<b>Alpha Cell Dysfunction in Type 2 Diabetes: The Role of Insulin Resistance and Reduced Insulin Secretion</b>

<b>Introduction:</b> This study examined the role of insulin resistance and impaired insulin secretion in hyperglucagonemia during oral glucose tolerance tests (OGTT) in type 2 diabetes (T2DM).<b>Research Design and Methods:</b> A retrospective analysis included 247 patients with T2DM treated at Tianjin Medical University General Hospital from October 2022 to March 2025. All underwent a 75g 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 Matsuda index(MI), while insulin secretion was evaluated using C-peptide area under the curve (AUCcp), homeostasis model assessment of beta cell function (HomaB), and first-phase and second-phase insulin secretion during OGTT (1st PH and 2nd 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 confidence intervals.<b>Results:</b> Glucagon levels during the OGTT were significantly elevated in patients with severe insulin resistance (HomaIR Q3) and in those with the lowest insulin sensitivity (MI Q1), even after adjusting for confounders. In contrast, groups with the poorest insulin secretion (AUCcp Q1, HomaB Q1, 1st PHQ1, and 2nd PHQ1) did not show elevated glucagon levels compared to 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 Cook’s distance and by applying bootstrapped confidence intervals, produced consistent results, thereby affirming the robustness of the model.<b>Conclusions:</b> In T2DM, impaired glucagon suppression during OGTT is associated with insulin resistanceclosely, highlighting insulin resistance as a key factor in alpha-cell dysfunction.<br>