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Growth Hormone and Counterregulation in the Pathogenesis of Diabetes

  • Pathogenesis of Type 2 Diabetes and Insulin Resistance (M-E Patti, Section Editor)
  • Published:
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Abstract

Purpose of Review

Canonical growth hormone (GH)-dependent signaling is essential for growth and counterregulatory responses to hypoglycemia, but also may contribute to glucose homeostasis (even in the absence of hypoglycemia) via its impact on metabolism of carbohydrates, lipids and proteins, body composition, and cardiovascular risk profile. The aim of this review is to summarize recent data implicating GH action in metabolic control, including both IGF-1-dependent and -independent pathways, and its potential role as target for T2D therapy.

Recent Findings

Experimental blockade of the GHR can modulate glucose metabolism. Moreover, the soluble form of the GH receptor (GHR, or GHBP) was recently identified as a mediator of improvement in glycemic control in patients with T2D randomized to bariatric surgery vs. medical therapy. Reductions in GHR were accompanied by increases in plasma GH, but unchanged levels of both total and free IGF-1. Likewise, hepatic GHR expression is reduced following both RYGB and VSG in rodents.

Summary

Emerging data indicate that GH signaling is important for regulation of long-term glucose metabolism in T2D. Future studies will be required to dissect tissue-specific GH signaling and sensitivity and their contributions to systemic glucose metabolism.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Libianto R, Ekinci EI. New agents for the treatment of type 2 diabetes. Crit Care Clin. 2019;35:315–28.

    Article  PubMed  Google Scholar 

  2. Simonson DC, Halperin F, Foster K, Vernon A, Goldfine AB. Clinical and patient-centered outcomes in obese patients with type 2 diabetes 3 years after randomization to Roux-en-Y gastric bypass surgery versus intensive lifestyle management: the SLIMM-T2D study. Diabetes Care. 2018;41:670–9.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Schauer PR, Bhatt DL, Kirwan JP, Wolski K, Aminian A, Brethauer SA, Navaneethan SD, Singh RP, Pothier CE, Nissen SE, Kashyap SR, Investigators S. Bariatric surgery versus intensive medical therapy for diabetes — 5-year outcomes. N Engl J Med. 2017;376:641–51.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Cummings DE, Arterburn DE, Westbrook EO, Kuzma JN, Stewart SD, Chan CP, Bock SN, Landers JT, Kratz M, Foster-Schubert KE, Flum DR. Gastric bypass surgery vs intensive lifestyle and medical intervention for type 2 diabetes: the CROSSROADS randomised controlled trial. Diabetologia. 2016;59:945–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Mingrone G, Panunzi S, De Gaetano A, Guidone C, Iaconelli A, Capristo E, Chamseddine G, Bornstein SR, Rubino F. Metabolic surgery versus conventional medical therapy in patients with type 2 diabetes: 10-year follow-up of an open-label, single-centre, randomised controlled trial. Lancet. 2021;397:293–304.

    Article  PubMed  Google Scholar 

  6. • Dreyfuss JM, Yuchi Y, Dong X, Efthymiou V, Pan H, Simonson DC, Vernon A, Halperin F, Aryal P, Konkar A, Sebastian Y, Higgs BW, Grimsby J, Rondinone CM, Kasif S, Kahn BB, Foster K, Seeley R, Goldfine A, Djordjilovic V, Patti ME. High-throughput mediation analysis of human proteome and metabolome identifies mediators of post-bariatric surgical diabetes control. Nat Commun. 2021;12:6951. This paper identified reductions in GHR as a mediator of metabolic changes after bariatric surgery in patients with T2D as well as increases in IGFBP1/2. Moreover, experimental modulation of GHR altered metabolism in hepatocytes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Waters MJ. The growth hormone receptor. Growth Horm IGF Res. 2016;28:6–10.

    Article  CAS  PubMed  Google Scholar 

  8. Argetsinger LS, Campbell GS, Yang X, Witthuhn BA, Silvennoinen O, Ihle JN, Carter-Su C. Identification of JAK2 as a growth hormone receptor-associated tyrosine kinase. Cell. 1993;74:237–44.

    Article  CAS  PubMed  Google Scholar 

  9. Carter-Su C, Schwartz J, Smit LS. Molecular mechanism of growth hormone action. Annu Rev Physiol. 1996;58:187–207.

    Article  CAS  PubMed  Google Scholar 

  10. Chia DJ, Ono M, Woelfle J, Schlesinger-Massart M, Jiang H, Rotwein P. Characterization of distinct Stat5b binding sites that mediate growth hormone-stimulated IGF-I gene transcription. J Biol Chem. 2006;281:3190–7.

    Article  CAS  PubMed  Google Scholar 

  11. Woelfle J, Chia DJ, Rotwein P. Mechanisms of growth hormone (GH) action. Identification of conserved Stat5 binding sites that mediate GH-induced insulin-like growth factor-I gene activation. J Biol Chem. 2003;278:51261–6.

    Article  CAS  PubMed  Google Scholar 

  12. Dehkhoda F, Lee CMM, Medina J, Brooks AJ. The growth hormone receptor: mechanism of receptor activation, cell signaling, and physiological aspects. Front Endocrinol (Lausanne). 2018;9:35.

