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

• Published in: American journal of physiology: endocrinology and metabolism 2015-05, Vol.308 (9), p.E770-E777
• Main Authors: Malin, Steven K, Kirwan, John P, Sia, Chang Ling, González, Frank
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Case-Control Studies; Cells, Cultured; Female; Glucose Tolerance Test; Humans; Hyperglycemia - immunology; Hyperglycemia - metabolism; Inflammation - metabolism; Inflammation - physiopathology; Insulin-Secreting Cells - physiology; NF-kappa B - metabolism; Obesity - metabolism; Obesity - physiopathology; Polycystic Ovary Syndrome - immunology; Polycystic Ovary Syndrome - metabolism; Polycystic Ovary Syndrome - physiopathology; Young Adult
• ISSN: 0193-1849; 1522-1555
• DOI: 10.1152/ajpendo.00510.2014

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.