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Metformin Therapy Increases Insulin-Stimulated Release of D-Chiro-Inositol-Containing Inositolphosphoglycan Mediator in Women with Polycystic Ovary Syndrome

Department of Medicine (J.-P.B.), Université de Sherbrooke, Sherbrooke, J1H SN4 Canada; Departments of Medicine (M.J.I., T.A., N.H., J.E.N.) and Obstetrics and Gynecology (J.E.N.), Virginia Commonwealth University, Richmond, Virginia 23298-0111; and Hospital de Clinicas Caracas (D.J.J.), 1040 Caracas, Venezuela

Address all correspondence and requests for reprints to: John E. Nestler, M.D., Medical College of Virginia, P.O. Box 980111, Richmond, Virginia 23298-0111. E-mail: nestler{at}hsc.vcu.edu.

Some actions of insulin are mediated by putative inositolphosphoglycan mediators, and a deficiency in D-chiro-inositol-containing inositolphosphoglycan (DCI-IPG) may contribute to insulin resistance in women with polycystic ovary syndrome (PCOS). Furthermore, similar effects of DCI and metformin, an insulin-sensitizing drug, have been demonstrated in PCOS women. To determine whether metformin improves insulin actions by increasing biologically active DCI-IPG in women with PCOS, we analyzed DCI-IPG during an oral glucose tolerance test in 19 obese women with PCOS before and after 4–8 wk of metformin or placebo. After treatment, the mean (±SE) area under the curve (AUC) during the oral glucose tolerance test of insulin (AUC_insulin) decreased significantly more in the metformin group, compared with the placebo group [-3574 ± 962 vs. +1367 ± 1021 µIU/min·ml (-26 ± 7 vs. +10 ± 7 nmol/min·liter), P = 0.003], but the AUC of DCI-IPG (AUC_DCI-IPG) decreased similarly in both groups (-1452 ± 968 vs. -2207 ± 1021%/min, P = 0.60). However, the ratio of AUC_DCI-IPG/AUC_insulin increased by 160% after metformin and decreased by 29% after placebo (P = 0.002 between groups). Moreover, metformin seemed to improve the positive correlation between AUC_DCI-IPG and AUC_insulin but not placebo (r = 0.32, P = 0.68 at baseline; r = 0.52, P = 0.12 after metformin; and r = -0.39, P = 0.30 after placebo). We conclude that in obese women with PCOS, metformin may improve the action of insulin in part by improving insulin-mediated release of DCI-IPG mediators, as evidenced by increased bioactive DCI-IPG released per unit of insulin.

This work was supported in part by National Institutes of Health Grants R01HD35629 and K24HD40237 (both to J.E.N.) and grants from the Fond de Recherche en Santé du Québec (to J.-P.B.).

Abbreviations: AUC, Area under the curve; BMI, body mass index; CI, confidence interval; DCI, D-chiro-inositol; DCI-IPG, DCI-containing IPG; IPG, inositolphosphoglycan; NAD, ß-nicotinamide adenine dinucleotide; NADH, reduced form of NAD; OGTT, oral glucose tolerance test; PCOS, polycystic ovary syndrome; PDH, pyruvate dehydrogenase; PDP, pyruvate dehydrogenase phosphatase.

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