Pancreatic β-cell dysfunction in polycystic ovary syndrome: role of hyperglycemia-induced nuclear factor-κB activation and systemic inflammation

In polycystic ovary syndrome (PCOS), oxidative stress is implicated in the development of beta-cell dysfunction. However, the role of mononuclear cell (MNC)-derived inflammation in this process is unclear. We determined the relationship between beta-cell function and MNC-derived nuclear factor-kappa B (NF-kappa B) activation and tumor necrosis factor-alpha (TNF-alpha) 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 beta-cell function was calculated as glucose-stimulated insulin secretion (insulin/glucose area under the curve for 0-30 and 60-120 min, respectively) x insulin sensitivity (Matsuda Index derived from the OGTT). Glucose-stimulated NF-kappa B activation and TNF-alpha 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 beta-cell function was lower compared with lean and obese controls. Compared with lean controls, women with PCOS had greater change from baseline in NF-kappa B activation and TNF-alpha secretion, and higher plasma TBARS. beta-cell function was inversely related to NF-kappa B activation (1st and 2nd) and TNF-alpha secretion (1st), and plasma TBARS and hs-CRP (1st and 2nd). First-and second-phase beta-cell function also remained independently linked to NF-kappa B activation after adjustment for body fat percentage and TBARS. In conclusion, beta-cell dysfunction in PCOS is linked to hyperglycemia-induced NF-kappa B 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.