title: Exposure of mouse embryonic pancreas to metformin enhances the number of pancreatic progenitors.
abstract: OBJECTIVE
  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
  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.
authors.affiliation: Department of Pediatrics, Division of Endocrinology, Diabetes and Metabolism, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Brigid
authors.initials: B
authors.lastname: Gregg
authors.forename: Lynda
authors.initials: L
authors.lastname: Elghazi
authors.forename: Emilyn U
authors.initials: EU
authors.lastname: Alejandro
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Smith
authors.forename: Manuel
authors.initials: M
authors.lastname: Blandino-Rosano
authors.forename: Deena
authors.initials: D
authors.lastname: El-Gabri
authors.forename: Corentin
authors.initials: C
authors.lastname: Cras-Méneur
authors.forename: Ernesto
authors.initials: E
authors.lastname: Bernal-Mizrachi
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D005260:Female; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D050417:Insulin-Secreting Cells / Q000187:drug effects*; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D010179:Pancreas / Q000187:drug effects* / Q000196:embryology; D011247:Pregnancy
chemical_list: D007004:Hypoglycemic Agents; D008687:Metformin