    Article  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  14. Clemmons DR, Moses AC, McKay MJ, Sommer A, Rosen DM, Ruckle J. The combination of insulin-like growth factor I and insulin-like growth factor-binding protein-3 reduces insulin requirements in insulin-dependent type 1 diabetes: evidence for in vivo biological activity. J Clin Endocrinol Metab. 2000;85:1518–24.

    CAS  PubMed  Google Scholar 

  15. Kofoed EM, Hwa V, Little B, Woods KA, Buckway CK, Tsubaki J, Pratt KL, Bezrodnik L, Jasper H, Tepper A, Heinrich JJ, Rosenfeld RG. Growth hormone insensitivity associated with a STAT5b mutation. N Engl J Med. 2003;349:1139–47.

    Article  CAS  PubMed  Google Scholar 

  16. Moller N, Jorgensen JO. Effects of growth hormone on glucose, lipid, and protein metabolism in human subjects. Endocr Rev. 2009;30:152–77.

    Article  PubMed  CAS  Google Scholar 

  17. Clemmons DR. Metabolic actions of insulin-like growth factor-I in normal physiology and diabetes. Endocrinol Metab Clin N Am. 2012;41:425–43, vii-viii.

    Article  CAS  Google Scholar 

  18. Lu M, Flanagan JU, Langley RJ, Hay MP, Perry JK. Targeting growth hormone function: strategies and therapeutic applications. Signal Transduct Target Ther. 2019;4:3.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Vila G, Jorgensen JOL, Luger A, Stalla GK. Insulin resistance in patients with acromegaly. Front Endocrinol (Lausanne). 2019;10:509.

    Article  Google Scholar 

  20. • Pedersen MH, Svart MV, Lebeck J, Bidlingmaier M, Stodkilde-Jorgensen H, Pedersen SB, Moller N, Jessen N, Jorgensen JOL. Substrate metabolism and insulin sensitivity during fasting in obese human subjects: impact of GH blockade. J Clin Endocrinol Metab. 2017;102:1340–9. This clinical study demonstrated the short-term metabolic effects of GHR blockade with pegvisomant in humans with obesity.

    Article  PubMed  Google Scholar 

  21. Yakar S, Liu JL, Fernandez AM, Wu Y, Schally AV, Frystyk J, Chernausek SD, Mejia W, Le Roith D. Liver-specific igf-1 gene deletion leads to muscle insulin insensitivity. Diabetes. 2001;50:1110–8.

    Article  CAS  PubMed  Google Scholar 

  22. Haluzik M, Yakar S, Gavrilova O, Setser J, Boisclair Y, LeRoith D. Insulin resistance in the liver-specific IGF-1 gene-deleted mouse is abrogated by deletion of the acid-labile subunit of the IGF-binding protein-3 complex: relative roles of growth hormone and IGF-1 in insulin resistance. Diabetes. 2003;52:2483–9.

    Article  CAS  PubMed  Google Scholar 

  23. Yakar S, Setser J, Zhao H, Stannard B, Haluzik M, Glatt V, Bouxsein ML, Kopchick JJ, LeRoith D. Inhibition of growth hormone action improves insulin sensitivity in liver IGF-1-deficient mice. J Clin Invest. 2004;113:96–105.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Brooks AJ, Waters MJ. The growth hormone receptor: mechanism of activation and clinical implications. Nat Rev Endocrinol. 2010;6:515–25.

    Article  CAS  PubMed  Google Scholar 

  25. Zhu T, Ling L, Lobie PE. Identification of a JAK2-independent pathway regulating growth hormone (GH)-stimulated p44/42 mitogen-activated protein kinase activity. GH activation of Ral and phospholipase D is Src-dependent. J Biol Chem. 2002;277:45592–603.

    Article  CAS  PubMed  Google Scholar 

  26. Nielsen C, Gormsen LC, Jessen N, Pedersen SB, Moller N, Lund S, Jorgensen JO. Growth hormone signaling in vivo in human muscle and adipose tissue: impact of insulin, substrate background, and growth hormone receptor blockade. J Clin Endocrinol Metab. 2008;93:2842–50.

    Article  CAS  PubMed  Google Scholar 

  27. Jessen N, Djurhuus CB, Jorgensen JO, Jensen LS, Moller N, Lund S, Schmitz O. Evidence against a role for insulin-signaling proteins PI 3-kinase and Akt in insulin resistance in human skeletal muscle induced by short-term GH infusion. Am J Physiol Endocrinol Metab. 2005;288:E194-199.

    Article  CAS  PubMed  Google Scholar 

  28. Jorgensen JO, Jessen N, Pedersen SB, Vestergaard E, Gormsen L, Lund SA, Billestrup N. GH receptor signaling in skeletal muscle and adipose tissue in human subjects following exposure to an intravenous GH bolus. Am J Physiol Endocrinol Metab. 2006;291:E899-905.

    Article  PubMed  CAS  Google Scholar 

  29. Kopchick JJ, Berryman DE, Puri V, Lee KY, Jorgensen JOL. The effects of growth hormone on adipose tissue: old observations, new mechanisms. Nat Rev Endocrinol. 2020;16:135–46.

    Article  PubMed  Google Scholar 

  30. Sharma VM, Vestergaard ET, Jessen N, Kolind-Thomsen P, Nellemann B, Nielsen TS, Vendelbo MH, Moller N, Sharma R, Lee KY, Kopchick JJ, Jorgensen JOL, Puri V. Growth hormone acts along the PPARgamma-FSP27 axis to stimulate lipolysis in human adipocytes. Am J Physiol Endocrinol Metab. 2019;316:E34–42.

