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Submitted on March 15, 2007
Accepted on July 20, 2007
cells
Departments of Immunobiology and Medicine Yale University, New Haven, CT; Department of Pediatrics and the Naomi Berrie Diabetes Center, College of Physicians and Surgeons, Columbia University, New York, NY; Children's Hospital of Philadelphia, Division of Endocrinology, University of Pennsylvania School of Medicine, Philadelphia, PA; Diabetes Center, Department of Medicine, University of California at San Francisco, San Francisco, CA; Julia McFarlane Diabetes Research Centre and Department of Microbiology and Infectious Diseases, University of Calgary, Calgary, Alberta, Canada
* To whom correspondence should be addressed. E-mail: kevan.herold{at}yale.edu.
Immune modulators can arrest loss of insulin secretion in T1DM, but they have not caused permanent disease remission or restored normal insulin secretion. We tested whether Exendin-4, a GLP-1 receptor agonist would enhance remission of T1DM in NOD mice treated with anti-CD3 mAb, and studied the effects of Exendin-4 treatment on cellular and metabolic responses of 
cells. Diabetic NOD mice treated with anti-CD3 mAb and Exendin-4 had a higher rate of remission (44%) than mice treated with anti-CD3 mAb alone (37%) or Exendin-4 (0%) or insulin or IgG alone (0%)(p<0.01). The effect of Exendin-4 on reversal of diabetes after anti-CD3 mAb was greatest in mice with a glucose of < 350 mg/dl at diagnosis (63% vs 39%, p<0.05). Exendin-4 did not affect cell area, replication, or apoptosis, or reduce the frequency of diabetogenic or regulatory T cells, or modulate the antigenicity of islet cells. Reversal of T1DM with anti-CD3 mAb was associated with recovery of insulin in GLUT-2+insulin- islet cells that were identified at diagnosis. Glucose tolerance and insulin responses improved in mice treated with combination therapy, and Exendin-4 increased insulin content and insulin release from cells. We conclude that treatment with GLP-1 receptor agonist enhances remission of T1DM in NOD mice treated with anti-CD3 mAb by enhancing the recovery of the residual islets. This combinatorial approach may be useful in treatment of patients with new onset T1DM.
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