Abstract
A small-molecule inhibitor of the MAP3 Kinase TPL2 improves nutrient-induced bêta-cell dysfunction and deathIntroduction : Evidences suggest that nutrient-induced metabolic stresses such as chronic hyperglycemia provide a link between type 2 diabetes and bêta-cell dysfunction and death. If The MAP3 kinase 8, Tumor progression locus 2 (TPL2), plays an important role in bêta-cell death after cytokine exposure, its involvement in bêta-cell dysfunction and death induced by chronic hyperglycemia is unknown.Methods : Insulin secretion is measured by HTRF. Protein expressions (TPL2, cleaved caspase 3 and JNK1 / 2 (death markers), are assessed by Western blotting. Icer mRNA expression is measured by RT-qPCR.Results : We found TPL2 is overexpressed in islets of diabetic GK rats and db/db mice. Chronic hyperglycemia increases TPL2 expression in bêta-cells and human islets. Treatment of db/db mice with a small molecule inhibitor of TPL2 results in a reduction of diabetes progression with decreased fasting hyperglycemia and hyperinsulinemia, improved glucose tolerance, without affecting insulin sensitivity. Inhibition of TPL2 improves the detrimental effects of hyperglycemia on glucose-induced insulin secretion, reduces apoptosis of bêta-cells, and prevents the mRNA upregulation of Icer, a transcriptional repressor of insulin and key exocytotic proteins genes, and c-Jun N-terminal kinases 1/2 (JNK1/2) activation. Combination of a GLP-1 receptor agonist (GLP-1RA, exendin-4) with the TPL2 inhibitor totally prevented the apoptosis of bêta-cells induced by hyperglycemia.Conclusion : Our results identify TPL2 inhibition, alone or in combination with a GLP-1RA, as potential new therapeutic avenues to prevent bêta-cell dysfunction and apoptosis and to slow down T2D development.