Diabetes & Metabolism Journal

Original Article

FTO Gene Variants Are Associated with PCOS Susceptibility and Hyperandrogenemia in Young Korean Women: Do Kyeong Song, Hyejin Lee, Jee-Young Oh, Young Sun Hong, Yeon-Ah Sung; Diabetes Metab J. 2014;38(4):302-310. Published online August 20, 2014; DOI: https://doi.org/10.4093/dmj.2014.38.4.302

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Background

The fat mass and obesity-associated (FTO) gene is associated with obesity and type 2 diabetes mellitus. Obesity and insulin resistance are also common features of polycystic ovary syndrome (PCOS). Therefore, the FTO gene might be a candidate gene for PCOS susceptibility. The aim of the present study was to evaluate the effects of FTO gene variants on PCOS susceptibility and metabolic and reproductive hormonal parameters.

Methods

We recruited 432 women with PCOS (24±5 years) and 927 healthy women with regular menstrual cycles (27±5 years) and performed a case-control association study. We genotyped the single nucleotide polymorphisms rs1421085, rs17817449, and rs8050136 in the FTO gene and collected metabolic and hormonal measurements.

Results

Logistic regression revealed that the G/G genotype (rs1421085, 1.6%), the C/C genotype (rs17817449, 1.6%), and the A/A genotype (rs8050136, 1.6%) were strongly associated with an increased risk of PCOS (odds ratio, 2.551 to 2.559; all P<0.05). The strengths of these associations were attenuated after adjusting for age and BMI. The women with these genotypes were more obese and exhibited higher free androgen indices (P<0.05) and higher free testosterone levels (P=0.053 to 0.063) compared to the other genotypes. However the significant differences disappeared after adjusting for body mass index (BMI). When we analyzed the women with PCOS and the control groups separately, there were no significant differences in the metabolic and reproductive hormonal parameters according to the FTO gene variants.

Conclusion

The rs1421085, rs17817449, and rs8050136 variants of the FTO gene were associated with PCOS susceptibility and hyperandrogenemia in young Korean women. These associations may be mediated through an effect of BMI.

Citations

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Review

Insulin Resistance in Polycystic Ovary Syndrome.: Yeon Ah Sung; Korean Diabetes J. 2008;32(1):1-6. Published online February 1, 2008; DOI: https://doi.org/10.4093/kdj.2008.32.1.1

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Abstract PDF

Polycystic ovary syndrome (PCOS) is the commonest endocrine disorder in women of reproductive age and now recognized as an important metabolic and reproductive disorder. The majority of women with PCOS have insulin resistance and this is regarded to have a central etiological role in PCOS. Insulin resistance and concomitant hyperinsulinemia modifies reproductive function by driving androgen production, suppression of sex hormone-binding globulin (SHBG) and disruption of insulin signaling pathways in the central nervous system. Insulin resistance, together with defects in insulin secretion, confers markedly increased risk for type 2 diabetes mellitus and metabolic syndrome. There are post-binding defects in insulin receptor signaling, with selective resistance to insulin's metabolic actions and preserved other actions. Genetic and environmental abnormalities interact to produce peripheral insulin resistance in PCOS. The numerous in vivo and in vitro data supporting the central role of insulin resistance in the pathogenesis of PCOS have led a new therapy for PCOS with insulin-sensitizing agents.

Citations

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Epidemiology and Diagnostic Criteria of Polycystic Ovary Syndrome
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Hanyang Medical Reviews.2012; 32(4): 197. CrossRef
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Original Articles

Peroxisome Proliferator-activated Receptor-gamma (PPARgamma) Polymorphism in Korean Women with Polycystic Ovary Syndrome.: Jee Young Oh, Hyejin Lee, Young Sun Hong, Yeon Ah Sung, Hye Won Chung; Korean Diabetes J. 2007;31(6):480-487. Published online November 1, 2007; DOI: https://doi.org/10.4093/jkda.2007.31.6.480

