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

'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.

However, glycemic control is just a particular aspect of T2D. Beyond the glycemic aspect, T2D patients present a variety of highly prevalent non-glycemic diseases of T2D, which drive T2D morbidity and mortality (Box 1). Thus, T2D patients are overweight or obese, dyslipidemic [hypertriglyceridemia, small dense low-density lipoprotein-cholesterol (sdLDL-C), low high-density lipoprotein (HDL)-C], and hypertensive, while most present non-alcoholic fatty liver disease (NAFLD). Concomitantly, T2D patients present a variety of 'microvascular' diseases, including Highlights The current paradigm of type 2 diabetes (T2D) is gluco-centric. However, the disease course of T2D/metabolic syndrome (MetS) is dictated by the non-glycemic diseases of T2D/MetS.
In contrast to glycemic control being driven by resistance to insulin, the nonglycemic diseases of T2D/MetS are fully responsive to insulin.
The current gluco-centric/insulin resistance paradigm of T2D/MetS fails to account for the disconcordance between response and resistance to insulin in shaping the pathogenesis and treatment of T2D/MetS, calling for an alternative paradigm.
The 'mammalian target of rapamycin complex 1 (mTORC1) syndrome' (TorS) paradigm implies a cohesive disease entity driven by an upstream hyperactive mTORC1 and which drives the glycemic and non-glycemic diseases of TorS.
The TorS paradigm may account for the pathophysiology of TorS diseases, the mode-of-action of current SOC treatments for T2D/MetS, and may generate novel treatments for TorS.

Box 1. T2D/MetS: broad deranged metabolic phenotype
The current paradigm of T2D views hyperglycemia as primary target and considers glycemic control its ultimate treatment goal. Thus, diagnosis of T2D, as well as pre-T2D, is currently defined by respective glycemic criteria, namely, fasting plasma glucose (FPG), 2-h glucose tolerance, and/or glycated Hb (HbA1C) [1]. In line with that, the American Diabetes Association maintains that 'measurement of plasma glucose is sufficient to diagnose diabetes'. Also, 'knowing the plasma glucose is critical because, in addition to confirming that symptoms are due to diabetes, it will inform management decisions' [1]. T2D hyperglycemia is driven by resistance to insulin in liver, muscle, and adipose fat, combined with beta-cell failure in producing and/or secreting insulin. Resistance to insulin implies insulin failure to inhibit liver gluconeogenesis, to activate glucose uptake in muscle and adipose tissue, to activate glycogen synthesis in liver and muscle, and to suppress adipose lipolysis. Insulin resistance is proposed to reflect inhibition of signaling through the insulin receptor(IR)/Akt transduction pathway, due to serine phosphorylation of IRS1,2 by diglyceride-activated nPKC [61] and/or by TNFalpha-activated JNK [62]. Concomitantly, beta-cell damage and failure is proposed to be due to glucolipotoxicity resulting in ER stress, oxidative stress, mitochondrial dysfunction, and inflammation [63,64] (but see [65]). The cause/result relationship between beta-cell failure and peripheral resistance to insulin still remains unresolved by the current paradigm of T2D [22].

