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

Abstract

Aims 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 diabetes, alters intracellular energy status in part by increasing AMP-activated protein kinase (AMPK) signaling. This study examined the effect of metformin on the developing pancreas and beta cells. Methods Pancreatic rudiments at embryonic day 13.0 (E13.0) were cultured with metformin or AICAR (an AMPK activator) or vehicle control in vitro. In another set of studies, pregnant mice were treated with metformin throughout gestation. Embryonic (E14.0) and neonatal pancreata were then analyzed for their morphometry. Results In vitro metformin treatment led to an increase in the proliferation and number of 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 NGN3+ 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 gestational metformin exposure modulates early steps of beta cell development (prior to E14.0) to increase the number of pancreatic and endocrine progenitors and 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.

The effects of metformin on fibroblast growth factor 19, 21 and fibroblast growth factor receptor 1 in high-fat diet and streptozotocin induced diabetic rats

“…Recent finding suggested that metformin could also interact with mammalian target of rapamycin complex 1 (mTORC1) signaling as well as pancreatic and duodenal homeobox 1 (PDX1) thus affecting pancreatic functions [21]. Besides, metformin has been shown to affect Farnesoid X Receptor (FXR) activities through AMPK-FXR crosstalk [22].…”

Metformin Reduces Lipotoxicity-Induced Meta-Inflammation in β-Cells through the Activation of GPR40-PLC-IP3 Pathway

“…Increasing evidence indicates that metformin directly acts on pancreatic β-cells [1]; nevertheless, the effect of metformin on β-cells remains controversial. Studies have shown that metformin inhibits β-cell apoptosis induced by hyperglycemia or hyperlipidemia [2,3] and enhances the number of pancreatic progenitor cells in the mouse embryonic pancreas [4], while other studies have indicated that metformin has a dual role in MIN6 pancreatic β-cell function through the AMPK-dependent autophagy pathway [5]. Therefore, the exact regulation mechanisms of metformin on β-cells need to be further investigated.…”

Metformin from mother to unborn child – Are there unwarranted effects?

“…The results imply that prenatal exposure of metformin can affect long-term metabolic reprogramming in offspring. These concerns were also echoed in in vitro studies by Gregg et al [ 29 ] and Vazquez-Martin et al [ 59 ]. When metformin is introduced to mESCs and developing mouse pancreata, both showed significant changes in expression levels of markers reflective of their functions and specific characteristics: pluripotency factors in mESCs [ 59 ] and pancreatic progenitor markers in prenatal pancreatic islets [ 29 ].…”

“…1 ). Gregg et al showed that in utero exposure to metformin leads to more cells expressing Pdx1 (a pancreatic progenitor marker), but less cells expressing Ngn3 (a later pancreatic endocrine progenitor marker) in mouse embryos [ 29 ]. As the endocrine progenitors are the precursors of mature pancreatic beta cells, the decrease in endocrine progenitor population will likely cause a decrease in the eventual proportion of mature beta cells.…”