Effects of Exenatide Alone and in Combination With Daclizumab on β-Cell Function in Long-Standing Type 1 Diabetes

  1. Kristina I. Rother, MD, MHSC1,
  2. Lisa M. Spain, PHD1,
  3. Robert A. Wesley, PHD1,
  4. Benigno J. Digon III, MD1,
  5. Alain Baron, MD2,
  6. Kim Chen, PHD2,
  7. Patric Nelson, MPH2,
  8. H.-Michael Dosch, MD3,
  9. Jerry P. Palmer, MD4,
  10. Barbara Brooks-Worrell, PHD4,
  11. Michael Ring, MD1 and
  12. David M. Harlan, MD1
  1. 1National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland;
  2. 2Amylin Pharmaceuticals, San Diego, California;
  3. 3The Hospital for Sick Children, Toronto, Ontario, Canada;
  4. 4Department of Medicine, Division of Metabolism, Endocrinology, and Nutrition, Veterans Affairs Puget Sound Health Care System, University of Washington, Seattle, Washington.
  1. Corresponding author: Kristina I. Rother, kristina.rother{at}nih.gov.

Abstract

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

RESEARCH DESIGN AND METHODS For this study, 20 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 crossover 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 β-cells responded to physiological (mixed-meal) and pharmacological (arginine) stimuli. During exenatide treatment, patients lost 4.1 ± 2.9 kg body wt and insulin requirements declined significantly (total daily dose on exenatide 0.48 ± 0.11 vs. 0.55 ± 0.13 units · kg−1 · day−1 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 β-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 β-cells.

Footnotes

  • Clinical trial reg. no. NCT00064714, www.clinicaltrials.gov.

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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

  1. Diabetes Care vol. 32 no. 12 2251-2257
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