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Abstract PDF: BACKGROUND
Polycystic ovary syndrome (PCOS) is a common endocrine disease affecting 5~10% of women with reproductive age. Familial aggregation suggests the evidence supporting a genetic basis for PCOS. The mode of inheritance of PCOS is not yet clear, however, probably polygenic and might be related to insulin resistance. Polymorphism of peroxisome proliferator-activated receptor (PPAR)-gamma gene is a susceptible gene for the development of obesity and diabetes. In this study, we examined the frequency and genetic effect of PPAR-gamma polymorphism on insulin resistance or hyperandrogenemia in Korean women with PCOS. METHODS: One-hundred twenty five Korean women with PCOS were evaluated for their metabolic and reproductive hormonal status. PPAR-gamma polymorphism was analyzed. RESULTS: Genetic frequency of PPAR-gamma was not significantly different between women with PCOS (n = 125) and those with regular menstrual cycles (n = 344). PCOS with Pro12Ala polymorphism had significantly higher levels of waist circumference and subcutaneous fat area compared with those with Pro12Pro genotype. They also had tendency of higher levels of fasting glucose concentration, body mass index (BMI) and visceral fat area. After BMI adjustment, this polymorphism was related to lower fasting insulin and higher insulin sensitivity index, and higher sex hormone binding globulin and lower free testosterone levels. CONCLUSION: Pro12Ala polymorphism of PPAR-gamma gene might be associated with obesity. However, after BMI adjustment, it may have favorable effect on insulin resistance and hyperandrogenemia. Because this study has limitations to conclude the genetic causality, further study is needed to support these findings.

Usefulness of Insulin Sensitivity Indexes derived from Oral Glucose Tolerance Test in Women with Polycystic Ovary Syndrome.: Hyo Jeong Kim, Eun Kyung Byun, Jee Young Oh, Yeon Ah Sung, Hye Won Chung; Korean Diabetes J. 2006;30(4):277-284. Published online July 1, 2006; DOI: https://doi.org/10.4093/jkda.2006.30.4.277

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Abstract PDF

BACKGROUND
Insulin resistance is prevalent in women with polycystic ovary syndrome (PCOS), and it makes them to have high risk for development of type 2 diabetes. Evaluation of insulin sensitivity would be important to predict their risks. Although the euglycemic-hyperinsulinemic clamp technique is the gold standard for measuring insulin sensitivity, it is too hard to practice in large epidemiologic studies. The aim of this study is to verify the validity of various insulin sensitivity indexes from oral glucose tolerance test (OGTT) in women with PCOS. METHODS: We performed euglycemic-hyperinsulinemic clamp (target glucose; 90 mg/dL, insulin ;~1 mU/kg.min) to obtain insulin-mediated glucose disposal rate (M-value) in 62 non-diabetic women with PCOS (BMI < 23 kg/m2; n = 37, BMI > or = 23 kg/m2; n = 25). Homeostasis model assessment [HOMA(IR)], quantitative insulin sensitivity check index (QUICKI), glucose to insulin ratio (G/I ratio), whole body insulin sensitivity index [ISI(COMP)], metabolic clearance rate of glucose [MCR(est)-OGTT(1,2)], and insulin sensitivity indexes [ISI(est)-OGTT(1,2)] were calculated from plasma glucose and insulin levels from standard 75-g OGTT. The correlations of various insulin sensitivity indexes from OGTT with M-value were evaluated. RESULTS: In lean women with PCOS (BMI < 23 kg/m2, n = 37), ISI(COMP) (r = 0.36, P < 0.05), MCRest-OGTT1 (r = 0.49, P < 0.01), ISI(est)-OGTT(1) (r = 0.50, P < 0.01), MCR(est)-OGTT(2) (r = 0.45, P < 0.01) and ISI(est)-OGTT(2) (r = 0.40, P < 0.05) were significantly correlated with M-value. In overweight and obese women with PCOS (BMI > or = 23 kg/m2, n = 25), HOMA(IR) (r = -0.40, P < 0.05), QUICKI (r = 0.40, P < 0.05), MCR(est)-OGTT(1) (r = 0.76, P < 0.001), ISI(est)-OGTT(1) (r = 0.63, P < 0.001), MCR(est)-OGTT(2) (r = 0.58, P < 0.01) and ISI(est)-OGTT(2) (r = 0.42, P < 0.05) showed significant correlations with M-value. CONCLUSION: MCR(est)-OGTT(1) and ISI(est)-OGTT(1) were the most reliable and easily accessible insulin sensitivity indexes obtained from OGTT for measuring of insulin sensitivity in women with PCOS regardless of obesity.

Citations

Citations to this article as recorded by

Insulin resistance in a large cohort of women with polycystic ovary syndrome: a comparison between euglycaemic-hyperinsulinaemic clamp and surrogate indexes
Flavia Tosi, Enzo Bonora, Paolo Moghetti
Human Reproduction.2017; 32(12): 2515. CrossRef

Insulin Resistance in Normal Weight Women with Polycystic Ovary Syndrome.: Eun Kyung Byun, Hye Jin Lee, Jee Young Oh, Young Sun Hong, Hye Won Chung, Yeon Ah Sung; Korean Diabetes J. 2004;28(4):315-323. Published online August 1, 2004

