Invited review
mTOR inhibitors and diabetes

https://doi.org/10.1016/j.diabres.2015.09.014Get rights and content

Abstract

The mammalian target of rapamycin (mTOR) inhibitors are drugs, primarily used as immunosuppressors that are now frequently used as antineoplastic therapies in various cancers (such as advanced renal cell carcinoma, advanced breast cancer, progressive pancreatic neuroendocrine tumors). They act on mTOR signaling pathway which plays a key role in regulating cell growth as well as lipid and glucose metabolism. Treatment with mTOR inhibitors is associated with a high incidence of hyperglycemia and new-onset diabetes, ranging from 13% to 50% in the clinical trials in which they have been used as anticancer therapies. The rate of severe hyperglycemia is also increased, ranging from 4 to 12% in the main phase III clinical trials. Due to limited human studies, the pathophysiology of mTOR inhibitor-induced hyperglycemia has not yet been totally clarified. However, data from animal studies suggest that the mechanisms responsible for hyperglycemia with mTOR inhibitors are likely due to the combination of impaired insulin secretion and insulin resistance. Due to the high rate of hyperglycemia associated with the use of mTOR inhibitors, a close and personalized follow-up of blood glucose is recommended in all patients.

Introduction

The mammalian target of rapamycin (mTOR) inhibitors are drugs that are potent immunosuppressors used for prevention of acute rejection following solid-organ transplantation [1]. They have more recently been developed as antineoplastic targeted therapies in various cancers because of their inhibiting effects on signaling pathways involved in cell growth and metabolism [2], [3], [4], [5], [6], [7]. mTOR inhibitors have several metabolic adverse events including hyperlipidemia and hyperglycemia [8]. The rate of diabetes induced by mTOR inhibitors is high and patients receiving such treatment need careful follow-up of blood glucose levels. In this review, we will briefly mention the main indications of mTOR inhibitors, present the mTOR signaling system and the actions of mTOR on glucose metabolism, present the effects of mTOR inhibitors on glycemia, analyze the possible pathophysiological mechanisms responsible for the hyperglycemia induced by mTOR inhibitors and discuss the management of hyperglycemia induced by mTOR inhibitors.

Section snippets

Main indications of mTOR inhibitors

mTOR inhibitors were first used as anti-rejection agents for transplantation before being developed as targeted anti-cancer therapies [1]. Both sirolimus (i.e., rapamycin) and everolimus are used as anti-rejection treatment when everolimus and temsirolimus are used as targeted anti-cancer therapies. Everolimus is used for both indications but with lower doses for anti-rejection (1.5–3.0 mg/day) than for anti-cancer (5–10 mg/day) treatment.

mTOR inhibitors are agents that inhibit signaling in the

mTOR signaling

mTOR is a serine/threonine protein kinase, belonging to the PI3K-related kinase family, playing a key role in regulating cell growth as well as lipid and glucose metabolism. The protein mTOR is expressed throughout the body and is present in brain, cardiopulmonary system, gastrointestinal tract, immune system, skeletal system and the reproductive system [9]. mTOR exists in two distinct large multi-protein complexes: mTOR complex 1 (mTORC1) and complex 2 (mTORC2) [10], [11].

mTORC1 is composed of

mTOR and glucose metabolism

The effects of mTOR on glucose homeostasis are complex with some opposite results depending on the level of mTORC1 activity [11]. mTORC1 promotes insulin resistance in adipose tissue through the S6K1-mediated inhibition of insulin signaling, linked to the serine-phosphorylation of insulin receptor substrate-1 (IRS-1) that disrupts the recruitment and activation of PI3K [12], [19]. Several studies showed increased mTORC1 activity with elevated S6K1 activity in insulin-target tissues (adipose

Effects of mTOR inhibitors on glycemia

The perturbation in glucose homeostasis with mTOR inhibitors is a major metabolic complication for this class of drugs.

Pathophysiology of hyperglycemia induced by mTOR inhibitors

The role of mTOR pathway and its manipulation with mTOR inhibitors is undoubtedly complex. Notably, there are some still unexplained discrepancies between both in vitro and in vivo preclinical studies in rodents and clinical data from phase II/III studies with everolimus in humans.

It seems that mTOR inhibitors exert a “Janus effect” on glucose metabolism. Indeed, based on the observation that chronic activation of mTORC1 promotes insulin resistance, it could be hypothesized that the chronic

Management of hyperglycemia induced by mTOR inhibitors

Due to the significant effect of mTOR inhibitors on glucose metabolism, a specific management of mTOR-induced hyperglycemia has been proposed by a Task Force of the US National Cancer Institute Investigational Drug Steering Committee [53] and a French expert committee [54].

It is recommended to perform baseline measurement of fasting plasma glucose (FPG) and HbA1c before initiating a treatment with an mTOR inhibitor in order to diagnose potential pre-existing glucose metabolism disorders

Conflict of interest statement

The authors declare that there is no conflict of interest related to this review article.

Acknowledgement

This work did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

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