1176-P: Maternal Hyperglycemia Leads to Distinct Differences in Metabolism and Pancreatic Beta-Cell Function in Male and Female Offspring

Abstract

Maternal hyperglycemia is a major risk factor for future T2D risk in the offspring. To better understand T2D pathogenesis in this context, we used a mouse model of hyperglycemia induced by high-fat, high-sugar (HFHS) feeding from before mating through to weaning. This resulted in increased adiposity, reduced insulin sensitivity, hyperinsulinemia and impaired glucose tolerance pre-pregnancy. Pregnancy further worsened the metabolic health of dams resulting in reduced insulin levels in addition to glucose intolerance at gestational day 16. By weaning, HFHS-fed dams had fasting hyperglycemia. Maternal hyperglycemia had no impact on offspring body weight and composition at postnatal day 2. However, male offspring of HFHS-fed dams experienced decelerated postnatal growth in the first 2 weeks of life followed by catch-up growth by weaning. Despite comparable body weight, relative fat mass was increased and relative lean mass decreased from 3 to 8 weeks of age in exposed offspring. In males, this was not linked to changes in food intake and metabolic activity measured at 7 weeks. In contrast, daily energy expenditure was increased in female offspring of hyperglycemic dams. At 8 weeks old, despite normal glucose tolerance and insulin sensitivity, male offspring of HFHS-fed dams were hyperinsulinemic during a glucose tolerance test. In contrast, female offspring had reduced insulin sensitivity and higher plasma insulin concentration at baseline and 45 min. Interestingly, insulin secretion was increased only in islets from male offspring characterised by a marked increase in 1st phase and a trend towards higher 2nd phase secretion. Insulin secretion in response to potassium chloride was also increased in these islets. Thus, our data suggest that there are sex-specific mechanisms contributing to future T2D risk in offspring exposed to maternal hyperglycemia with primary hyperinsulinemia being an early feature in males and insulin resistance in females. Disclosure S.E.O'hara: None. K.M.Gembus: None. G.S.Clarke: None. A.J.Page: None. L.M.Nicholas: None. Funding National Health and Medical Research Council of Australia (GNT1092158)