Alpha cell dysfunction in type 2 diabetes: associations with insulin resistance and reduced insulin secretion

Abstract

Abstract Introduction This study examined how insulin resistance and impaired insulin secretion are associated with hyperglucagonemia during oral glucose tolerance tests (OGTT) in type 2 diabetes mellitus (T2DM). Research design and methods A retrospective analysis included 247 patients with T2DM treated at Tianjin Medical University General Hospital from October 2022 to March 2025. All underwent a 75 g OGTT, with blood samples collected at 0, 0.5, 1, 2, and 3 hours for glucose, insulin, C-peptide, and glucagon measurement. Insulin resistance was assessed via homeostasis model assessment of insulin resistance (HomaIR) and C-peptide immunoreactivity insulin resistance (CPRIR), while insulin secretion was evaluated using C-peptide area under the curve (AUCcp), homeostasis model assessment of beta cell function (HomaB), first-phase and second-phase insulin secretion during OGTT (first PH and second PH). Generalized linear models and mediation analyses examined associations between glucagon levels and above indices. Model fitness and robustness were evaluated via residual diagnostics, Cook’s distance, and bootstrapped CIs. Results Glucagon levels during the OGTT were significantly elevated in patients with severe insulin resistance (HomaIR Q3 and CPRIR Q1), even after adjusting for confounders. In contrast, groups with the poorest insulin secretion (AUCcp Q1, HomaB Q1, first PH Q1, and second PH Q1) did not show elevated glucagon levels compared with those with better secretion. Mediation analysis confirmed that neither AUCcp nor HomaB mediated the relationship between insulin resistance and glucagon levels. Residual diagnostics demonstrated a satisfactory model fit. Furthermore, sensitivity analyses, both by excluding influential points identified via Cook’s distance and by applying bootstrapped CIs, yielded consistent results, thereby affirming the robustness of the model. Conclusions In T2DM, impaired glucagon suppression during OGTT is associated with insulin resistance closely, highlighting insulin resistance as a key factor in alpha-cell dysfunction.