Crimson Publishers Publish With Us Reprints e-Books Video articles

Full Text

Intervention in Obesity & Diabetes

The Impact of IGFBP-3/IGFBP-3R System on Obesity-associated Insulin Resistance

Qing Cai and Youngman Oh*

Department of Pathology, School of Medicine, Virginia Commonwealth University, VA, USA

*Corresponding author:Youngman Oh, Department of Pathology, School of Medicine, Virginia Commonwealth University, VA, USA

Submission:December 17, 2019;Published: January 13, 2020

DOI: 10.31031/IOD.2020.03.000563

ISSN 2578-0263
Volume3 Issue3


Obesity is a major risk factor associated with insulin resistance [1-4]. The Visceral fat in obesity secretes various pro-inflammatory and pro-atherogenic adipokines resulting in chronic systemic inflammation and insulin resistance [5,6]. Insulin-like growth factor binding protein-3 (IGFBP-3) inhibits production of proinflammatory adipokines, cytokines as well as inflammatory NF-κB activity through the receptor (IGFBP-3R), which may improve many metabolic disorders including insulin resistance in obesity [7,8]. However, the IGFBP-3/IGFBP-3R system appears to be dysregulated in obesity due to neutrophil serine protease (NSP)-induced IGFBP-3 proteolysis in circulation, thereby resulting in loss of its antiinflammatory function [8]. The complete characterization of the underlying mechanism of the NSP/ IGFBP-3/IGFBP-3R cascade in obesity will be benefit for identifying diagnostic and prognostic value of the IGFBP-3/IGFBP-3R axis and therapeutic potential of IGFBP-3R agonists and NSP inhibitors for insulin resistance.

Keywords:IGFBP-3; IGFBP-3R; Insulin resistance; Neutrophil serine proteases inhibitors

Abbreviations: T2DM: Diabetes Mellitus; CVD: Cardiovascular Disease; IR: Insulin Resistance; IGF: Insulin-like Growth Factor; IGFBPs: IGF-Binding Proteins; NSP: Neutrophil Serine Proteases; IGFBP-3R: IGFBP-3 Receptor

Obesity-Associated Insulin Resistance

Nearly two thirds of the adults are overweight or obesity in the United States [9,10]. Overweight and obesity is the significant cause of premature death [11-13]. Obesity is a major risk factor for serious comorbidities including hypertension, type 2 diabetes mellitus (T2DM), and other metabolic disorders [14-18]. Most of obesity related comorbidities are associated with insulin resistance (IR) [19-22]. Low grade adipose tissue inflammation contributes to the burden of IR [23,24]. However, the pathophysiology of IR is complex and multifactorial [25]. Thus, elucidation of the mechanisms leading to obesity associated IR is necessary to identify novel targets for the prevention and treatment of many IR driven conditions [1,26].

IGF System

The insulin-like growth factor (IGF) system is complex, consisting of IGF ligands (IGF-I and IGF-II), the IGF receptors (IGF-IR and IGF-IIR), and six high affinity IGF-binding proteins (IGFBPs) [7,27] Ample evidence indicates that the IGF system plays an important role in cell growth and proliferation [7,27,28] In addition to alteration in other metabolic pathways, perturbations in the IGF-I axis have been implicated in the pathogenesis of IR [28-31]. IGF-I has structural homology with insulin, and also promotes the peripheral uptake of glucose and fatty acids [32]. IGFBP-3, the major binding protein for IGF-I in circulation, forms the 150kDa ternary complex consisting of IGFBP-3, acid labile subunit (ALS) and IGF-I [33-35]. This ternary complex reduces the passage of IGF-I to the extravascular compartment to extend its half-life [36,37]. In addition to its role as a carrier protein, ample studies point to an IGFIGF receptor independent action of IGFBP-3 in a variety of human diseases including asthma, other inflammatory diseases and cancer [7,27,32,37-42]. Moreover, a novel IGFBP-3 specific receptor (IGFBP-3R) has been identified, and it is expressed in a variety of human tissue and mediates IGFBP-3’s intrinsic biological functions including anti-inflammatory functions [7,39,42].

