Abstract
Type 1 diabetes is an autoimmune disease caused by the destruction of the insulin-producing β-cells. An ideal immunotherapy should combine the blockade of the autoimmune response with the recovery of functional target cell mass. With the aim to develop new therapies for type 1 diabetes that could contribute to β-cell mass restoration, a drug repositioning analysis based on systems biology was performed to identify the β-cell regenerative potential of commercially available compounds. Drug repositioning is a strategy used for identifying new uses for approved drugs that are outside the scope of the medical indication. A list of 28 non-synonymous repurposed drug candidates was obtained, and 16 were selected as diabetes mellitus type 1 treatment candidates regarding pancreatic β-cell regeneration. Drugs with poor safety profile were further filtered out. Lastly, we selected liraglutide for its predictive efficacy values for neogenesis, transdifferentiation of α-cells, and/or replication of pre-existing β-cells. Liraglutide is an analog of glucagon-like peptide-1, a drug used in patients with type 2 diabetes. Liraglutide was tested in immunodeficient NOD-Scid IL2rg−/− (NSG) mice with type 1 diabetes. Liraglutide significantly improved the blood glucose levels in diabetic NSG mice. During the treatment, a significant increase in β-cell mass was observed due to a boost in β-cell number. Both parameters were reduced after withdrawal. Interestingly, islet bihormonal glucagon+insulin+ cells and insulin+ ductal cells arose during treatment. In vitro experiments showed an increase of insulin and glucagon gene expression in islets cultured with liraglutide in normoglycemia conditions. These results point to β-cell replacement, including transdifferentiation and neogenesis, as aiding factors and support the role of liraglutide in β-cell mass restoration in type 1 diabetes. Understanding the mechanism of action of this drug could have potential clinical relevance in this autoimmune disease.
Highlights
An essential requirement to cure type 1 diabetes is the recovery of β-cells lost after the autoimmune destruction
To elucidate whether liraglutide acts in a similar manner as insulin administration, an Insulin tolerance test (ITT) was performed in normoglycemic NOD mice
The liraglutide-treated group displayed an increase in glycemia until 30 min, which was normalized at 60 min to the insulin-treated animals (Figure 1E)
Summary
An essential requirement to cure type 1 diabetes is the recovery of β-cells lost after the autoimmune destruction. Drug repositioning is a strategy for identifying new uses for approved drugs that are outside the scope of the medical indication This approach uses a bioinformatics tool, based on networks of drugs, proteins, and diseases, which screens approved compounds that can be repurposed for other diseases [5]. We aimed to look for drugs that can induce β-cell replacement through α-cell to β-cell transdifferentiation [9], neogenesis from multipotent ductal progenitors [1], and/or replication of preexisting β-cells [10] This resulted in the identification of liraglutide—an analog of glucagon-like peptide-1 (aGLP-1), a drug used in patients with type 2 diabetes [11], especially those with obesity [12]
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