    Article  CAS  PubMed  Google Scholar 

  31. Wheatcroft SB, Kearney MT. IGF-dependent and IGF-independent actions of IGF-binding protein-1 and -2: implications for metabolic homeostasis. Trends Endocrinol Metab. 2009;20:153–62.

    Article  CAS  PubMed  Google Scholar 

  32. Yakar S, Liu JL, Stannard B, Butler A, Accili D, Sauer B, LeRoith D. Normal growth and development in the absence of hepatic insulin-like growth factor I. Proc Natl Acad Sci U S A. 1999;96:7324–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Hedbacker K, Birsoy K, Wysocki RW, Asilmaz E, Ahima RS, Farooqi IS, Friedman JM. Antidiabetic effects of IGFBP2, a leptin-regulated gene. Cell Metab. 2010;11:11–22.

    Article  CAS  PubMed  Google Scholar 

  34. Munzer T, Rosen CJ, Harman SM, Pabst KM, St Clair C, Sorkin JD, Blackman MR. Effects of GH and/or sex steroids on circulating IGF-I and IGFBPs in healthy, aged women and men. Am J Physiol Endocrinol Metab. 2006;290:E1006-1013.

    Article  CAS  PubMed  Google Scholar 

  35. Wheatcroft SB, Kearney MT, Shah AM, Ezzat VA, Miell JR, Modo M, Williams SC, Cawthorn WP, Medina-Gomez G, Vidal-Puig A, Sethi JK, Crossey PA. IGF-binding protein-2 protects against the development of obesity and insulin resistance. Diabetes. 2007;56:285–94.

    Article  CAS  PubMed  Google Scholar 

  36. Al-Regaiey K, Alshubrami S, Al-Beeshi I, Alnasser T, Alwabel A, Al-Beladi H, Al-Tujjar O, Alnasser A, Alfadda AA, Iqbal M. Effects of gastric sleeve surgery on the serum levels of GH, IGF-1 and IGF-binding protein 2 in healthy obese patients. BMC Gastroenterol. 2020;20:199.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Faramia J, Hao Z, Mumphrey MB, Townsend RL, Miard S, Carreau AM, Nadeau M, Frisch F, Baraboi ED, Grenier-Larouche T, Noll C, Li M, Biertho L, Marceau S, Hould FS, Lebel S, Morrison CD, Munzberg H, Richard D, Carpentier AC, Tchernof A, Berthoud HR, Picard F. IGFBP-2 partly mediates the early metabolic improvements caused by bariatric surgery. Cell Rep Med. 2021;2:100248.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Waters MJ, Shang CA, Behncken SN, Tam SP, Li H, Shen B, Lobie PE. Growth hormone as a cytokine. Clin Exp Pharmacol Physiol. 1999;26:760–4.

    Article  CAS  PubMed  Google Scholar 

  39. Lobie PE, Mertani H, Morel G, Morales-Bustos O, Norstedt G, Waters MJ. Receptor-mediated nuclear translocation of growth hormone. J Biol Chem. 1994;269:21330–9.

    Article  CAS  PubMed  Google Scholar 

  40. Mertani HC, Raccurt M, Abbate A, Kindblom J, Tornell J, Billestrup N, Usson Y, Morel G, Lobie PE. Nuclear translocation and retention of growth hormone. Endocrinology. 2003;144:3182–95.

    Article  CAS  PubMed  Google Scholar 

  41. Ardail D, Debon A, Perret-Vivancos C, Biol-N’Garagba MC, Krantic S, Lobie PE, Morel G. Growth hormone internalization in mitochondria decreases respiratory chain activity. Neuroendocrinology. 2010;91:16–26.

    Article  CAS  PubMed  Google Scholar 

  42. Herington AC, Ymer S, Stevenson J. Identification and characterization of specific binding proteins for growth hormone in normal human sera. J Clin Invest. 1986;77:1817–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Mannor DA, Winer LM, Shaw MA, Baumann G. Plasma growth hormone (GH)-binding proteins: effect on GH binding to receptors and GH action. J Clin Endocrinol Metab. 1991;73:30–4.

    Article  CAS  PubMed  Google Scholar 

  44. Milward A, Metherell L, Maamra M, Barahona MJ, Wilkinson IR, Camacho-Hubner C, Savage MO, Bidlingmaier M, Clark AJ, Ross RJ, Webb SM. Growth hormone (GH) insensitivity syndrome due to a GH receptor truncated after Box1, resulting in isolated failure of STAT 5 signal transduction. J Clin Endocrinol Metab. 2004;89:1259–66.

    Article  CAS  PubMed  Google Scholar 

  45. Kurtoglu S, Hatipoglu N. Growth hormone insensitivity: diagnostic and therapeutic approaches. J Endocrinol Invest. 2016;39:19–28.

    Article  CAS  PubMed  Google Scholar 

  46. Hansen BS, Hjorth S, Welinder BS, Skriver L, De Meyts P. The growth hormone (GH)-binding protein cloned from human IM-9 lymphocytes modulates the down-regulation of GH receptors by 22- and 20-kilodalton human GH in IM-9 lymphocytes and the biological effects of the hormone in Nb2 lymphoma cells. Endocrinology. 1993;133:2809–17.

