Study of the Correlation Between IGF-I and Glycaemic Control in Type 1 Diabetes
Subgroup: Volume 2, Issue 1, Winter
Date: March 2004
Type: Original Article
Start Page: 13
End Page: 18
- Zarghami N Department of Clinical Biochemistry and RIA, Drug Applied Research Center, Tabriz, IR. Iran
- Khosrowbeygi A Department of Clinical Biochemistry and RIA, Drug Applied Research Center, Tabriz, IR. Iran
- Eshtiaghi R Department of Internal Medicine, Endocrine Unit, Imam Hospital, Urumia University of Medical Sciences, Urumia, IR. Iran
- Dayer D Department of Clinical Biochemistry, Urumia University of Medical Sciences, Urumia, IR. Iran
City, Province: Tabriz,
Country: IR. Iran
Diabetes is a common endocrine disease and its complications are major stimuli for the enhancment of efforts towards its control. At present, glycosylated hemoglobin (HbAlc) is used for long term control of glucose levels in diabetic patients, but due to lack of availability of a standard control method, recent findings suggest that insulin-like growth factor-I (IGF-I) may be used as a biomarker for glycaemic control. The aim of this study was to examine the correlation between IGF-I and glycaemic control measured as fasting plasma glucose (FPG) and HbAlc in Type 1 diabetes.
Materials and Methods:We designed a crosssectional case-control study with systematic random sampling. The study included 26 newly diagnosed patients with Type 1 diabetes (15 male and 11 female; mean age 23.7±9.1years) and 26 healthy controls (9 male and 17 female; mean age 24.1±4.4years). The concentrations of FPG, IGF-I, HbAlc and IGF-binding protein-3 (IGFBP-3)were measured in both groups. FPG was measured by the enzymatic glucose oxidase method and the colorimetric method was used to measure HbAlc. Determination of serum IGF-I and IGFBP-3 total levels was carried out using immunoassay.
Keywords: Type 1 diabetes;IGF-I;HbAlc;FPG
Diabetes is a common endocrine disease and its complications are major stimuli for the enhancement of efforts towards its control. At present, measurement of glycosylated hemoglobin (HbAlc) is used for long term control of glucose levels in diabetic patients. However, its application is limited due to the lack of availability of an internationally accepted standard method for its measurement and also to the interfering effects of the other forms of hemoglobin such as HbF and HbS. Current methods for measuring HbAlc present different results, the coefficients of variation of which range from 3.5% to 16.5%.1 Recent findings suggest that insulin like growth factor-I (IGF-I) may be used as a biomarker for glycemic control in diabetes patients.l' IGF-I is a polypeptide hormone that has 48% aminoacid sequence identity with proinsulin. Although the affinity of IGFI for the insulin receptor is 0.5% that of insulin in vitro, when infused into animals and human subjects, IGF-I has approximately one twelfth the glucose-lowering capacity of insulin.r" Most of the circulating IGF-I is derived from its synthesis in the liver, regulated by the growth hormone (GH), insulin, and nutritional intake. It has profound effects on the regulation of proliferation and differentiation of many cell types, as well as metabolic effects, which are similar to those of insulin, including actions on glucose metabolism.i" It has been hypothesized that IGF-l.. working through its own receptor, functions to enhance insulin sensitivity and that this accounts for part of its glucose-lowering activity.' Further verification of this hypothesis has come from studies in patients with extreme insulin resistance and in patients with Type 2 diabetes, demonstrating that there is a substantial improvement in insulin sensitivity during recombinant human IGF-I adrninistration. 8 . 9 Patients with extreme insulin resistance, treated for periods as long as 12 months, have shown substantial reduction in HbAle, indicating that IGF-I not only improves insulin sensitivity but also improves glycemic control." Large trials of several hundred patients with Type 2 diabetes show that when IGF-I is given for 3 months, either as monotherapy or with insulin, there is substantial improvement in HbAle. Administration ofIGF-l to patients with Type 1 diabetes resulted in a 10% reduction in mean daily glucose levels, while reducing required insulin dosage by 28%.11
IGF-I binds to specific binding proteins in circulation known as IGF-binding proteins (IGFBPs). The IGFBPs family controls IGF access to receptors and modulates IGF-I action. IGFBP-3 appears to be the primary regulator of IGF levels in response to changes in circulating growth hormone levels and serves as a storage pool for IGF-I,
whereas IGFBP-I appears to be the primary regulator of IGF-I levels in response to changes in circulating insulin levels.3,4
Studies that examined IGF-I and glycaemic control, as measured by HbAle, have had conflicting findings. IGF-I has been found to be negatively correlated with HbAle,12 negatively correlated only in pubertal children,13 and not correlated to HbAlc.2 .14 Because of controversial findings regarding the relationship
between IGF-I concentration and glycaemic control, we designed a cross-sectional case-control study using systematic random sampling to show whether there is a relationship between serum levels of total IGF-I and glycaemic control in newly diagnosed patients with Type 1 diabetes.
