Asian females without diabetes are protected from obesity-related dysregulation of glucose metabolism compared with males.

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.

Dynamic assessment of insulin secretion and insulin resistance in Asians with prediabetes.

AIMS/HYPOTHESIS: Prediabetes and type 2 diabetes are highly prevalent in Asia. Understanding the pathophysiology of abnormal glucose homeostasis in Asians will have important implications for reducing disease burden, but there have been conflicting reports on the relative contributions of insulin secretion and action in disease progression. In this study, we aimed to assess the contribution of ß-cell dysfunction and insulin resistance in the Asian prediabetes phenotype. METHODS: We recruited 1679 Asians with prediabetes (n = 659) or normoglycemia (n = 1020) from a multi-ethnic population in Singapore. Participants underwent an oral glucose tolerance test, an intravenous glucose challenge, and a hyperinsulinemic-euglycemic clamp procedure to determine glucose tolerance, ß-cell responsivity, insulin secretion, insulin clearance and insulin sensitivity. RESULTS: Participants with prediabetes had significantly higher glucose concentrations in the fasting state and after glucose ingestion than did normoglycemic participants. Insulin sensitivity (M/I ratio) was ~15% lower, acute insulin response (AIR) to intravenous glucose and ß-cell responsivity to oral glucose were ~35% lower, but total insulin secretion rate in the fasting state and after glucose ingestion was ~10% greater in prediabetic than in normoglycemic participants. The decrease in ß-cell function with worsening glucose homeostasis in Asians with prediabetes was associated with progressively greater defects in AIR rather than M/I. However, analysis using static surrogate measures (HOMA indices) of insulin resistance and ß-cell function revealed a different pattern. CONCLUSIONS: Lower AIR to intravenous glucose and ß-cell responsivity to oral glucose, on a background of mild insulin resistance, are the major contributors to the dysregulation of glucose homeostasis in Asians with prediabetes.