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 β-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 multiethnic population in Singapore. Participants underwent an oral glucose tolerance test, an intravenous glucose challenge, and a hyperinsulinemic-euglycemic clamp procedure to determine glucose tolerance, β-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 β-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 β-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 β-cell function revealed a different pattern. Conclusions: Lower AIR to intravenous glucose and β-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.
