Abstract

Type 1 diabetes is an autoimmune disease caused by the destruction of the insulin-producing β-cells. To revert type 1 diabetes, the suppression of the autoimmune attack should be combined with a β-cell replacement strategy. It has been previously demonstrated that liraglutide, a glucagon-like peptide-1 receptor agonist, restores β-cell mass in type 1 diabetes, via α-cell transdifferentiation and neogenesis. We report here that treatment with liraglutide does not prevent type 1 diabetes in the spontaneous non-obese diabetic (NOD) mouse model, but it tends to reduce leukocytic islet infiltration. However, in combination with an immunotherapy based on tolerogenic liposomes, it is effective in ameliorating hyperglycaemia in diabetic NOD mice. Importantly, liraglutide is not detrimental for the tolerogenic effect that liposomes exert on dendritic cells from patients with type 1 diabetes in terms of membrane expression of molecules involved in antigen presentation, immunoregulation and activation. Moreover, the in vivo effect of the combined therapy was tested in mice humanised with peripheral blood mononuclear cells from patients with type 1 diabetes, showing no adverse effects in leukocyte subsets. In conclusion, the combination therapy with liraglutide and a liposome-based immunotherapy is a promising candidate strategy for type 1 diabetes.

Highlights

  • Type 1 diabetes is an autoimmune disease caused by the destruction of the insulin-producing β-cells

  • Type 1 diabetes (T1D) is a metabolic disease caused by the autoimmune destruction of the insulin-producing pancreatic β-cells

  • Our previous work demonstrated the ability of apoptotic β-cells to induce self-tolerance through efferocytosis by dendritic cells (DCs), preventing T1D in the non-obese diabetic (NOD) mouse ­model[7]

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Summary

Introduction

Type 1 diabetes is an autoimmune disease caused by the destruction of the insulin-producing β-cells. In combination with an immunotherapy based on tolerogenic liposomes, it is effective in ameliorating hyperglycaemia in diabetic NOD mice. Because anti-IL21 has systemic effects in the immune system, antigen-specific immunotherapies could be safer and help to overcome the side-effect issues derived from total immunosuppression All these data indicate that combined therapies both targeting the autoimmune attack and promoting β-cell regeneration could result in a greater beneficial outcome for the treatment of T1D. With the aim to combine this immunotherapy with a regenerative strategy, we previously performed a Drug Repurposing analysis to search for already-existing compounds able to promote β-cell regeneration. Liraglutide administration ameliorated hyperglycaemia in immunodeficient NOD-Scid I­ L2rg-/- (NSG) mice rendered diabetic by Streptozotocin This improvement correlated with the appearance of bihormonal i­nsulin+glucagon+ cells and ­insulin+ cells in the ductal a­ reas[12]. Ongoing clinical trials aim to assess the effect of liraglutide in subjects with T1D (NCT02617654 and NCT02516657)

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