    Article  CAS  PubMed  Google Scholar 

  47. Asada N, Takahashi Y, Honjo M. Effects of 22K or 20K human growth hormone on lipolysis, leptin production in adipocytes in the presence and absence of human growth hormone binding protein. Horm Res. 2000;54:203–7.

    CAS  PubMed  Google Scholar 

  48. Mullis PE, Eble A, Wagner JK, Holl RW, Silbergeld A, Laron Z. Effect of different serum concentrations of growth hormone-binding protein (GHBP) on the regulation of GH receptor/GHBP gene transcription in a human hepatoma cell line. Horm Res. 1997;47:73–80.

    Article  CAS  PubMed  Google Scholar 

  49. Amit T, Youdim MB, Hochberg Z. Clinical review 112: Does serum growth hormone (GH) binding protein reflect human GH receptor function? J Clin Endocrinol Metab. 2000;85:927–32.

    Article  CAS  PubMed  Google Scholar 

  50. Schilbach K, Bidlingmaier M. Growth hormone binding protein — physiological and analytical aspects. Best Pract Res Clin Endocrinol Metab. 2015;29:671–83.

    Article  CAS  PubMed  Google Scholar 

  51. Ezzat S, Forster MJ, Berchtold P, Redelmeier DA, Boerlin V, Harris AG. Acromegaly. Clinical and biochemical features in 500 patients. Medicine (Baltimore). 1994;73:233–40.

    Article  CAS  Google Scholar 

  52. Clemmons DR. Roles of insulin-like growth factor-I and growth hormone in mediating insulin resistance in acromegaly. Pituitary. 2002;5:181–3.

    Article  CAS  PubMed  Google Scholar 

  53. 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;31:663–9.

    Article  CAS  PubMed  Google Scholar 

  54. Higham CE, Rowles S, Russell-Jones D, Umpleby AM, Trainer PJ. Pegvisomant improves insulin sensitivity and reduces overnight free fatty acid concentrations in patients with acromegaly. J Clin Endocrinol Metab. 2009;94:2459–63.

    Article  CAS  PubMed  Google Scholar 

  55. Palmer AJ, Chung MY, List EO, Walker J, Okada S, Kopchick JJ, Berryman DE. Age-related changes in body composition of bovine growth hormone transgenic mice. Endocrinology. 2009;150:1353–60.

    Article  CAS  PubMed  Google Scholar 

  56. Kopchick JJ, Bellush LL, Coschigano KT. Transgenic models of growth hormone action. Annu Rev Nutr. 1999;19:437–61.

    Article  CAS  PubMed  Google Scholar 

  57. Holt RI, Simpson HL, Sonksen PH. The role of the growth hormone-insulin-like growth factor axis in glucose homeostasis. Diabet Med. 2003;20:3–15.

    Article  CAS  PubMed  Google Scholar 

  58. • Young J, Bell S, Qian Y, Hyman C, Berryman DE. Mouse models of growth hormone insensitivity. Rev Endocr Metab Disord. 2021;22:17–29. This is a comprehensive review of GH resistance and its effects on systemic metabolism.

    Article  CAS  PubMed  Google Scholar 

  59. Laron Z, Ginsberg S, Lilos P, Arbiv M, Vaisman N. Body composition in untreated adult patients with Laron syndrome (primary GH insensitivity). Clin Endocrinol (Oxf). 2006;65:114–7.

    Article  CAS  Google Scholar 

  60. Junnila RK, Duran-Ortiz S, Suer O, Sustarsic EG, Berryman DE, List EO, Kopchick JJ. Disruption of the GH receptor gene in adult mice increases maximal lifespan in females. Endocrinology. 2016;157:4502–13.

    Article  CAS  PubMed  Google Scholar 

  61. Fan Y, Menon RK, Cohen P, Hwang D, Clemens T, DiGirolamo DJ, Kopchick JJ, Le Roith D, Trucco M, Sperling MA. Liver-specific deletion of the growth hormone receptor reveals essential role of growth hormone signaling in hepatic lipid metabolism. J Biol Chem. 2009;284:19937–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. List EO, Berryman DE, Funk K, Jara A, Kelder B, Wang F, Stout MB, Zhi X, Sun L, White TA, LeBrasseur NK, Pirtskhalava T, Tchkonia T, Jensen EA, Zhang W, Masternak MM, Kirkland JL, Miller RA, Bartke A, Kopchick JJ. Liver-specific GH receptor gene-disrupted (LiGHRKO) mice have decreased endocrine IGF-I, increased local IGF-I, and altered body size, body composition, and adipokine profiles. Endocrinology. 2014;155:1793–805.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. List EO, Berryman DE, Buchman M, Parker C, Funk K, Bell S, Duran-Ortiz S, Qian Y, Young JA, Wilson C, Slyby J, McKenna S, Jensen EA, Kopchick JJ. Adipocyte-specific GH receptor-null (AdGHRKO) mice have enhanced insulin sensitivity with reduced liver triglycerides. Endocrinology. 2019;160:68–80.