Glossary
Beta-cells failure: failure of pancreatic beta-cells to produce and secrete sufficient insulin, in face of peripheral resistance to insulin. Gluco-centric view of T2D: T2D is currently defined by respective glycemic criteria, namely, fasting plasma glucose (FPG), 2-h glucose tolerance, and/or glycated Hb (HbA1C) [1]. Also, primary goals of treatment of T2D focus on glycemic control, defined by FPG and/or HbA1C targets, while avoiding hypoglycemia [1]. Glucolipotoxicity: the combined, deleterious effects of elevated glucose and fatty acid levels on pancreatic beta-cell function, resulting in oxidative stress, ER stress, mitochondrial dysfunction, impaired insulin gene expression, decreased insulin secretion, and beta-cell apoptosis [63,64] (but see [65]). Metabolic syndrome (MetS): clustering of at least three of the following five medical conditions: obesity, high blood pressure, high blood glucose, high serum triglycerides, and low serum high-density lipoprotein (HDL). Mitochondrial complex I: the first of five mitochondrial complexes that carry out mitochondrial oxidative phosphorylation. Non-glycemic diseases of T2D: including obesity, diabetic dyslipidemia, hypertension, diabetic macrovascular/ cardiovascular disease, diabetic microvascular disease (nephropathy, retinopathy, neuropathy), non-alcoholic fatty liver disease, some cancers, neurodegeneration (dementia, AD), polycystic ovary syndrome, psoriasis, and others. Resistance to insulin: insulin failure to inhibit liver gluconeogenesis, to activate glucose uptake in muscle and adipose tissue, to activate glycogen synthesis in liver and muscle, and to suppress adipose lipolysis. diabetic nephropathy, retinopathy, and peripheral polyneuropathy. Most importantly, T2D 'macrovascular' disease (cardiovascular/cerebrovascular/peripheral vascular) accounts for half of all T2D deaths. Also, T2D patients present high incidence of dementia/Alzheimer disease (AD), PCOS, psoriasis, and a variety of cancers. Hence, the glycemic aspect of T2D is just a particular tip of a deranged metabolic iceberg. In realizing this, the gluco-centric view of T2D has been reshaped by incorporating the hyperglycemia, obesity, dyslipidemia, and hypertension biomarkers into the broader context of a MetS [2], whereby the non-glycemic diseases of T2D/MetS are viewed as 'risk factors' and/or 'outcomes' and/or 'comorbidities' of T2D 'glucolipotoxicity'/'insulin resistance' [3,4]. However, the non-glycemic diseases of T2D/MetS may already become fully evident during the prediabetes stage of T2D, namely prior to the appearance of solid hyperglycemia [5]. Also, the cardio-renal and non-glycemic diseases of T2D/MetS are unaffected, or only mildly affected by strict glycemic control [6]. Most importantly, recent 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 in non-T2D patients altogether [7,8], calling for an alternative exhaustive T2D/MetS paradigm.
'Insulin resistance': one-sided counterproductive T2D/MetS paradigm Importantly, in contrast to glycemic control being driven by resistance to insulin, most nonglycemic aspects of T2D/MetS appear to be fully responsive to insulin, implying an apparent context-dependent 'selective insulin resistance' [9] (Box 1). Thus, the obesity of T2D/MetS reflects insulin-responsive fat gain in face of resistance to insulin of adipose lipolysis [10]. Also, liver steatosis of T2D/MetS reflects insulin-responsive hepatic lipogenesis and triglyceride synthesis [11,12]. Similarly, the hypertension disease of T2D/MetS reflects insulin-responsive sympathetic activity, combined with insulin-responsive renal sodium reabsorption [13]. Also, the cancer risk of T2D/MetS reflects insulin-responsive cell proliferation and metastasis [14]. Hence, the interplay between response and resistance to insulin in shaping T2D/MetS pathophysiology still remains unresolved. Moreover, the unresolved pathophysiology results in an ambivalent treatment approach to T2D/MetS. Thus, in contrast to T2D glycemic control being effectively managed by insulin(s), insulin may promote, rather than alleviate the non-glycemic diseases of T2D/MetS (see later), in particular, the cardiovascular disease [15,16] which accounts for most T2D/MetS mortality. The disconcordance between response and resistance to insulin in shaping the pathogenesis and treatment of T2D/MetS, calls for an alternative unifying T2D/MetS pathophysiology/treatment paradigm.