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Abstract PDF: BACKGROUND
Insulin resistance is considered a regular component of polycystic ovary syndrome (PCOS). However, several studies have failed to confirm insulin resistance in non-obese women with PCOS. The aim of the study was to identify whether insulin resistance is present in normal weight women with PCOS and the factors associated with insulin sensitivity. METHODS: Twenty-two normal weight (body mass index, BMI < 25 kg/m2) women with PCOS, and 16 age and BMI comparable control women with regular menstrual cycles were examined during their early follicular phase. The levels of serum hormones and lipids were measured. The visceral fat area was assessed by computed tomography at umbilical level. The standard 75g oral glucose tolerance test was performed to determine the glucose tolerance status. The insulin sensitivity was measured using the euglycemic hyperinsulinemic clamp technique (target glucose 90 mg/dL, insulin~1 mu/kg/min). RESULTS: The levels of free testosterone (1.9+/-0.6 pg/mL vs. 0.8+/-0.3 pg/mL, p<0.001), androstenedione (14.5+/-3.7 nmol/L vs. 8.8+/-1.3 nmol/L, p<0.001), LH (10.7+/-4.5 IU/L vs 4.6+/-4.8 IU/L, p<0.001) and FSH (5.8+/-1.7 IU/L vs. 4.2+/-2.4 IU/L, p<0.05) of the women with PCOS were significantly higher than those of the control subjects. The fasting plasma glucose (4.92+/-0.31 mmol/L vs. 4.42+/-0.61 mmol/L, p<0.01) and post glucose load plasma insulin (233.2+/-119.5pmol/L vs. 109.0+/-46.4 pmol/L, p<001) levels of women with PCOS were significantly higher than those of the control subjects. The glucose disposal rate (M value) was significantly lower in women with PCOS compared to the controls (5.3+/-1.2 mg/kg min vs. 6.7+/-1.6 mg/kg min, p<0.05), even after adjusting for age and BMI. There was no significant correlation of the M value with the anthropometric and a metabolic indices, and a multiple regression analysis of the M value showed no significant variables. CONCLUSION: Our non-obese women with PCOS showed significant insulin resistance compared to their age and BMI comparable control subjects, and-their insulin resistance may be an intrinsic defect not associated with other features, such as hyperandrogenemia or body fat distribution patterns.

Association of High Intracellular Calcium Levels with Insulin Resistance in Women with Polycystic Ovary Syndrome.: Jee Young Oh, Hye Jin Lee, Young Sun Hong, Hye Won Chung, Yeon Ah Sung; Korean Diabetes J. 2004;28(2):101-110. Published online April 1, 2004

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Abstract PDF: BACKGROUND
Insulin resistance is an intrinsic defect of polycystic ovary syndrome (PCOS), and elevated levels of cytosolic free calcium in insulin target cells may cause insulin resistance. To our knowledge, the relationship between intracellular calcium and insulin resistance in PCOS has not been investigated. The purpose of this study was to determine whether the levels of intracelluar calcium are changed and if they have any association with insulin resistance in women with PCOS. METHODS: The intracellular calcium levels in the platelets and the insulin sensitivity were measured by fluorescent spectrophotometry and the euglycemic hyperinsulinemic clamp technique, respectively, in 16 women with PCOS and 6 normal cycling women. A 2h, 75 g oral glucose tolerance test was performed to determine the glucose tolerance. RESULTS: The insulin sensitivity measured by the glucose disposal rate(the M-value), was significantly lower in women with PCOS(4.6+/-1.5mg/kg/min vs. 7.0+/-1.3mg/kg/min, p<0.01), but the intracellular calcium levels were significantly higher in women with PCOS compared to the controls(122.7+/-36.7 vs 59.1+/-29.3mmol/L, p<0.01). When the women with PCOS were divided into the overweight or obese(n=9, BMI ?23kg/m2) and lean(n=7, BMI<23kg/m2) groups, both groups had significantly lower M values compared to the control subjects(3.9+/-1.3, 5.5+/-1.2 vs. 7.0+/-1.3mumg/kg/min, p<0.001), and these levels between the overweight/obese and lean PCOS groups showed a significant difference(p<0.001). The overweight/ obese and lean women with PCOS had significantly higher levels of intracellular calcium compared to the control subjects(131.3+/-39.6, 111.7+/-31.8 vs. 59.1+/-29.3nmol/L, p<0.01), but these levels did not differ significantly between the overweight/obese and lean women with PCOS. The intracellular calcium levels showed a significant positive correlation with age, and a negative correlation with the M value(r=-0.55, p<0.05). The BMI-adjusted partial correlation showed marginal significance between elevated levels of intracellular calcium and insulin sensitivity (r=-0.47, p=0.07). CONCLUSION: Women with PCOS showed both insulin resistance and increased levels of intracellular calcium compared to the control subjects. Increased levels of intracellular calcium were associated with insulin resistance in women with PCOS.

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