Effects of Exenatide Alone and in Combination with Daclizumab on Beta Cell Function in Long-Standing Type 1 Diabetes Mellitus

  1. Kristina I. Rother, M.D., M.H.Sc. (kristina.rother{at}nih.gov)1,
  2. Lisa M. Spain, Ph.D.1,
  3. Robert A. Wesley, Ph.D.1,
  4. Benigno J. Digon, 3rd, M.D1,
  5. Alain Baron, M.D.2,
  6. Kim Chen, Ph.D.2,
  7. Patric Nelson, M.P.H.2,
  8. H.-Michael Dosch, M.D.3,
  9. Jerry Palmer, M.D.4,
  10. Barbara Brooks-Worrell, Ph.D.4,
  11. Michael Ring, M.D.1 and
  12. David M. Harlan, M.D.1
  1. 1 National Institute of Diabetes, Digestive and Kidney Disease, National Institutes of Health, Bethesda, Maryland
  2. 2 Amylin Pharmaceuticals, San Diego, CA 92121
  3. 3 The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8
  4. 4 Veterans Affairs Puget Sound Health Care System, Department of Medicine, Division of Metabolism, Endocrinology, and Nutrition, University of Washington, Seattle, WA 98108, USA

    Abstract

    Objective - In patients with long-standing type 1 diabetes, we investigated whether improved beta-cell function can be achieved by combining intensive insulin therapy with agents that may 1) promote beta-cell growth and/or limit beta-cell apoptosis, and 2) weaken the anti-beta-cell autoimmunity.

    Research Design and Methods - Twenty individuals (mean age 39.5 ± 11.1 years) with long-standing type 1 diabetes (21.3 ± 10.7 years) were enrolled in this prospective, open-label, cross-over trial. After achieving optimal blood glucose control, 16 subjects were randomized to exenatide with or without daclizumab. Endogenous insulin production was determined by repeatedly measuring serum C-peptide.

    Results - In 85% of individuals with long-standing type 1 diabetes who were screened for participation in this trial, C-peptide levels ≥ 0.05 ng/mL (0.02 nmol/L) were found. Residual beta-cells responded to physiological (mixed meal) and pharmacological (arginine) stimuli. During exenatide treatment, patients lost 4.1 ± 2.9 kg body weight, and insulin requirements declined significantly (total daily dose on exenatide 0.48 ± 0.11 u/kg/d versus 0.55 ± 0.13 u/kg/d without exenatide; p=0.0062). No signs of further activation of the underlying autoimmune disease were observed. Exenatide delayed gastric emptying, suppressed endogenous incretin levels, but did not increase C-peptide secretion.

    Conclusions - In long-standing type 1 diabetes, which remains an active autoimmune disease even decades after its onset, surviving beta-cells secrete insulin in a physiologically regulated manner. However, the combination of intensified insulin therapy, exenatide, and daclizumab did not induce improved function of these remaining beta-cells.

    Footnotes

      • Received April 24, 2009.
      • Accepted September 18, 2009.

    This Article

    1. Diabetes Care
    1. All Versions of this Article:
      1. dc09-0773v1
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