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Pharmacological Treatment of Insulin Resistance at Two Different Stages in the Evolution of Type 2 Diabetes: Impact on Glucose Tolerance and ß-Cell Function

Departments of Preventive Medicine (A.H.X., R.K.P., S.T., H.N.H., S.P.A.), Obstetrics and Gynecology (S.L.K., T.A.B.), and Medicine (J.G., C.O., A.M., H.N.H., T.A.B.), University of Southern California Keck School of Medicine, Los Angeles, California 90033

Address all correspondence and requests for reprints to: Thomas A. Buchanan, M.D., Room 6602 GNH, 1200 North State Street, Los Angeles, California 90089-9317. E-mail: buchanan{at}usc.edu.

The purpose of this study was to compare the impact of treating insulin resistance with a thiazolidinedione drug before vs. at the onset of diabetes on glucose levels and ß-cell function.

Nondiabetic Hispanic women of Mexican or Central American descent with prior gestational diabetes mellitus (GDM) were randomized to troglitazone (early intervention), 400 mg/d, or placebo (later intervention). Women who developed diabetes were placed on open-label troglitazone. Glucose tolerance, insulin resistance, and ß-cell function were measured at randomization, at the diagnosis of diabetes, and 8 months post trial to determine the long-term impact of the two treatment strategies on glucose levels and ß-cell function.

During a mean follow-up of 4.3 yr between baseline and posttrial tests, glucose tolerance (oral glucose tolerance test glucose area, P = 0.04) and insulin resistance (MINMOD S_I, P = 0.02) worsened more in women randomized to late intervention (n = 69) than to early intervention (n = 57). Insulin secretion (acute insulin response in the iv glucose tolerance test, P = 0.09) and ß-cell compensation for insulin resistance (disposition index, P = 0.07) also tended to worsen more in the late intervention group. Among women in the late intervention group who developed diabetes, oral glucose tolerance test glucose area (P = 0.0001) and ß-cell function (P 0.04) deteriorated significantly during development of diabetes on placebo and then did not change significantly (P > 0.50) during treatment with troglitazone and posttreatment washout.

In high-risk Hispanic women, amelioration of insulin resistance can stabilize glycemia at the time diabetes develops. These findings highlight the role of insulin resistance in the genesis of progressive ß-cell dysfunction during the evolution of type 2 diabetes.

This work was supported by Research Grant PD-991-053, Parke-Davis Pharmaceutical Research; M01-RR-43 from the General Clinical Research Branch, National Center for Research Resources, National Institutes of Health (NIH); Clinical Research Award from the American Diabetes Association; and R01-DK-46374 from the National Institute of Diabetes and Digestive and Kidney Diseases, NIH.

Abbreviations: AIRg, Acute insulin response to iv glucose; DI, disposition index; GDM, gestational diabetes mellitus; ivGTT, iv glucose tolerance test; Kg, glucose disappearance; oGTT, oral glucose tolerance test; S_I, insulin sensitivity_; T2DM, type 2 diabetes mellitus; TRIPOD, Troglitazone in Prevention of Diabetes (study); UKPDS, United Kingdom Prospective Diabetes Study.

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