IGFBP-3/IGFBP-3R Axis and Insulin Resistance

Current dogma of adipocyte biology indicates that visceral adipocytes not only function as a fuel tank for the storage of lipids and triglycerides but also play more active endocrine role through production of a variety of adipokines and cytokines including leptin, adiponectin, interleukin-6 (IL-6), monocyte chemotactic protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-α) [43-49]. In obesity, visceral adipocytes enhance the inflammatory milieu by directly secreting pro-inflammatory cytokines and recruiting in situ inflammatory cells including macrophages and lymphocytes [50-53]. IGFBP-3 has been implicated in the pathogenesis of IR [8,54]. Interestingly, recent studies demonstrated that IGFBP-3, via activation of IGFBP-3R, inhibits cytokine-induced NF-κB activity, restore insulin signaling, and negates the TNF-α-induced inhibition of glucose uptake in human primary adipocytes [8]. However, these anti-inflammatory actions of IGFBP-3 appear to be dysregulated in obesity due to degradation of serum-circulating IGFBP-3 in obesity. Recent study has shown that individuals with obesity demonstrate increases in proteolytic IGFBP-3 fragments and IGFBP-3 protease activity, and corresponding decreases in functional intact IGFBP-3 levels when compared with their normal weight counterparts [8]. Furthermore, IGFBP-3 proteolysis positively correlates with adiposity parameters such as waist circumference, body mass index (BMI), fasting insulin, and insulin resistance index (HOMAIR) in overweight and obese individual [8].

Obesity is associated with activation of neutrophils and the innate immune system [55,56]. Activated neutrophils secret proteinase 3 (PR3) involving in bacterial defense and regulating non-infectious inflammatory processes by modulating the activities of cytokines such as TNF-α, IL-1β, IL-8, IL-18 and IL-32 [57-61]. Recent studies suggest that neutrophil serine proteases (NSPs) such as PR3, neutrophil elastase (NE) and cathepsin G (CG), contribute to neutrophil-dependent inflammation and progression of chronic inflammatory disease including diabetes, cystic fibrosis and glomerulonephritis [62-66]. Conversely, NSP inhibitors such as α-1-antitrypsin (AAT) have been proposed as treatments in patients with chronic inflammatory diseases including diabetes, cystic fibrosis and ischemic heart disease [67-74]. Interestingly, recent studies reported that increased PR3 and IGFBP-3 fragments in the urine of diabetic patients and in the serum of obese individuals [75-77]. In addition, it has shown that PR3 represents an IGFBP-3 specific protease in the serum of obese individuals, whereas AAT completely inhibits PR3-induced IGFBP-3 proteolysis in vitro [75-77]. These findings strongly suggest that IGFBP-3 proteolysis induced by NSPs such as PR3 may result in loss of IGFBP-3R binding ability and subsequent its anti-inflammatory function, and further linking the NSP/IGFBP-3/IGFBP-3R axis in IR and T2DM.


The rapidly increasing prevalence of obesity, IR and T2DM continues to be a great health problem so that more effective preventive and therapeutic strategies are needed. Thus, a clearer understanding of pathophysiology and the mechanisms involved in obesity-associated IR is necessary to identify novel targets for the prevention and treatment of many IR-driven conditions. The chronic low-grade adipose tissue inflammation contributes substantially to the burden of IR. Recent findings on existence of functional IGFBP-3/IGFBP-3R system in insulin target cells and obesity-induced proteolysis of IGFBP-3 strongly suggest that this anti-inflammatory IGFBP-3/IGFBP-3R signaling plays a critical role during the processes of obesity-associated IR. In this respect, further investigation of the NSP/IGFBP-3/IGFBP-3R axis in obesity will warrant identification of diagnostic or prognostic value of IGFBP-3, IGFBP-3 proteolysis and NSPs, and therapeutic potential of IGFBP-3R agonists (IGFBP-3 and IGFBP-3 mimetics) and NSP inhibitors (AAT and novel small peptide inhibitors) in obesityassociated IR, T2DM and diabetes complications.


