Integrated In Vivo Quantitative Proteomics and Nutrient Tracing Reveals Age-Related Metabolic Rewiring of Pancreatic β Cell Function
Matthew Wortham,
Jacqueline R. Benthuysen,
Martina Wallace,
Jeffrey N. Savas,
Francesca Mulas,
Ajit S. Divakaruni,
Fenfen Liu,
Verena Albert,
Brandon L. Taylor,
Yinghui Sui,
Enrique Saez,
Anne N. Murphy,
John R. Yates, III,
Christian M. Metallo,
Maike Sander
Affiliations
Matthew Wortham
Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, CA 92093, USA
Jacqueline R. Benthuysen
Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, CA 92093, USA
Martina Wallace
Department of Bioengineering, University of California, San Diego, La Jolla, CA 92037, USA
Jeffrey N. Savas
Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA
Francesca Mulas
Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, CA 92093, USA
Ajit S. Divakaruni
Department of Pharmacology, University of California, San Diego, La Jolla, CA 92037, USA
Fenfen Liu
Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, CA 92093, USA
Verena Albert
Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA
Brandon L. Taylor
Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, CA 92093, USA
Yinghui Sui
Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, CA 92093, USA
Enrique Saez
Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA
Anne N. Murphy
Department of Pharmacology, University of California, San Diego, La Jolla, CA 92037, USA
John R. Yates, III
Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA
Christian M. Metallo
Department of Bioengineering, University of California, San Diego, La Jolla, CA 92037, USA
Maike Sander
Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, CA 92093, USA; Corresponding author
Summary: 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. : Organismal age impacts fundamental aspects of β cell physiology. Wortham et al. apply proteomics and targeted metabolomics to islets from juvenile and adult mice, revealing age-related changes in metabolic enzyme abundance and production of coupling factors that enhance insulin secretion. This work provides insight into age-associated changes to the β cell. Keywords: β cell, SILAM MudPIT mass spectrometry, quantitative proteomics, insulin secretion, β cell maturation, aging, isotope tracing, triggering pathway, amplifying pathway, TCA cycle
