ArticleMolecular and cellular biology2001
Mammalian target of rapamycin pathway regulates insulin signaling via subcellular redistribution of insulin receptor substrate 1 and integrates nutritional signals and metabolic signals of insulin.
Article in Molecular and cellular biology, 2001. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 98 papers, 1 of them a synthesis that pooled it.
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Who cites it
98 citing papers in PubMed, 1 synthesis or guideline pooled it, 250 citations in OpenAlex.
- Dietary Protein Consumption and the Risk of Type 2 Diabetes: A Systematic Review and Meta-Analysis of Cohort Studies.Nutrients · 2017Pooled it
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- Middle-aged overweight South Asian men exhibit a different metabolic adaptation to short-term energy restriction compared with Europeans.Diabetologia · 2015Trial
- The effects of an amino acid supplement on glucose homeostasis, inflammatory markers, and incretins after laparoscopic gastric bypass.Journal of the American College of Surgeons · 2011Trial
- Diabetes Mellitus and Cardiopulmonary Bypass (CPB): Pathophysiological Mechanisms Related to Inflammation and Cardiovascular Disease.Current issues in molecular biology · 2025Review
- Transcriptomic and metabolomic analysis of prebiotics utilization by Bifidobacterium animalis.World journal of microbiology & biotechnology · 2024Article
- Mechanism of Obesity-Related Lipotoxicity and Clinical Perspective.Advances in experimental medicine and biology · 2024Review
- Regulation of Macronutrients in Insulin Resistance and Glucose Homeostasis during Type 2 Diabetes Mellitus.Nutrients · 2023Review
- VAPB-mediated ER-targeting stabilizes IRS-1 signalosomes to regulate insulin/IGF signaling.Cell discovery · 2023Article
- Research progress in the role and mechanism of Leucine in regulating animal growth and development.Frontiers in physiology · 2023Review
- The Potential Role of R4 Regulators of G Protein Signaling (RGS) Proteins in Type 2 Diabetes Mellitus.Cells · 2022Review
- Activating mTOR Mutations Are Detrimental in Nutrient-Poor Conditions.Cancer research · 2022Article
- Cullin neddylation inhibitor attenuates hyperglycemia by enhancing hepatic insulin signaling through insulin receptor substrate stabilization.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Targeting the mTOR pathway using novel ATP‑competitive inhibitors, Torin1, Torin2 and XL388, in the treatment of glioblastoma.International journal of oncology · 2021Article
- Culprits or consequences: Understanding the metabolic dysregulation of muscle in diabetes.World journal of biological chemistry · 2021Review
- Limited survival and impaired hepatic fasting metabolism in mice with constitutive Rag GTPase signaling.Nature communications · 2021Article
- The autophagy protein Becn1 improves insulin sensitivity by promoting adiponectin secretion via exocyst binding.Cell reports · 2021Article
- Dietary intake of branched-chain amino acids and survival after colorectal cancer diagnosis.International journal of cancer · 2021Article
- A platform for post-translational spatiotemporal control of cellular proteins.Synthetic biology (Oxford, England) · 2021Article
- Aging and Protein Kinases.Advances in experimental medicine and biology · 2021Article
38 more citing papers are in PubMed but not listed here.
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
A pathway sensitive to rapamycin, a selective inhibitor of mammalian target of rapamycin (mTOR), down-regulates effects of insulin such as activation of Akt (protein kinase B) via proteasomal degradation of insulin receptor substrate 1 (IRS-1). We report here that the pathway also plays an important role in insulin-induced subcellular redistribution of IRS-1 from the low-density microsomes (LDM) to the cytosol. After prolonged insulin stimulation, inhibition of the redistribution of IRS-1 by rapamycin resulted in increased levels of IRS-1 and the associated phosphatidylinositol (PI) 3-kinase in both the LDM and cytosol, whereas the proteasome inhibitor lactacystin increased the levels only in the cytosol. Since rapamycin but not lactacystin enhances insulin-stimulated 2-deoxyglucose (2-DOG) uptake, IRS-1-associated PI 3-kinase localized at the LDM was suggested to be important in the regulation of glucose transport. The amino acid deprivation attenuated and the amino acid excess enhanced insulin-induced Ser/Thr phosphorylation and subcellular redistribution and degradation of IRS-1 in parallel with the effects on phosphorylation of p70 S6 kinase and 4E-BP1. Accordingly, the amino acid deprivation increased and the amino acid excess decreased insulin-stimulated activation of Akt and 2-DOG uptake. Furthermore, 2-DOG uptake was affected by amino acid availability even when the degradation of IRS-1 was inhibited by lactacystin. We propose that subcellular redistribution of IRS-1, regulated by the mTOR-dependent pathway, facilitates proteasomal degradation of IRS-1, thereby down-regulating Akt, and that the pathway also negatively regulates insulin-stimulated glucose transport, probably through the redistribution of IRS-1. This work identifies a novel function of mTOR that integrates nutritional signals and metabolic signals of insulin.
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