The role of mammalian target of rapamycin (mTOR) in the regulation of pancreatic β-cell mass: implications in the development of type-2 diabetes

Abstract

Type-2 diabetes mellitus (T2DM) is a disorder that is characterized by high blood glucose concentration in the context of insulin resistance and/or relative insulin deficiency. It causes metabolic changes that lead to the damage and functional impairment of organs and tissues resulting in increased morbidity and mortality. It is this form of diabetes whose prevalence is increasing at an alarming rate due to the 'obesity epidemic', as obesity is a key risk factor in the development of insulin resistance. However, the majority of individuals who have insulin resistance do not develop diabetes due to a compensatory increase in insulin secretion in response to an increase in insulin demand. This adaptive response is sustained by an increase in both β-cell function and mass. Importantly, there is increasing evidence that the Serine/Threonine kinase mammalian target of rapamycin (mTOR) plays a key role in the regulation of β-cell mass and therefore likely plays a critical role in β-cell adaptation. Therefore, the primary focus of this review is to summarize our current understanding of the role of mTOR in stimulating pancreatic β-cell mass and thus, in the prevention of type-2 diabetes.

Fig. 1

Downstream substrates regulated by the mTOR complexes. Both mTOR complexes are comprised of mTOR, G_β-like protein mLST8 (for mammalian ortholog of lethal with sec 13, also known as GβL) [87], DEPTOR (for DEP domain-containing mTOR interacting protein) [118], GRp58 (for 58 KDa glucose-regulated protein, also referred to as ERp57) [124], Tti1 (Tel 2 interacting protein 1), Tel2 (telomere maintenance 2) [83] and Rac1 (Ras-related C3 botulinum toxin substrate 1) [132]. mTORC1 specific components include RAPTOR (for regulatory-associated protein of mTOR) [86] and PRAS40 (for Pro-rich Akt substrate of 40 kDa) [44, 112, 135, 166, 167]. mTORC2 specific components consist of RICTOR (for rapamycin-insensitive companion of TOR) [136], PROTOR (for protein observed with RICTOR) [114] and mSIN1 (mammalian stress activated protein kinase interacting protein 1) [45, 79, 179]. mTORC1 substrates include 4EBP (eukaryotic initiation factor 4E binding proteins) [9, 19] and S6K [ribosomal protein S6 (rpS6) kinase] [23, 28]. S6K phosphorylates rpS6 [6, 94], SKAR (S6K1 Aly/REF-like target) [126], eIF4B [125], PDCD4 (programmed cell death protein 4) [34], eEF2K [eukaryotic elongation factor 2 (eEF2) kinase] [17, 169], CBP80 (for 80 KDa nuclear cap-binding protein, also known as nuclear cap binding protein subunit 1 or NCBP1) [172] and insulin receptor substrates (IRS) [165]. The effect of mTORC1 on lipogenesis is mediated through the transcription factor SREBP (sterol regulatory element-binding protein) [38, 120], which has recently been shown to be controlled by mTORC1-mediated lipin1 nuclear import [119]. mTORC1 also upregulates the expression of genes implicated in mitochondrial metabolism through the YY1 (Ying Yang 1)-PGC1α (peroxisome proliferator-activated receptor gamma coactivator 1-α) transcription factor complex [30]. mTORC1 also increases the expression of Grb10 (growth factor receptor-bound protein 10), which inhibits insulin signalling via the inhibition of IRS [70, 182]. Other mTORC1 targets include TFIIIC (transcription factor 3C) [85], IMP2 (insulin-like growth factor 2 (IGF2) mRNA binding protein) [31], STAT3 (signal transducers and activator 3) [181] and HIF1 (hypoxia-induced factor 1) [74]. Another major function of mTORC1 is the regulation of autophagy. mTOR directly phosphorylates ULK1 and Atg13 and inhibits autophagosome formation [48, 68, 82], although it also inhibits DAP1, a negative regulator of autophagy which is activated under nutrient deprivation, via direct phosphorylation on Ser3 and Ser51 [92]. mTORC2 is responsible for the phosphorylation and activation of several AGC (for protein kinase A, G and C) kinases, including PKB [79, 138], SGK1 (serum/glucocorticoid-induced kinase 1) [50], conventional PKCs (cPKC) and PKCε (one of the novel PKCs or nPKCs) [42, 75, 136]

