mTORC1 and mTORC2 regulate insulin secretion through Akt in INS-1 cells

Abstract

Regulated associated protein of mTOR (Raptor) and rapamycin-insensitive companion of mTOR (rictor) are two proteins that delineate two different mTOR complexes, mTORC1 and mTORC2 respectively. Recent studies demonstrated the role of rictor in the development and function of b-cells. mTORC1 has long been known to impact b-cell function and development. However, most of the studies evaluating its role used either drug treatment (i.e. rapamycin) or modification of expression of proteins known to modulate its activity, and the direct role of raptor in insulin secretion is unclear. In this study, using siRNA, we investigated the role of raptor and rictor in insulin secretion and production in INS-1 cells and the possible cross talk between their respective complexes, mTORC1 and mTORC2. Reduced expression of raptor is associated with increased glucose-stimulated insulin secretion and intracellular insulin content. Downregulation of rictor expression leads to impaired insulin secretion without affecting insulin content and is able to correct the increased insulin secretion mediated by raptor siRNA. Using dominant-negative or constitutively active forms of Akt, we demonstrate that the effect of both raptor and rictor is mediated through alteration of Akt signaling. Our finding shed new light on the mechanism of control of insulin secretion and production by the mTOR, and they provide evidence for antagonistic effect of raptor and rictor on insulin secretion in response to glucose by modulating the activity of Akt, whereas only raptor is able to control insulin biosynthesis.

Is REDD1 a Metabolic Éminence Grise ?

“…Consistent with this idea and the fact that REDD1 acts to negatively regulate mTORC1, β cell failure has been shown to coincide with mTORC1 hyperactivation, an effect demonstrated in mice harbouring a β cell-specific deletion of TSC2, a key negative upstream regulator of mTORC1 [80]. Conversely, disruption of mTORC1 function by silencing the expression of raptor, a key component of the mTORC1 complex, was shown to concur with increased glucose-stimulated insulin secretion and intracellular insulin content in pancreatic INS-1 cells [81]. Therefore, the anticipated hyperactivation of mTORC1 in response to a loss of REDD1 may act to reduce insulin production and secretion, as well potentiate β cell failure, as observed in the diabetic state.…”

Milk is not just food but most likely a genetic transfection system activating mTORC1 signaling for postnatal growth

“…Xu et al [22] demonstrated that leucine induced translation initiation by phosphorylation of 4E-BP-1 (formerly termed PHAS-I) and S6K, through the mTORC1-signaling pathway of pancreatic β-cells. In β-cells, leucine activates mTORC1 [19,20] that regulates insulin secretion and β-cell mass expansion [23-25]. Leucine not only increases insulin secretion but also enhances insulin signaling in insulin target tissues [26].…”

Evaluation of the In Vivo Therapeutic Effects of Radix Paeoniae Rubra Ethanol Extract with the Hypoglycemic Activities Measured from Multiple Cell‐Based Assays

“…Among the four PRExt constituents described here, only pentagalloylglucose and PEF enhanced glucose-stimulated insulin secretion. Considering functional insulin receptors are known to present in pancreatic beta cells and provide important role in regulating glucose-mediated insulin secretion; insulinotropic effect of pentagalloylglucose might result from its insulin mimetic property [29–31]. On the other hand, the underlying mechanism to explain insulinotropic effect of PEF remained to be investigated.…”