar U, Hasdai D, Richardson DM, Cohen P, Lerman A (2000) Insulin and insulin-like growth factor-I cause vasorelaxation in human vessels in vitro. Coron Artery Dis 11:69–76PubMed

110.

Juul A, Scheike T, Davidsen M, Gyllenborg J, Jorgensen T (2002) Low serum insulin-like growth factor I is associated with increased risk of ischemic heart disease: a population-based case–control study. Circulation 106:939–944PubMed

111.

Spallarossa P, Brunelli C, Minuto F, Caruso D, Battistini M, Caponnetto S, Cordera R (1996) Insulin-like growth factor-I and angiographically documented coronary artery disease. Am J Cardiol 77:200–202PubMed

112.

van den Beld AW, Bots ML, Janssen JA, Pols HA, Lamberts SW, Grobbee DE (2003) Endogenous hormones and carotid atherosclerosis in elderly men. Am J Epidemiol 157:25–31PubMed

113.

Vaessen N, Heutink P, Janssen JA, Witteman JC, Testers L, Hofman A, Lamberts SW, Oostra BA, Pols HA, van Duijn CM (2001) A polymorphism in the gene for IGF-I: functional properties and risk for type 2 diabetes and myocardial infarction. Diabetes 50:637–642PubMed

114.

Wallander M, Norhammar A, Malmberg K, Ohrvik J, Rydén L, Brismar K (2007) IGF binding protein 1 predicts cardiovascular morbidity and mortality in patients with acute myocardial infarction and type 2 diabetes. Diabetes Care 30:2343–2348PubMed

115.

Gazzaruso C, Gola M, Karamouzis I, Giubbini R, Giustina A (2014) Cardiovascular risk in adult patients with growth hormone (GH) deficiency and following substitution with GH—an update. J Clin Endocrinol Metab 99:18–29PubMed

116.

Maison P, Tropeano AI, Macquin-Mavier I, Giustina A, Chanson P (2007) Impact of somatostatin analogs on the heart in acromegaly: a metaanalysis. J Clin Endocrinol Metab 92:1743–1747PubMed

117.

Giustina A, Casanueva FF, Cavagnini F, Chanson P, Frohman LA, Gaillard R, Ghigo E, Ho K, Jaquet P, Kleinberg DL, Lamberts SW, Lombardi G, Sheppard M, Strasburger CJ, Vance ML, Wass JA, Melmed S, Pituitary Society and the European Neuroendocrine Association (2003) Diagnosis and treatment of acromegaly complications. J Endocrinol Invest 26:1242–1247PubMed

118.

Rieu M, Binoux M (1985) Serum levels of insulin-like growth factor (IGF) and IGF binding protein in insulin-dependent diabetics during an episode of severe metabolic decompensation and the recovery phase. J Clin Endocrinol Metab 60:781–785PubMed

119.

Ekman B, Nystrom F, Arnqvist HJ (2000) Circulating IGF-I concentrations are low and not correlated to glycaemic control in adults with type 1 diabetes. Eur J Endocrinol 143:305–310

120.

Hanaire-Broutin H, Sallerin-Caute B, Poncet MF, Tauber M, Bastide R, Chalé JJ, Rosenfeld R, Tauber JP (1996) Effect of intraperitoneal insulin delivery on growth hormone binding protein, insulin-like growth factor (IGF)-I, and IGF-binding protein-3 in IDDM. Diabetologia 39:1498–1504PubMed

121.

Hedman CA, Frystyk J, Lindström T, Oskarsson P, Arnqvist HJ (2014) Intraperitoneal insulin delivery to patients with type 1 diabetes results in higher serum IGF-I bioactivity than continuous subcutaneous insulin infusion. Clin Endocrinol 81:58–62

122.

Bereket A, Lang CH, Blethen SL, Ng LC, Wilson TA (1996) Insulin treatment normalizes reduced free insulin-like growth factor-I concentrations in diabetic children. Clin Endocrinol 45:321–326

123.

Ekström K, Salemyr J, Zachrisson I, Carlsson-Skwirut C, Ortqvist E, Bang P (2007) Normalization of the IGF-IGFBP axis by sustained nightly insulinization in type 1 diabetes. Diabetes Care 30:1357–1363PubMed

124.

