Skip to main content

Advertisement

SpringerLink
Log in

IGF-I overexpression does not promote compensatory islet cell growth in diet-induced obesity

  • Original Article
  • Published:
Endocrine Aims and scope Submit manuscript

Abstract

Although IGF-I was known to stimulate the growth of pancreatic islet cells from early in vitro experiments and in vivo reports on rodents, recent gene targeting experiments have indicated that IGF-I and its receptor do not play a major role in normal islet cell growth. In our previous reports, liver- or pancreatic-specific IGF-I deficiency caused no decrease in β-cell mass; a general and β-cell-enriched IGF-I overexpression caused no change in normal islet cell growth. On the other hand, increased metabolic demands (such as in obesity and insulin resistance) result in β-cell compensation in cell number and insulin secretion. In order to test whether IGF-I could promote islet cell growth and facilitate islet compensation due to obesity-induced insulin resistance, we have challenged MT-IGF mice to a high-fat diet. After 28 weeks, both MT-IGF mice and wild-type littermates gained comparable 40–57% of body weight, with similar increases in fat masses; all mice maintained a normal sensitivity to insulin and did not become severely hyperglycemic. Nevertheless, compared to wild-type littermates, the equally obese MT-IGF mice maintained improved glucose tolerance and a diminished insulin level; similar to when fed a normal chow diet. More importantly, under IGF-I overexpression, there was no further increase in β-cell mass caused by obesity. Thus, IGF-I overexpression had no significant effect on weight gain and islet cell compensation in response to high-fat diet-induced obesity.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. D. LeRoith, Insulin-like growth factors. N. Engl. J. Med. 336, 633–640 (1997)

    Article  CAS  Google Scholar 

  2. J.P. Liu, J. Baker, A.S. Perkins, E.J. Robertson, A. Efstratiadis, Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-1) and type 1 IGF receptor (Igf1r). Cell 75, 59–72 (1993)

    CAS  PubMed  Google Scholar 

  3. L. Powell-Braxton, P. Hollingshead, C. Warburton et al., IGF-I is required for normal embryonic growth in mice. Genes Dev. 7, 2609–2617 (1993)

    Article  CAS  PubMed  Google Scholar 

  4. J.L. Liu, D. LeRoith, Insulin-like growth factor I is essential for postnatal growth in response to growth hormone. Endocrinology 140, 5178–5184 (1999)

    Article  CAS  PubMed  Google Scholar 

  5. A. Rabinovitch, C. Quigley, T. Russell, Y. Patel, D.H. Mintz, Insulin and multiplication stimulating activity (an insulin-like growth factor) stimulate Islet beta-cell replication in neonatal rat pancreatic monolayer cultures. Diabetes 31, 160–164 (1982)

    Article  CAS  PubMed  Google Scholar 

  6. S.R. Hugl, M.F. White, C.J. Rhodes, Insulin-like growth factor I (IGF-I)-stimulated pancreatic beta-cell growth is glucose-dependent. Synergistic activation of insulin receptor substrate-mediated signal transduction pathways by glucose and IGF-I in INS-1 cells. J. Biol. Chem. 273, 17771–17779 (1998)

    Article  CAS  PubMed  Google Scholar 

  7. M. George, E. Ayuso, A. Casellas, C. Costa, J.C. Devedjian, F. Bosch, Beta cell expression of IGF-I leads to recovery from type 1 diabetes. J. Clin. Invest. 109, 1153–1163 (2002)

    CAS  PubMed  Google Scholar 

  8. R.N. Kulkarni, M. Holzenberger, D.Q. Shih et al., Beta-cell-specific deletion of the Igf1 receptor leads to hyperinsulinemia and glucose intolerance but does not alter beta-cell mass. Nat. Genet. 31, 111–115 (2002)

    CAS  PubMed  Google Scholar 

  9. S. Xuan, T. Kitamura, J. Nakae et al., Defective insulin secretion in pancreatic beta cells lacking type 1 IGF receptor. J. Clin. Invest. 110, 1011–1019 (2002)

    CAS  PubMed  Google Scholar 

  10. J.L. Liu, Does IGF-I stimulate pancreatic islet cell growth? Cell. Biochem. Biophy. 48, 115–125 (2007)

    Article  CAS  Google Scholar 

  11. R. Yu, S. Yakar, Y.L. Liu et al., Liver-specific IGF-I gene deficient mice exhibit accelerated diabetes in response to streptozotocin, associated with early onset of insulin resistance. Mol. Cell. Endocrinol. 204, 31–42 (2003)