Materials and Methods
The study group consisted of 26 randomly selected patients, newly diagnosed with Type 1 diabetes (15 male and 11 female; mean age, 23.7±9.1 years), with no diabetic complications such as nephropathy, neuropathy, and retinopathy, as confirmed by an experienced internal medicine specialist. The patients were diagnosed according to 1985 World Health Organization (WHO) criteria. IS The control group included 26 non-diabetic healthy individuals (9 male and 17 female; mean age 24.1±4.4 years). Neither group had any clinical conditions threatening normal GH production (i.e. malnutrition, chronic diseases states or excess production of GH and acromegaly).
Blood samples were collected from both patients and controls between 08:00-09:00 after an overnight fast. The last insulin injection for type 1 diabetics was administered the day prior to blood sampling.
Total IGF-I was measured by a commercially available radioimmunoassay (RIA) kit (BioSource, Eroupe).4 Intra- and inter-assay coefficients of variation for serum total IGF -1 were 6.1% and 9.9%, respectively. The immunoradiometric assay (IRMA) kit (Bio- Source, Euroupe) was used for the measurement of IGFBP-3.4 Intra- and inter-assay coefficients of variation for serum IGFBP-3 were 0.56% and 1.9%, respectively. Hemoglobin Ale (HbAlc) was measured by the WHO colorimetric method16 (Mahsayaran Kit, Iran, normal rang 5.0-7.5%). Fasting plasma glucose (FPG) concentration was measured using the enzymatic glucose oxidase method (Pars Azmun, Iran). Intra- and inter-assay coefficients of variation for FPG were 1.74% and 4.9%, respectively.
Differences between quantitative variables were tested with Student's t-test. Correlations were measured by Pearson's correlation coefficient. A two-sided p value
Initially, we measured biochemical markers including FPG, HbA1c, and serum levels of total IGF-I and IGFBP-3 in 26 patients newly diagnosed with Type 1 diabetes and in 26 non-diabetic healthy controls, the results of which are presented in Table 1. Mean levels of both FPG and HbAlc in the case group were significantly higher than in the controlgroup (pwas correlated directly with FPG in the patients (r= 0.826, p<0.05) and controls (r = 0.4l3, p<0.05). No correlation was found between IGF-I and HbAlc in the patients, nor was any observed between IGF-I and FPG in this group. IGF -I correlated inversely with age in the patient group (r = -0.47, p<0.05; Fig. 1), but not in the control group.
Table 1. Characteristics of FPG, HbAlc, IGFI, and IGFBP-3 in case and control groups.
b P< 0.001;c P
Fig. 1. Correlation between IGF-I concentration and age in the case group (P
This study showed that serum total IGF-I levels in newly diagnosed patients with Type 1 diabetes were significantly lower than in the control group. IGFBP-3 total levels however did not show any significant difference between the two groups. Our study also showed no correlation between IGF-I and glycaemic control in patients with Type 1 diabetes. One limitation of our study was that the criteria to include Type 1 diabetes and to exclude Type 2 were based on clinical judgment according to 1985 WHO criteria, without measurement of other markers such as glutamic acid decarboxylase autoantibodies and islet cell autoantibodies.
Dills et al. investigated the relationship between IGF-I and glycaemic control in l37 subjects aged 17 years and younger with recently diagnosed insulin-dependent diabetes mellitus in a population-based cohort study conducted between 3 and 11 months after diagnosis.12
They found that IGF-I levels were strongly related to age (r=0.74, pEkman ei al. studied the correlation between circulating IGF-I concentration and glycaemic control in Type 1 diabetes.2 Their case group consisted of 79 men and 55 women aged 20-60 years compared with 80 men and 83 women aged 20-60 years as a reference population. They found that mean IGF-I level was significantly lower in diabetics as compared to the controls. They also observed that IGF-I was negatively correlated with age in patients and controls. No correlation was found between IGF-I and glycaemic control measured as HbAlc in the patients. They concluded that subcutaneous insulin substitution is inefficient in normalizing circulating IGF-I concentrations in patients without endogenous insulin secretion. Our study results were very similar to these findmgs.
