Kruit JK^1#, Hribar K^1#, Giralt A², van Oosten A³, Mulder NL¹, Koster MH¹, Smit M¹, Bongiovanni L^4,5, Sanders M², de Bruin A^1,4, Kraus MRC², van der Beek EM^1,2

¹University Medical Center Groningen, Netherlands. ²Nestlé Institute of Health Sciences, Societé Produits Nestlé, Switzerland ⁴Utrecht University, Netherlands. ⁵University of Teramo, Italy. #These authors contributed equally

Abstract

Background and aims: Gestational diabetes mellitus (GDM) is associated with an increased risk of type 2 diabetes and metabolic dysfunction-associated steatotic liver disease (MASLD) in mothers postpartum. There has been growing interest in the potential health benefits of non-psychoactive cannabinoids, particularly their therapeutic potential for metabolic diseases. This study aimed to determine whether cannabidiolic acid (CBDA) could ameliorate the development of postpartum MASLD in a GDM mouse model.

Methods: GDM was induced in female C57BL/6N mice by high-fat diet and low-dose streptozotocin injections. Control dams received either high-fat (HF) or low-fat (LF) diets. The effect of a 6-week CBDA or vehicle treatment post-weaning on glucose homeostasis and MASLD development was assessed.

Results: The transient hyperglycaemic phenotype observed in GDM dams during pregnancy was followed by hyperglycaemia after lactation. CBDA treatment in GDM dams improved glucose tolerance (glucose AUC; GDM Vehicle 2776.4 ± 356.2 vs GDM CBDA 2337.0 ± 315.01, p<0.001) and insulin sensitivity (HOMA-IR; GDM Vehicle 9.71 ± 2.7 vs GDM CBDA 7.3 ± 1.7, p<0.05) without affecting body weight. Hepatic triglyceride levels were increased in vehicle treated GDM dams compared to HF and LF controls, but CBDA supplementation eliminated this difference (GDM Vehicle 108.0 ± 12.3 vs GDM CBDA 65.9 ± 17.8 μmol triglyceride/g liver, p<0.001). CBDA supplementation decreased metabolic dysfunction-associated steatosis activity scores in the livers of GDM dams (GDM vehicle 4 ± 0.6 vs GDM CBDA 2.9 ± 0.3, p<0.05). Liver gene expression analyses in GDM dams revealed stimulation of pathways linked to lipid oxidation by CBDA.

Conclusion: This study demonstrates that CBDA supplementation after lactation can improve glucose tolerance and liver steatosis associated with GDM postpartum in mice. Postpartum supplementation of CBDA, therefore, might be beneficial to mitigate T2D and MASLD risk in women with previous GDM.