Abstract
Objective Poor 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. Method Pancreatic 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. Results We 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. Conclusion Together, 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 560-573 |
| Number of pages | 14 |
| Journal | Molecular Metabolism |
| Volume | 6 |
| Issue number | 6 |
| DOIs | |
| State | Published - Jun 2017 |
Bibliographical note
Funding Information:This work was supported by National Institutes of Health Grant RO1-DK-073716 (to E.B.-M.), DK084236 (EB-M) and Juvenile Diabetes Research Foundation 17-2013-416 (EB-M). The authors acknowledge support from the Microscopy and Image-analysis core (MIL) at the University of Michigan, Department of Cell & Developmental Biology. The Morphology Core from Washington University Digestive Diseases Research Core Center for histology sections (DDRCC). We would like to thank Lauren See for her the technical assistance with histology sections.
Funding Information:
This work was supported by National Institutes of Health Grant RO1-DK-073716 (to E.B.-M.), DK084236 (EB-M) and Juvenile Diabetes Research Foundation 17-2013-416 (EB-M). The authors acknowledge support from the Microscopy and Image-analysis core (MIL) at the University of Michigan , Department of Cell & Developmental Biology . The Morphology Core from Washington University Digestive Diseases Research Core Center for histology sections (DDRCC). We would like to thank Lauren See for her the technical assistance with histology sections.
Publisher Copyright:
© 2017
Keywords
- Development
- Islets
- Nutrients
- Pancreas
- Rapamycin
- mTOR
- β-cells
