The capacity of ?-cells to expand in response to insulin resistance is critical to develop type-2 diabetes and ?-cell proliferation is a major component for these adaptive responses. The long-term goal of our previous and proposed studies under this award is the understanding of the molecular mechanisms that regulate ?-cell mass with emphasis in proliferation. During the current funding period, we focused on the mechanisms by which Akt and the tuberous sclerosis complex 2 (TSC2) regulate ?-cell mass and cell cycle progression. These studies identified the TSC2 and the mTOR/raptor complex (mTORC1) as important molecules regulating ?-cell mass and proliferation. mTORC1 controls growth and proliferation by activation of 4E-BP and S6 kinases (S6K). Moreover, mTORC1 also mediates a negative feedback loop to attenuate Akt signaling. However, uncertainty remains as to the underlying mechanism and key downstream effectors responsible for controlled ?-cell expansion by mTORC1. The objective of this application is to understand how mTORC1 targets regulate ?-cell mass and proliferation. We hypothesize that ?-cell mass expansion by mTORC1 signaling is mediated by a balance between two processes: activation of downstream targets and negative feedback inhibition of IRS/Akt signaling.
The specific aims are (1) to establish how mTORC1 targets regulate ?-cell mass expansion. These studies will evaluate the individual contributions of S6K1 and 4E-BP on regulation of cell growth and proliferation. (2) Determine how decreased Akt signaling by mTORC1-mediated negative feedback modulates ?-cell mass expansion. These experiments will evaluate the role of GSK3? and FoxO on mTORC1-S6K mediated feedback inhibition on IRS/Akt signaling. This proposal will provide important insights into the molecular mechanisms that govern ?-cell mass expansion by mTORC1. This information can be used to expand drug development opportunities for diabetes.
Failure of ?-cells to expand or adapt to insulin resistance results in type 2 diabetes. The current evidence support the concept that mTORC1 is active in states of increased insulin demand and plays a major role in ?- cell adaptation to insulin resistance The goal of this application is to unravel how mTORC1 regulates ?-cell mass in an effort to develop strategies to identify pharmacological targets to improve ?-cell mass and function for the treatment of diabetes.
| Navarro, Guadalupe; Allard, Camille; Morford, Jamie J et al. (2018) Androgen excess in pancreatic ? cells and neurons predisposes female mice to type 2 diabetes. JCI Insight 3: |
| Gregg, Brigid E; Botezatu, Nathalie; Brill, Joshua D et al. (2018) Gestational exposure to metformin programs improved glucose tolerance and insulin secretion in adult male mouse offspring. Sci Rep 8:5745 |
| Blandino-Rosano, Manuel; Barbaresso, Rebecca; Jimenez-Palomares, Margarita et al. (2017) Loss of mTORC1 signalling impairs ?-cell homeostasis and insulin processing. Nat Commun 8:16014 |
| Elghazi, Lynda; Blandino-Rosano, Manuel; Alejandro, Emilyn et al. (2017) Role of nutrients and mTOR signaling in the regulation of pancreatic progenitors development. Mol Metab 6:560-573 |
| Alejandro, Emilyn U; Bozadjieva, Nadejda; Blandino-Rosano, Manuel et al. (2017) Overexpression of Kinase-Dead mTOR Impairs Glucose Homeostasis by Regulating Insulin Secretion and Not ?-Cell Mass. Diabetes 66:2150-2162 |
| Bozadjieva, Nadejda; Blandino-Rosano, Manuel; Chase, Jennifer et al. (2017) Loss of mTORC1 signaling alters pancreatic ? cell mass and impairs glucagon secretion. J Clin Invest 127:4379-4393 |
| Cras-Méneur, Corentin; Conlon, Megan; Zhang, Yaqing et al. (2016) Early pancreatic islet fate and maturation is controlled through RBP-J?. Sci Rep 6:26874 |
| Cras-Méneur, Corentin; Elghazi, Lynda; Fort, Patrice et al. (2016) Noninvasive in vivo imaging of embryonic ?-cell development in the anterior chamber of the eye. Islets 8:35-47 |
| Blandino-Rosano, Manuel; Scheys, Joshua O; Jimenez-Palomares, Margarita et al. (2016) 4E-BP2/SH2B1/IRS2 Are Part of a Novel Feedback Loop That Controls ?-Cell Mass. Diabetes 65:2235-48 |
| Alejandro, Emilyn U; Bozadjieva, Nadejda; Kumusoglu, Doga et al. (2015) Disruption of O-linked N-Acetylglucosamine Signaling Induces ER Stress and ? Cell Failure. Cell Rep 13:2527-2538 |
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