Murine Model Of Gestational Diabetes Mellitus Reveals Markers Of Hepatic Mitochondrial Dysfunction

INTRODUCTION: Gestational Diabetes Mellitus (GDM) affects roughly 1 in 10 pregnancies in the United States and results in metabolic dysfunction associated steatotic liver disease (MASLD) in 30% of these women. However, mechanistic insight into the links between GDM and MASLD are lacking. PURPOSE: Here, we sought to investigate the potential role of hepatic mitochondrial function in GDM and MASLD. METHODS: Mice were fed either a high-fat, high-sucrose diet to induce a model of GDM or control diet (CD) 1-week prior to conception and throughout pregnancy. Livers were collected at day 0, 6.5, 13.5 and 17.5 of pregnancy (N = 2-10/group). Hepatic markers of mitochondrial biogenesis, autophagy, mitophagy, content, and function were assessed. Analyses were completed using two-way ANOVAs. Results are reported as mean ± standard error. RESULTS: GDM mice exhibited significant reductions in hepatic citrate synthase (mitochondrial content) and β-HAD activity (mitochondrial function) compared to CD mice (CD: 74.67 ± 1.63, GDM: 64.9 ± 2.08, p < 0.05) (CD: 2.2 ± 1.5, GDM: 0.03 ± 0.8, p < 0.01) at day 17.5 vs 0. While hepatic markers of mitochondrial biogenesis, autophagy, and mitophagy markers decreased throughout gestation irrespective of diet (p < 0.05), GDM mice had significant upregulation in the mitochondrial biogenesis marker tfam (CD: 0.44 ± 0.02, GDM: 0.60 ± 0.05, p < 0.05) and autophagy marker sqstm1 (CD: 0.46 ± 0.04, GDM: 0.73 ± 0.08, p < 0.05) at day 17.5. Further, liver triglycerides were increased in GDM mice (CD: 14.2 ± 0.8, GDM: 47.5 ± 2.2 mg/mL, p < 0.0001) at day 17.5. CONCLUSION: Interestingly, pregnancy alone, regardless of diet, alters liver mitochondrial health. GDM-induced model specifically alters mitochondrial content, function, biogenesis, and autophagy. Paired with increases in liver triglycerides, this finding shows that GDM significantly impacts liver mitochondrial health and sheds light on the potential mechanisms between MASLD and GDM.