  1. Kahn BB, Flier JS (2000) Obesity and insulin resistance. J Clin Invest 106(4): 473-481.
  2. Bacha F, Saad R, Gungor N, Arslanian SA (2006) Are obesity-related metabolic risk factors modulated by the degree of insulin resistance in adolescents? Diabetes Care 29(7): 1599-1604.
  3. Kahn SE, Hull RL, Utzschneider KM (2006) Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature 444(7121): 840-846.
  4. Barazzoni R, Cappellari GG, Ragni M, Nisoli E (2018) Insulin resistance in obesity: An overview of fundamental alterations. Eat Weight Disord 23(2): 149-157.
  5. Ouchi N, Parker JL, Lugus JJ, Walsh K (2011) Adipokines in inflammation and metabolic disease. Nat Rev Immunol 11(2): 85-97.
  6. Oikonomou EK, Antoniades C (2019) The role of adipose tissue in cardiovascular health and disease. Nat Rev Cardiol 16(2): 83-99.
  7. Lee YC, Brahim SJ, Lee DY, Han J, Harada A, et al. (2011) Insulin-like growth factor-binding protein-3 (IGFBP-3) blocks the effects of asthma by negatively regulating NF-kappaB signaling through IGFBP-3R-mediated activation of caspases. J Biol Chem 286(20): 17898-17909.
  8. Mohanraj L, Kim HS, Li W, Cai Q, Kim KE, et al. (2013) IGFBP-3 inhibits cytokine-induced insulin resistance and early manifestations of atherosclerosis. PLoS One 8(1): e55084.
  9. Flegal KM, Moran DK, Carroll MD, Fryar CD, Ogden CL (2016) Trends in obesity among adults in the United States, 2005 to 2014. JAMA 315(21): 2284-2291.
  10. Ogden CL, Carroll MD, Lawman HG, Fryar CD, Moran DK, et al. (2016) Trends in obesity prevalence among children and adolescents in the United States, 1988-1994 through 2013-2014. JAMA 315(21): 2292-2299.
  11. Franks PW, Hanson RL, Knowler WC, Sievers ML, Bennett PH, et al. (2010) Childhood obesity, other cardiovascular risk factors, and premature death. N Engl J Med 362(6): 485-493.
  12. Di Angelantonio E, Bhupathiraju Sh N, Wormser D, Gao P, Kaptoge S, et al. (2016) Body-mass index and all-cause mortality: Individual-participant-data meta-analysis of 239 prospective studies in four continents. Lancet 388(10046): 776-786.
  13. Hruby A, Manson JE, Qi L, Malik VS, Rimm EB, et al. (2016) Determinants and consequences of obesity. Am J Public Health 106(9): 1656-1662.
  14. Dubuc PU (1976) The development of obesity, hyperinsulinemia, and hyperglycemia in ob/ob mice. Metabolism 25(12): 1567-1574.
  15. Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, et al. (2005) Diagnosis and management of the metabolic syndrome. An American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation 112(17): 2735-2752.
  16. Guilherme A, Virbasius JV, Puri V, Czech MP (2008) Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes. Nat Rev Mol Cell Biol 9(5): 367-377.
  17. Lumeng CN, Saltiel AR (2011) Inflammatory links between obesity and metabolic disease. J Clin Invest 121(6): 2111-2117.
  18. Censin JC, Peters SAE, Bovijn J, Ferreira T, Pulit SL, et al. (2019) Causal relationships between obesity and the leading causes of death in women and men. PLoS Genet 15(10): e1008405.
  19. DeFronzo RA (2004) Pathogenesis of type 2 diabetes mellitus. Med Clin North Am 88(4): 787-835.
  20. Pi Sunyer X (2009) The medical risks of obesity. Postgrad Med 121(6): 21-33.
