Objective: The impact of obesity on the risk for type 2 diabetes differs between males and females; however, the underlying reasons are unclear. This study aimed to investigate the effect of sex on obesity-driven changes in the mechanisms regulating glucose metabolism (insulin sensitivity and secretion) among Asian individuals without diabetes in Singapore.

Methods: The study assessed glucose tolerance using oral glucose tolerance test, insulin-mediated glucose uptake using hyperinsulinemic-euglycemic clamp, acute insulin response using an intravenous glucose challenge, and insulin secretion rates in the fasting state and in response to glucose ingestion using mathematical modeling in 727 males and 952 females who had normal body weight (n = 602, BMI < 23 kg/m²), overweight (n = 662, 23 ≤ BMI < 27.5), or obesity (n = 415, BMI ≥ 27.5).

Results: There were no sex differences among lean individuals. Obesity gradually worsened metabolic function, and the progressive adverse effects of obesity on insulin action and secretion were more pronounced in males than females, such that among participants with obesity, females had greater insulin sensitivity, lower insulin secretion, and lower fasting insulin concentration than males. The increase in waist to hip ratio with increasing BMI was more pronounced in males than females.

Conclusions: The female sex exerts a protective effect on obesity-driven dysregulation of glucose metabolism in Asian individuals without diabetes.