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

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

Research output: Contribution to journalArticle

10 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)2566-2575
Number of pages10
JournalDiabetologia
Volume57
Issue number12
DOIs
StatePublished - Sep 24 2014
Externally publishedYes

Fingerprint

Metformin
Pancreas
AMP-Activated Protein Kinases
Parturition
Pregnancy
Gestational Diabetes
Homeobox Genes
Inbred C57BL Mouse
Cell Count
Food

Keywords

  • AICAR
  • AMPK
  • Developmental programming
  • Metformin
  • MTOR
  • Pancreas development

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Exposure of mouse embryonic pancreas to metformin enhances the number of pancreatic progenitors. / Gregg, Brigid; Elghazi, Lynda; Alejandro, Emilyn U.; Smith, Michelle R.; Blandino Rosano, Manuel; El-Gabri, Deena; Cras-Méneur, Corentin; Bernal Mizrachi, Ernesto.

In: Diabetologia, Vol. 57, No. 12, 24.09.2014, p. 2566-2575.

Research output: Contribution to journalArticle

Gregg, Brigid ; Elghazi, Lynda ; Alejandro, Emilyn U. ; Smith, Michelle R. ; Blandino Rosano, Manuel ; El-Gabri, Deena ; Cras-Méneur, Corentin ; Bernal Mizrachi, Ernesto. / Exposure of mouse embryonic pancreas to metformin enhances the number of pancreatic progenitors. In: Diabetologia. 2014 ; Vol. 57, No. 12. pp. 2566-2575.
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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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AU - Alejandro, Emilyn U.

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AU - Blandino Rosano, Manuel

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AU - Cras-Méneur, Corentin

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