Resistance to insulin in the glycemic context Insulin resistance in the glycemic context is proposed to be driven by disruption of the insulin receptor (IR)-Akt(PKB) transduction pathway by hyperactive mTORC1/S6K1. Thus, serine phosphorylation of IRS1,2(Ser312, 636/639) and IRS1,2(Ser307, 1101) by hyperactive mTORC1 kinase and its downstream S6K1 kinase, respectively, results in suppressing the phosphorylation of IRS tyrosines, followed by IRS ubiquitination and degradation [17]. Also, hyperactive mTORC1 phosphorylates and stabilizes GRB10(Ser476), resulting in its binding to the IR, followed by IR ubiquitination and degradation [18]. The IR-Akt transduction pathway may further be disrupted by suppression of mTORC2 kinase activity by hyperactive mTORC1/S6K1, resulting in Akt suppression [19]. Disruption of the IR-Akt pathway by hyperactive mTORC1/S6K1 results in liver gluconeogenesis and glycogenolysis, inhibition of muscle and adipose glucose uptake, and unrestrained hyperglycemia [20]. Hence, hyperactive mTORC1 may account for resistance to insulin in the glycemic context. Box 2. mTORC1 mTORC1 controls growth and metabolism by phosphorylating and/or affecting its downstream targets S6K1, 4EBP, CRTC2, lipin, ATF4, HIF1a, PPARg, PPARa, ULK1, TFEB, and others [79]. mTORC1 controls G1/S transition and G2/M progression, activates ribosome biogenesis and CAP-dependent mRNA translation, drives purine and pyrimidine biosynthesis, mitochondrial biogenesis, adipogenesis, lipogenesis and lipid synthesis, promotes glycolysis and the pentose shunt, and suppresses fatty acid oxidation and ketogenesis [79]. Most importantly, mTORC1 blocks autophagy [80], mitophagy [81], and lysosome biogenesis [82]. mTORC1 activity may range between hyperactive and less active kinase, as a function of genetic and/or epigenetic and/or tissue and/or context-dependent factors that may determine its sensitivity to growth factors, nutrients, and stress. mTORC1 kinase activity may be hyperactivated by growth factors (e.g., insulin, IGF1), energy/nutrients excess (e.g., glucose, leucine, arginine, cholesterol), and inflammation (e.g., NFkB/IKK), while being suppressed by a variety of metabolic stresses (e.g., hypoxic, hyperosmotic, oxidative, acidic, DNA damage) [79,83], including caloric restriction [84,85], bariatric surgery [86], sustained physical exercise [87][88][89], carbohydrate restriction [90,91], or ketogenic diets [92,93]. When applied, these measures are effective in increasing health span and predicting an increase in life span ( Figure I)  Beta-cell function and failure mTORC1 drives beta-cell proliferation, cell size, and insulin production [21]. Hence, concomitant hyperactivation of mTORC1 in liver, muscle, adipose fat, and beta-cells may account for the close association between peripheral insulin resistance in the glycemic context and 'compensatory' hyperinsulinemia during the prediabetes stage of T2D, resulting in apparent glycemic control [22]. However, hyperactive mTORC1 suppresses lysosomal autophagy/mitophagy and/or proteasomal degradation, resulting in unresolved endoplasmic reticulum (ER) stress and beta-cell apoptosis [23]. Thus, hyperactive mTORC1 may concomitantly account for the hyperplastichypertrophic growth of beta-cells and the progressive beta-cell failure of T2D. These two concomitant contrasting aspects of beta-cell hyperactive mTORC1 may dynamically evolve during the clinical sequel of T2D, whereby the hyperplastic-hypertrophic initial feature yields progressively to an apoptosis outcome and beta-cell failure [24].
The cardiovascular disease of T2D/MetS In particular, hyperactive mTORC1 may offer a unifying pathophysiology paradigm for the cardiovascular disease of T2D/MetS. Indeed, hyperactive mTORC1 may drive both diabetic ASCVD [25] together with diabetic cardiomyopathy (namely, heart failure not accounted for by coronary artery disease or hypertension) [26], resulting in T2D/MetS macrovascular/cardiovascular disease. Indeed, mTORC1 is reported to be upregulated in human diabetic cardiomyopathy, in human non-ischemic dilated cardiomyopathy, and in animal models of heart failure [27]. Also, pressure overload-induced cardiomyopathy, genetic cardiomyopathy, and T2D/MetS cardiomyopathy IR IRS  Concomitantly, the insulin-driven IR/Erk(p90RSK)/mTORC1 pathway may transduce beta-cell failure and the nonglycemic diseases of T2D/MetS. The reciprocal relationship between the IR/Akt(PKB) and the IR/Erk(p90RSK) transduction pathways (B) [33] implies enhancement of the IR/Erk(p90RSK)/mTORC1 activity upon inhibition of the IR/ Akt pathway by hyperactive mTORC1. Abbreviations: NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis. may be improved by promoting cardiac autophagy or by rapamycin, implying a pathogenic role of hyperactive mTORC1 in heart failure [27].
