Aging and sleep deprivation induce the unfolded protein response in the pancreas: implications for metabolism

Authors

  • Nirinjini Naidoo,

    Corresponding author
    1. Division of Sleep Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
    2. Center for Sleep and Circadian Neurobiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
    • Correspondence

      Dr. Nirinjini Naidoo, 125 South 31st street, 2100 TRL, Philadelphia, 19104 PA, USA. Tel.: +1 215 7464811; fax: +1 215 7464814; e-mail: naidoo@mail.med.upenn.edu

      Dr. Joseph A. Baur, 3400 Civic Center Blvd, SCTR 12-114, Philadelphia, PA 19066, USA. Tel.: +1 215 746 4585; fax: +1 215 898 5408; e-mail: baur@mail.med.upenn.edu

    Search for more papers by this author
  • James G. Davis,

    1. Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
    2. Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
    Search for more papers by this author
  • Jingxu Zhu,

    1. Center for Sleep and Circadian Neurobiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
    Search for more papers by this author
  • Maya Yabumoto,

    1. Center for Sleep and Circadian Neurobiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
    Search for more papers by this author
  • Kristan Singletary,

    1. Center for Sleep and Circadian Neurobiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
    Search for more papers by this author
  • Marishka Brown,

    1. Center for Sleep and Circadian Neurobiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
    Search for more papers by this author
  • Raymond Galante,

    1. Center for Sleep and Circadian Neurobiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
    Search for more papers by this author
  • Beamon Agarwal,

    1. Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
    2. Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
    Current affiliation:
    1. Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Hospital, Kharghar, Navi Mumbai, India
    Search for more papers by this author
  • Joseph A. Baur

    Corresponding author
    1. Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
    2. Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
    • Correspondence

      Dr. Nirinjini Naidoo, 125 South 31st street, 2100 TRL, Philadelphia, 19104 PA, USA. Tel.: +1 215 7464811; fax: +1 215 7464814; e-mail: naidoo@mail.med.upenn.edu

      Dr. Joseph A. Baur, 3400 Civic Center Blvd, SCTR 12-114, Philadelphia, PA 19066, USA. Tel.: +1 215 746 4585; fax: +1 215 898 5408; e-mail: baur@mail.med.upenn.edu

    Search for more papers by this author

Summary

Sleep disruption has detrimental effects on glucose metabolism through pathways that remain poorly defined. Although numerous studies have examined the consequences of sleep deprivation (SD) in the brain, few have directly tested its effects on peripheral organs. We examined several tissues in mice for induction of the unfolded protein response (UPR) following acute SD. In young animals, we found a robust induction of BiP in the pancreas, indicating an active UPR. At baseline, pancreata from aged animals exhibited a marked increase in a pro-apoptotic transcription factor, CHOP, that was amplified by SD, whereas BiP induction was not observed, suggesting a maladaptive response to cellular stress with age. Acute SD increased plasma glucose levels in both young and old animals. However, this change was not overtly related to stress in the pancreatic beta cells, as plasma insulin levels were not lower following acute SD. Accordingly, animals subjected to acute SD remained tolerant to a glucose challenge. In a chronic SD experiment, young mice were found to be sensitized to insulin and have improved glycemic control, whereas aged animals became hyperglycemic and failed to maintain appropriate plasma insulin concentrations. Our results show that both age and SD cooperate to induce the UPR in pancreatic tissue. While changes in insulin secretion are unlikely to play a major role in the acute effects of SD, CHOP induction in pancreatic tissues suggests that chronic SD may contribute to the loss or dysfunction of endocrine cells and that these effects may be exacerbated by normal aging.

Ancillary