Human duct cells contribute to ß cell compensation in insulin resistance.

The identification of new sources of ß cells is an important endeavor with therapeutic implications for diabetes. Insulin resistance, in physiological states such as pregnancy or in pathological states such as type 2 diabetes (T2D), is characterized by a compensatory increase in ß cell mass. To explore the existence of a dynamic ß cell reserve, we superimposed pregnancy on the liver-specific insulin receptor-KO (LIRKO) model of insulin resistance that already exhibits ß cell hyperplasia and used lineage tracing to track the source of new ß cells. Although both control and LIRKO mice displayed increased ß cell mass in response to the relative insulin resistance of pregnancy, the further increase in mass in the latter supported a dynamic source that could be traced to pancreatic ducts. Two observations support the translational significance of these findings. First, NOD/SCID-γ LIRKO mice that became pregnant following cotransplantation of human islets and human ducts under the kidney capsule showed enhanced ß cell proliferation and an increase in ductal cells positive for transcription factors expressed during ß cell development. Second, we identified duct cells positive for immature ß cell markers in pancreas sections from pregnant humans and in individuals with T2D. Taken together, during increased insulin demand, ductal cells contribute to the compensatory ß cell pool by differentiation/neogenesis.