Chisalita SI, Arnqvist HJ (2004) Insulin-like growth factor I receptors are more abundant than insulin receptors in human micro- and macrovascular endothelial cells. Am J Physiol Endocrinol Metab 286:E896–E901PubMed

125.

Federici M, Zucaro L, Porzio O, Massoud R, Borboni P, Lauro D, Sesti G (1996) Increased expression of insulin/insulin-like growth factor-I hybrid receptors in skeletal muscle of noninsulin-dependent diabetes mellitus subjects. J Clin Invest 98:2887–2893PubMedCentralPubMed

126.

Belfiore A, Frasca F, Pandini G, Sciacca L, Vigneri R (2009) Insulin receptor isoforms and insulin receptor/insulin-like growth factor receptor hybrids in physiology and disease. Endocr Rev 30:586–623PubMed

127.

Federici M, Porzio O, Lauro D, Borboni P, Giovannone B, Zucaro L, Hribal ML, Sesti G (1998) Increased abundance of insulin/insulin-like growth factor-I hybrid receptors in skeletal muscle of obese subjects is correlated with in vivo insulin sensitivity. J Clin Endocrinol Metab 83:2911–2915PubMed

128.

Federici M, Porzio O, Zucaro L, Giovannone B, Borboni P, Marini MA, Lauro D, Sesti G (1997) Increased abundance of insulin/IGF-I hybrid receptors in adipose tissue from NIDDM patients. Mol Cell Endocrinol 135:41–47PubMed

129.

Federici M, Giaccari A, Hribal ML, Giovannone B, Lauro D, Morviducci L, Pastore L, Tamburrano G, Lauro R, Sesti G (1999) Evidence for glucose/hexosamine in vivo regulation of insulin/IGF-I hybrid receptor assembly. Diabetes 48:2277–2285PubMed

130.

Federici M, Lauro D, D’Adamo M, Giovannone B, Porzio O, Mellozzi M, Tamburrano G, Sbraccia P, Sesti G (1998) Expression of insulin/IGF-I hybrid receptors is increased in skeletal muscle of patients with chronic primary hyperinsulinemia. Diabetes 47:87–92PubMed

131.

Belfiore A (2007) The role of insulin receptor isoforms and hybrid insulin/IGFI receptors in human cancer. Curr Pharm Des 13:671–686PubMed

132.

Kurtzhals P, Schaffer L, Sorensen A, Kristensen C, Jonassen I, Schmid C, Trub T (2000) Correlations of receptor binding and metabolic and mitogenic potencies of insulin analogs designed for clinical use. Diabetes 49:999–1005PubMed

133.

Pierre-Eugene C, Pagesy P, Nguyen T, Neuille M, Tschank G, Tennagels N, Hampe C, Issad T (2012) Effect of insulin analogues on insulin/IGF1 hybrid receptors: increased activation by glargine but not by its metabolites M1 and M2. PLoS ONE 7:e41992PubMedCentralPubMed

134.

Weinstein D, Simon M, Yehezkel E, Laron Z, Werner H (2008) Insulin analogues display IGF-1-like mitogenic and anti-apoptotic activities in cultured cancer cells. Diabetes Metab Res Rev 25:41–49

135.

Ciaraldi TP, Carter L, Seipke G, Mudaliar S, Henry RR (2001) Effects of the long-acting insulin analog insulin glargine on cultured human skeletal muscle cells: comparisons to insulin and IGF-I. J Clin Endocrinol Metab 86:5838–5847PubMed

136.

Hemkens LG, Grouven U, Bender R, Gunster C, Gutschmidt S, Selke GW, Sawicki PT (2009) Risk of malignancies in patients with diabetes treated with human insulin or insulin analogues: a cohort study. Diabetologia 52:1732–1744PubMedCentralPubMed

137.

Mannucci E, Monami M, Balzi D, Cresci B, Pala L, Melani C, Lamanna C, Bracali I, Bigiarini M, Barchielli A, Marchionni N, Rotella CM (2010) Doses of insulin and its analogues and cancer occurrence in insulin-treated type 2 diabetic patients. Diabetes Care 33:1997–2003PubMedCentralPubMed

138.

Slawik M, Schories M, Grawitz AB, Reincke M, Petersen KG (2006) Treatment with insulin glargine does not suppress serum IGF-1. Diabet Med 23:814–817PubMed

139.

Home PD, Lagarenne P (2009) Combined randomised controlled trial experience of malignancies in studies using insulin glargine. Diabetologia 52:2499–2506PubMedCentralPubMed

140.

