Preservation of Pancreatic β-Cell Function and Prevention of Type 2 Diabetes by Pharmacological Treatment of Insulin Resistance in High-Risk Hispanic Women

  1. Thomas A. Buchanan123,
  2. Anny H. Xiang34,
  3. Ruth K. Peters34,
  4. Siri L. Kjos23,
  5. Aura Marroquin1,
  6. Jose Goico1,
  7. Cesar Ochoa1,
  8. Sylvia Tan4,
  9. Kathleen Berkowitz2,
  10. Howard N. Hodis134 and
  11. Stanley P. Azen34
  1. 1Department of Medicine, University of Southern California Keck School of Medicine, Los Angeles, California
  2. 2Department of Obstetrics and Gynecology, University of Southern California Keck School of Medicine, Los Angeles, California
  3. 3Diabetes Research Center, University of Southern California Keck School of Medicine, Los Angeles, California
  4. 4Department of Preventive Medicine, University of Southern California Keck School of Medicine, Los Angeles, California

    Abstract

    Type 2 diabetes frequently results from progressive failure of pancreatic β-cell function in the presence of chronic insulin resistance. We tested whether chronic amelioration of insulin resistance would preserve pancreatic β-cell function and delay or prevent the onset of type 2 diabetes in high-risk Hispanic women. Women with previous gestational diabetes were randomized to placebo (n = 133) or the insulin-sensitizing drug troglitazone (400 mg/day; n = 133) administered in double-blind fashion. Fasting plasma glucose was measured every 3 months, and oral glucose tolerance tests (OGTTs) were performed annually to detect diabetes. Intravenous glucose tolerance tests (IVGTTs) were performed at baseline and 3 months later to identify early metabolic changes associated with any protection from diabetes. Women who did not develop diabetes during the trial returned for OGTTs and IVGTTs 8 months after study medications were stopped. During a median follow-up of 30 months on blinded medication, average annual diabetes incidence rates in the 236 women who returned for at least one follow-up visit were 12.1 and 5.4% in women assigned to placebo and troglitazone, respectively (P < 0.01). Protection from diabetes in the troglitazone group 1) was closely related to the degree of reduction in endogenous insulin requirements 3 months after randomization, 2) persisted 8 months after study medications were stopped, and 3) was associated with preservation of β-cell compensation for insulin resistance. Treatment with troglitazone delayed or prevented the onset of type 2 diabetes in high-risk Hispanic women. The protective effect was associated with the preservation of pancreatic β-cell function and appeared to be mediated by a reduction in the secretory demands placed on β-cells by chronic insulin resistance.

    Footnotes

    • Address correspondence and reprint requests to Thomas A. Buchanan, Room 6602 GNH, 1200 N. State St., Los Angeles, CA, 90033. E-mail: buchanan{at}usc.edu.

      Received for publication 18 March 2002 and accepted in revised form 5 June 2002.

      K.B. is currently affiliated with the School of Medicine, University of California at Irvine, Irvine, California.

      AIRg, acute insulin response to intravenous glucose; DI, disposition index; GDM, gestational diabetes mellitus; HR, hazard ratio; IVGTT, intravenous glucose tolerance test; Kg, glucose disappearance rate; OGTT, oral glucose tolerance test; SI, insulin sensitivity; TRIPOD, Troglitazone in Prevention of Diabetes.

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