Introduction: Gestational diabetes mellitus (GDM) is a global health issue that imposes serious health problems for both mother and baby. Infection and/or inflammation are key regulators of insulin resistance associated with GDM. Phytophenols such as nobiletin and resveratrol decrease inflammation and improve insulin sensitivity in animal models of diabetes. Using bacterial and viral products (LPS and poly(I:C), respectively) and the pro-inflammatory cytokine TNF-α as models of GDM, we examined the effects of nobiletin and resveratrol on: inflammation in placenta and adipose tissue, and insulin resistance in skeletal muscle tissue from pregnant women. We also studied the in vivo effects of nobiletin and resveratrol on the pregnant db/+ GDM mouse model.
Methods: Pro-inflammatory cytokine mRNA expression and were determined by qRT-PCR and ELISA, respectively. Insulin signalling components was determined by Western blotting and glucose uptake assays. Resveratrol and nobiletin were administered daily to pregnant mice (day 1-17 of pregnancy), a glucose tolerance test was performed on d17 and tissues were collected at d18.
Results: In vitro, nobiletin and resveratrol significantly reduced LPS, poly(I:C) and TNF-α-stimulated IL-6, IL-8, IL-1α/β and MCP-1 mRNA expression and release from human placenta and adipose tissue. In human skeletal muscle tissue, nobiletin and resveratrol restored insulin-mediated glucose uptake impaired by LPS, poly(I:C) and TNF-α. Our in vivo studies found nobiletin and resveratrol significantly improved glucose tolerance in GDM mice. Nobiletin also significantly decreased maternal adiposity in GDM mice.
Conclusion: Nobiletin and resveratrol can reduce inflammation in placenta and adipose tissue and improve skeletal muscle glucose uptake in an in vitro model of GDM. These exciting findings suggest that phytophenols can disrupt key pathways involved in the pathogenesis of GDM. Longer term studies on offspring growth and development are currently underway; however, our findings indicate that phytophenols may have potential benefits in the prevention of GDM.