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

Abstract

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.

Anti-inflammatory action of exendin-4 in human islets is enhanced by phosphodiesterase inhibitors: potential therapeutic benefits in diabetic patients

“…Continuous infusion of GLP-1 also delayed the onset of diabetes in NOD mice [30]. Other studies have used exendin-4 in combination with anti-inflammatory agents to demonstrate a more significant blocking of insulitis and diabetes onset in NOD mice [31][32][33]. Furthermore, a recent study has reported that increasing the levels of circulating GLP-1 by inhibiting dipeptidyl peptidase-IV results in prolonged islet graft survival and decreased insulitis in diabetic NOD mice [34].…”

Four-year metabolic outcome of a randomised controlled CD3-antibody trial in recent-onset type 1 diabetic patients depends on their age and baseline residual beta cell mass

“…It is conceivable that residual beta cells are lost because the autoimmune reactivity had only been transiently suppressed; their survival and/or function may also have been affected by the chronic state of hyperglycaemia. Since the beta cell mass is already markedly reduced at clinical onset of type 1 diabetes [18,19], it is likely that any immune-modulating intervention will have to be associated with, or followed by, a beta cell replacement therapy, as recently tested in rodents [20]; a combination with other methods for tolerance-induction should also be considered [21,22].…”

DsAAV8-mediated expression of glucagon-like peptide-1 in pancreatic beta-cells ameliorates streptozotocin-induced diabetes

“…Zhang et al 5 have demonstrated that continuous infusion of GLP-1 in pre-diabetic NOD mice results in significant delay in the onset of diabetes as a result of increased beta-cell proliferation coupled with decrease in beta-cell apoptosis. Furthermore, combination therapies using GLP-1 or exendin-4 with gastrin, 48 anti-lymphocyte serum 49 or anti-CD3 immunotherapy 50 have been shown to restore normoglycemia in acutely diabetic NOD mice by increasing insulin stores and reducing beta-cell apoptosis. Thus, GLP-1-receptor agonists may be useful in therapeutic management of individuals with either type-1 or type-2 diabetes.…”