Current evidence suggests that alteration in cellular metabolism leads to pancreatic β-cell dysfunction and loss in type 1 diabetes (T1D). The mammalian target of rapamycin, mTOR is a key regulator of cell survival and growth in response to intracellular energy levels, nutrients, and growth factor signaling. Dysregulated mTOR complex 1 (mTORC1) has been implicated in β-cell loss and dysfunction in T2D but has not been well studied in T1D. We hypothesized that genes associated with three pathways involved in the regulation of mTORC1 would display altered expression in T1D organ donor pancreata compared to nondiabetic controls. We isolated total RNA from 30 T1D and 30 unaffected control human organ donor pancreata obtained from the Network for Pancreatic Organ donors with Diabetes (nPOD) program and performed real-time qPCR on 26 genes related to these pathways, all of which demonstrated significant (p<0.05) induction. In relation to cellular energy balance, we observed induction of the AMPK-related genes. Concerning nutrient availability and the GCN2/ATF4 pathway, genes associated with all Sestrins and the GATOR 1 and GATOR 2 complexes were induced. In relation to growth factor signaling, components of the PI3K/AKT pathway were induced (Table 1). Both AMPK and PI3K/AKT pathways converge on TSC2, which had the largest degree of induction observed (22.4x). To conclude, our results clearly indicate dysregulation of mTORC1 in the T1D donor pancreas.
B.S. Bruggeman: None. D. Beachy: None. L.M. Jacobsen: None. H.S. Nick: None. M.A. Atkinson: None. D. Schatz: None. C. Wasserfall: None.