Influence of peroxisome proliferator-activated receptor-γ exon 2 and exon 6 and insulin receptor substrate (IRS)-1 Gly972Arg polymorphisms on insulin resistance and beta-cell function in southern mediterranean women with polycystic ovary syndrome

Annalisa Giandalia; Maria Angela Pappalardo; Giuseppina T Russo; Elisabetta L Romeo; Angela Alibrandi; Flavia Di Bari; Roberto Vita; Domenico Cucinotta; Salvatore Benvenga

doi:10.1016/j.jcte.2018.05.002

Influence of peroxisome proliferator-activated receptor-γ exon 2 and exon 6 and insulin receptor substrate (IRS)-1 Gly972Arg polymorphisms on insulin resistance and beta-cell function in southern mediterranean women with polycystic ovary syndrome

J Clin Transl Endocrinol. 2018 May 24:13:1-8. doi: 10.1016/j.jcte.2018.05.002. eCollection 2018 Sep.

Affiliations

¹ Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.
² Department of Economics, University of Messina, Viale Gazzi, 98125 Messina, Italy.
³ Master Program on Childhood, Adolescent and Women's Endocrine Health, University of Messina, Viale Gazzi, 98125 Messina, Italy.
⁴ Interdepartmental Program of Molecular & Clinical Endocrinology, and Women's Endocrine Health, University Hospital Policlinico G. Martino, Viale Gazzi, 98125 Messina, Italy.

Abstract

Background and objective: The Pro12Ala (exon 2) and His447His (exon 6) polymorphisms of PPAR-γ, and Gly972Arg polymorphism of IRS-1 have been implicated in insulin resistance (IR) and adiposity. Our aim was to investigate the influence of these polymorphisms on metabolic features of polycystic ovary syndrome (PCOS).

Methods: Fifty-three PCOS women and 26 control women underwent a clinical and biochemical evaluation, including a 75-g oral glucose tolerance test. Insulin secretion and insulin sensitivity indices were calculated.

Results: Frequencies of PPAR-γ polymorphisms did not differ from those predicted by the Hardy-Weinberg equilibrium. Instead, the IRS-1 Gly972Arg allele was significantly more frequent in the PCOS group compared to controls. The most frequent allelic combinations were IRS1+/exon2-/exon6- (which prevailed in PCOS) and IRS-1-/exon2-/exon6- (which prevailed in controls). Among PCOS women, compared with the wild type patients, carriers of the Gly972Arg IRS-1 allele had lower E2 levels, while carriers of the Pro12Ala PPAR-γ (exon 2) allele had lower free testosterone levels. No other significant relationships were noted. When compared with the wild type, in PCOS group IR and beta-cell function were: (i) trendwise greater in carriers of the variant IRS-1 allele; (ii) trendwise lower in carriers of the variant PPAR-γ exon 6 allele; (iii) significantly lower in carriers of the variant PPAR-γ exon 2 allele.

Conclusions: Our data support the protective influence of PPAR-γ-exon 2 and exon 6 variants on IR and beta cell function, whereas IRS-1 polymorphism is associated with an unfavorable metabolic profile. However, these associations do not fully explain the high metabolic risk associated with PCOS.

Keywords: 17-OHP, 17-hydroxyprogesterone; AE-PCOS, Androgen Excess and Polycystic Ovary Syndrome Society; BMI, body mass index; DI, disposition index; E2, 17β-estradiol; FSH, follicular stimulating hormone; HDL, high-density lipoprotein; HOMA-IR, homeostasis model assessment; IGI, insulinogenic index; IRS, insulin receptor substrate; Insulin receptor substrate-1; LDL, low-density lipoprotein; LH, luteinizing hormone; OGTT, oral glucose tolerance test; PCOS, polycystic ovary syndrome; PCR, polymerase chain reaction; PPAR-γ, peroxisome proliferator activated receptor-γ; Peroxisome proliferator-activated-receptor-gamma; Polycystic ovary syndrome; Polymorphisms; SHBG, sex hormone binding globulin.