کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
5618750 1406036 2017 14 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Original ArticleRole of nutrients and mTOR signaling in the regulation of pancreatic progenitors development
موضوعات مرتبط
علوم زیستی و بیوفناوری علم عصب شناسی سیستم های درون ریز و اتونومیک
پیش نمایش صفحه اول مقاله
Original ArticleRole of nutrients and mTOR signaling in the regulation of pancreatic progenitors development
چکیده انگلیسی


- Leucine concentrations modulate proliferation of pancreatic progenitors.
- mTOR signaling plays a critical role in regulating pancreatic and endocrine growth.
- Inactivation of mTOR in pancreatic progenitors leads to pancreatic agenesis.
- Inactivation of Raptor in pancreatic progenitors leads to pancreatic hypoplasia.

ObjectivePoor fetal nutrition increases the risk of type 2 diabetes in the offspring at least in part by reduced embryonic β-cell growth and impaired function. However, it is not entirely clear how fetal nutrients and growth factors impact β-cells during development to alter glucose homeostasis and metabolism later in life. The current experiments aimed to test the impact of fetal nutrients and growth factors on endocrine development and how these signals acting on mTOR signaling regulate β-cell mass and glucose homeostasis.MethodPancreatic rudiments in culture were used to study the role of glucose, growth factors, and amino acids on β-cell development. The number and proliferation of pancreatic and endocrine progenitor were assessed in the presence or absence of rapamycin. The impact of mTOR signaling in vivo on pancreas development and glucose homeostasis was assessed in models deficient for mTOR or Raptor in Pdx1 expressing pancreatic progenitors.ResultsWe found that amino acid concentrations, and leucine in particular, enhance the number of pancreatic and endocrine progenitors and are essential for growth factor induced proliferation. Rapamycin, an mTORC1 complex inhibitor, reduced the number and proliferation of pancreatic and endocrine progenitors. Mice lacking mTOR in pancreatic progenitors exhibited hyperglycemia in neonates, hypoinsulinemia and pancreatic agenesis/hypoplasia with pancreas rudiments containing ductal structures lacking differentiated acinar and endocrine cells. In addition, loss of mTORC1 by deletion of raptor in pancreatic progenitors reduced pancreas size with reduced number of β-cells.ConclusionTogether, these results suggest that amino acids concentrations and in particular leucine modulates growth responses of pancreatic and endocrine progenitors and that mTOR signaling is critical for these responses. Inactivation of mTOR and raptor in pancreatic progenitors suggested that alterations in some of the components of this pathway during development could be a cause of pancreatic agenesis/hypoplasia and hyperglycemia.

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ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Molecular Metabolism - Volume 6, Issue 6, June 2017, Pages 560-573
نویسندگان
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