    Article  CAS  PubMed  Google Scholar 

  64. List EO, Berryman DE, Funk K, Gosney ES, Jara A, Kelder B, Wang X, Kutz L, Troike K, Lozier N, Mikula V, Lubbers ER, Zhang H, Vesel C, Junnila RK, Frank SJ, Masternak MM, Bartke A, Kopchick JJ. The role of GH in adipose tissue: lessons from adipose-specific GH receptor gene-disrupted mice. Mol Endocrinol. 2013;27:524–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Vijayakumar A, Wu Y, Sun H, Li X, Jeddy Z, Liu C, Schwartz GJ, Yakar S, LeRoith D. Targeted loss of GHR signaling in mouse skeletal muscle protects against high-fat diet-induced metabolic deterioration. Diabetes. 2012;61:94–103.

    Article  CAS  PubMed  Google Scholar 

  66. Wu Y, Liu C, Sun H, Vijayakumar A, Giglou PR, Qiao R, Oppenheimer J, Yakar S, LeRoith D. Growth hormone receptor regulates beta cell hyperplasia and glucose-stimulated insulin secretion in obese mice. J Clin Invest. 2011;121:2422–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Lu C, Kumar PA, Sun J, Aggarwal A, Fan Y, Sperling MA, Lumeng CN, Menon RK. Targeted deletion of growth hormone (GH) receptor in macrophage reveals novel osteopontin-mediated effects of GH on glucose homeostasis and insulin sensitivity in diet-induced obesity. J Biol Chem. 2013;288:15725–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Young JA, Jensen EA, Stevens A, Duran-Ortiz S, List EO, Berryman DE, Kopchick JJ. Characterization of an intestine-specific GH receptor knockout (IntGHRKO) mouse. Growth Horm IGF Res. 2019;46–47:5–15.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. List EO, Berryman DE, Ikeno Y, Hubbard GB, Funk K, Comisford R, Young JA, Stout MB, Tchkonia T, Masternak MM, Bartke A, Kirkland JL, Miller RA, Kopchick JJ. Removal of growth hormone receptor (GHR) in muscle of male mice replicates some of the health benefits seen in global GHR−/− mice. Aging (Albany NY). 2015;7:500–12.

    Article  CAS  Google Scholar 

  70. Jara A, Liu X, Sim D, Benner CM, Duran-Ortiz S, Qian Y, List EO, Berryman DE, Kim JK, Kopchick JJ. Cardiac-specific disruption of GH receptor alters glucose homeostasis while maintaining normal cardiac performance in adult male mice. Endocrinology. 2016;157:1929–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. List EO, Duran-Ortiz S, Kopchick JJ. Effects of tissue-specific GH receptor knockouts in mice. Mol Cell Endocrinol. 2020;515:110919.

    Article  CAS  PubMed  Google Scholar 

  72. Furigo IC, Teixeira PDS, de Souza GO, Couto GCL, Romero GG, Perello M, Frazao R, Elias LL, Metzger M, List EO, Kopchick JJ, Donato J Jr. Growth hormone regulates neuroendocrine responses to weight loss via AgRP neurons. Nat Commun. 2019;10:662.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Cady G, Landeryou T, Garratt M, Kopchick JJ, Qi N, Garcia-Galiano D, Elias CF, Myers MG Jr, Miller RA, Sandoval DA, Sadagurski M. Hypothalamic growth hormone receptor (GHR) controls hepatic glucose production in nutrient-sensing leptin receptor (LepRb) expressing neurons. Mol Metab. 2017;6:393–405.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Lee KY, Russell SJ, Ussar S, Boucher J, Vernochet C, Mori MA, Smyth G, Rourk M, Cederquist C, Rosen ED, Kahn BB, Kahn CR. Lessons on conditional gene targeting in mouse adipose tissue. Diabetes. 2013;62:864–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Scacchi M, Pincelli AI, Cavagnini F. Growth hormone in obesity. Int J Obes Relat Metab Disord. 1999;23:260–71.

    Article  CAS  PubMed  Google Scholar 

  76. Iranmanesh A, Lizarralde G, Veldhuis JD. Age and relative adiposity are specific negative determinants of the frequency and amplitude of growth hormone (GH) secretory bursts and the half-life of endogenous GH in healthy men. J Clin Endocrinol Metab. 1991;73:1081–8.

    Article  CAS  PubMed  Google Scholar 

  77. Veldhuis JD, Liem AY, South S, Weltman A, Weltman J, Clemmons DA, Abbott R, Mulligan T, Johnson ML, Pincus S, et al. Differential impact of age, sex steroid hormones, and obesity on basal versus pulsatile growth hormone secretion in men as assessed in an ultrasensitive chemiluminescence assay. J Clin Endocrinol Metab. 1995;80:3209–22.

    CAS  PubMed  Google Scholar 

  78. Garlaschi C, di Natale B, del Guercio MJ, Caccamo A, Gargantini L, Chiumello G. Effect of physical exercise on secretion of growth hormone, glucagon, and cortisol in obese and diabetic children. Diabetes. 1975;24:758–61.

    Article  CAS  PubMed  Google Scholar 

  79. Ferini-Strambi L, Franceschi M, Cattaneo AG, Smirne S, Calori G, Caviezel F. Sleep-related growth hormone secretion in human obesity: effect of dietary treatment. Neuroendocrinology. 1991;54:412–5.

