Plasma Diaphanous Related Formin 1 Levels Are Associated with Altered Glucose Metabolism and Insulin Resistance in Patients with Polycystic Ovary Syndrome: A Case Control Study

Background Diaphanous related formin 1 (DIAPH1) is a novel component of advanced glycation end product (AGE) signal transduction that was recently found to participate in diabetes-related disorders, obesity, and androgen hormones. We investigated whether plasma DIAPH1 levels were a potential prognostic predictor for polycystic ovary syndrome (PCOS). Methods The levels of circulating plasma DIAPH1 and indicators of glucose, insulin, lipid metabolism, liver enzymes, kidney function, sex hormones, and inflammation were measured in 75 patients with PCOS and 77 healthy participants. All of the participants were divided into normal-weight (NW) and overweight/obese (OW) subgroups. Statistical analyses were performed with R studio. Results PCOS patients manifested hyperandrogenism, increased luteinizing hormone/follicle-stimulating hormone (LH/FSH), and accumulated body fat and insulin resistance. Plasma DIAPH1 levels were significantly decreased in women with PCOS compared to control participants, and DIAPH1 levels were distinctly reduced in OW PCOS compared to OW control subjects (P < 0.001). DIAPH1 levels correlated with fasting blood glucose (FBG), total cholesterol (TC), the homeostasis model assessment of β-cell function (HOMA-β), and LH/FSH in all participants (FBG: r = 0.351, P < 0.0001; TC: r = 0.178, P = 0.029; HOMA-β: r = −0.211, P = 0.009; LH/FSH: r = −0.172, P = 0.040). Multivariate logistic regression analysis revealed that plasma DIAPH1 levels were an independent risk factor for PCOS. A model containing DIAPH1, BMI, FBG, and testosterone was constructed to predict the risk of PCOS, with a sensitivity of 92.0% and a specificity of 80.9%. A nomogram was constructed to facilitate clinical diagnosis. Conclusions These findings suggest the association of plasma DIAPH1 with glucose metabolism, insulin resistance, and sex hormones and support DIAPH1 as a potential predictive factor for PCOS.

[1]  L. Rashed,et al.  Nanocurcumin Modulates miR-223-3p and NF-κB Levels in the Pancreas of Rat Model of Polycystic Ovary Syndrome to Attenuate Autophagy Flare, Insulin Resistance and Improve ß Cell Mass , 2021, Journal of experimental pharmacology.

[2]  A. Schmidt,et al.  AGE/RAGE/DIAPH1 axis is associated with immunometabolic markers and risk of insulin resistance in subcutaneous but not omental adipose tissue in human obesity , 2021, International Journal of Obesity.

[3]  Haiyan Yang,et al.  Uric acid participating in female reproductive disorders: a review , 2021, Reproductive Biology and Endocrinology.

[4]  A. Duszewska,et al.  Chronic Low Grade Inflammation in Pathogenesis of PCOS , 2021, International journal of molecular sciences.

[5]  V. Pietiäinen,et al.  Loss of DIAPH1 causes SCBMS, combined immunodeficiency and mitochondrial dysfunction. , 2021, The Journal of allergy and clinical immunology.

[6]  L. Rashed,et al.  Nanocurcumin alleviates insulin resistance and pancreatic deficits in polycystic ovary syndrome rats: Insights on PI3K/AkT/mTOR and TNF-α modulations. , 2020, Life sciences.

[7]  H. Alzamil.  Elevated Serum TNF-α Is Related to Obesity in Type 2 Diabetes Mellitus and Is Associated with Glycemic Control and Insulin Resistance , 2020, Journal of obesity.

[8]  L. Lerman,et al.  Effect of Metformin on Microvascular Endothelial Function in Polycystic Ovary Syndrome. , 2019, Mayo Clinic proceedings.

[9]  R. Ramasamy,et al.  The Receptor for Advanced Glycation End Products (RAGE) and DIAPH1: Implications for vascular and neuroinflammatory dysfunction in disorders of the central nervous system , 2019, Neurochemistry International.

