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Exendin-4 Improves Reversal of Diabetes in NOD Mice Treated with Anti-CD3 Monoclonal Antibody by Enhancing Recovery of β-Cells

Departments of Immunobiology and Medicine (W.C., M.G., A.-M.B.B., K.C.H.), Yale University, New Haven, Connecticut 06520; Department of Pediatrics and the Naomi Berrie Diabetes Center (N.A.S., K.C.H.), College of Physicians and Surgeons, Columbia University, New York, New York 10032; Children’s Hospital of Philadelphia (J.A.K., A.-M.B.B.), Division of Endocrinology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19019; Diabetes Center (Q.T., J.A.B.), Department of Medicine, University of California at San Francisco, San Francisco, California 94143; and Julia McFarlane Diabetes Research Centre and Department of Microbiology and Infectious Diseases (S.T., P.S.), University of Calgary, Calgary, Alberta, Canada T2N 1N4

Address all correspondence and requests for reprints to: Kevan C. Herold, M.D., Department of Immunobiology, Yale University, 300 Cedar Street, S155B, New Haven, Connecticut 06520. E-mail: kevan.herold{at}yale.edu.

Immune modulators can arrest loss of insulin secretion in type 1 diabetes mellitus (T1DM), but they have not caused permanent disease remission or restored normal insulin secretion. We tested whether exendin-4, a glucagon-like peptide-1 receptor agonist, would enhance remission of T1DM in NOD mice treated with anti-CD3 monoclonal antibody (mAb) and studied the effects of exendin-4 treatment on cellular and metabolic responses of β-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 level of less than 350 mg/dl at diagnosis (63 vs. 39%, P < 0.05). Exendin-4 did not affect β-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 glucose transporter-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 β-cells. We conclude that treatment with glucagon-like peptide-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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