    Article  CAS  PubMed  Google Scholar 

  12. Y. Lu, P.L. Herrera, Y. Guo et al., Pancreatic-specific inactivation of IGF-I gene causes enlarged pancreatic islets and significant resistance to diabetes. Diabetes 53, 3131–3141 (2004)

    Article  CAS  PubMed  Google Scholar 

  13. K. Robertson, Y. Lu, K. De Jesus et al., A general and islet cell-enriched overexpression of IGF-I results in normal islet cell growth, hypoglycemia, and significant resistance to experimental diabetes. Am. J. Physiol. Endocrinol. Metab. 294, E928–E938 (2008)

    Article  CAS  PubMed  Google Scholar 

  14. J. Nielsen, E. Galsgaard, A. Moldrup et al., Regulation of beta-cell mass by hormones and growth factors. Diabetes 50, S25–S29 (2001)

    Article  CAS  PubMed  Google Scholar 

  15. M. Johansson, G. Mattsson, A. Andersson, L. Jansson, P.O. Carlsson, Islet endothelial cells and pancreatic beta-cell proliferation: studies in vitro and during pregnancy in adult rats. Endocrinology 147, 2315–2324 (2006)

    Article  CAS  PubMed  Google Scholar 

  16. J.H. Nielsen, S. Linde, B.S. Welinder, N. Billestrup, O.D. Madsen, Growth hormone is a growth factor for the differentiated pancreatic beta-cell. Mol. Endocrinol. 3, 165–173 (1989)

    Article  CAS  PubMed  Google Scholar 

  17. C. Huang, F. Snider, J.C. Cross, Prolactin receptor is required for normal glucose homeostasis and modulation of beta-cell mass during pregnancy. Endocrinology 150, 1618–1626 (2009)

    Article  CAS  PubMed  Google Scholar 

  18. R.L. Sorenson, T.C. Brelje, Adaptation of islets of Langerhans to pregnancy: beta-cell growth, enhanced insulin secretion and the role of lactogenic hormones. Horm. Metab. Res. (Hormon- und Stoffwechselforschung) 29, 301–307 (1997)

    Article  CAS  Google Scholar 

  19. K. Robertson, J.J. Kopchick, J.L. Liu, Growth hormone receptor gene deficiency causes delayed insulin responsiveness in skeletal muscles without affecting compensatory islet cell overgrowth in obese mice. Am. J. Physiol. Endocrinol. Metab. 291, E491–E498 (2006)

    Article  CAS  PubMed  Google Scholar 

  20. K. Ohneda, M.H. Ulshen, C.R. Fuller, A.J. D’Ercole, P.K. Lund, Enhanced growth of small bowel in transgenic mice expressing human insulin-like growth factor I. Gastroenterology 112, 444–454 (1997)

    Article  CAS  PubMed  Google Scholar 

  21. P. Ye, J. Carson, A.J. D’Ercole, In vivo actions of insulin-like growth factor-I (IGF-I) on brain myelination: studies of IGF-I and IGF binding protein-1 (IGFBP-1) transgenic mice. J. Neurosci. 15, 7344–7356 (1995)

    CAS  PubMed  Google Scholar 

  22. J.L. Liu, K.T. Coschigano, K. Robertson et al., Disruption of growth hormone receptor gene causes diminished pancreatic islet size and increased insulin sensitivity in mice. Am. J. Physiol. 287, E405–E413 (2004)

    CAS  Google Scholar 

  23. L.S. Mathews, R.E. Hammer, R.R. Behringer et al., Growth enhancement of transgenic mice expressing human insulin-like growth factor I. Endocrinology 123, 2827–2833 (1988)

    Article  CAS  PubMed  Google Scholar 

  24. K. De Jesus, X. Wang, J.L. Liu, A general IGF-I overexpression effectively rescued somatic growth and bone deficiency in mice caused by growth hormone receptor knockout. Growth Factors (2009) (in press)

  25. T. Okada, C.W. Liew, J. Hu, et al., Insulin receptors in beta-cells are critical for islet compensatory growth response to insulin resistance. Proc. Natl Acad. Sci. USA 104, 8977–8982 (2007)

    Article  CAS  PubMed  Google Scholar 

  26. F.M. Gregoire, C.M. Smas, H.S. Sul, Understanding adipocyte differentiation. Physiol. Rev. 78, 783–809 (1998)

    CAS  PubMed  Google Scholar 

  27. D.B. Hausman, M. DiGirolamo, T.J. Bartness, G.J. Hausman, R.J. Martin, The biology of white adipocyte proliferation. Obes. Rev. 2, 239–254 (2001)

