Evidence for rapamycin toxicity in pancreatic β-cells and a review of the underlying molecular mechanisms

Abstract

Rapamycin is used frequently in both transplantation and oncology. Although historically thought to have little diabetogenic effect, there is growing evidence of β-cell toxicity. This Review draws evidence for rapamycin toxicity from clinical studies of islet and renal transplantation, and of rapamycin as an anticancer agent, as well as from experimental studies. Together, these studies provide evidence that rapamycin has significant detrimental effects on β-cell function and survival and peripheral insulin resistance. The mechanism of action of rapamycin is via inhibition of mammalian target of rapamycin (mTOR). This Review describes the complex mTOR signaling pathways, which control vital cellular functions including mRNA translation, cell proliferation, cell growth, differentiation, angiogenesis, and apoptosis, and examines molecular mechanisms for rapamycin toxicity in β-cells. These mechanisms include reductions in β-cell size, mass, proliferation and insulin secretion alongside increases in apoptosis, autophagy, and peripheral insulin resistance. These data bring into question the use of rapamycin as an immunosuppressant in islet transplantation and as a second-line agent in other transplant recipients developing new-onset diabetes after transplantation with calcineurin inhibitors. It also highlights the importance of close monitoring of blood glucose levels in patients taking rapamycin as an anticancer treatment, particularly those with preexisting glucose intolerance.

FIG. 1.

mTOR signaling pathways. After stimulation by insulin and other growth factors, phosphatidylinositol 3-kinase (PI3K) converts phosphatidylinositol 4,5-bisphosphate (PIP₂) into phosphatidylinositol 3,4,5-triphosphate (PIP₃), which localizes PKB to the membrane where it is activated by PDK1 and mTORC2. Activated PKB phosphorylates and inhibits tuberous sclerosis complex (TSC1/2). Rheb, a small GTPase that is inhibited by TSC2, positively modulates mTORC1 activity. mTORC1 phosphorylates S6 kinase 1/2 and 4EBP1, resulting in increased mRNA translation. Amino acid sufficiency activates mTORC1 via Rag A/B and C/D. Under low-energy conditions, the AMP-to-ATP ratio rises and activates AMP kinase (AMPK), which phosphorylates and activates the TSC1/2 complex, resulting in mTORC1 inhibition. mTORC2 activity is mediated via predominantly unknown pathways. mTORC2 phosphorylates and activates PKB, serum- and glucocorticoid-induced protein kinase 1 (SGK1), and PKC. Arrows, stimulatory effects; block ends, inhibitory effects; solid lines, direct effects, dashed lines, indirect effects. Atg13, autophagy-related protein 13; DAP1, death-associated protein 1; Deptor, DEP domain–containing mTOR-interacting protein; 4EBP, eIF4E-binding protein; GβL- G, protein β-subunit-like protein; HIF1, hypoxia-induced factor 1; IMP2, insulin-like growth factor 2 mRNA-binding protein; mLST8, mammalian lethal with Sec13 protein 8; PDK1, phosphoinositide-dependent protein kinase 1; Protor, protein observed with Rictor; Raptor, regulatory associated protein of mTOR; Rictor, rapamycin-insensitive companion of mTOR; Sin1, stress-activated protein kinase–interacting protein 1; TFIIIC, transcription factor 3C; ULK1, Unc-51–like kinase 1.