ارتباط پلی مورفیسم3'UTR(C>A) از ژن گیرنده (IGF2R)IGF2 با شاخص‌های مقاومت به انسولین در بیماران مبتلا به دیابت نوع2 و افراد غیردیابتی

Background and objective: Association of 6q loci, where IGF2R gene is located, with insulin resistance has been well established. In this study, relationship between 3'UTR and type 2 diabetes and insulin resistance indices in non diabetic subjects was investigated. Materials and Methods: 350 participants (175 diabetic type 2 patient and 175 non-diabetic individuals) were entered in this study. Demographic data were collected. BMI and serum levels of glucose, lipid profiles and IGF2 of all participants were measured. Genotype polymorphism of studied participants was determined by PCR-RFLP method. Then, the relationship between genotypes and insulin resistance indices was measured and analyzed using statistical procedures of ANOVA and post hoc analysis. Results: The genotypes frequency comprised CC (6.85%), AA (33.45%), and CA (59.55%), indicating that the frequency of carrier with CA genotype polymorphism was significantly (P<0.05) higher in type 2 diabetic patients (80.6%) than in non-diabetic participants. Serum FBS levels of CA carriers were significantly (P=0.001) higher than carriers of other two genotypes (CC and AA). The mean levels of serum IGF2 in participants carrying CC and CA genotypes were significantly (P= 0.001) more than other participants carrying genotype AA. Conclusion: (C>A) IGF2R3′UTR polymorphism was associated with type 2 diabetes and some insulin resistance indices especially FBS. However, the A allele may have a protective effect on developing type 2 diabetes. References 1- Shaw JE, Sicree RA, Zimmet PZ. Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res Clin Pract. 2010 87: 4-14. 2- Pettitt DJ, Talton J, Dabelea D, et al. Prevalence of diabetes mellitus in U.S. youth in 2009: The search for diabetes in youth study. Diabetes Care. 2014 37: 402-8. 3- Hossain P, Kawar B, El Nahas M. Obesity and diabetes in the developing world — a growing challenge. N Engl J Med. 2007 18: 213-5. 4- Hegele RA, Pollex RL. Gentic and physiological insights into metabolic syndrome. Am J Physiol Regul Integr Comp Physiol. 2005 289: 663-9. 5- Tritos NA, Mantzoros CS. Clinical review 97: syndromes of severe insulin resistance. J Clin Endocrinol Metab. 1998 83: 3025-30. 6- Laureys G, Barton DE, Ullrich A, Francke U. Chromosomal mapping of the gene for the type II insulin-like growth factor receptor/cation-independent mannose 6-phosphate receptor in man and mouse. Genomics. 1988 3: 224-29. 7- Riesewijk AM, Xu YQ, Schepens MT, et al. Absence of an obvious molecular imprinting mechanism in a human fetus with monoallelic IGF2R expression. Biochem Biophys Res Commun. 1998 245: 272-77. 8- Brown J, Gilbert R, Delanie C. Structure and functional analysis of the IGF-II/IGF2R interaction. EMBO J. 2008 27: 265-76. 9- Ong KK, Dunger DB. Developmental aspects in the pathogenesis of type 2 diabetes. Mol Cell Endocrinol. 2001 185: 145-49. 10- Müller MJ, Lagerpusch M, Enderle J, Schautz B, Heller M, Bosy-Westphal A. Beyond the body mass index: tracking body composition in the pathogenesis of obesity and the metabolic syndrome. Obes Rev. 2012 13: 6-13 11- Ludwig T, Eggenschwiler J, Fisher P, D’Ercole AJ, Davenport ML, Efstratiadis A. Mouse mutants lacking the type 2 IGF receptor (IGF2R) are rescued from perinatal lethality in IGF2 and IGF1R null backgrounds. Developmental Biology. 1996 177: 517-35. 12- Binici DN, Karaman A, Coşkun M, Oğlu AU, Uçar F. Genomic damage in patients with type-2 diabetes mellitus. Genet Couns. 2013 24:149-56. 13- Duggirala R, Blangero J, Almasy L, et al. A major locus for fasting insulin concentrations and insulin resistance on chromosome 6q with strong pleiotropic effects on obesity-related phenotypes in nondiabetic Mexican Americans. Am J Hum Genet. 2001 68: 1149-64. 14- Villuendas G, Carretero JIB, Bermejo AL, et al. The ACAA-insertion/deletion polymorphism at the 30 UTR of the IGF-II receptor gene is associated with type 2 diabetes and surrogate markers of insulin resistance. Eur J Endocrin. 2006 155: 331-36. 15- Lv K, Guo Y, Zhang Y, Wang K, Jia K, Sun S. Allele-specific targeting of hsa-miR-657 to human IGF2R creates a potential mechanism underlying the association of ACAA-insertion/deletion polymorphism with type 2 diabetes. Biochem Biophys Res Commun. 2008 374: 101-5. 16- Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. 1. Diagnosis and classification of diabetes mellitus, provisional report of a WHO consultation. Diabet Med 1998 15: 539-53. 17- Dalton M, Cameron AJ, Zimmet PZ, et al. Waist circumference, waist-hip ratio and body mass index and their correlation with cardiovascular disease risk factors in Australian adults. J Intern Med. 2005 254: 555-63. 18- Matsuda M, DeFronzo R. Insulin sensitivity indices obtained from oral glucose tolerance testing. Diabetes Care. 1999 22:1462-70. 19- Fridwald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972 18: 499-502. 20- Bloomgarden MD. Concepts of insulin resistance. Metab Synd Related Disord. 2005 3: 284-93. 21- Bouche C, Serdy S, Kahn CR, Goldfine AB. The cellular fate of glucose and its relevance in type 2 diabetes. Endocr Rev. 2004 25: 807-30. 22- San Millan JL, Corton M, Villuendas G, Sancho J, Peral B, Escobar-Morreale HF. Association of the polycystic ovary syndrome with genomic variants related to insulin resistance, type 2 diabetes mellitus, and obesity. J Clin Endocrinol Metab. 2004 89: 2640-46. 24- Di Bacco A, Gill G. The secreted glycoprotein CREG inhibits cell growth dependent on the 5 mannose-6-phosphate/insulin-like growth factor II receptor. Oncogene. 2003 22: 5436-45.