  21. Castro AV, Kolka CM, Kim SP, Bergman RN (2014) Obesity, insulin resistance and comorbidities? Mechanisms of association. Arq Bras Endocrinol Metabol 58(6): 600-609.
  22. Zheng Y, Ley SH, Hu FB (2018) Global aetiology and epidemiology of type 2 diabetes mellitus and its complications. Nat Rev Endocrinol 14(2): 88-98.
  23. Piya MK, McTernan PG, Kumar S (2013) Adipokine inflammation and insulin resistance: The role of glucose, lipids and endotoxin. J Endocrinol 216(1): T1-T15.
  24. Burhans MS, Hagman DK, Kuzma JN, Schmidt KA, Kratz M (2018) Contribution of adipose tissue inflammation to the development of type 2 diabetes mellitus. Compr Physiol 9(1): 1-58.
  25. Johnson AM, Olefsky JM (2013) The origins and drivers of insulin resistance. Cell 152(4): 673-684.
  26. Czech MP (2017) Insulin action and resistance in obesity and type 2 diabetes. Nat Med 23(7): 804-814.
  27. Brahim SJ, Feldman D, Oh Y (2009) Unraveling insulin-like growth factor binding protein-3 actions in human disease. Endocr Rev 30(5): 417-437.
  28. Osher E, Macaulay VM (2019) Therapeutic targeting of the IGF axis. Cells 8(8).
  29. 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(3): 198-211.
  30. Rajpathak SN, Gunter MJ, Wylie RJ, Ho GY, Kaplan RC, et al. (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(1): 3-12.
  31. Lewitt MS, Dent MS, Hall K (2014) The insulin-like growth factor system in obesity, insulin resistance and type 2 diabetes mellitus. J Clin Med 3(4): 1561-1574.
  32. Le Roith D (1997) Seminars in medicine of the Beth Israel deaconess medical center: Insulin-like growth factors. N Engl J Med 336(9): 633-640.
  33. Baxter RC, Martin JL (1989) Structure of the Mr 140,000 growth hormone-dependent insulin-like growth factor binding protein complex: Determination by reconstitution and affinity-labeling. Proc Natl Acad Sci USA 86(18): 6898-6902.
  34. Leong SR, Baxter RC, Camerato T, Dai J, Wood WI (1992) Structure and functional expression of the acid-labile subunit of the insulin-like growth factor-binding protein complex. Mol Endocrinol 6(6): 870-876.
  35. Ertl DA, Gleiss A, Sagmeister S, Haeusler G (2014) Determining the normal range for IGF-I, IGFBP-3, and ALS: New reference data based on current internal standards. Wien Med Wochenschr 164(17-18): 343-352.
  36. Allard JB, Duan C (2018) IGF-binding proteins: Why do they exist and why are there so many? Front Endocrinol (Lausanne) 9: 117.
  37. Hwa V, Oh Y, Rosenfeld RG (1999) The insulin-like growth factor-binding protein (IGFBP) superfamily. Endocr Rev 20(6): 761-787.
  38. Xu H, Barnes GT, Yang Q, Tan G, Yang D, et al. (2003) Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 112(12): 1821-1830.
  39. Ingermann AR, Yang YF, Han J, Mikami A, Garza AE, et al. (2010) Identification of a novel cell death receptor mediating IGFBP-3-induced anti-tumor effects in breast and prostate cancer. J Biol Chem 285(39): 30233-30246.
  40. Liss ES, Friedrich N, Dorr M, Schminke U, Volzke H, et al. (2011) Serum insulin-like growth factor I and its binding protein 3 in their relation to intima-media thickness: results of the study of health in Pomerania (SHIP). Clin Endocrinol (Oxf) 75(1): 70-75.
