Integrated In Vivo Quantitative Proteomics and Nutrient Tracing Reveals Age-Related Metabolic Rewiring of Pancreatic β Cell Function

Cell Rep. 2018 Dec 4;25(10):2904-2918.e8. doi: 10.1016/j.celrep.2018.11.031.


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.

Keywords: SILAM MudPIT mass spectrometry; TCA cycle; aging; amplifying pathway; insulin secretion; isotope tracing; quantitative proteomics; triggering pathway; β cell; β cell maturation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging
  • Animals
  • Carbon / metabolism
  • Cell Respiration / drug effects
  • Cellular Senescence*
  • Citric Acid Cycle / drug effects
  • Female
  • Gene Expression Regulation
  • Glucose / metabolism
  • Glucose / pharmacology
  • Insulin Secretion
  • Insulin-Secreting Cells / metabolism*
  • Male
  • Metabolomics / methods*
  • Mice, Inbred C57BL
  • Proteome / metabolism
  • Proteomics / methods*


  • Proteome
  • Carbon
  • Glucose