Ann Pediatr Endocrinol Metab.  2013 Mar;18(1):9-12. 10.6065/apem.2013.18.1.9.

Role of insulin-like growth factor binding protein-3 in glucose and lipid metabolism

Affiliations
  • 1Department of Pediatrics, Severance Children's Hospital, Yonsei University College of Medicine, Seoul, Korea. kimho@yuhs.ac

Abstract

Insulin-like growth factor binding protein (IGFBP)-3 has roles in modulating the effect of IGFs by binding to IGFs and inhibiting cell proliferation in an IGF-independent manner. Although recent studies have been reported that IGFBP-3 has also roles in metabolic regulation, their exact roles in adipose tissue are poorly understood. In this review, we summarized the studies about the biological roles in glucose and lipid metabolism. IGFBP-3 overexpression in transgenic mice suggested that IGFBP-3 results in glucose intolerance, and insulin resistance. IGFBP-3 knockout (KO) mice exhibited normal insulin level and glucose response after glucose challenge. More recent study in IGFBP-3 KO mice with a high-fat diet demonstrated that IGFBP-3 KO mice exhibited elevated fasting glucose and insulin, but normal response to glucose challenge, suggesting that IGFBP-3 KO mice may induce insulin resistance even though preserved insulin sensitivity. In vitro and in vivo studies using 3T3-L1 adipocytes and rat, IGFBP-3 induced insulin resistance by inhibiting glucose uptake. In contrast, the reduced levels of IGFBP-3 in obesity might induce insulin resistance by suppression of IGFBP-3's anti-inflammatory function, suggesting IGFBP-3 has a protective effect on insulin resistance. Also, proteolysis of IGFBP-3 might contribute to the insulin resistance in obesity and type 2 diabetes mellitus. In addition, IGFBP-3 inhibited adipocyte differentiation, suggesting IGFBP-3 may contribute to the insulin insensitivity. Taken together, it is not yet certain that IGFBP-3 has a protective effect or enhancing effect on insulin resistance, and more studies will be needed to clarify the roles of IGFBP-3 in metabolic regulation.

Keyword

Insulin-like growth factor binding protein-3; Insulin resistance; Adipocytes; Metabolism

MeSH Terms

Adipocytes
Adipose Tissue
Animals
Carrier Proteins
Cell Proliferation
Diabetes Mellitus, Type 2
Diet, High-Fat
Fasting
Glucose
Glucose Intolerance
Insulin
Insulin Resistance
Insulin-Like Growth Factor Binding Protein 3
Lipid Metabolism
Mice
Mice, Transgenic
Obesity
Proteolysis
Rats
Carrier Proteins
Glucose
Insulin
Insulin-Like Growth Factor Binding Protein 3

