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

This study investigated how insulin resistance and impaired insulin secretion affect hyperglucagonemia during an oral glucose tolerance test (OGTT) in type 2 diabetes (T2DM).We conducted a retrospective analysis of 247 individuals with T2DM who underwent a 75g OGTT, measuring glucose, insulin, C-peptide, and glucagon. Insulin resistance was assessed via insulin sensitivity index (ISI) and homeostasis model assessment of insulin resistance (HomaIR), while residual β-cell function was evaluated using area under the C-peptide curve (AUCcp) and homeostasis model assessment of β-cell function (Homa-β). Generalized linear models and mediation analysis were used to examine associations between glucagon secretion, insulin resistance, and insulin secretion.Participants with the lowest insulin sensitivity (ISI Q1) and highest insulin resistance (HomaIRQ3) displayed significantly higher glucagon levels during OGTT. However, no significant elevation in glucagon levels was observed in those with the lowest residual insulin secretion (AUCcpQ1 or Homa-βQ1). Mediation analysis confirmed that neither AUCcpnor Homa-βmediated the link between insulin resistance (ISI/HomaIR) and glucagon levels, even after adjusting for confounders.In T2DM, impaired glucagon suppression during OGTT is linked to insulin resistance but not to reduced insulin secretion, underscoring insulin resistance's key role in alpha-cell dysfunction.