Exendin-4 improves reversal of diabetes in NOD mice treated with anti-CD3 monoclonal antibody by enhancing recovery of beta-cells.
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 beta-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 beta-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 beta-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.
Sherry
Nicole A
NA
Department of Immunobiology, Yale University, New Haven, CT 06520, USA.
Chen
Wei
W
Kushner
Jake A
JA
Glandt
Mariela
M
Tang
Qizhi
Q
Tsai
Sue
S
Santamaria
Pere
P
Bluestone
Jeffrey A
JA
Brillantes
Anne-Marie B
AM
Herold
Kevan C
KC
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D017252:CD3 Complex / Q000276:immunology*; D002478:Cells, Cultured; D003131:Combined Modality Therapy; D003922:Diabetes Mellitus, Type 1 / Q000473:pathology / Q000628:therapy*; D000077270:Exenatide; D005260:Female; D000067757:Glucagon-Like Peptide-1 Receptor; D007167:Immunotherapy; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010455:Peptides / Q000494:pharmacology* / Q000627:therapeutic use*; D018027:Receptors, Glucagon / Q000819:agonists; D012074:Remission Induction; D014688:Venoms / Q000494:pharmacology* / Q000627:therapeutic use*
D000911:Antibodies, Monoclonal; D017252:CD3 Complex; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D010455:Peptides; D018027:Receptors, Glucagon; D014688:Venoms; D000077270:Exenatide