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

Background: 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. Methods: 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. Results: may contribute to adipose tissue hypoxia and impair insulin sensitivity, particularly in males. Conclusions: 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.