    Article  CAS  PubMed  Google Scholar 

  80. Vahl N, Jorgensen JO, Skjaerbaek C, Veldhuis JD, Orskov H, Christiansen JS. Abdominal adiposity rather than age and sex predicts mass and regularity of GH secretion in healthy adults. Am J Physiol. 1997;272:E1108-1116.

    CAS  PubMed  Google Scholar 

  81. Clasey JL, Weltman A, Patrie J, Weltman JY, Pezzoli S, Bouchard C, Thorner MO, Hartman ML. Abdominal visceral fat and fasting insulin are important predictors of 24-hour GH release independent of age, gender, and other physiological factors. J Clin Endocrinol Metab. 2001;86:3845–52.

    Article  CAS  PubMed  Google Scholar 

  82. Roelen CA, Koppeschaar HP, de Vries WR, Snel YE, Doerga ME, Zelissen PM, Thijssen JH, Blankenstein MA. Visceral adipose tissue is associated with circulating high affinity growth hormone-binding protein. J Clin Endocrinol Metab. 1997;82:760–4.

    Article  CAS  PubMed  Google Scholar 

  83. Hochberg Z, Hertz P, Colin V, Ish-Shalom S, Yeshurun D, Youdim MB, Amit T. The distal axis of growth hormone (GH) in nutritional disorders: GH-binding protein, insulin-like growth factor-I (IGF-I), and IGF-I receptors in obesity and anorexia nervosa. Metabolism. 1992;41:106–12.

    Article  CAS  PubMed  Google Scholar 

  84. Kratzsch J, Dehmel B, Pulzer F, Keller E, Englaro P, Blum WF, Wabitsch M. Increased serum GHBP levels in obese pubertal children and adolescents: relationship to body composition, leptin and indicators of metabolic disturbances. Int J Obes Relat Metab Disord. 1997;21:1130–6.

    Article  CAS  PubMed  Google Scholar 

  85. Rasmussen MH, Ho KK, Kjems L, Hilsted J. Serum growth hormone-binding protein in obesity: effect of a short-term, very low calorie diet and diet-induced weight loss. J Clin Endocrinol Metab. 1996;81:1519–24.

    CAS  PubMed  Google Scholar 

  86. Fernandez-Real JM, Granada ML, Ruzafa A, Casamitjana R, Ricart W. Insulin sensitivity and secretion influence the relationship between growth hormone-binding-protein and leptin. Clin Endocrinol (Oxf). 2000;52:159–64.

    Article  CAS  Google Scholar 

  87. Erman A, Veilleux A, Tchernof A, Goodyer CG. Human growth hormone receptor (GHR) expression in obesity: I. GHR mRNA expression in omental and subcutaneous adipose tissues of obese women. Int J Obes (Lond). 2011;35:1511–9.

    Article  CAS  Google Scholar 

  88. Postel-Vinay MC, Saab C, Gourmelen M. Nutritional status and growth hormone-binding protein. Horm Res. 1995;44:177–81.

    Article  CAS  PubMed  Google Scholar 

  89. Nam SY, Lee EJ, Kim KR, Cha BS, Song YD, Lim SK, Lee HC, Huh KB. Effect of obesity on total and free insulin-like growth factor (IGF)-1, and their relationship to IGF-binding protein (BP)-1, IGFBP-2, IGFBP-3, insulin, and growth hormone. Int J Obes Relat Metab Disord. 1997;21:355–9.

    Article  CAS  PubMed  Google Scholar 

  90. Minuto F, Barreca A, Del Monte P, Fortini P, Resentini M, Morabito F, Giordano G. Spontaneous growth hormone and somatomedin-C/insulin-like growth factor-I secretion in obese subjects during puberty. J Endocrinol Invest. 1988;11:489–95.

    Article  CAS  PubMed  Google Scholar 

  91. Skaggs SR, Crist DM. Exogenous human growth hormone reduces body fat in obese women. Horm Res. 1991;35:19–24.

    Article  CAS  PubMed  Google Scholar 

  92. Van Vliet G, Bosson D, Rummens E, Robyn C, Wolter R. Evidence against growth hormone-releasing factor deficiency in children with idiopathic obesity. Acta Endocrinol Suppl (Copenh). 1986;279:403–10.

    Article  Google Scholar 

  93. Loche S, Cappa M, Borrelli P, Faedda A, Crino A, Cella SG, Corda R, Muller EE, Pintor C. Reduced growth hormone response to growth hormone-releasing hormone in children with simple obesity: evidence for somatomedin-C mediated inhibition. Clin Endocrinol (Oxf). 1987;27:145–53.

    Article  CAS  Google Scholar 

  94. Frystyk J, Vestbo E, Skjaerbaek C, Mogensen CE, Orskov H. Free insulin-like growth factors in human obesity. Metabolism. 1995;44:37–44.

    Article  CAS  PubMed  Google Scholar 

  95. Argente J, Caballo N, Barrios V, Pozo J, Munoz MT, Chowen JA, Hernandez M. Multiple endocrine abnormalities of the growth hormone and insulin-like growth factor axis in prepubertal children with exogenous obesity: effect of short- and long-term weight reduction. J Clin Endocrinol Metab. 1997;82:2076–83.

    CAS  PubMed  Google Scholar 

  96. Maccario M, Tassone F, Gauna C, Oleandri SE, Aimaretti G, Procopio M, Grottoli S, Pflaum CD, Strasburger CJ, Ghigo E. Effects of short-term administration of low-dose rhGH on IGF-I levels in obesity and Cushing’s syndrome: indirect evaluation of sensitivity to GH. Eur J Endocrinol. 2001;144:251–6.