Edwards KL, Riche DM, Stroup JS, Goldman-Levine JD, Padiyara RS, Cross LB, Kane MP (2010) Insulin glargine and cancer risk: an opinion statement of the Endocrine and Metabolism Practice and Research Network of the American College of Clinical Pharmacy. Pharmacotherapy 30:955–965PubMed

141.

Nishimura E, Sorensen AR, Hansen BF et al (2010) Insulin degludec: a new ultra-long, basal insulin designed to maintain full metabolic effect while minimizing mitogenic potential. Diabetologia 53(Suppl 1):S388

142.

Nishimura E, Sorensen A, Hansen BF et al (2010) Insulin degludec is a new generation ultra-long acting basal insulin designed to maintain full metabolic effect while minimizing mitogenic potential. Diabetes 59(Suppl 1):A375

143.

Wang F, Surh J, Kaur M (2012) Insulin degludec as an ultralong-acting basal insulin once a day: a systematic review. Diabetes Metab Syndr Obes 5:191–204PubMedCentralPubMed

144.

Pollak M, Russell-Jones D (2010) Insulin analogues and cancer risk: cause for concern or cause celebre? Int J Clin Pract 64:628–636PubMed

145.

Zib I, Raskin P (2006) Novel insulin analogues and its mitogenic potential. Diabetes Obes Metab 8:611–620PubMed

146.

Bordeleau L, Yakubovich N, Dagenais GR, Rosenstock J, Probstfield J, Chang YuP, Ryden LE, Pirags V, Spinas GA, Birkeland KI, Ratner RE, Marin-Neto JA, Keltai M, Riddle MC, Bosch J, Yusuf S, Gerstein HC, for the ORIGIN Trial Investigators (2014) The association of basal insulin glargine and/or n-3 fatty acids with incident cancers in patients with dysglycemia. Diabetes Care 37:1360–1366PubMed

147.

Ioacara S, Guja C, Ionescu-Tirgoviste C, Fica S, Roden M (2014) Cancer specific mortality in insulin-treated type 2 diabetes patients. PLoS ONE 9:e93132PubMedCentralPubMed

148.

Simo R, Plana-Ripoli O, Puente D, Morros R, Mundel X, Vilca LM, Hernandez C, Fuents I, Procupet A, Tabernero JM, Violan C (2013) Impact of glucose-lowering agents on the risk of cancer in type 2 diabetic patients. The barcelona case–control study. PLoS ONE 8:e79968PubMedCentralPubMed

149.

Sturmer T, Marquis MA, Zhou H, Meigs JB, Lim S, Blonde L, Macdonald E, Wang R, Lavange LM, Pate V, Buse JB (2013) Cancer incidence among those initiating insulin therapy with glargine versus human NPH insulin. Diabetes Care 36:3517–3525PubMedCentralPubMed

150.

Bolli GB, Hahn AD, Schmidt R, Eisenblaetter T, Dahmen R, Heise T, Becker RH (2012) Plasma exposure to insulin glargine and its metabolites M1 and M2 after subcutaneous injection of therapeutic and supratherapeutic doses of glargine in subjects with type 1 diabetes. Diabetes Care 35:2626–2630PubMedCentralPubMed

151.

Sommerfel MR, Müller G, Tschank G, Seipke G, Habermann P, Kurrle R, Tennagels N (2010) In vitro metabolic and mitogenic signaling of insulin glargine and its metabolites. PLOsONE 5:e9540

152.

Owens DR, Matfin G, Monnier L (2014) Basal insulin analogues in the management of diabetes mellitus: what progress have we made? Diabetes Metab Res Rev 30:104–119PubMed

153.

Schalch DS, Turman NJ, Marcsisin VS, Heffernan M, Guler HP (1993) Short-term effects of recombinant human insulin-like growth factor I on metabolic control of patients with type II diabetes mellitus. J Clin Endocrinol Metab 77:1563–1568PubMed

154.

Carroll PV, Umpleby M, Alexander EL, Egel VA, Callison KV, Sönksen PH, Russell-Jones DL (1998) Recombinant human insulin-like growth factor-I (rhIGF-I) therapy in adults with type 1 diabetes mellitus: effects on IGFs, IGF-binding proteins, glucose levels and insulin treatment. Clin Endocrinol 49:739–746

155.

