Abstract
Background: Epidemiologic studies have linked abnormal maternal nutrition to increased offspring susceptibility to type 2 diabetes (T2D). The developing pancreas is extremely sensitive to metabolic stressors, and exposure to energy or nutrient imbalances during gestation impacts its development leading to long‐term changes in β‐cell mass and function (β‐cell programming). How nutrients affect developing β‐cells to induce long‐lasting consequences is unclear, but signaling pathways that convey information about energy and nutrient status are prime candidates. The AMP‐activated protein kinase (AMPK) is a nutrient sensor that it is indirectly activated by metformin, the most widely used oral agent for T2D.
Objective: To establish how metformin administration during pregnancy impacts β‐cell mass and susceptibility to diabetes later in life in a rodent model.
Methods: Metformin was delivered in drinking water to c57bl/6 mice from embryonic day 0.5 (E0.5) and continued throughout gestation (Met group). Animals were examined during embryonic stages, at birth and as adults.
Results: Pancreatic buds were examined at E14 by staining for markers of pancreatic and endocrine progenitor populations, Pancreatic and duodenal homeobox 1 (Pdx‐1) and neurogenin 3 (Ngn3) respectively. Met embryos had an increase in Ngn3 and Pdx‐1 number. The Met offspring did not differ from controls in terms of birth weight or length but had a lower random glucose. Met neonates were found to have increased β‐cell mass at birth when compared to controls. On examining offspring for adult metabolic phenotype, the Met animals displayed improved glucose tolerance and insulin secretion compared to controls.
Conclusions: In utero exposure to metformin may have a positive impact on regulation of endocrine cell development. Metformin is currently in clinical trials for use in gestational diabetes. Thus, careful characterization of the effect of in utero exposure to metformin on offspring metabolic phenotype is essential.
Grant Funding Source: Supported by DK‐084236‐03‐S1