Diabetic nephropathy, retinopathy, and neuropathy Similarly, disease categories, which have been classically considered within a 'microvascular' context of T2D, are proposed to be driven by hyperactive mTORC1. Thus, diabetic nephropathy, characterized by detachment and loss of glomerular podocytes, combined with interstitial fibrosis of proximal tubule cells, appears to be driven by hyperactive mTORC1 [28] and delayed/ prevented by rapamycin treatment [29], or by curtailing podocyte and/or proximal tubule mTORC1 [30]. Hyperactive mTORC1 may further offer a unifying pathophysiological paradigm for diabetic retinopathy [31] and DPN [32].
Other non-glycemic diseases of T2D/MetS Due to the redundancy of the IR/Akt and IR/Erk(p90RSK) pathways in activating mTORC1, disruption of the IR/Akt transduction pathway by hyperactive mTORC1 may still allow for sustained hyperactivation of mTORC1 by insulin, being mediated by the IR/Erk(p90RSK)/mTORC1 transduction pathway [33] (Figure 1). Moreover, the reciprocal relationship between the IR/Akt and the IR/Erk(p90RSK) pathways [33] implies enhancement of the IR/Erk(p90RSK) activity upon inhibition of the IR/Akt pathway by hyperactive mTORC1. Hence, in face of resistance to insulin in the glycemic context, insulin-driven Erk(p90RSK) may still activate mTORC1, thereby transducing and promoting a variety of mTORC1-driven non-glycemic disease aspects of T2D/MetS (e.g., obesity [34], NAFLD/NASH [35], dyslipidemia [36], hypertension [37], neurodegeneration [38], cancer [39], and others. In summary, the TorS paradigm may offer a unifying view for T2D/MetS pathophysiology, while solving the apparent disconcordance between response and resistance to insulin in shaping the exhaustive pathogenesis of T2D/MetS. Of note, in contrast to the current paradigm of 'insulin resistance' viewed as an upstream driver of T2D/MetS, the proposed TorS paradigm considers hyperactive mTORC1 as an upstream driver of TorS. Hyperactive mTORC1 is proposed to drive resistance to insulin in the glycemic context of TorS, while, concomitantly, driving a plethora of insulin-responsive non-glycemic diseases of TorS, including obesity, dyslipidemia, hypertension, ASCVD, diabetic cardiomyopathy, diabetic nephropathy, DPN, NAFLD/NASH, some cancers, neurodegeneration, PCOS, psoriasis, and others ( Figure 1). The TorS paradigm does not exclude secondary mutual interactions between downstream diseases of TorS, in addition to the primary role played by hyperactive mTORC1 in driving TorS.
Of note, mTORC1 regulates metabolism across life cycle stages. Thus, active mTORC1 controls growth and development (Box 2) during early age and blocking its activity or maintaining its constitutive activity during the early age (e.g., through TSC1,2 null mutations) may result in pathology and disease. However, genetic, epigenetic, environmental, dietary, or behavioral conditions that sustain the hyperactivity of mTORC1 later in life may drive TorS and its disease components. Indeed, suppression of mTORC1 activity in adult animal models is reported to increase health span and life span [40]. The proposed TorS paradigm does not exclude additional mTORC1independent drivers that may modulate the specific disease phenotype of TorS patients.

