Also, this view fails to realize the potential double-edged role of insulin in treating hyperglycemia while driving the non-glycemic diseases of T2D. is usually proposed to act as double-edged agent, namely, to interfere with glycemic control by disrupting the insulin receptor-Akt transduction pathway, while concomitantly driving the non-glycemic diseases of T2D. The mTORC1-centric paradigm may offer a novel perspective for T2D in terms of pathogenesis, clinical focus and treatment strategy. Specifically, mTORC1 hyper activation may be driven by chronic dietary carbohydrate excess of high glycemic index, resulting in concomitant activation of the glucose-induced RagA/B.GTP and the insulin-induced Rheb.GTP drivers of mTORC1. Hyper activation of mTORC1 may similarly be driven by chronic dietary excess of proteins rich in leucine and arginine. These amino acids may stimulate insulin secretion, resulting concomitantly in amino acid-induced RagA/B.GTP and insulin-induced Rheb.GTP. In line with that, caloric restriction, in particular carbohydrate restriction, may DM1-SMCC inhibit mTORC1 activity by repressing the Rag and Rheb arms due to nutrient and insulin restriction, respectively. Of note, modulation of mTORC1 activity by nutrients / energy excess / metabolites may further be affected by genetic and/or epigenetic and/or tissue and/or context-dependent factors that may determine the sensitivity of the Rag and Rheb arms to respective DM1-SMCC environmental / metabolic / nutrient conditions. Also, primary metabolic effects due to hyperactive mTORC1 may further be modulated by downstream secondary outcomes. Glycemic context of T2D. Resistance to insulin Peripheral resistance to insulin in the glycemic context is proposed to be driven by disruption of the IR-Akt transduction pathway by hyperactive mTORC1 and its downstream S6K1 in liver, muscle and adipose tissue, namely, the main organs that control glucose production and its utilization. Thus, phosphorylation of IRS1(Ser307, 1101) by hyperactive S6K1, and phosphorylation of IRS1(Ser636/639, 422) by hyperactive mTORC1, result in suppressing IRS tyrosines phosphorylation by the IR tyrosine kinase, followed by IRS ubiquitination and degradation [113C115]. Also, phosphorylation of GRB10 by hyperactive mTORC1 results in disrupting IR/IRS by phospho-GRB10 [116, 117]. The IR-Akt transduction pathway is usually further disrupted by inhibition of Akt(Ser473) phosphorylation by mTORC2, due to suppression of mTORC2 kinase activity by hyperactive S6K1 [118, 119] (Fig.?5). Disruption of the IR-Akt pathway by hyperactive mTORC1/S6K1 results in liver and muscle glycogenolysis, liver gluconeogenesis, GLUT4 sequestration and unrestrained hyperglycemia. In line with that, genetic deletion of S6K1 protects mice from HFD-induced diabetes [120, 121]. Hence, resistance to insulin in the glycemic context is proposed to be congruent with mTORC1/S6K1 hyper activation. Open in a separate window Fig. 5 Resistance and response to insulin by mTORC1. PTPRC Hyperactive mTORC1 inhibits the IR-Akt transduction pathway resulting DM1-SMCC in resistance to insulin and deranged glycemic control. Concomitantly, insulin-induced hyperactivation of mTORC1 by the IR-Erk/RSK transduction pathway drives the non-glycemic diseases of T2D. Inhibition of the IR-Akt transduction pathway by hyperactive DM1-SMCC mTORC1 results in activating the IR-Erk/RSK pathway and in mTORC1 hyper activation Non-glycemic context of T2D. Response to insulin Disruption of the IR-Akt transduction pathway by hyperactive mTORC1 may still allow for sustained hyper activation of mTORC1 by insulin, being mediated by the IR/Ras/Raf/MEK/Erk/p90RSK/TSC/Rheb/mTORC1 transduction pathway, implying redundancy of IR-Akt and IR-Erk/RSK in activating mTORC1 [122, 123] (Figs.?4, ?,5).5). Moreover, the reciprocal relationship between the IR-Akt and the IR-Erk/RSK pathways, due to inhibitory phosphorylation of Raf(Ser259) by activated Akt [124, 125], implies enhancement of the IR-Erk/RSK activity upon inhibiting the IR-Akt pathway by hyperactive mTORC1. Hence, in face of resistance to insulin in the glycemic context, insulin-driven Erk/RSK may transduce a variety of mTORC1-mediated disease aspects of T2D (e.g., beta cell failure, obesity, NAFLD, dyslipidemia, hypertension, diabetes macro- and micro-vascular disease) as outlined below (Fig. ?(Fig.5).5). Indeed, IR knockout results in hyperglycemia, but also in protecting from non-glycemic diseases of T2D , implying an obligatory role for insulin and IR in driving the non-glycemic diseases of T2D. Progressive beta cells failure The IR-Erk/RSK transduction pathway is usually fully active in beta cells [126, 127], allowing for mTORC1 hyper activation in beta cells in response to nutrient excess, independently of the IR-Akt transduction pathway. Thus, nutrient excess is proposed to account for both, peripheral resistance to insulin in the glycemic context due to suppression of the IR-Akt transduction pathway by hyper active mTORC1 in liver, muscle DM1-SMCC and adipose tissue (III3), with concomitant increase in insulin production due to IR-Erk/RSK-induced.