IGFBP-3 appears to be the primary binding protein of IGF-I in circulation and serves as a storage pool for IGF_I,3,4 which is the reason why we measured its total circulating concentration. As there was no significant difference in total IGFBP-3 between the two groups, decline in total IGF-I levels in patients could not be related to this binding protein.
Quattrin et al. conducted a 12-yveek trial comparing insulin and recombinant human IGF-I (rhIGF-I) to insulin and placebo in patients with Type 1 diabetes mellitus aged 11- 66 years. The average decrease of HbA 1c from baseline was higher in the rhIGF-I treated group as compared to the placebo group. They concluded that rhIGF-I cotherapy could playa role in adolescents and young adults with Type 1 diabetes mellitus. 19
Insulin regulates hepatic IGF-I production and has an independent as well as an additive effect to that of GH.20 ,21 As the major source of circulating IGF-I is the liver and IGF-I levels are inappropriately low for the higher GH levels seen in Type 1 diabetes, it is thought that there is an acquired state of hepatic GH resistance. Several days of rhGH treatment has little effect on IGF-I levels in patients with Type 1 diabetes. This points to the importance of portal insulin for hepatic IGF-I secretion." The route of insulin administration in Type I diabetes appears important, as insulin delivered by the hepatic portal route (as occurs normally in vivo) is better at normalizing IGF-I levels and hepatic IGF-I expression in diabetic rats than subcutaneous insulin despite no difference in glycaemic control. When insulin is given to patients with Type 1 diabetes by continuous intraperitoneal infusion using an implantable pump (CPII), portal insulin levels increase and there is near-normalization of IGF-I levels.23 Low circulating IGF-I may explain the increased GH secretion seen in Type 1 diabetes through reduced negative feedback control. rhIGF-I replacement therapy in adolescents and adults with Type 1 diabetes results in a reduction in overnight GH secretion, indicating restoration of the normal negative feedback on pituitary GH secretion. Thus IGF-I may exert its effect on glucose metabolism directly or indirectly by inhibiting GH secretion.24
In summary, our findings show that total IGF-I levels are low in patients with Type I diabetes and no relationship was found between IGF-I and glycaernic control. However, it is recommended that more comprehensive studies are needed to further investigate this relationship and verify these findings .
- King H, Aubert RE, Herman WHo Global burden of diabetes, 1995-2025: prevalence, numerical estimates, and projections. Diabetes Care. 1998 Sep;21 (9): 1414-31.
- Ekman B, Nystrom F, Arnqvist HJ. Circulating lGF-l concentrations are low and not correlated to glycaemic control in adults with type I diabetes. Eur J Endocrinol. 2000 Oct; 143(4):505-10.
- Clemmons DR, Moses AC, McKay MJ, Sommer A, Rosen OM, 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 I diabetes: evidence for in vivo biological activity. J Clin Endocrinol Metab. 2000 Apr;85(4): 1518-24.
- Janssen JA, Jacobs ML, Derkx FH, Weber RF,van der Lely AJ, Lamberts SW.Free and total insulin-like growth factor I (lGF-I), IGF-binding protein-I (IGFBP-I), and lGFBP-3 and their relationships to the presence of diabetic retinopathy and glomerular hypertiltration in insulindependent diabetes mellitus. J Clin Endocrinol Metab. 1997 Sep;82(9):2809-15
- Thissen JP, Ketelslegers JM, Underwood LE. Nutritional regulation of the insulin-like growth factors. Endocr Rev. 1994 Feb; 15( 1): 80-101.
- 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 USA. 1999 Jun 22;96(13):7324-9.
- Holt RI, Simpson HL, Sonksen PH. The role of the growth hormone-insulin-like growth factor axis in glucose homeostasis. Diabct Med. 2003 Jan;20(1):3-15.
- Moses AC, Young SCJ, Morrow LA, O'Brien M, Clemmons DR. Recombinant human insulin-like growth factor l increases insulin sensitivity and improves glycemic control in type II diabetes. Diabetes 1996; 45: 95-100.