[10]  V. D’Agati,et al.  Deletion of the formin Diaph1 protects from structural and functional abnormalities in the murine diabetic kidney. , 2018, American journal of physiology. Renal physiology.

[11]  L. Moran,et al.  Metabolic syndrome in polycystic ovary syndrome: a systematic review, meta‐analysis and meta‐regression , 2018, Obesity reviews : an official journal of the International Association for the Study of Obesity.

[12]  L. Moran,et al.  Ethnicity, obesity and the prevalence of impaired glucose tolerance and type 2 diabetes in PCOS: a systematic review and meta-regression , 2018, Human reproduction update.

[13]  H. Escobar-Morreale.  Polycystic ovary syndrome: definition, aetiology, diagnosis and treatment , 2018, Nature Reviews Endocrinology.

[14]  Z. Merhi,et al.  Relationship between Advanced Glycation End Products and Steroidogenesis in PCOS , 2016, Reproductive Biology and Endocrinology.

[15]  William J. Astle,et al.  A gain-of-function variant in DIAPH1 causes dominant macrothrombocytopenia and hearing loss. , 2016, Blood.

[16]  E. Diamanti-Kandarakis,et al.  Advanced glycation end products: A link between metabolic and endothelial dysfunction in polycystic ovary syndrome? , 2015, Metabolism: clinical and experimental.

[17]  M. Geyer,et al.  Formins as effector proteins of Rho GTPases , 2014, Small GTPases.

[18]  M. Sewer,et al.  Regulation of adrenocortical steroid hormone production by RhoA–diaphanous 1 signaling and the cytoskeleton , 2013, Molecular and Cellular Endocrinology.

[19]  B. Yıldız,et al.  Prevalence, phenotype and cardiometabolic risk of polycystic ovary syndrome under different diagnostic criteria. , 2012, Human reproduction.

[20]  H. Randeva,et al.  Cardiometabolic aspects of the polycystic ovary syndrome. , 2012, Endocrine reviews.

[21]  A. Schmidt,et al.  Signal Transduction in Receptor for Advanced Glycation End Products (RAGE) , 2011, The Journal of Biological Chemistry.

[22]  H. Escobar-Morreale,et al.  Circulating inflammatory markers in polycystic ovary syndrome: a systematic review and metaanalysis. , 2011, Fertility and sterility.

[23]  S. Narumiya,et al.  Rho-mDia1 pathway is required for adhesion, migration, and T-cell stimulation in dendritic cells. , 2010, Blood.

[24]  M. Antoni,et al.  Insulin resistance, obesity, inflammation, and depression in polycystic ovary syndrome: biobehavioral mechanisms and interventions. , 2010, Fertility and sterility.

[25]  M. Sewer,et al.  RhoA and DIAPH1 mediate adrenocorticotropin-stimulated cortisol biosynthesis by regulating mitochondrial trafficking. , 2010, Endocrinology.

[26]  V. D’Agati,et al.  Interaction of the RAGE Cytoplasmic Domain with Diaphanous-1 Is Required for Ligand-stimulated Cellular Migration through Activation of Rac1 and Cdc42* , 2008, Journal of Biological Chemistry.

[27]  G. Hotamisligil,et al.  Inflammation and metabolic disorders , 2006, Nature.

[28]  Bei-fan Zhou.  Predictive values of body mass index and waist circumference for risk factors of certain related diseases in Chinese adults--study on optimal cut-off points of body mass index and waist circumference in Chinese adults. , 2002, Biomedical and environmental sciences : BES.

[29]  A. de Leiva,et al.  Assessment of insulin sensitivity and beta-cell function from measurements in the fasting state and during an oral glucose tolerance test , 2000, Diabetologia.

[30]  Z. Merhi,et al.  Advanced glycation end products and their relevance in female reproduction. , 2014, Human reproduction.

[31]  J. Uribarri,et al.  Advanced Glycation End Products (AGE) and Diabetes: Cause, Effect, or Both? , 2013, Current Diabetes Reports.

[32]  Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. , 2004, Fertility and sterility.