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Diabetologia
Published in: Diabetologia 12/2014

01-12-2014 | Article

Exposure of mouse embryonic pancreas to metformin enhances the number of pancreatic progenitors

Authors: Brigid Gregg, Lynda Elghazi, Emilyn U. Alejandro, Michelle R. Smith, Manuel Blandino-Rosano, Deena El-Gabri, Corentin Cras-Méneur, Ernesto Bernal-Mizrachi

Published in: Diabetologia | Issue 12/2014

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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.
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Metadata
Title
Exposure of mouse embryonic pancreas to metformin enhances the number of pancreatic progenitors
Authors
Brigid Gregg
Lynda Elghazi
Emilyn U. Alejandro
Michelle R. Smith
Manuel Blandino-Rosano
Deena El-Gabri
Corentin Cras-Méneur
Ernesto Bernal-Mizrachi
Publication date
01-12-2014
Publisher
Springer Berlin Heidelberg
Published in
Diabetologia / Issue 12/2014
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-014-3379-5

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