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.
|Alejandro, Emilyn U; Gregg, Brigid; Blandino-Rosano, Manuel et al. (2015) Natural history of ?-cell adaptation and failure in type 2 diabetes. Mol Aspects Med 42:19-41|
|Bernal-Mizrachi, Ernesto; Kulkarni, Rohit N; Scott, Donald K et al. (2014) Human ?-cell proliferation and intracellular signaling part 2: still driving in the dark without a road map. Diabetes 63:819-31|
|Parlee, Sebastian D; Simon, Becky R; Scheller, Erica L et al. (2014) Administration of saccharin to neonatal mice influences body composition of adult males and reduces body weight of females. Endocrinology 155:1313-26|
|Gregg, Brigid; Elghazi, Lynda; Alejandro, Emilyn U et al. (2014) Exposure of mouse embryonic pancreas to metformin enhances the number of pancreatic progenitors. Diabetologia 57:2566-75|
|Gregg, Brigid; Lumeng, Carey N; Bernal-Mizrachi, Ernesto (2014) Fractalkine signaling in regulation of insulin secretion: Mechanisms and potential therapeutic implications? Islets 6:|
|Alejandro, Emilyn U; Gregg, Brigid; Wallen, Taylor et al. (2014) Maternal diet-induced microRNAs and mTOR underlie ? cell dysfunction in offspring. J Clin Invest 124:4395-410|
|Blandino-Rosano, Manuel; Chen, Angela Y; Scheys, Joshua O et al. (2012) mTORC1 signaling and regulation of pancreatic ýý-cell mass. Cell Cycle 11:1892-902|
|Blandino-Rosano, M; Alejandro, E U; Sathyamurthy, A et al. (2012) Enhanced beta cell proliferation in mice overexpressing a constitutively active form of Akt and one allele of p21Cip. Diabetologia 55:1380-9|
|Wicksteed, Barton; Brissova, Marcela; Yan, Wenbo et al. (2010) Conditional gene targeting in mouse pancreatic ýý-Cells: analysis of ectopic Cre transgene expression in the brain. Diabetes 59:3090-8|
|Bernal-Mizrachi, Ernesto; Cras-Meneur, Corentin; Ye, Bo Ra et al. (2010) Transgenic overexpression of active calcineurin in beta-cells results in decreased beta-cell mass and hyperglycemia. PLoS One 5:e11969|
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