Extensive epidemiological evidence in humans and animal models suggests that poor maternal nutrition increases the susceptibility of the offspring to develop type-2 diabetes. Alterations in ?-cell development, leading to long-term defects in ?-cell mass and function is a major component of this phenotype. These observations identified the phenomena of fetal ?-cell programming. Although the importance of nutrition during ?-cell development as a risk for diabetes has been demonstrated, it is not entirely clear how nutrient signals regulate the differentiation program of the pancreas. The objective of this proposal is to determine the role of mTOR signaling on ?-cell development and programming by nutrient signals. The central hypothesis to be tested is that nutrient signals acting on mTOR modulate ?-cell development and susceptibility to diabetes by regulating pancreatic progenitor proliferation and survival. This will be tested by the following approach:
Specific Aims 1 and 2 directly address how different nutrient signals acting through mTOR regulate proliferation and survival of pancreatic progenitors and ?-cell development.
Aim 3 will identify the critical developmental window during which modulation of mTOR signaling regulates ?-cell programming and susceptibility to diabetes using inducible models with gain and loss of mTOR function. Long-term metabolic effects of transient inhibition of mTOR signaling during different stages of development will establish the critical window. Rescue of hyperglycemia in growth-retarded fetuses by transient activation of mTOR signaling during critical developmental period will also be performed. These studies will enhance our understanding of the molecular mechanisms that govern pancreas development and the long-term metabolic consequences of ?- cell programming by nutrient signals. This information can be used to design novel therapeutic approaches to improve ?-cell mass and function in diabetics and to modulate the differentiation program of pancreatic progenitors for therapeutic purposes. Finally, understanding the pathophysiology of glucose intolerance associated in individuals with intrauterine growth retardation is important for both prevention and therapy.

Public Health Relevance

The mechanisms by which adverse intrauterine environment increases the susceptibility to develop glucose intolerance and type 2 diabetes are not well understood but a primary developmental insult to the ?-cell has been described. The goal of this application is to elucidate the mechanisms responsible for regulating pancreas development and ?-cell programming by nutrient signals in an effort to develop strategies to prevent diabetes in growth retarded fetuses and to identify pharmacological targets to improve ?-cell mass and function.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Sato, Sheryl M
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University of Michigan Ann Arbor
Internal Medicine/Medicine
Schools of Medicine
Ann Arbor
United States
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Cras-Méneur, Corentin; Elghazi, Lynda; Fort, Patrice et al. (2016) Noninvasive in vivo imaging of embryonic β-cell development in the anterior chamber of the eye. Islets 8:35-47
Cras-Méneur, Corentin; Conlon, Megan; Zhang, Yaqing et al. (2016) Early pancreatic islet fate and maturation is controlled through RBP-Jκ. Sci Rep 6:26874
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 β-Cell Mass. Diabetes 65:2235-48
Um, Sung Hee; Sticker-Jantscheff, Melanie; Chau, Gia Cac et al. (2015) S6K1 controls pancreatic β cell size independently of intrauterine growth restriction. J Clin Invest 125:2736-47
Stewart, Andrew F; Hussain, Mehboob A; García-Ocaña, Adolfo et al. (2015) Human β-cell proliferation and intracellular signaling: part 3. Diabetes 64:1872-85
Sadagurski, Marianna; Landeryou, Taylor; Cady, Gillian et al. (2015) Transient early food restriction leads to hypothalamic changes in the long-lived crowded litter female mice. Physiol Rep 3:
Jiménez-Palomares, Margarita; López-Acosta, José Francisco; Villa-Pérez, Pablo et al. (2015) Cyclin C stimulates β-cell proliferation in rat and human pancreatic β-cells. Am J Physiol Endocrinol Metab 308:E450-9
Alejandro, Emilyn U; Gregg, Brigid; Blandino-Rosano, Manuel et al. (2015) Natural history of β-cell adaptation and failure in type 2 diabetes. Mol Aspects Med 42:19-41
Arvan, Peter; Bernal-Mizrachi, Ernesto; Liu, Ming et al. (2015) Molecular aspects of pancreatic beta cell failure and diabetes. Mol Aspects Med 42:1-2
Alejandro, Emilyn U; Bozadjieva, Nadejda; Kumusoglu, Doga et al. (2015) Disruption of O-linked N-Acetylglucosamine Signaling Induces ER Stress and β Cell Failure. Cell Rep 13:2527-38

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