Chronic Inhibition of Mammalian Target of Rapamycin Signaling Downregulates Insulin Receptor Substrates 1 and 2 and AKT Activation

Abstract

Overactivation of the mammalian target of rapamycin (mTOR) branch downstream of the phosphatidylinositol 3-kinase-AKT pathway critically modulates insulin and growth factor signaling by insulin receptor substrates (IRS). On the basis of in vitro studies, the mTOR inhibitor rapamycin has been reported to lead to enhanced activation of AKT by relieving this feedback inhibition on IRS function. In view of the critical role of AKT in insulin signaling and tumorigenesis, the in vivo expression and activation of this kinase and of IRS-1 and IRS-2 were explored in PBMC of 30 patients who were treated long term with rapamycin. A marked decrease of basal and insulin-stimulated AKT phosphorylation, which correlated with the increase of patients' insulin resistance, and a significant increase of IRS total protein expression, together with a lower (IRS-2) or absent (IRS-1) increase of insulin-induced tyrosine phosphorylation, were found. Therefore, contrary to the expectations, long-term exposure to rapamycin caused the impairment of IRS signaling and AKT activation, and this would help to explain the antiproliferative effect and the possible deterioration of glucose metabolism that are observed in rapamycin-treated patients. These findings may form a novel basis for improved understanding of the role of mTOR inhibition in human diseases, such as diabetes and cancer.

ENDOCRINE SIDE EFFECTS OF ANTI-CANCER DRUGS: Effects of anti-cancer targeted therapies on lipid and glucose metabolism

“…Moreover, it has been shown recently that chronic treatment with rapamycin disrupts mTORC2 complex and blocks its inhibiting activity on hepatic gluconeogenesis (69). Similar results were observed with a selective mTOR kinase inhibitor AZD8055, with an increase in blood glucose levels in treated mice (70). In humans, long-term treatment with rapamycin impaired insulin signaling assessed by the phosphorylation of Akt in circulating mononuclear cells (PBMC) of kidney-transplanted patients (71).…”

mTORC1 signaling and regulation of pancreatic β-cell mass

“…However, it is important to note that in vivo studies designed to reveal the importance of mTORC1 using rapamycin are less than ideal because of modulation of insulin sensitivity. 63,64 In addition, it is now accepted that a major limitation of rapamycin for in vivo and in vitro studies is the inhibition of mTORC1 activity toward only a subset of mTORC1 substrates. 8,9,[65][66][67] Therefore, inhibiting mTORC1 signaling in vivo by genetic deletion of Raptor in β cells will provide new insights into the role of this pathway in nutrient-and growth factor-dependent regulation of β-cell proliferation.…”

“…Chronic administration of rapamycin has been associated with higher incidence of diabetes, although the relative contribution of β-cell dysfunction and insulin resistance to this effect is difficult to dissect. 63,64 It is possible that the alterations in insulin sensitivity could result from the signals from growth factors and nutrients, 69,[100][101][102][103][104][105] induces controlled growth and is rarely associated with malignancy. 106,107 The current evidence supports the concept that mTORC1 is active in states of increased insulin demand and plays a major role in β-cell expansion and proliferation induced by AKT and insulin resistance.…”

Efficacy of everolimus in patients with metastatic insulinoma and refractory hypoglycemia

“…Thus, long-term administration of everolimus may alter insulin secretion, as well as insulin-mediated peripheral glucose utilization and insulin-mediated suppression of hepatic glucose production (40), leading to hyperglycemia. In addition, insulin resistance may be worsened by ectopic triglyceride deposition (18).…”

“…Indeed, Bourcier et al (11) reported the successful control of refractory hypoglycemia due to malignant insulinoma with the use of sirolimus, and a hyperglycemic effect with temsirolimus has been reported in patients treated for pNET and kidney cancer (12,13,14). To explain the occurrence of hyperglycemia in these patients, several hypotheses have been raised, including that a decrease in insulin production and release or an increase in peripheral insulin resistance may have been the cause (15,16,17,18,19). Kulke et al (20) first reported the symptomatic response of four patients treated with everolimus for uncontrolled hypoglycemia related to a metastatic insulinoma.…”