Impaired maternal β-cell adaptation to pregnancy: effects on glucose homeostasis in mother and offspring

Gestational Diabetes Mellitus (GDM) is associated with deleterious outcomes for both mother and baby, and the incidence of this metabolic disorder is on the increase.

The complex phenotype of GDM - including obesity, insulin resistance, dyslipidemia and hyperglycemia – make it difficult to identify causal events for the deleterious outcomes so we have developed a novel mouse model (β-GPR54-/- mouse) in which β-cell adaptations to pregnancy are defective, leading to impaired insulin secretion and glucose intolerance during pregnancy.

We plan to use these mice to specifically assess the effects of maternal hyperglycaemia during pregnancy on subsequent glucose homeostasis in both mothers and offspring.

We will determine whether glucose intolerance during pregnancy predisposes the mother to hyperglycemia in later life, particularly when exposed to the metabolic stress of a high fat diet.

We will assess the effects of maternal hyperglycemia during pregnancy on the subsequent glucose homeostasis of the offspring, using glucose tolerance tests, insulin tolerance tests and measurements of plasma hormone levels.

We will focus on β-cell development and function in the offspring as a likely target for the deleterious glycemic control we have seen in preliminary studies, and on epigenetic modification of β-cell DNA as the underlying mechanism.