Zenobi PD, Graf S, Ursprung H, Froesch ER (1992) Effects of insulin like growth factor-I on glucose tolerance, insulin levels, and insulin secretion. J Clin Invest 89:1908–1913PubMedCentralPubMed

156.

Schmid C, Bianda T, Zwimpfer C, Zapf J, Wiesli P (2005) Changes in insulin sensitivity induced by short-term growth hormone (GH) and insulin-like growth factor I (IGF-I) treatment in GH deficient adults are not associated with changes in adiponectin levels. Growth Horm IGF Res 15:300–303PubMed

157.

Zenobi PD, Glatz Y, Keller A, Graf S, Jaeggi-Groisman SE, Riesen WF, Schoenle EJ, Froesch ER (1994) Beneficial metabolic effects of insulin-like growth factor I in patients with severe insulin resistant diabetes type A. Eur J Endocrinol 131:251–257PubMed

158.

Morrow LA, O’Brien MB, Moller DE, Flier JS, Moses AC (1994) Recombinant human insulin-like growth factor-I therapy improves glycemic control and insulin action in the type A syndrome of severe insulin resistance. J Clin Endocrinol Metab 79:205–210PubMed

159.

Cheetham TD, Holly JM, Clayton K, Cwyfan-Hughes S, Dunger DB (1995) The effects of repeated daily recombinant human insulin-like growth factor I administration in adolescents with type 1 diabetes. Diabet Med 12:885–892PubMed

160.

Moses AC, Young SC, Morrow LA, O’Brien M, Clemmons DR (1996) Recombinant human insulin-like growth factor I increases insulin sensitivity and improves glycemic control in type II diabetes. Diabetes 45:91–100PubMed

161.

Pratipanawatr T, Pratipanawatr W, Rosen C, Berria R, Bajaj M, Cusi K, Mandarino L, Kashyap S, Belfort R, DeFronzo RA (2002) Effect of IGF-I on FFA and glucose metabolism in control and type 2 diabetic subjects. Am J Physiol Endocrinol Metab 282:E1360–E1368PubMed

162.

Saukkonen T, Amin R, Williams RM, Fox C, Yuen KC, White MA, Umpleby AM, Acerini CL, Dunger DB (2004) Dose-dependent effects of recombinant human insulin-like growth factor (IGF)-I/IGF binding protein-3 complex on overnight growth hormone secretion and insulin sensitivity in type 1 diabetes. J Clin Endocrinol Metab 89:4634–4641PubMed

163.

Zenobi PD, Jaeggi-Groisman SE, Riesen WF, Roder ME, Froesch ER (1992) Insulin-like growth factor-I improves glucose and lipid metabolism in type 2 diabetes mellitus. J Clin Invest 90:2234–2241PubMedCentralPubMed

164.

Thankamony A, Capalbo D, Marcovecchio ML, Sleigh A, Jørgensen SW, Hill NR, Mooslehner K, Yeo GS, Bluck L, Juul A, Vaag A, Dunger DB (2014) Low circulating levels of IGF-I in healthy adults are associated with reduced β-cell function, increased intramyocellular lipid and enhanced fat utilisation during fasting. J Clin Endocrinol Metab 99:2198–2207PubMedCentralPubMed

165.

Ripa P, Robertson I, Cowley D, Harris M, Masters IB, Cotterill AM (2002) The relationship between insulin secretion, the insulin-like growth factor axis and growth in children with cystic fibrosis. Clin Endocrinol 56:383–389

166.

Rennert NJ, Caprio S, Sherwin RS (1993) Insulin-like growth factor I inhibits glucose-stimulated insulin secretion but does not impair glucose metabolism in normal humans. J Clin Endocrinol Metab 76:804–806PubMed

167.

Porksen N, Hussain MA, Bianda TL, Nyholm B, Christiansen JS, Butler PC, Veldhuis JD, Froesch ER, Schmitz O (1997) IGF-I inhibits burst mass of pulsatile insulin secretion at supraphysiological and low IGF-I infusion rates. Am J Physiol Endocrinol Metab 272:E352–E358

168.

Xuan S, Kitamura T, Nakae J, Politi K, Kido Y, Fisher PE, Morroni M, Cinti S, White MF, Herrera PL, Accili D, Efstratiadis A (2002) Defective insulin secretion in pancreatic beta cells lacking type 1 IGF receptor. J Clin Invest 110:1011–1019PubMedCentralPubMed

169.

