Multiparity: a novel model to understanding gestational diabetes mellitus

Gestational diabetes mellitus (GDM) develops when maternal beta-cells fail to meet the increased metabolic demands of pregnancy. In both humans and rodents, multiparity is associated with increased risk of GDM potentially due to beta-cell dysfunction PMID: 36910494, 37903900. Prior research shows that multiparity can increase adiposity and inflammation in several tissues PMID: 22127227. We have observed that multiparous C57BL/6J dams develop glucose intolerance only during gestation and exhibit increased beta-cell mass compared to age-matched primiparous dams (Old P1 n=5; Old P4 n=5). Therefore, to determine whether glucose intolerance in multiparous mice originates from impaired pancreatic function, we measured beta-cell proliferation, quantified alpha-cell and beta-cell mass, and assessed the frequency of bihormonal cells in the pancreas. We hypothesized that an increase in bihormonal cells, alpha-cell mass, and proliferation contribute to an increase in the observed beta-cell mass. Old P1 (n=3) and multiparous Old P4 (n=3) C57BL/6J dam pancreases were harvested and evaluated at gestational day (GD) 17.5. We performed immunofluorescence staining to quantify beta-cell proliferation with Ki-67, identify bihormonal insulin- and glucagon-positive cells, and functional alpha-cell mass, in paraffin wax embedded pancreatic tissues. Proliferation of beta-cells, measured by presence of Ki-67 (P=0.5441) was comparable between Old P1 and Old P4. Additionally, no changes were observed in the frequency of bihormonal cells (P=0.5628) nor functional alpha-cell mass (P=0.8066). Altogether, this data suggests that glucose intolerance may arise from physiological changes outside the pancreas. These findings suggest that factors outside of beta-cell dysfunction could be contributing to impaired glucose tolerance in multiparous mice. In conclusion, multiparity-induced glucose intolerance likely reflects physiological strain across multiple organ systems rather than inadequate beta-cell function alone. Since pregnancy requires coordinated metabolic, hormonal, immune, and cardiovascular adaptation, disruptions in any of these networks may contribute to GDM development. Ongoing studies will evaluate tissue-specific insulin sensitivity in skeletal muscle, liver, and adipose tissue to further define the source of insulin resistance in this model. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.