  41. Kielczewski JL, Hu P, Shaw LC, Li Calzi S, Mames RN, et al. (2011) Novel protective properties of IGFBP-3 result in enhanced pericyte ensheathment, reduced microglial activation, increased microglial apoptosis, and neuronal protection after ischemic retinal injury. Am J Pathol 178(4): 1517-1528.
  42. Han J, Jogie Brahim S, Harada A, Oh Y (2011) Insulin-like growth factor-binding protein-3 suppresses tumor growth via activation of caspase-dependent apoptosis and cross-talk with NF-kappaB signaling. Cancer Lett 307(2): 200-210.
  43. Robache GS, Morand V, Bruneau JM, Schoot B, Tagat E, et al. (1995) In vitro processing of human tumor necrosis factor-alpha. J Biol Chem 270(40): 23688-23692.
  44. Ouchi N, Kihara S, Funahashi T, Nakamura T, Nishida M, et al. (2003) Reciprocal association of C-reactive protein with adiponectin in blood stream and adipose tissue. Circulation 107(5): 671-674.
  45. Neels JG, Olefsky JM (2006) Inflamed fat: What starts the fire? J Clin Invest 116(1): 33-35.
  46. Olefsky JM, Glass CK (2010) Macrophages, inflammation, and insulin resistance. Annu Rev Physiol 72: 219-246.
  47. Choe SS, Huh JY, Hwang IJ, Kim JI, Kim JB (2016) Adipose tissue remodeling: Its role in energy metabolism and metabolic disorders. Front Endocrinol (Lausanne) 7: 30.
  48. Kusminski CM, Bickel PE, Scherer PE (2016) Targeting adipose tissue in the treatment of obesity-associated diabetes. Nat Rev Drug Discov 15(9): 639-660.
  49. Chouchani ET, Kajimura S (2019) Metabolic adaptation and maladaptation in adipose tissue. Nat Metab 1(2): 189-200.
  50. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, et al. (2003) Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 112(12): 1796-1808.
  51. Sartipy P, Loskutoff DJ (2003) Monocyte chemoattractant protein 1 in obesity and insulin resistance. Proc Natl Acad Sci U S A 100(12): 7265-7270.
  52. Zeyda M, Stulnig TM (2007) Adipose tissue macrophages. Immunol Lett 112(2): 61-67.
  53. Arendt LM, McCready J, Keller PJ, Baker DD, Naber SP, et al. (2013) Obesity promotes breast cancer by CCL2-mediated macrophage recruitment and angiogenesis. Cancer Res 73(19): 6080-6093.
  54. Hjortebjerg R, Laugesen E, Hoyem P, Oxvig C, Gron BS, et al. (2017) The IGF system in patients with type 2 diabetes: Associations with markers of cardiovascular target organ damage. Eur J Endocrinol 176(5): 521-531.
  55. Nijhuis J, Rensen SS, Slaats Y, van Dielen FM, Buurman WA, et al. (2009) Neutrophil activation in morbid obesity, chronic activation of acute inflammation. Obesity (Silver Spring) 17(11): 2014-2018.
  56. McLaughlin T, Ackerman SE, Shen L, Engleman E (2017) Role of innate and adaptive immunity in obesity-associated metabolic disease. J Clin Invest 127(1): 5-13.
  57. Coeshott C, Ohnemus C, Pilyavskaya A, Ross S, Wieczorek M, et al. (1999) Converting enzyme-independent release of tumor necrosis factor alpha and IL-1beta from a stimulated human monocytic cell line in the presence of activated neutrophils or purified proteinase 3. Proc Natl Acad Sci U S A 96(11): 6261-6266.
  58. Sugawara S, Uehara A, Nochi T, Yamaguchi T, Ueda H, et al. (2001) Neutrophil proteinase 3-mediated induction of bioactive IL-18 secretion by human oral epithelial cells. J Immunol 167(11): 6568-6575.
  59. Novick D, Rubinstein M, Azam T, Rabinkov A, Dinarello CA, et al. (2006) Proteinase 3 is an IL-32 binding protein. Proc Natl Acad Sci USA 103(9): 3316-3321.