Current SOC treatments of T2D/MetS target TorS
The 'gluco-centric/insulin-resistance' paradigm of T2D/MetS has generated a variety of antidiabetic SOC treatments for T2D patients, including therapeutic lifestyle change (TLC) measures and metformin, glitazones, SGLT2i, GLP-1RA, DPP4i, and alpha-glucosidase inhibitors designed to overcome hyperglycemia and 'glucolipotoxicity' by inducing glucose excretion or by counteracting beta-cell failure, insulin resistance, and carbohydrate load. However, these treatment measures are reported now to induce pleiotropic activities beyond the glycemic context, including a decrease in ASCVD, cardiomyopathy, nephropathy, blood pressure, blood lipids, endothelial dysfunction, inflammatory markers, liver steatosis, cancer, PCOS, neurodegeneration, and others. Most importantly, the cardio-renal disease and some other non-glycemic diseases of TorS appear to be alleviated by the respective SOC treatments independently of glucose lowering, insulin resistance, and in non-T2D patients altogether [7,8], thereby refuting the current 'gluco-centric/insulin-resistance' paradigm as the primary mode-of-action of the concerned SOC measures. Indeed, TLC measures, metformin, glitazones, SGLT2i, and GLP-1RA all appear to suppress mTORC1 kinase activity [41][42][43][44], implying that the proposed TorS paradigm may offer a unified mode-of action of current antidiabetic SOC treatments, accounting for their efficacy in treating the glycemic and non-glycemic disease aspects of TorS.
Also, in trying to cope with the cardiovascular disease of T2D/MetS, being still an unmet need in spite of strict glycemic control [6], the current poly-drug approach to T2D/MetS consists of addon statins, aspirin, and hypotensive drugs (in particular RAS inhibitors). Each of these add-ons has its own discrete rational, namely, alleviating dyslipidemia, vascular thrombosis, and hypertension, respectively. However, in addition to their respective targets, these add-ons are reported now to suppress mTORC1 kinase activity in a variety of experimental systems [45][46][47], accounting for their beneficial pleiotropic activities in the TorS context beyond dyslipidemia, thrombosis, or hypertension.
In particular, insulin-activated mTORC1 may promote the cardiovascular disease of TorS and its morbidity/mortality sequel as a function of insulin dose and length of treatment period [15]. The cardiovascular disease of TorS accounts for most of the morbidity and mortality of TorS, being still an unmet need in spite of strict glycemic control [6,49].
Hyperactive mTORC1 drives diabetic nephropathy and renal failure, implying advanced renal disease by insulin-activated mTORC1 [30]. Similarly, insulin therapy may promote diabetic retinopathy as a function of insulin dose and length of treatment period [31].
While controlling hyperglycemia by triggering the IR/Akt pathway, insulin may concomitantly suppress this same pathway by hyperactivating mTORC1 through IR/Erk(p90RSK)/mTORC1 [33], implying that insulin treatment may counteract its own hypoglycemic activity (Figures 1 and 2). Indeed, insulinoma patients are resistant to insulin and recover to normal sensitivity only upon tumor resection [50]. In line with that, insulin treatment of T2D patients frequently results in insulin-refractory hyperglycemia, thereby requiring a progressive increase in insulin doses for maintaining glycemic control.
Of note, insulin treatment is generally applied during advanced stages of T2D, whereby patients are older and present longer duration of T2D, multiple comorbidities, and failure to control hyperglycemia by non-insulin SOC treatments. Thus, the non-glycemic diseases of advanced T2D/ MetS patients may apparently be ascribed to the disease profile of insulin-treated patients, rather than being promoted by insulin per se. Also, the increased risk of mortality with insulin treatment may apparently be ascribed to hypoglycemic episodes induced by insulin treatment. However, most of the data implicating insulin in driving the non-glycemic diseases of TorS, including cardiovascular and renal diseases, relate to non-hypoglycemic T2D patients treated with insulin(s), compared with patients treated with non-insulin SOC. Hence, insulin presents a double-edged agent, being required for overcoming resistance to insulin in the glycemic context while promoting the non-glycemic diseases of TorS, in particular cardiovascular and renal diseases, which account for most of TorS morbidity and mortality. The double-edged role of insulin in the TorS context implies caution in applying insulin treatment in TorS patients. If ultimately required to overcome hyperglycemia, combination treatment using add-on antidiabetic SOC drugs that suppress mTORC1 kinase activity may allow for decreased insulin doses.

