Cardiac remodelling, recognition memory deficits and accelerated ageing in a rat model of gestational diabetes

Aims/hypothesis: Women with prior gestational diabetes mellitus (GDM) have higher incidence of age-associated diseases, including type 2 diabetes, CVD and cognitive impairment. Human studies cannot readily determine whether GDM causes these conditions or the underlying mechanisms. Here we used a well-validated rat model of GDM to address these questions. Methods: Rats with beta cell-specific expression of human amylin, a pancreatic hormone, were used as a GDM model. Five-month-old female rats were randomly assigned to no-pregnancy, one-pregnancy and two-pregnancies experimental groups. GTTs and transthoracic echocardiography were performed at baseline and during the postpartum period. At 18 months of age, the novel object recognition test was administered, followed by euthanasia and organ collection. Results: All female rats developed glucose intolerance and showed cardiac remodelling and impaired left ventricular relaxation with ageing. Glucose intolerance was exacerbated in rats with prior GDM pregnancies compared with nulliparous rats, with significant differences starting at 9 months of age. However, blood glucose levels were comparable in the three groups during the course of the study. Rats with two GDM-complicated pregnancies had increased left ventricular mass compared with the other groups following the second pregnancy and until the end of the study. At 18 months of age, rats with prior GDM pregnancies presented aggravated demyelination, particularly in the hippocampus and mid-brain region, oxidative stress and neuroinflammation, and had a lower recognition index in the novel object recognition test compared with nulliparous rats. Higher parity exacerbated these effects. Shorter telomeres and reduced mitochondrial DNA content, two hallmarks of biological ageing, were found in the brain, heart and pancreas of rats with prior GDM. Conclusions/interpretation: These findings support the concept that GDM is a sex-specific risk factor for ageing-related diseases, and point to accelerated cellular ageing as a contributing mechanism. Data availability: Cardiac echocardiography and GTT data are available at Dataverse under the identifier https://doi.org/10.7910/DVN/R2HITG