β-Cell Glucose Sensitivity determines hyperglycaemia in Polycystic Ovary Syndrome

Aims To investigate the mechanism of hyperglycaemia in women with Polycystic Ovary Syndrome (PCOS) by modelling physiological insulin secretion. Methods 45 non-diabetic women with PCOS (defined by Rotterdam criteria) and 47 controls were studied. Insulin secretion was modelled from glucose and C-peptide concentrations during a 6-point oral glucose tolerance test (OGTT) and insulin resistance (IR) was determined by the Matsuda Insulin Sensitivity Index (ISI). Results (1). β-Cell Glucose Sensitivity (βCGS) is not intrinsically impaired in PCOS, but IR is increased. (2) However, women with PCOS and 2-hour hyperglycaemia (glucose >7.5 mmol/l]) were characterized by worse βCGS compared with women with 2-hour glucose <7.5 mmol/l (mean [SD]) 43.5 [23.6] versus 109.0 [68.5] pmol/min/ml/mmol; p = 0.04), and had higher waist circumference (116.8 [15.8] vs 93.5 [15.9] cm; p < 0.01) and 120 minute insulin concentrations (964.0 [579.2–1214.7] vs 328.2 [242.2–475.7] pmol/l; p = 0.01). (3). In contrast, lean, insulin sensitive women with PCOS were euglycemic, even in the presence of poor βCGS, and exhibited favourable cardiometabolic risk profiles. Conclusions βCGS is not intrinsically impaired in PCOS, but it is the critical determinant of hyperglycaemia. Women with low βCGS, who also have central adiposity and IR exhibit 2-hour hyperglycaemia, whereas women with high βCGS are able to maintain euglycaemia despite central adiposity and IR. These findings show that (i) waist circumference and 2-hour glucose identify women at higher risk of diabetes, and confirm that (ii) obesity and IR are the key reversible targets for diabetes prevention in women with PCOS.