Sex-specific aspects in the development of tissue metabolic damage in a non-obese prediabetic model

Recent studies suggest that the development of prediabetes and its associated comorbidities may depend on sex and reproductive status. While the exact mechanism is unclear, differences in insulin sensitivity, body fat distribution, and glucose and lipid metabolism may play a role. In this study, we investigated how sex differences in metabolic and inflammatory parameters affect the development of prediabetic conditions in a non-obese rat model with severe dyslipidaemia.

Wistar Kyoto (WKY) rats served as the control group, while age-matched Hereditary Hypertriglyceridaemic (HHTg) rats were used as a non-obese, prediabetic model with genetically determined hypertriglyceridaemia, insulin resistance and impaired glucose tolerance.

Compared to WKY controls, the HHTg strain exhibited increased serum triacylglyceroles (TAG) as well as ectopic TAG accumulation in the liver, heart and skeletal muscle which was more pronounced in HHTg females. However, this higher ectopic TAG accumulation in HHTg females was not associated with increased lipotoxic diacylglyceroles. The HHTg strain showed increased visceral adiposity, which was distributed differently: HHTg females had increased perimetrial adipose tissue, while HHTg males had increased perirenal adipose tissue. Impaired insulin sensitivity was observed in both sexes of the HHTg strain in skeletal muscle and adipose tissue. Insulin resistance in the HHTg strain may be due to elevated leptin and NEFA levels, as well as decreased GLUT4 in skeletal muscle. In addition, the HHTg strain showed impaired glucose tolerance, as well as hyperinsulinaemia, which was more pronounced in HHTg males. Increased lipogenesis (mRNA Scd1), oxidative stress (decreased SOD activity) and inflammation (mRNA Tnfα) in the liver may contribute to the development of hepatic steatosis and hepatic lipid accumulation. In visceral adipose tissue, increased mRNA Hif1 may contribute to adipose tissue hypoxia and impair insulin sensitivity, particularly in males.

Despite having more pronounced dyslipidaemia, ectopic lipid accumulation, and visceral adiposity, prediabetic females have better glucose tolerance and insulin sensitivity markers than prediabetic males. These sex differences may be due to variations in fat distribution, lipid metabolism and chronic inflammation. Our findings suggest that males are more susceptible to developing early prediabetic damage, such as insulin resistance and fatty liver, regardless of obesity.