title: Pancreatic β-cell dysfunction in polycystic ovary syndrome: role of hyperglycemia-induced nuclear factor-κB activation and systemic inflammation.
abstract: In polycystic ovary syndrome (PCOS), oxidative stress is implicated in the development of β-cell dysfunction. However, the role of mononuclear cell (MNC)-derived inflammation in this process is unclear. We determined the relationship between β-cell function and MNC-derived nuclear factor-κB (NF-κB) activation and tumor necrosis factor-α (TNF-α) secretion in response to a 2-h 75-g oral glucose tolerance test (OGTT) in normoglycemic women with PCOS (15 lean, 15 obese) and controls (16 lean, 14 obese). First- and second-phase β-cell function was calculated as glucose-stimulated insulin secretion (insulin/glucose area under the curve for 0-30 and 60-120 min, respectively) × insulin sensitivity (Matsuda Index derived from the OGTT). Glucose-stimulated NF-κB activation and TNF-α secretion from MNC, and fasting plasma thiobarbituric acid-reactive substances (TBARS) and high-sensitivity C-reactive protein (hs-CRP) were also assessed. In obese women with PCOS, first- and second-phase β-cell function was lower compared with lean and obese controls. Compared with lean controls, women with PCOS had greater change from baseline in NF-κB activation and TNF-α secretion, and higher plasma TBARS. β-Cell function was inversely related to NF-κB activation (1st and 2nd) and TNF-α secretion (1st), and plasma TBARS and hs-CRP (1st and 2nd). First- and second-phase β-cell function also remained independently linked to NF-κB activation after adjustment for body fat percentage and TBARS. In conclusion, β-cell dysfunction in PCOS is linked to hyperglycemia-induced NF-κB activation from MNC and systemic inflammation. These data suggest that in PCOS, inflammation may play a role in impairing insulin secretion before the development of overt hyperglycemia.
authors.affiliation: Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio; Department of Nutrition, School of Medicine, Case Western Reserve University, Cleveland, Ohio; and.
authors.forename: Steven K
authors.initials: SK
authors.lastname: Malin
authors.affiliation: Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio; Department of Nutrition, School of Medicine, Case Western Reserve University, Cleveland, Ohio; and.
authors.forename: John P
authors.initials: JP
authors.lastname: Kirwan
authors.affiliation: Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Chang Ling
authors.initials: CL
authors.lastname: Sia
authors.affiliation: Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, Indiana gonzalef@iupui.edu.
authors.forename: Frank
authors.initials: F
authors.lastname: González
mesh_terms: D000293:Adolescent; D000328:Adult; D016022:Case-Control Studies; D002478:Cells, Cultured; D005260:Female; D005951:Glucose Tolerance Test; D006801:Humans; D006943:Hyperglycemia / Q000276:immunology / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism / Q000503:physiopathology; D050417:Insulin-Secreting Cells / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism / Q000503:physiopathology; D011085:Polycystic Ovary Syndrome / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology*; D055815:Young Adult
chemical_list: D016328:NF-kappa B
keywords: androgens; glucose intolerance; insulin resistance; insulin secretion; insulin sensitivity; mononuclear cells; obesity