mTOR Inhibitor Therapy and Metabolic Consequences: Where Do We Stand?

Author:

Kezic Aleksandra12ORCID,Popovic Ljiljana13,Lalic Katarina13ORCID

Affiliation:

1. Faculty of Medicine, University of Belgrade, Dr Subotica 8, 11000 Belgrade, Serbia

2. Clinic for Nephrology, Clinical Center of Serbia, Pasterova 2, 11000 Belgrade, Serbia

3. Clinic for Endocrinology, Diabetes and Metabolic Diseases, Clinical Center of Serbia, Dr Subotica 13, 11000 Belgrade, Serbia

Abstract

mTOR (mechanistic target of rapamycin) protein kinase acts as a central integrator of nutrient signaling pathways. Besides the immunosuppressive role after solid organ transplantations or in the treatment of some cancers, another promising role of mTOR inhibitor as an antiaging therapeutic has emerged in the recent years. Acute or intermittent rapamycin treatment has some resemblance to calorie restriction in metabolic effects such as an increased insulin sensitivity. However, the chronic inhibition of mTOR by macrolide rapamycin or other rapalogs has been associated with glucose intolerance and insulin resistance and may even provoke type II diabetes. These metabolic adverse effects limit the use of mTOR inhibitors. Metformin is a widely used drug for the treatment of type 2 diabetes which activates AMP-activated protein kinase (AMPK), acting as calorie restriction mimetic. In addition to the glucose-lowering effect resulting from the decreased hepatic glucose production and increased glucose utilization, metformin induces fatty acid oxidations. Here, we review the recent advances in our understanding of the metabolic consequences regarding glucose metabolism induced by mTOR inhibitors and compare them to the metabolic profile provoked by metformin use. We further suggest metformin use concurrent with rapalogs in order to pharmacologically address the impaired glucose metabolism and prevent the development of new-onset diabetes mellitus after solid organ transplantations induced by the chronic rapalog treatment.

Funder

Ministry of Science and Technology of the Republic of Serbia

Publisher

Hindawi Limited

Subject

Cell Biology,Aging,General Medicine,Biochemistry

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