    Article  CAS  PubMed  Google Scholar 

  97. Jorgensen JO, Pedersen SB, Borglum J, Frystyk J, Ho KK, Christiansen JS, Orskov H, Blum WF, Richelsen B. Serum concentrations of insulin-like growth factors (IGFs), IGF binding proteins 1 and 3 and growth hormone binding protein in obese women and the effects of growth hormone administration: a double-blind, placebo-controlled study. Eur J Endocrinol. 1995;133:65–70.

    Article  CAS  PubMed  Google Scholar 

  98. Muller AF, Kopchick JJ, Flyvbjerg A, van der Lely AJ. Clinical review 166: growth hormone receptor antagonists. J Clin Endocrinol Metab. 2004;89:1503–11.

    Article  CAS  PubMed  Google Scholar 

  99. Lee AP, Mulligan K, Schambelan M, Murphy EJ, Weiss EJ. Growth hormone receptor antagonism with pegvisomant in insulin resistant non-diabetic men: a phase II pilot study. F1000Res. 2017;6:614.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  100. Winter RJ, Phillips LS, Klein MN, Traisman HS, Green OC. Somatomedin activity and diabetic control in children with insulin-dependent diabetes. Diabetes. 1979;28:952–4.

    Article  CAS  PubMed  Google Scholar 

  101. Rogers DG, Sherman LD, Gabbay KH. Effect of puberty on insulinlike growth factor I and HbA1 in type I diabetes. Diabetes Care. 1991;14:1031–5.

    Article  CAS  PubMed  Google Scholar 

  102. Mercado M, Molitch ME, Baumann G. Low plasma growth hormone binding protein in IDDM. Diabetes. 1992;41:605–9.

    Article  CAS  PubMed  Google Scholar 

  103. Kratzsch J, Keliner K, Zilkens T, Schmidt-Gayk H, Selisko T, Scholz GH. Growth hormone-binding protein related immunoreactivity is regulated by the degree of insulinopenia in diabetes mellitus. Clin Endocrinol (Oxf). 1996;44:673–8.

    Article  CAS  Google Scholar 

  104. Frystyk J, Skjaerbaek C, Vestbo E, Fisker S, Orskov H. Circulating levels of free insulin-like growth factors in obese subjects: the impact of type 2 diabetes. Diabetes Metab Res Rev. 1999;15:314–22.

    Article  CAS  PubMed  Google Scholar 

  105. Hanaire-Broutin H, Sallerin-Caute B, Poncet MF, Tauber M, Bastide R, Chale JJ, Rosenfeld R, Tauber JP. Effect of intraperitoneal insulin delivery on growth hormone binding protein, insulin-like growth factor (IGF)-I, and IGF-binding protein-3 in IDDM. Diabetologia. 1996;39:1498–504.

    Article  CAS  PubMed  Google Scholar 

  106. Thankamony A, Tossavainen PH, Sleigh A, Acerini C, Elleri D, Dalton RN, Jackson NC, Umpleby AM, Williams RM, Dunger DB. Short-term administration of pegvisomant improves hepatic insulin sensitivity and reduces soleus muscle intramyocellular lipid content in young adults with type 1 diabetes. J Clin Endocrinol Metab. 2014;99:639–47.

    Article  CAS  PubMed  Google Scholar 

  107. Storr HL, Chatterjee S, Metherell LA, Foley C, Rosenfeld RG, Backeljauw PF, Dauber A, Savage MO, Hwa V. Nonclassical GH insensitivity: characterization of mild abnormalities of GH action. Endocr Rev. 2019;40:476–505.

    Article  PubMed  Google Scholar 

  108. Soendergaard C, Young JA, Kopchick JJ. Growth hormone resistance—special focus on inflammatory bowel disease. Int J Mol Sci. 2017;18(5):1019. https://doi.org/10.3390/ijms18051019.

  109. Yamamoto M, Iguchi G, Fukuoka H, Suda K, Bando H, Takahashi M, Nishizawa H, Seino S, Takahashi Y. SIRT1 regulates adaptive response of the growth hormone—insulin-like growth factor-I axis under fasting conditions in liver. Proc Natl Acad Sci U S A. 2013;110:14948–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Ben-Zvi D, Meoli L, Abidi WM, Nestoridi E, Panciotti C, Castillo E, Pizarro P, Shirley E, Gourash WF, Thompson CC, Munoz R, Clish CB, Anafi RC, Courcoulas AP, Stylopoulos N. Time-dependent molecular responses differ between gastric bypass and dieting but are conserved across species. Cell Metab. 2018;28:310-323 e316.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Davey HW, Xie T, McLachlan MJ, Wilkins RJ, Waxman DJ, Grattan DR. STAT5b is required for GH-induced liver IGF-I gene expression. Endocrinology. 2001;142:3836–41.

