Sobering study. But again, chronically ill patients on daily immunosuppressive agents, and some very high dosing in the in vitro data.
Seems the evidence in this paper is strongly associated with mTOR2 suppression, and glucose/insulin dysregulation and implies NODAT (new onset diabetes) from change in β-cell function/toxicity via “chronic” administration.
“Given the suggestion that both rapamycin b-cell toxicity and insulin resistance may be mediated predominantly via mTORC2 rather than mTORC1 (36,55), the question arises whether an mTORC1-specific inhibitor would retain the immunosuppressive effects of rapamycin without any
mTORC2-mediated toxicity. However, this involves the assumption that the immunosuppressive effects of rapamycin are indeed mediated predominantly via mTORC1 which is not currently known”
Currently was in 2013, 9 years ago.
Fast forward 2018…
mTORC2 Signaling: A Path for Pancreatic β Cell’s Growth and Function
https://sci-hub.se/https://doi.org/10.1016/j.jmb.2018.02.013
“While mTORC1 signaling has been extensively studied in islet/ β-cell biology, recent findings demonstrate a distinct role for mTORC2 in the regulation of pancreatic β-cell function and mass. mTORC2, a key component of the growth factor receptor signaling, is declined in β-cells under diabetogenic conditions and in pancreatic islets from patients with type 2 diabetes. β-cell selective
mTORC2 inactivation leads to glucose intolerance and acceleration of diabetes as a result of
reduced β-cell mass, proliferation and impaired glucose-stimulated insulin secretion”
Seems mTOR2 to be highly implicated.
Hold on…2018 on MTOR1 (still looks like it shows how diabetes hyper elevates TOR1, but blunting via TOR1 inhibition can trigger TOR2 suppression)
mTORC1 Signaling: A Double-Edged Sword in Diabetic b Cells
https://www.cell.com/action/showPdf?pii=S1550-4131(17)30672-1
“Genetic or chemical inhibition of mTORC1-S6K1 signaling restores insulin secretion in isolated
human islets from patients with T2D, suggesting that elevated mTORC1 impairs b cell function (Yuan et al., 2017). The higher mTORC1 activity observed in islets and b cells of individuals with T2D is consistent with findings in animal models of T2D and is probably due to chronic hyperglycemia”
“But the critical function of mTORC1 as regulator of nutrient sensing and cellular metabolism under physiological conditions makes mTORC1 a challenging therapeutic target, and the establishment of an ‘‘mTORC1 therapeutic window’’ to target only the ‘‘pathogenic arm’’ of mTORC1 signaling in T2D will be very difficult. Moreover, no specific mTORC1 inhibitor
has been discovered so far. One important consideration in the development of mTORC1-targeted therapeutics is to what extent and how specifically a given drug can achieve its intended action without off-target adverse effects”
“The emerging paradigm by which chronic mTORC1 activation can cause b cell failure in T2D has underscored the importance of understanding the complexity of the mTOR network in the regulation of b cells’ metabolic plasticity in response to inappropriately elevated nutrients. This complexity includes the diversity of nutritional inputs (glucose, FFA, amino acids, etc.) and mechanistic outputs, as well as the transformation of initially anabolic mTORC1 signals into deleterious outcomes. While physiological mTORC1 stimulation is essential for the maintenance of b cell physiology and acts as a homeostatic signal for b cell adaptation, chronic mTORC1 activation may lead to progressive loss of b cell function and mass by several mTOR-regulated processes such as impaired insulin and mTORC2 signaling, impairment of autophagy, and development of unresolvable ER stress”
I am measuring the basic glucose/insulin parameters in my panels, and if trending towards dysregulation, would most certainly add a c-peptide test.
But wait, hasn’t the “gold standard” ITP on chronically treated Rapamycin mice, notwithstanding primary longevity extension end point, measured mTOR2, glucose and insulin dysregulation, pancreatic b-cell function/apoptosis? Is this dynamic at play in these murine models, yet manifests as eventual general neoplasms/cancer, not granulated for b-cell function?
