Critical role for the Tsc1-mTORC1 pathway in β-cell mass in Pdx1-deficient mice

Mutations in the pancreatic duodenal homeobox (PDX1) gene are associated with diabetes in humans. Pdx1-haploinsufficient mice also develop diabetes, but the molecular mechanism is unknown. To this end, we knocked down Pdx1 gene expression in mouse MIN6 insulinoma cells. Pdx1 suppression not only increased apoptotic cell death but also decreased cell proliferation, which was associated with a decrease in activity of mechanistic target of rapamycin complex 1 (mTORC1). We found that in Pdx1-deficient mice, tuberous sclerosis 1 (Tsc1) ablation in pancreatic β-cells restores β-cell mass, increases β-cell proliferation and size, decreases the number of TUNEL-positive cells and restores glucose tolerance after glucose challenge. In addition, Tsc1 ablation in pancreatic β-cells increases phosphorylation of initiation factor 4E-binding protein 1 (4E-BP1) phosphorylation and 40S ribosomal protein S6, two downstream targets of mTORC1 indicating that Tsc1 mediates mTORC1 downregulation induced by Pdx1 suppression. These results suggest that the Tsc1-mTORC1 pathway plays an important role in mediating the decrease in β-cell proliferation and growth and the reduction in β-cell mass that occurs in Pdx1-deficient diabetes. Thus, mTORC1 may be target for therapeutic interventions in diabetes associated with reductions in β-cell mass.