    Article  CAS  PubMed  Google Scholar 

  112. Udy GB, Towers RP, Snell RG, Wilkins RJ, Park SH, Ram PA, Waxman DJ, Davey HW. Requirement of STAT5b for sexual dimorphism of body growth rates and liver gene expression. Proc Natl Acad Sci U S A. 1997;94:7239–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Greenhalgh CJ, Metcalf D, Thaus AL, Corbin JE, Uren R, Morgan PO, Fabri LJ, Zhang JG, Martin HM, Willson TA, Billestrup N, Nicola NA, Baca M, Alexander WS, Hilton DJ. Biological evidence that SOCS-2 can act either as an enhancer or suppressor of growth hormone signaling. J Biol Chem. 2002;277:40181–4.

    Article  CAS  PubMed  Google Scholar 

  114. Heidt AB, Black BL. Transgenic mice that express Cre recombinase under control of a skeletal muscle-specific promoter from mef2c. Genesis. 2005;42:28–32.

    Article  CAS  PubMed  Google Scholar 

  115. Nagarajan A, Srivastava H, Jablonsky J, Sun LY. Tissue-specific GHR knockout mice: an updated review. Front Endocrinol (Lausanne). 2020;11:579909.

    Article  Google Scholar 

  116. Seminara S, Filpo A, La Cauza F, Faedda A, Miola A, Pellizzone S, Casati M, Loche S. Growth hormone binding protein activity in obese children. J Endocrinol Invest. 1998;21:441–4.

    Article  CAS  PubMed  Google Scholar 

  117. Saitoh H, Kamoda T, Nakahara S, Hirano T, Nakamura N. Serum concentrations of insulin, insulin-like growth factor(IGF)-I, IGF binding protein (IGFBP)-1 and -3 and growth hormone binding protein in obese children: fasting IGFBP-1 is suppressed in normoinsulinaemic obese children. Clin Endocrinol (Oxf). 1998;48:487–92.

    Article  CAS  Google Scholar 

  118. Nam SY, Kim KR, Song YD, Lim SK, Lee HC, Huh KB. GH-binding protein in obese men with varying glucose tolerance: relationship to body fat distribution, insulin secretion and the GH-IGF-I axis. Eur J Endocrinol. 1999;140:159–63.

    Article  CAS  PubMed  Google Scholar 

  119. Arslanian SA, Menon RK, Gierl AP, Heil BV, Foley TP Jr. Insulin therapy increases low plasma growth hormone binding protein in children with new-onset type 1 diabetes. Diabet Med. 1993;10:833–8.

    Article  CAS  PubMed  Google Scholar 

  120. Holl RW, Siegler B, Scherbaum WA, Heinze E. The serum growth hormone-binding protein is reduced in young patients with insulin-dependent diabetes mellitus. J Clin Endocrinol Metab. 1993;76:165–7.

    CAS  PubMed  Google Scholar 

  121. Massa G, Dooms L, Bouillon R, Vanderschueren-Lodeweyckx M. Serum levels of growth hormone-binding protein and insulin-like growth factor I in children and adolescents with type 1 (insulin-dependent) diabetes mellitus. Diabetologia. 1993;36:239–43.

    Article  CAS  PubMed  Google Scholar 

  122. Menon RK, Arslanian S, May B, Cutfield WS, Sperling MA. Diminished growth hormone-binding protein in children with insulin-dependent diabetes mellitus. J Clin Endocrinol Metab. 1992;74:934–8.

    Article  CAS  PubMed  Google Scholar 

  123. Clayton KL, Holly JM, Carlsson LM, Jones J, Cheetham TD, Taylor AM, Dunger DB. Loss of the normal relationships between growth hormone, growth hormone-binding protein and insulin-like growth factor-I in adolescents with insulin-dependent diabetes mellitus. Clin Endocrinol (Oxf). 1994;41:517–24.

    Article  CAS  Google Scholar 

  124. Munoz MT, Barrios V, Pozo J, Argente J. Insulin-like growth factor I, its binding proteins 1 and 3, and growth hormone-binding protein in children and adolescents with insulin-dependent diabetes mellitus: clinical implications. Pediatr Res. 1996;39:992–8.

    Article  CAS  PubMed  Google Scholar 

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Funding

X. D. received funding from the Zhejiang Provincial Natural Science Foundation of China (Grant No. LY21H070002). L. S. received funding from National Natural Science Foundation of China (Award No. 81701367). M. E. P. received grant support related to this project from National Institutes of Health R01 DK121995 and P30 DK036836 (DRC, Joslin Diabetes Center).

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  1. Xuehong Dong

    Present address: Department of Endocrinology, Diabetes & Metabolism, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China

  2. Lei Su

    Present address: Department of Geriatrics, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China

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  1. Integrative Physiology and Metabolism, Research Division, Joslin Diabetes Center, Boston, MA, USA

    Xuehong Dong, Lei Su & Mary-Elizabeth Patti

  2. Harvard Medical School, Boston, MA, USA

    Xuehong Dong, Lei Su & Mary-Elizabeth Patti

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X. D. and L. S. declare that they have no conflict of interest related to this manuscript. M. E. P. reports personal fees from Astra Zeneca, Fractyl, Hanmi Pharmaceutical, MBX Biosciences, Recordati, Poxel, Eiger Pharmaceuticals, and Xeris and grants from Chan-Zuckerberg Initiative, Dexcom, and Helmsley Trust, outside the submitted work.

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Dong, X., Su, L. & Patti, ME. Growth Hormone and Counterregulation in the Pathogenesis of Diabetes. Curr Diab Rep 22, 511–524 (2022). https://doi.org/10.1007/s11892-022-01488-7

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