A novel model of gestational diabetes: Acute high fat high sugar diet results in insulin resistance and beta cell dysfunction during pregnancy in mice

Abstract

Gestational diabetes mellitus (GDM) affects 7-18% of all pregnancies. Despite its high prevalence, there is no widely accepted animal model. To address this, we recently developed a mouse model of GDM. The goal of this work was to further characterize this animal model by assessing insulin resistance and beta cell function. Mice were randomly assigned to either control (CD) or high fat, high sugar (HFHS) diet and mated 1 week later. At day 0 (day of mating) mice were fasted and intraperitoneal insulin tolerance tests (ipITT) were performed. Mice were then euthanized and pancreata were collected for histological analysis. Euglycemic hyperinsulinemic clamp experiments were performed on day 13.5 of pregnancy to assess insulin resistance. Beta cell function was assessed by glucose stimulated insulin secretion (GSIS) assay performed on day 0, 13.5 and 17.5 of pregnancy. At day 0, insulin tolerance and beta cell numbers were not different. At day 13.5, glucose infusion and disposal rates were significantly decreased (p<0.05) in Pregnant (P) HFHS animals (p<0.05) suggesting development of insulin resistance in P HFHS dams. Placental and fetal glucose uptake was significantly increased (p<0.01) in P HFHS dams at day 13.5 of pregnancy and by day 17.5 of pregnancy fetal weights were increased (p<0.05) in P HFHS dams compared to P CD dams. Basal and secreted insulin levels were increased in HFHS fed females at day 0, however at day 13.5 and 17.5 GSIS was decreased (p<0.05) in P HFHS dams. In conclusion, this animal model results in insulin resistance and beta cell dysfunction by mid-pregnancy further validating its relevance in studying the pathophysiology GDM.