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 proceedingChapter

Abstract

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.
Pages365-378
Number of pages14
ISBN (Print)9780128027332
DOIs
StatePublished - 26 Feb 2016

Fingerprint

Sirolimus
Mitochondria
NAD
Oxidation-Reduction
Poly Adenosine Diphosphate Ribose
Hyperglycemia
Regeneration
Transplants

Keywords

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

Cite this

Yan, L-J., & Cai, Z. (2016). Chronic mTOR Inhibition by Rapamycin and Diabetes: What is the Role of Mitochondria? In Molecules to Medicine with mTOR: Translating Critical Pathways into Novel Therapeutic Strategies (pp. 365-378). Elsevier Inc.. https://doi.org/10.1016/B978-0-12-802733-2.00009-8
Yan, Liang-Jun ; Cai, Zhiyou. / Chronic mTOR Inhibition by Rapamycin and Diabetes : What is the Role of Mitochondria?. Molecules to Medicine with mTOR: Translating Critical Pathways into Novel Therapeutic Strategies. Elsevier Inc., 2016. pp. 365-378
@inbook{c43e36dadecd42c4bba33dc930daefa6,
title = "Chronic mTOR Inhibition by Rapamycin and Diabetes: What is the Role of Mitochondria?",
abstract = "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.",
keywords = "Complex I, Diabetes, Glucotoxicity, Hyperglycemia, Insulin, MTOR, Mitochondria, Rapamycin, Redox imbalance",
author = "Liang-Jun Yan and Zhiyou Cai",
year = "2016",
month = "2",
day = "26",
doi = "10.1016/B978-0-12-802733-2.00009-8",
language = "English",
isbn = "9780128027332",
pages = "365--378",
booktitle = "Molecules to Medicine with mTOR",
publisher = "Elsevier Inc.",

}

Yan, L-J & Cai, Z 2016, Chronic mTOR Inhibition by Rapamycin and Diabetes: What is the Role of Mitochondria? in Molecules to Medicine with mTOR: Translating Critical Pathways into Novel Therapeutic Strategies. Elsevier Inc., pp. 365-378. https://doi.org/10.1016/B978-0-12-802733-2.00009-8

Chronic mTOR Inhibition by Rapamycin and Diabetes : What is the Role of Mitochondria? / Yan, Liang-Jun; Cai, Zhiyou.

Molecules to Medicine with mTOR: Translating Critical Pathways into Novel Therapeutic Strategies. Elsevier Inc., 2016. p. 365-378.

Research output: Chapter in Book/Report/Conference proceedingChapter

TY - CHAP

T1 - Chronic mTOR Inhibition by Rapamycin and Diabetes

T2 - What is the Role of Mitochondria?

AU - Yan, Liang-Jun

AU - Cai, Zhiyou

PY - 2016/2/26

Y1 - 2016/2/26

N2 - 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.

AB - 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.

KW - Complex I

KW - Diabetes

KW - Glucotoxicity

KW - Hyperglycemia

KW - Insulin

KW - MTOR

KW - Mitochondria

KW - Rapamycin

KW - Redox imbalance

UR - http://www.scopus.com/inward/record.url?scp=84967585450&partnerID=8YFLogxK

U2 - 10.1016/B978-0-12-802733-2.00009-8

DO - 10.1016/B978-0-12-802733-2.00009-8

M3 - Chapter

AN - SCOPUS:84967585450

SN - 9780128027332

SP - 365

EP - 378

BT - Molecules to Medicine with mTOR

PB - Elsevier Inc.

ER -

Yan L-J, Cai Z. Chronic mTOR Inhibition by Rapamycin and Diabetes: What is the Role of Mitochondria? In Molecules to Medicine with mTOR: Translating Critical Pathways into Novel Therapeutic Strategies. Elsevier Inc. 2016. p. 365-378 https://doi.org/10.1016/B978-0-12-802733-2.00009-8