Alterations in mitochondrial function mediate cardiovascular disease in male offspring of gestational diabetes mothers

Background: Gestational diabetes mellitus (GDM) is a common medical complication of pregnancy that is associated with adverse cardiovascular outcomes in adult offspring. Studies show that offspring of mothers with GDM may face increased cardiovascular disease risk due to unknown mechanisms. Hypothesis: GDM causes cardiac dysfunction in adult offspring. Aim: To determine the mechanisms underlying cardiac dysfunction in adult offspring of GDM mothers. Methods: Pregnant mice were divided into control and GDM groups (GDM was induced during pregnancy with 30nmol S961, an insulin receptor antagonist). Male offspring from both groups were followed up to 40 weeks after delivery. Blood glucose levels were measured with a glucometer. Cardiac structure and function were measured by high-resolution ultrasound echocardiography (VEVO 3100). Exercise tolerance test was performed on a treadmill (Columbus Instrument). Heart tissues were collected for mitochondrial isolation. Intact mitochondrial respiration was measured simultaneously with reactive oxygen species (mtROS; amplex red) or calcium influx (calcium green) using the Oroboros O2k-FluoRespirometer. Cardiac kinome activity was assessed by Pamgene kinome analysis. Data were analyzed by 2-way ANOVA, and results are expressed as mean ± standard error of the mean. Results: Male offspring of mothers with GDM exhibit hyperglycemia (163.4 ± 7.2 vs. 129.1 ± 6.7mg/dL, P < 0.001) and insulin intolerance. Echocardiography analysis revealed diastolic dysfunction, associated with increased left ventricular mass and wall thickness (1.01 ± 0.04 vs. 0.76 ± 0.03mg/dL, P < 0.004), with no changes in systolic function. Mitochondrial respiration analysis demonstrated decreased cardiac mitochondrial function, leading to increased ROS production in hearts from male offspring of mothers with GDM. In addition, males from mothers with GDM exhibit decreased cardiac mitochondrial calcium influx, respiratory control ratio, and complex IV activity, suggesting a decline in the efficiency of cardiac mitochondrial ATP production. Cardiac kinome analysis of protein tyrosine kinases (PTKs) revealed elevated activity of fibroblast growth factor receptors (FGFR2, FGFR3, FGFR4) and Bruton's tyrosine kinase (BTK), all of which are involved in cardiac fibrosis and hypertrophy. Conclusion: These results suggest that adult male offspring from GDM mothers exhibit cardiac dysfunction. However, upregulation of cardiac FGFR and BTK signaling is involved in GDM-induced left ventricular hypertrophy and cardiac mitochondrial dysfunction, which might be the mechanism underlying cardiac dysfunction in adult male offspring of mothers with GDM. Funding: This work was supported by grants from the NIGMS (P20GM104357-02 and 5P30GM149404) and NIH COBRE Pilot Grant. 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.