    Article  CAS  PubMed  Google Scholar 

  28. J. Nougues, Y. Reyne, B. Barenton, T. Chery, V. Garandel, J. Soriano, Differentiation of adipocyte precursors in a serum-free medium is influenced by glucocorticoids and endogenously produced insulin-like growth factor-I. Int. J. Obes. Relat. Metab. Disord. 17, 159–167 (1993)

    CAS  PubMed  Google Scholar 

  29. T.G. Ramsay, M.E. White, C.K. Wolverton, Insulin-like growth factor 1 induction of differentiation of porcine preadipocytes. J. Anim. Sci. 67, 2452–2459 (1989)

    CAS  PubMed  Google Scholar 

  30. W. Schmidt, G. Poll-Jordan, G. Loffler, Adipose conversion of 3T3-L1 cells in a serum-free culture system depends on epidermal growth factor, insulin-like growth factor I, corticosterone, and cyclic AMP. J. Biol. Chem. 265, 15489–15495 (1990)

    CAS  PubMed  Google Scholar 

  31. P.J. Smith, L.S. Wise, R. Berkowitz, C. Wan, C.S. Rubin, Insulin-like growth factor-I is an essential regulator of the differentiation of 3T3–L1 adipocytes. J. Biol. Chem. 263, 9402–9408 (1988)

    CAS  PubMed  Google Scholar 

  32. A. Lukanova, S. Soderberg, P. Stattin et al., Nonlinear relationship of insulin-like growth factor (IGF)-I and IGF-I/IGF-binding protein-3 ratio with indices of adiposity and plasma insulin concentrations (Sweden). Cancer Causes Control 13, 509–516 (2002)

    Article  PubMed  Google Scholar 

  33. A. Doglio, C. Dani, G. Fredrikson, P. Grimaldi, G. Ailhaud, Acute regulation of insulin-like growth factor-I gene expression by growth hormone during adipose cell differentiation. EMBO J. 6, 4011–4016 (1987)

    CAS  PubMed  Google Scholar 

  34. K. Sjogren, K. Wallenius, J.L. Liu et al., Liver-derived IGF-I is of importance for normal carbohydrate and lipid metabolism. Diabetes 50, 1539–1545 (2001)

    Article  CAS  PubMed  Google Scholar 

  35. M. Scacchi, A.I. Pincelli, F. Cavagnini, Growth hormone in obesity. Int. J. Obes. Relat. Metab. Disord. 23, 260–271 (1999)

    Article  CAS  PubMed  Google Scholar 

  36. Y. Guo, Y. Lu, D. Houle et al., Pancreatic islet-specific expression of an IGF-I transgene compensates islet cell growth in growth hormone receptor gene deficient mice. Endocrinology 146, 2602–2609 (2005)

    Article  CAS  PubMed  Google Scholar 

  37. M.S. Islam, T. Loots du, Diabetes, metallothionein, and zinc interactions: a review. Biofactors 29, 203–212 (2007)

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgment

This work was supported by funding from Canadian Institutes of Health Research (MOP-84389), National Science and Engineering Research Council of Canada (341205-07), and Qingdao Municipal of Science and Technology Commission (NO. 07-2-1-4-nsh), Shandong, China. Scholarship support to JLL was provided by JR & CM Fraser Memorial Fund and Fonds de la recherché en santé Quebec. KR received studentship support from MUHC Research Institute. MT-IGF mice were provided by Dr. J. D’Ercole of University of North Carolina.

Author information

Authors and Affiliations

  1. Fraser Laboratories for Diabetes Research, Department of Medicine, McGill University Health Centre, Room H5-21, Royal Victoria Hospital, 687 Pine Avenue West, Montreal, QC, H3A 1A1, Canada

    Katie Robertson, Kristine De Jesus & Jun-Li Liu

  2. Physiology Department of Medical College, Qingdao University, Shandong, China

    Jing Dong

  3. Montreal Diabetes Research Centre, Montreal, QC, Canada

    Jun-Li Liu

Authors
  1. Katie Robertson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jing Dong
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kristine De Jesus
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jun-Li Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jun-Li Liu.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Robertson, K., Dong, J., De Jesus, K. et al. IGF-I overexpression does not promote compensatory islet cell growth in diet-induced obesity. Endocr 37, 47–54 (2010). https://doi.org/10.1007/s12020-009-9259-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12020-009-9259-y

Keywords

Search

Navigation