Metformin Improves Glucose Effectiveness, Not Insulin Sensitivity: Predicting Treatment Response in Women With Polycystic Ovary Syndrome

Abstract

Although metformin is widely used to improve insulin resistance in women with PCOS, its mechanism of action is complex with inconsistent effects on insulin sensitivity and variability in treatment response. The objective of this open label, interventional study was to delineate the effect of metformin on glucose and insulin parameters, determine additional treatment outcomes, and predict patients with PCOS who will respond to treatment. The subjects of this study were women with PCOS (n=36), diagnosed by the NIH criteria, who underwent fasting blood samples, an intravenous glucose tolerance test (IVGTT), dual-energy X-ray absorptiometry scan, trans-vaginal ultrasound and hCG-stimulated androgen levels before and after 12 weeks of treatment with metformin ER 1500 mg/day. Interval visits were performed to monitor metabolic parameters, anthropomorphic measurements, and ovulatory menstrual cycles. The results of this study showed that after metformin treatment insulin sensitivity did not change despite weight loss. However, glucose effectiveness (p=0.002) and the acute insulin response to glucose (p=0.002) increased and basal glucose levels (p=0.001) and testosterone decreased. Furthermore, women with improved ovulatory function (61%) had lower baseline testosterone levels and lower baseline and stimulated testosterone and androstenedione levels after metformin treatment (all p<0.05). In conclusion, using an IVGTT, which distinguishes improvements in glucose effectiveness and insulin sensitivity, metformin does not improve insulin sensitivity in women with PCOS, but does improve glucose effectiveness. The improvement in glucose effectiveness may be partially mediated by decreased glucose levels. Testosterone levels also decreased with metformin treatment. Ovulation during metformin treatment was associated with lower baseline testosterone levels and greater testosterone and androstenedione decreases during treatment, but not insulin or LH levels. Thus, the action of metformin in PCOS primarily affects glucose levels and steroidogenesis, which may be mediated by mechanisms that affect both pathways such as inhibition of mitochondrial respiratory complex I.