Chronic mTOR Inhibition by Rapamycin and Diabetes: What is the Role of Mitochondria?

Liang Jun Yan, Zhiyou Cai

Research output: Chapter in Book/Report/Conference proceedingChapterpeer-review


Inhibition of the mechanistic target of rapamycin (mTOR) by rapamycin is an approved clinical approach for organ transplant patients to suppress immune rejection. This therapeutic approach, unfortunately, often leads to new onset of diabetes after chronic administration of rapamycin. Hence, rapamycin has been regarded as a diabetogenic agent. Accordingly, there has been increasing interest in elucidating the mechanisms of rapamycin diabetogenesis. As diabetes is a redox imbalance disease driven by excess NADH (reduced nicotinamide adenine dinucleotide) derived from hyperglycemia-activated polyol pathway and diminished NAD+ (nicotinamide adenine dinucleotide) caused by activation of poly adenosine diphosphate ribose polymerase, we propose that mitochondrial complex I, an enzyme responsible for NAD+ regeneration from NADH, plays an important role in rapamycin diabetes. Studying complex I dysfunction downstream of the mTOR signaling pathway using the rapamycin diabetes platform not only will provide insights into the redox mechanisms of rapamycin diabetogenesis, but may also help devise novel strategies to reduce rapamycin toxicity during therapy.

Original languageEnglish
Title of host publicationMolecules to Medicine with mTOR
Subtitle of host publicationTranslating Critical Pathways into Novel Therapeutic Strategies
PublisherElsevier Inc.
Number of pages14
ISBN (Print)9780128027332
StatePublished - 26 Feb 2016


  • Complex I
  • Diabetes
  • Glucotoxicity
  • Hyperglycemia
  • Insulin
  • MTOR
  • Mitochondria
  • Rapamycin
  • Redox imbalance


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