mTORC1 syndrome (TorS): unified paradigm for diabetes/metabolic syndrome

Abstract

'Glucolipotoxicity' and 'insulin resistance' are claimed to drive type 2 diabetes (T2D) and the non-glycemic diseases of the metabolic syndrome (MetS) (obesity, dyslipidemia, hypertension). In line with that, glycemic and/or insulin control are considered to be primary goal in treating T2D/MetS. However, recent standard-of-care (SOC) treatments of T2D, initially designed to control T2D hyperglycemia, appear now to alleviate the cardio-renal and non-glycemic diseases of T2D/MetS independently of glucose lowering and insulin resistance, and in non-T2D patients altogether, calling for an alternative unifying pathophysiology/treatment paradigm for T2D/MetS. This opinion article proposes to replace the current 'glucolipotoxic/insulin-resistance' paradigm of T2D/MetS with an 'mammalian target of rapamycin complex 1 (mTORC1) syndrome' (TorS) paradigm, implying an exhaustive cohesive disease entity driven by an upstream hyperactive mTORC1, and which includes diabetic hyperglycemia, diabetic dyslipidemia, hypertension, diabetic macrovascular and microvascular disease, non-alcoholic fatty liver disease, some cancers, neurodegeneration, polycystic ovary syndrome (PCOS), psoriasis, and others. The TorS paradigm may account for the insulin-resistant glycemic context of TorS, combined with response to insulin of the non-glycemic diseases of TorS. The TorS paradigm may account for the efficacy of current antidiabetic SOC treatments in diabetic and nondiabetic patients. Most importantly, the TorS paradigm may generate novel treatments for TorS.

Keywords: diabetes; mTORC1; metabolic syndrome.