  60. Korkmaz B, Horwitz MS, Jenne DE, Gauthier F (2010) Neutrophil elastase, proteinase 3, and cathepsin G as therapeutic targets in human diseases. Pharmacol Rev 62(4): 726-759.
  61. Ng LL, Khan SQ, Narayan H, Quinn P, Squire IB, et al. (2011) Proteinase 3 and prognosis of patients with acute myocardial infarction. Clin Sci (Lond) 120(6): 231-238.
  62. Kakimoto K, Matsukawa A, Yoshinaga M, Nakamura H (1995) Suppressive effect of a neutrophil elastase inhibitor on the development of collagen-induced arthritis. Cell Immunol 165(1): 26-32.
  63. Carden DL, Korthuis RJ (1996) Protease inhibition attenuates microvascular dysfunction in postischemic skeletal muscle. Am J Physiol 271(5): 1947-1952.
  64. Piwowar A, Kordecka MK, Warwas M (2000) Concentration of leukocyte elastase in plasma and polymorphonuclear neutrophil extracts in type 2 diabetes. Clin Chem Lab Med 38(12): 1257-1261.
  65. Zou F, Schafer N, Palesch D, Brucken R, Beck A, et al. (2011) Regulation of cathepsin G reduces the activation of proinsulin-reactive T cells from type 1 diabetes patients. PLoS One 6(8): e22815.
  66. Lewis EC (2012) Expanding the clinical indications for alpha(1)-antitrypsin therapy. Mol Med 18: 957-970.
  67. Martin SL, Downey D, Bilton D, Keogan MT, Edgar J, et al. (2006) Safety and efficacy of recombinant alpha(1)-antitrypsin therapy in cystic fibrosis. Pediatr Pulmonol 41(2): 177-183.
  68. Toldo S, Seropian IM, Mezzaroma E, Van Tassell BW, Salloum FN, et al. (2011) Alpha-1 antitrypsin inhibits caspase-1 and protects from acute myocardial ischemia-reperfusion injury. J Mol Cell Cardiol 51(2): 244-251.
  69. Talukdar S, Oh DY, Bandyopadhyay G, Li D, Xu J, et al. (2012) Neutrophils mediate insulin resistance in mice fed a high-fat diet through secreted elastase. Nat Med 18(9): 1407-1412.
  70. Hashemi M, Naderi M, Rashidi H, Ghavami S (2007) Impaired activity of serum alpha-1-antitrypsin in diabetes mellitus. Diabetes Res Clin Pract 75(2): 246-248.
  71. Reeves EP, Dunlea DM, McQuillan K, O'Dwyer CA, Carroll TP, et al. (2019) Circulating truncated alpha-1 antitrypsin glycoprotein in patient plasma retains anti-inflammatory capacity. J Immunol 202(8): 2240-2253.
  72. Fahndrich S, Biertz F, Karch A, Kleibrink B, Koch A, et al. (2017) Cardiovascular risk in patients with alpha-1-antitrypsin deficiency. Respir Res 18(1): 171.
  73. McCarthy C, Reeves EP, McElvaney NG (2016) The role of neutrophils in alpha-1 antitrypsin deficiency. Ann Am Thorac Soc 13(4): S297-S304.
  74. McElvaney NG (2016) Alpha-1 antitrypsin therapy in cystic fibrosis and the lung disease associated with alpha-1 antitrypsin deficiency. Ann Am Thorac Soc 13(2): S191-S196.
  75. Oh Y, Cai Q, Robins JLW (2014) The NSP-IGFBP-3/IGFBP-3R axis is a new therapeutic target for obesity-induced insulin resistance and T2DM. Endocrine Reviews 35(3).
  76. Robins J, Cai Q, Oh Y (2013) Impact of proteinase 3 and insulin growth factor BP-3 proteolysis in obesity-induced cardiometabolic risk. Circulation 128(22).
  77. Robins J, Cai Q, Oh Y (2014) The impact of neutrophil proteinase 3 on IGFBP-3 proteolysis in obesity. Internal Medicine: open Access.

© 2020 Youngman Oh. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and build upon your work non-commercially.