Fig. 2

Schematic representation of signalling pathways that regulates mTORC1. a mTOR senses a wide range of upstream signals such as: amino acids availability, which modulates the activity of mTORC1 through Rag GTPases [88, 134]; glucose or oxygen levels through AMPK [AMP (5′-adenosine monophosphate) activated protein kinase] [78] and REDD1 (regulated in development and DNA damage responses 1) [18, 81, 149, 173]; growth factors, which activate MAPK (mitogen-activated protein kinase) and stimulate mTORC1 via ERK (extracellular signal-regulated kinases) and RSK (p90 ribosomal protein S6 kinase) [21, 22, 43, 101, 127, 128]; insulin via activation of PI3K (phosphoinositide 3-kinase), PKB (protein kinase B, also referred to as Akt) [52, 141], and inactivation of GSK3 (glycogen synthase kinase 3) [77] [n.b. the activity of PKB can be suppressed by TRB3 (mammalian homolog of Drosophila tribbles 3) [36]]. These pathways impinge on TSC1/2 (tuberous sclerosis complex 1/2), a GTPase activating protein (GAP) of the small G protein Rheb (Ras homolog enriched in brain), and GTP bound Rheb in turn activates mTORC1. b Sites of phosphorylation on TSC2 and their respective kinases, adapted from [73]. c The regulation of Rheb. TSC1/2 acts as a GAP for Rheb [139, 185], whereas TCTP (translationally controlled tumor protein) [71] and FKBP38 (FK506 binding protein 38) [4], have been proposed to act as a GNEF for Rheb

Fig. 3

Schematic representation of the involvement of protein targets downstream of mTORC1 and 2 in the control of pancreatic β-cell mass and function. Proteins circled in continuous line: function proved in β-cells; Proteins circled in dashed line: function reported in non β-cells, and yet to be studied in β-cells. a Effects of downstream targets of mTORC1 on β-cell function and mass. Using transgenic mouse models it has been shown that S6K1 [ribosomal protein S6 (rpS6) kinase 1] [116] and rpS6 [131] are crucial for the maintenance of β-cell size, although it remains a possibility that other S6K downstream targets, such as SKAR (S6K1 Aly/REF-like target) [126], eEF2 (eukaryotic elongation factor 2) [17, 169], PDCD4 (programmed cell death protein 4) [34] and eIF4B (eukaryotic initiation factor 4B) [125], also contribute to β-cell growth, presumably through their ability of regulating protein synthesis. Insulin resistance can be induced by the inhibition of IRS (insulin receptor substrate) resulted from the over-activation of S6K1 in β-cells [39]. Recently, it has also been reported that newly discovered mTORC1 substrate Grb10 (growth factor receptor-bound protein 10) negatively regulates insulin and IGF (insulin-like growth factor) signalling through the binding and inhibition of InsR (insulin receptor) and IGFR (IGF receptor) [70, 182], which may also contribute to insulin resistance. mTORC1-stimulated fat accumulation is driven by the activation of SREBP (sterol regulatory element-binding protein) [98, 145, 146] through the nuclear import of lipin1 [119]. It has been demonstrated in β-cells that mTORC1 directly phosphorylates IMP2 [insulin-like growth factor 2 (IGF2) mRNA binding protein] to promote IGF2 mRNA translation [31], and leptin-induced activation of STAT3 (signal transducers and activator 3) suppresses preproinsulin gene expression [96]. Furthermore, it can also be speculated that 4EBP [eukaryotic initiation factor 4E (eIF4E) binding proteins] controls β-cell proliferation, while YY1 (Ying Yang 1) and PGC1α (peroxisome proliferator-activated receptor gamma coactivator 1-α) [30] may play roles in β-cell mitochondrial metabolism. Circle colours represent: dark red β-cell size; yellow insulin resistance; black mitochondrial metabolism; tan IGF2 mRNA translation; blue β-cell replication; light green preproinsulin gene expression; purple lipid metabolism. b Downstream of mTORC2. Gu et al. [59] have demonstrated that mTORC2 is important in β-cell replication. In addition, mTORC2 is essential for the maintenance of β-cell viability and GSIS (Barlow AD, Xie J and Herbert TP, unpulished data). mTORC2 also controls the folding and protein stability of PKCα (protein kinase C α), PKCβ and PKCε [42, 75], which are known to play important roles in β-cell function and survival [13, 140]