Kulkarni RN (2005) New insights into the roles of insulin/IGF-I in the development and maintenance of beta-cell mass. Rev Endocr Metab Disord 6:199–210PubMed

170.

Ueki K, Okada T, Hu J, Liew CW, Assmann A, Dahlgren GM, Peters JL, Shackman JG, Zhang M, Artner I, Satin LS, Stein R, Holzenberger M, Kennedy RT, Kahn CR, Kulkarni RN (2006) Total insulin and IGF-I resistance in pancreatic beta cells causes overt diabetes. Nat Genet 38:583–588PubMed

171.

van Haeften TW, Twickler TB (2004) Insulin-like growth factors and pancreas beta cells. Eur J Clin Invest 34:249–255PubMed

172.

Jones PM, Persaud SJ (1994) Tyrosine kinase inhibitors inhibit glucose-stimulated insulin secretion. Biochem Soc Trans 22:209SPubMed

173.

Persaud SJ, Harris TE, Burns CJ, Jones PM (1999) Tyrosine kinases play a permissive role in glucose-induced insulin secretion from adult rat islets. J Mol Endocrinol 22:19–28PubMed

174.

Lu Y, Herrera PL, Guo Y, Sun D, Tang Z, LeRoith D, Liu JL (2004) Pancreatic-specific inactivation of IGF-I gene causes enlarged pancreatic islets and significant resistance to diabetes. Diabetes 53:3131–3141PubMed

175.

Liu JL (2007) Does IGF-I stimulate pancreatic islet cell growth? Cell Biochem Biophys 48:115–125PubMed

176.

Simpson HL, Jackson NC, Shoejaee-Moradie F, Jones RH, Russell-Jones DL, Sönksen PH, Dunger DB, Umpleby AM (2004) Insulin-like growth factor I has a direct effect on glucose and protein metabolism, but no effect on lipid metabolism in type 1 diabetes. J Clin Endocrinol Metab 89:425–432PubMed

177.

Williams RM, Amin R, Shojaee-Moradie F, Umpleby AM, Acerini CL, Dunger DB (2003) The effects of a specific growth hormone antagonist on overnight insulin requirements and insulin sensitivity in young adults with type 1 diabetes mellitus. Diabetologia 46:1203–1210PubMed

178.

Saukkonen T, Shojaee-Moradie F, Williams RM, Amin R, Yuen KC, Watts A, Acerini CL, Umpleby AM, Dunger DB (2006) Effects of recombinant human IGF-I/IGF-binding protein-3 complex on glucose and glycerol metabolism in type 1 diabetes. Diabetes 55:2365–2370PubMed

179.

Cusi K, DeFronzo R (2000) Recombinant human insulin-like growth factor I treatment for 1 week improves metabolic control in type 2 diabetes by ameliorating hepatic and muscle insulin resistance. J Clin Endocrinol Metab 85:3077–3084PubMed

180.

Rh in NIDDM Study Group (1996) Evidence from a dose ranging study that recombinant insulin-like growth factor-I (RhIGF-I) effectively and safely improves glycemic control in the noninsulin dependent diabetes mellitus. Diabetes 45:91–100

181.

Giustina A, Licini M, Bussi AR, Girelli A, Pizzocolo G, Schettino M, Negro-Vilar A (1993) Effects of sex and age on the growth hormone response to galanin in healthy human subjects. J Clin Endocrinol Metab 76:1369–1372PubMed

182.

Mauras N, Fox L, Englert K, Beck RW (2013) Continuous glucose monitoring in type 1 diabetes. Endocrine 43:41–50PubMed

183.

Higgins T (2013) HbA1c for screening and diagnosis of diabetes mellitus. Endocrine 43:266–273PubMed

Title: Insulin and GH–IGF-I axis: endocrine pacer or endocrine disruptor?
Authors: Andrea Giustina
R. Berardelli
C. Gazzaruso
G. Mazziotti
Publication date: 01-06-2015
Publisher: Springer Milan
Published in: Acta Diabetologica / Issue 3/2015
Print ISSN: 0940-5429
Electronic ISSN: 1432-5233
DOI: https://doi.org/10.1007/s00592-014-0635-6

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Insulin and GH–IGF-I axis: endocrine pacer or endocrine disruptor?

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