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.
|Title of host publication||Molecules to Medicine with mTOR|
|Subtitle of host publication||Translating Critical Pathways into Novel Therapeutic Strategies|
|Number of pages||14|
|State||Published - 26 Feb 2016|
- Complex I
- Redox imbalance