Reference

1. Jones JI, Clemmons DR. Insulin-like growth factors and their binding proteins: biological actions. Endocr Rev. 1995; 16:3–34. PMID: 7758431.
Article
2. Firth SM, Baxter RC. Cellular actions of the insulin-like growth factor binding proteins. Endocr Rev. 2002; 23:824–854. PMID: 12466191.
Article
3. Blat C, Delbe J, Villaudy J, Chatelain G, Golde A, Harel L. Inhibitory diffusible factor 45 bifunctional activity. As a cell growth inhibitor and as an insulin-like growth factor I-binding protein. J Biol Chem. 1989; 264:12449–12454. PMID: 2545709.
4. Cohen P, Lamson G, Okajima T, Rosenfeld RG. Transfection of the human insulin-like growth factor binding protein-3 gene into Balb/c fibroblasts inhibits cellular growth. Mol Endocrinol. 1993; 7:380–386. PMID: 7683373.
Article
5. Oh Y, Muller HL, Lamson G, Rosenfeld RG. Insulin-like growth factor (IGF)-independent action of IGF-binding protein-3 in Hs578T human breast cancer cells. Cell surface binding and growth inhibition. J Biol Chem. 1993; 268:14964–14971. PMID: 7686909.
Article
6. Valentinis B, Bhala A, DeAngelis T, Baserga R, Cohen P. The human insulin-like growth factor (IGF) binding protein-3 inhibits the growth of fibroblasts with a targeted disruption of the IGF-I receptor gene. Mol Endocrinol. 1995; 9:361–367. PMID: 7539889.
Article
7. Rajah R, Valentinis B, Cohen P. Insulin-like growth factor (IGF)-binding protein-3 induces apoptosis and mediates the effects of transforming growth factor-beta1 on programmed cell death through a p53- and IGF-independent mechanism. J Biol Chem. 1997; 272:12181–12188. PMID: 9115291.
Article
8. Gill ZP, Perks CM, Newcomb PV, Holly JM. Insulin-like growth factor-binding protein (IGFBP-3) predisposes breast cancer cells to programmed cell death in a non-IGF-dependent manner. J Biol Chem. 1997; 272:25602–25607. PMID: 9325280.
Article
9. Butt AJ, Firth SM, King MA, Baxter RC. Insulin-like growth factor-binding protein-3 modulates expression of Bax and Bcl-2 and potentiates p53-independent radiation-induced apoptosis in human breast cancer cells. J Biol Chem. 2000; 275:39174–39181. PMID: 10998426.
Article
10. Kim HS, Ingermann AR, Tsubaki J, Twigg SM, Walker GE, Oh Y. Insulin-like growth factor-binding protein 3 induces caspase-dependent apoptosis through a death receptor-mediated pathway in MCF-7 human breast cancer cells. Cancer Res. 2004; 64:2229–2237. PMID: 15026367.
Article
11. Kim HS, Lee WJ, Lee SW, Chae HW, Kim DH, Oh Y. Insulin-like growth factor binding protein-3 induces G1 cell cycle arrest with inhibition of cyclin-dependent kinase 2 and 4 in MCF-7 human breast cancer cells. Horm Metab Res. 2010; 42:165–172. PMID: 19960406.
Article
12. Murphy LJ, Molnar P, Lu X, Huang H. Expression of human insulin-like growth factor-binding protein-3 in transgenic mice. J Mol Endocrinol. 1995; 15:293–303. PMID: 8748136.
13. Murphy LJ, Rajkumar K, Molnar P. Phenotypic manifestations of insulin-like growth factor binding protein-1 (IGFBP-1) and IGFBP-3 overexpression in transgenic mice. Prog Growth Factor Res. 1995; 6:425–432. PMID: 8817686.
Article
14. Modric T, Silha JV, Shi Z, Gui Y, Suwanichkul A, Durham SK, et al. Phenotypic manifestations of insulin-like growth factor-binding protein-3 overexpression in transgenic mice. Endocrinology. 2001; 142:1958–1967. PMID: 11316761.
Article
15. Silha JV, Gui Y, Murphy LJ. Impaired glucose homeostasis in insulin-like growth factor-binding protein-3-transgenic mice. Am J Physiol Endocrinol Metab. 2002; 283:E937–E945. PMID: 12376320.
Article
16. Ning Y, Schuller AG, Bradshaw S, Rotwein P, Ludwig T, Frystyk J, et al. Diminished growth and enhanced glucose metabolism in triple knockout mice containing mutations of insulin-like growth factor binding protein-3, -4, and -5. Mol Endocrinol. 2006; 20:2173–2186. PMID: 16675541.
Article
17. Yakar S, Rosen CJ, Bouxsein ML, Sun H, Mejia W, Kawashima Y, et al. Serum complexes of insulin-like growth factor-1 modulate skeletal integrity and carbohydrate metabolism. FASEB J. 2009; 23:709–719. PMID: 18952711.
18. Yamada PM, Mehta HH, Hwang D, Roos KP, Hevener AL, Lee KW. Evidence of a role for insulin-like growth factor binding protein (IGFBP)-3 in metabolic regulation. Endocrinology. 2010; 151:5741–5750. PMID: 20926583.
Article
19. Chan SS, Twigg SM, Firth SM, Baxter RC. Insulin-like growth factor binding protein-3 leads to insulin resistance in adipocytes. J Clin Endocrinol Metab. 2005; 90:6588–6595. PMID: 16189260.
Article
20. Kim HS, Ali O, Shim M, Lee KW, Vuguin P, Muzumdar R, et al. Insulin-like growth factor binding protein-3 induces insulin resistance in adipocytes in vitro and in rats in vivo. Pediatr Res. 2007; 61:159–164. PMID: 17237715.
Article
21. Mohanraj L, Kim HS, Li W, Cai Q, Kim KE, Shin HJ, et al. IGFBP-3 inhibits cytokine-induced insulin resistance and early manifestations of atherosclerosis. PLoS One. 2013; 8:e55084. PMID: 23383064.
Article
22. Palau N, Rebuffat SA, Altirriba J, Piquer S, Hanzu FA, Gomis R, et al. Role of IGFBP-3 in the regulation of β-cell mass during obesity: adipose tissue/β-cell cross talk. Endocrinology. 2012; 153:177–187. PMID: 22067319.
Article
23. Chan SS, Schedlich LJ, Twigg SM, Baxter RC. Inhibition of adipocyte differentiation by insulin-like growth factor-binding protein-3. Am J Physiol Endocrinol Metab. 2009; 296:E654–E663. PMID: 19141684.
Article
24. de Silva HC, Firth SM, Twigg SM, Baxter RC. Interaction between IGF binding protein-3 and TGFβ in the regulation of adipocyte differentiation. Endocrinology. 2012; 153:4799–4807. PMID: 22910030.
Article
25. Penkov DN, Egorov AD, Mozgovaya MN, Tkachuk VA. Insulin resistance and adipogenesis: role of transcription and secreted factors. Biochemistry (Mosc). 2013; 78:8–18. PMID: 23379555.
26. Grohmann M, Sabin M, Holly J, Shield J, Crowne E, Stewart C. Characterization of differentiated subcutaneous and visceral adipose tissue from children: the influences of TNF-alpha and IGF-I. J Lipid Res. 2005; 46:93–103. PMID: 15489542.
27. Baxter RC, Twigg SM. Actions of IGF binding proteins and related proteins in adipose tissue. Trends Endocrinol Metab. 2009; 20:499–505. PMID: 19801194.
28. Yamanaka Y, Wilson EM, Rosenfeld RG, Oh Y. Inhibition of insulin receptor activation by insulin-like growth factor binding proteins. J Biol Chem. 1997; 272:30729–30734. PMID: 9388210.
29. Bang P, Brismar K, Rosenfeld RG. Increased proteolysis of insulin-like growth factor-binding protein-3 (IGFBP-3) in noninsulin-dependent diabetes mellitus serum, with elevation of a 29-kilodalton (kDa) glycosylated IGFBP-3 fragment contained in the approximately 130- to 150-kDa ternary complex. J Clin Endocrinol Metab. 1994; 78:1119–1127. PMID: 7513716.
30. Lee SW, Rhie YJ, Hwang IT, Han DK, Kim DH, Kim HS. The effect of obesity on serum growth factors, and insulin-like growth factor binding protein-3 proteolysis in children with simple obesity. J Korean Soc Pediatr Endocrinol. 2005; 10:195–203.
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