- Schoen Ie EJ, Zen obi PO, Toresarie T, Wender EA, Zachmann M, Froesch ER. Recombinant insulin like growth factor I (rh IGF-I) reduces hyperglycemia in patients with insulin resistance. Diabetologia 1999; 34: 675-679.
- Kuzuya H, Matsuura N, Sakamoto M, Makino H, Sakamoto Y, Kadowaki T, Suzuki Y, Kobayashi M, Akazawa Y, Nomura M, et al. Trial of insulinlike growth factor I therapy for patients with extreme insulin resistance syndromes. Diabetes. 1993 May;42(5) 696-705.
- Quattrin T, Thrailkill K, Baker L, Litton J, Dwigun K, Rearson M, Poppenheimer M, Giltinan 0, Gesundheit N, Martha P Jr. Dual hormonal replacement with insulin and recombinant human insulin-like growth factor I in IDDM. Effects on lycemic control, IGF-I levels, and safety profile. Diabetes Care. 1997 Mar;20(3):374-80.
- Dills DG, Allen C, Palta M, Zaccaro OJ, Klein R, D'Alessio D. Insulin-like growth factor-I is related to glycemic control in children and adolescents with newly diagnosed insulin-dependent diabetes. J Clin Endocrinol Metab. 1995 Jul;80(7):2139-43.
- Rogers DG, Sherman LD, Gabbay KH. Effect of puberty on insulinlike growth factor I and HbA I in type I diabetes. Diabetes Care. 1991 Nov;14(11):1031-5.
- Taylor AM, Dunger DB, Grant DB, Preece MA. Somatomedin-C/IGF-T measured by radioimmunoassay and somatomedin bioactivity in adolescents with insulin dependent diabetes compared with puberty matched controls. Diabetes Res. 1988 Dec;9(4): 177-8 J.
- WHO Expert Committee on Diabetes Mellitus. Technical Report Series 727. World Health Organisation, 1985.
- Alberti KG MM, Skrabalo Z. Standardization of biochemical methods in the diagnosis and management of diabetes: With particular reference to developing countries. WHO/IDF Bulletin 1982; January: 1-3.
- Nunez SB, Municchi G, Barnes KM, Rose SR. Insulin- like growth factor I (IGF-I) and IGf-binding protein-3 concentrations compared to stimulated and night growth hormone in the evaluation of short children--a clinical research center study. J Clin Endocrinol Metab. 1996 May;81(5): 1927-32
- Rudman 0, Kutner MH, Rogers CM, Lubin MF, Fleming GA, Bain RP. Impaired growth hormone secretion in the adult population: relation to age and adiposity. J Clin Invest. 1981 May; 67(5):1361-9.
- Quattrin T, Thrailkill K, Baker L, Kuntze J, Compton P, Martha P; rhIGF-I in 100M Study Group. Improvement of HbA 1c without increased hypoglycemia in adolescents and young adults with type 1 diabetes mellitus treated with recombinant human insulin-like growth factor-I and insulin. rhIGF-I in 100M Study Group. J Pediatr Endocrinol Metab. 200 I Mar; 14(3):267-77.
- Boni-Schnetzler M, Schmid C, Meier PJ, Froesch ER. Insulin regulates insulin-like growth factor I mRNA in rat hepatocytes, Am J Physiol 1991; 260: E846-51.
- Goya L, de la Puente A, Ramos S, Martin MA, Escriva F, Alvarez C, Pascual-Leone AM. Regulation of IGF-I and -II by insulin in primary cultures of fetal rat hepatocytes. Endocrinology. 2001 Dee; 142(12):5089-96.
- Sonksen PH, Russell-Jones D, Jones RH. Growth hormone and diabetes mellitus. A review of sixtythree years of medical research and a glimpse into the future? Horm Res. 1993;40( 1-3):68-79.
- 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, insulinlike growth factor (IGF)-I, and IGF-binding protein- 3 In IDDM. Diabetologia. 1996 Dec;39(12): 1498-504.
- Carroll PY, Umpleby M, Ward GS, Imuere S, Alexander E, Dunger D, Sonksen PH, Russell- Jones DL. rhIGF-I administration reduces insulin requirements, decreases growth hormone secretion, and improves the lipid profile in adults with IDDM. Diabetes. 1997 Sep;46(9): 1453-8.