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Open Access Publications from the University of California

Scholarly Works (4 results)

  • Thesis
  • Peer Reviewed
UC San Diego Electronic Theses and Dissertations (2016)

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.

    Cover page: Regulation of pancreatic beta cell proliferation and aging
    • Article
    • Peer Reviewed
    UC San Diego Previously Published Works (2016)
    In the past decade, new approaches have been explored that are aimed at restoring functional β cell mass as a treatment strategy for diabetes. The two most intensely pursued strategies are β cell replacement through conversion of other cell types and β cell regeneration by enhancement of β cell replication. The approach closest to clinical implementation is the replacement of β cells with human pluripotent stem cell-derived (hPSC-derived) cells, which are currently under investigation in a clinical trial to assess their safety in humans. In addition, there has been success in reprogramming developmentally related cell types into β cells. Reprogramming approaches could find therapeutic applications by inducing β cell conversion in vivo or by reprogramming cells ex vivo followed by implantation. Finally, recent studies have revealed novel pharmacologic targets for stimulating β cell replication. Manipulating these targets or the pathways they regulate could be a strategy for promoting the expansion of residual β cells in diabetic patients. Here, we provide an overview of progress made toward β cell replacement and regeneration and discuss promises and challenges for clinical implementation of these strategies.
      Cover page: Advances in β cell replacement and regeneration strategies for treating diabetes
      • Article
      • Peer Reviewed
      UC San Diego Previously Published Works (2018)
      Pancreatic β cell physiology changes substantially throughout life, yet the mechanisms that drive these changes are poorly understood. Here, we performed comprehensive in vivo quantitative proteomic profiling of pancreatic islets from juvenile and 1-year-old mice. The analysis revealed striking differences in abundance of enzymes controlling glucose metabolism. We show that these changes in protein abundance are associated with higher activities of glucose metabolic enzymes involved in coupling factor generation as well as increased activity of the coupling factor-dependent amplifying pathway of insulin secretion. Nutrient tracing and targeted metabolomics demonstrated accelerated accumulation of glucose-derived metabolites and coupling factors in islets from 1-year-old mice, indicating that age-related changes in glucose metabolism contribute to improved glucose-stimulated insulin secretion with age. Together, our study provides an in-depth characterization of age-related changes in the islet proteome and establishes metabolic rewiring as an important mechanism for age-associated changes in β cell function.
        Cover page: Integrated In Vivo Quantitative Proteomics and Nutrient Tracing Reveals Age-Related Metabolic Rewiring of Pancreatic β Cell Function
        • Article
        • Peer Reviewed
        UC San Diego Previously Published Works (2021)
        Genes involved in distinct diabetes types suggest shared disease mechanisms. Here we show that One Cut Homeobox 1 (ONECUT1) mutations cause monogenic recessive syndromic diabetes in two unrelated patients, characterized by intrauterine growth retardation, pancreas hypoplasia and gallbladder agenesis/hypoplasia, and early-onset diabetes in heterozygous relatives. Heterozygous carriers of rare coding variants of ONECUT1 define a distinctive subgroup of diabetic patients with early-onset, nonautoimmune diabetes, who respond well to diabetes treatment. In addition, common regulatory ONECUT1 variants are associated with multifactorial type 2 diabetes. Directed differentiation of human pluripotent stem cells revealed that loss of ONECUT1 impairs pancreatic progenitor formation and a subsequent endocrine program. Loss of ONECUT1 altered transcription factor binding and enhancer activity and NKX2.2/NKX6.1 expression in pancreatic progenitor cells. Collectively, we demonstrate that ONECUT1 controls a transcriptional and epigenetic machinery regulating endocrine development, involved in a spectrum of diabetes, encompassing monogenic (recessive and dominant) as well as multifactorial inheritance. Our findings highlight the broad contribution of ONECUT1 in diabetes pathogenesis, marking an important step toward precision diabetes medicine.
          Cover page: Mutations and variants of ONECUT1 in diabetes
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