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 to understand the molecular mechanisms that regulate ?-cell mass and function. During the current funding period, we identified mTOR/raptor complex (mTORC1) as a major player in regulating ?-cell mass and insulin secretion. We uncovered the individual contribution of the mTORC1 downstream targets 4E-BP, S6 kinases (S6K) and ULK on the regulation of ?-cell growth, proliferation, survival, insulin processing and secretion. We also discovered a novel mTORC1/4E-BP2/eIF4E/SH2B1 positive feedback loop that increases IRS2 signaling. However, uncertainty remains as to how mTORC1 acting on 4E-BP2, S6K and ULK controls ?-cell mass and insulin secretion. The objective of this application is to build on these observations and determine how mTORC1 regulates ?-cell mass and insulin secretion. We hypothesize that mTORC1 regulates (i) ?-cell mass in a 4E-BP2/SH2B1 and JNK3-dependent manner and (ii) insulin secretion by regulating stages proximal to calcium influx and autophagy mediated process.
The specific aims are (1) Establish how 4E-BP2/eIF4E acting on SH2B1 and JNK3 regulates ?-cell mass expansion. (2) Determine how mTORC1 modulates insulin secretion and adaptation to diabetogenic conditions. This proposal will provide important insights into the molecular mechanisms that govern ?-cell mass and insulin secretion 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 and insulin secretion 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|
|Jiménez-Palomares, Margarita; López-Acosta, José Francisco; Villa-Pérez, Pablo et al. (2015) Cyclin C stimulates ?-cell proliferation in rat and human pancreatic ?-cells. Am J Physiol Endocrinol Metab 308:E450-9|
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