The Role of Beta Cell Senescence in the Pathogenesis of Diabetes
Contact PI: Benjamin Glaser, MD
Diabetes mellitus is a critical health problem in developed and developing countries alike. The central role
of the pancreatic β-cell in the development and progression of diabetes is becoming increasingly
recognized, but the responsible mechanisms are not clear. Our human islet single cell RNAseq analysis
discovered a β-cell population expressing high levels of the senescence master regulator p16. Strikingly,
this subpopulation is more abundant in T1DM and T2DM donors than in non-diabetics. β-cell p16
expression increases with age, limiting proliferation potential, yet over-expression of p16 in β-cells of
transgenic mice was recently reported to enhance glucose stimulated insulin secretion (GSIS). Indeed, the
p16-high human β-cells in our single cell dataset display both senescence expression profile and activation
of key glucose metabolism genes. In contrast, p16-low β-cells in T2D islets show partial dedifferentiation.
We propose to follow-up our initial observation, studying the effect of p16 overexpression in human islets
by lentiviral overexpression of p16, followed by re-aggregation and perifusion GSIS assays. Paracrine
effects will be studied by mixing different proportions of p16-expressing and non-expressing cells in the
Opportunity Pool Project Sponsored by CTAR.
Awarded in 2018