Abstract
Aims/hypothesis Developing beta cells are vulnerable to nutrient environmental signals. Early developmental processes that alter the number of pancreatic progenitors can determine the number of beta cells present at birth. Metformin, the most widely used oral agent for treating diabetes, alters intracellular energy status in part by increasing AMP-activated protein kinase (AMPK) signalling. This study examined the effect of metformin on developing pancreas and beta cells. Methods Pancreatic rudiments from CD-1 mice at embryonic day 13.0 (E13.0) were cultured with metformin, 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR, an AMPK activator) or vehicle control in vitro. In another set of studies, pregnant C57BL/6 mice were treated with metformin throughout gestation. Embryonic (E14.0) and neonatal pancreases were then analysed for their morphometry. Results In vitro metformin treatment led to an increase in the proliferation and number of pancreatic duodenal homeobox 1-positive (PDX1+) progenitors. These results were reproduced by in vitro culture of embryonic pancreas rudiments with AICAR, suggesting that AMPK activation was involved. Similarly, metformin administration to pregnant dams induced an increase in both PDX1+ and neurogenin 3-positive progenitors in the embryonic pancreas at E14.0 and these changes resulted in an increased beta cell fraction in neonates. Conclusions/interpretation These results indicate that exposure to metformin during gestation modulates the early steps of beta cell development (prior to E14.0) towards an increase in the number of pancreatic and endocrine progenitors. These changes ultimately result in a higher beta cell fraction at birth. These findings are of clinical importance given that metformin is currently used for the treatment of gestational diabetes.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 2566-2575 |
| Number of pages | 10 |
| Journal | Diabetologia |
| Volume | 57 |
| Issue number | 12 |
| DOIs | |
| State | Published - Sep 24 2014 |
Bibliographical note
Funding Information:We would like to thank M. Javors (University of Texas Health Science Center, San Antonio, TX, USA) for measuring metformin levels and A. Chen (formerly of the University of Michigan, Ann Arbor, MI, USA) for sectioning the tissues used in this study. The processing and embedding of embryonic pancreas was performed in the Microscopy and Image-analysis Laboratory (MIL) at the University of Michigan, Department of Cell and Developmental Biology with the assistance of J. Poore. The MIL is a multi-user imaging facility supported by NIH-NCI 5P30CA046592-26, O’Brien Renal Center, UM Medical School, Endowment for the Basic Sciences (EBS), the CDB Department, and the University of Michigan. The neonatal tissue processing and embedding was performed at the University of Michigan Comprehensive Cancer Center Tissue Core supported by NIH-NCI 5P30CA046592-26. The authors acknowledge support from the Morphology and Image Analysis Core and Phenotyping Core from the Michigan Diabetes Research Center (MDRC) (P30 DK020572).
Funding Information:
This work was funded by National Institutes of Health Grant RO1-DK-084236 and 2R01DK073716 (to EB-M) and a supplement to this award RO1-DK-084236-03S1 supported the work of BG. BG was also supported by K12-HD028820. EUA was supported by an NIH training grant (2T32DK071212-06) and a post-doctoral fellowship from the Hartwell Foundation.
Publisher Copyright:
© Springer-Verlag Berlin Heidelberg 2014.
Keywords
- AICAR
- AMPK
- Developmental programming
- MTOR
- Metformin
- Pancreas development