Prospective treatments of TorS
Suppression of hyperactive mTORC1 may offer an all-in-one treatment for the glycemic and nonglycemic diseases of TorS. In principle, mTORC1 kinase activity may be suppressed by direct TOR kinase inhibitors, or indirectly, by targeting mTORC1 activators/suppressors. TOR kinase inhibitors (e.g., Torin) inhibit both mTORC1 and mTORC2, resulting in Akt suppression and uncontrolled T2D due to mTORC2 inhibition. Rapalogs inhibit mTORC1 specifically; however, chronic treatment with rapalogs results in inhibition of mTORC2 as well, resulting in uncontrolled T2D. Also, treatment with rapalogs results in side-effects and trials to bypass side-effects with intermittent treatment still remain to be accomplished. Moreover, suppression of mTORC1 kinase activity by rapalogs results in suppressing some (e.g., S6K1), but not all downstream targets of mTORC1 (e.g., 4EBP), implying a potential resistance to rapalogs in the treatment of TorS.
Hyperactive mTORC1 may be indirectly suppressed by a variety of metabolic stresses, including caloric restriction, bariatric surgery, carbohydrate restriction, ketogenic diets, or sustained physical exercise (Box 2). When applied, these measures are effective in treating the pleiotropic diseases of TorS, resulting in increased health span and predicting an increase in life span. However, compliance to the concerned dietary and exercise behavioral measures is poor and Sisyphic. Also, bariatric surgery is of limited relevance in coping with the TorS epidemic. Hence, TorS treatment calls for pharmacological measures that may generate a metabolic profile similar to that induced by caloric restriction, carbohydrate restriction, ketogenic diets, bariatric surgery, or sustained physical exercise. Clues to such measures may be projected from the mTORC1 connection of current anti T2D/MetS SOC treatments.
Indeed, current T2D/MetS SOC drugs that suppress mTORC1 kinase activity appear to inhibit mitochondrial complex I. Thus, targeting mitochondrial complex I is shared by metformin, glitazones, and SGLT2i [51][52][53], as well as by statins [54] and aspirin [55]. Moreover, mitochondrial complex I inhibitors (e.g., rotenone, PF-4708671), which have never been considered as agents in the T2D/MetS context, are reported to alleviate insulin resistance and beta-cell failure in T2D animal models [56,57], implying a mitochondrial/mTORC1 connection. Also, targeting mitochondrial complex I by long-chain fatty acyl analogs of the MEDICA platform is reported to treat TorS diseases, including T2D and a variety of cancers in respective animal models [58,59]. In line with that, mitochondrial complex I mutations, which decrease the rate of oxidative phosphorylation, promote longevity [60]. Suppression of hyperactive mTORC1 by mitochondrial complex I inhibitors may be ascribed to redox (NADH/NAD), energy (ATP/AMP), AMPK, and/or oxidative stress. Hence, mitochondrial complex I partial inhibitors may yield novel anti-TorS drugs.

Concluding remarks
The current gluco-centric paradigm of T2D/MetS fails to account for the pathophysiology of T2D/ MetS, whereby the disease course is mainly dictated by the non-glycemic diseases of T2D/MetS. Also, in contrast to glycemic control driven by resistance to insulin, most non-glycemic diseases of T2D/MetS appear to be fully responsive to insulin and are only mildly affected by strict glycemic control. Of note, recent SOC treatments of T2D alleviate the cardio-renal and non-glycemic diseases of T2D/MetS independently of glucose lowering, insulin resistance, and in non-T2D patients altogether, calling for an alternative unifying pathophysiology/treatment paradigm.
This opinion article proposes to replace the current gluco-centric/insulin resistance paradigm of T2D/MetS with a 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, NAFLD, some cancers, neurodegeneration, PCOS, psoriasis, and others. The TorS paradigm may account for the insulin-resistant glycemic context of TorS, combined with response to insulin of the nonglycemic diseases of TorS. The TorS paradigm may account for the mode-of-action of current SOC treatments and may generate novel treatments for TorS (see Outstanding questions).

Declaration of interests
No interests are declared.