UC San Diego

The replicative capacity of insulin-producing pancreatic beta cells is dynamically regulated during development, maturation, and aging. Early in life, beta cells proliferate rapidly to expand beta cell mass but quickly become quiescent with age. While this decline is well documented, the mechanisms that underlie this age-dependent beta cell replicative senescence are still poorly understood. Using mouse genetics and in vivo quantitative proteomics approaches, we found that nutrient sensing plays an important role in controlling the proliferation of beta cells. We show that the transcription factor Nkx6.1 is required for expanding beta cell mass during the early wave of rapid postnatal beta cell proliferation by regulating the expression of the nutrient sensing receptors Glut2 and Glp1r. Furthermore, by quantitatively comparing the proteome of islets from young and aged mice, we found dynamic regulation of not only cell cycle proteins, but also proteins critical for beta cell function. Proteins important for insulin secretion and metabolic regulation increased with age, while proteins involved in expanding cell number declined with age. From our proteomic screen, we identified a protein deacetylase upregulated during aging. Pharmacologic inhibition of this protein promoted both rodent and human beta cell proliferation ex vivo, indicating the deacetylation activity of this candidate represses beta cell proliferation. Beta cell-specific deletion of the protein deacetylase increased rodent beta cell proliferation and mass in diabetic mice in vivo. Importantly, inhibition of this protein in human islets ex vivo did not negatively affect beta cell function or survival. Finally, we show that the protein deacetylase specifically regulates beta cell proliferation in conditions of elevated blood glucose through modulating the glucose-dependent MAPK pathway. Overall, our studies have uncovered dynamic regulation of beta cell proliferation from birth to advanced age and identified a viable therapeutic target for enhancing beta cell mass for the treatment of diabetes.