Glucose–Insulin–Glucagon Interactions Evoked with Amino Acid Arginine in Participants with Type 2 Diabetes

Introduction and Objective: Type 2 diabetic β cells are characterized as glucose-specific sensing failure. We previously observed exaggerated secretion of insulin and glucagon in response to arginine challenges in subjects with insulin resistance and type 2 diabetes (Diabetes Care 30:2583-7, 2007). However, detailed glucose-insulin-glucagon interactions remain unclear. Methods: From November 2018 to October 2021, intravenous l-arginine (30 g) was administered to type 2 diabetic patients. Blood glucose (Glu), blood glucagon (IRG), and blood C-peptide (CPR) levels were measured at 0, 30, 60, 90, and 120 minutes. Fasting levels, Δ (delta values: peak - baseline), and area under the curve (AUC) of IRG were assayed using the Mercodia ELISA. Results: A total of 127 Japanese participants with diabetes (age 60 ± 15 years, diabetes duration 12.6 ± 12.4 years, HbA1c 8.6 ± 2.0%, baseline plasma glucose 155 ± 54 mg/dL) underwent the arginine challenge test. Baseline IRG, ΔIRG, and AUC IRG were positively correlated with fasting CPR, ΔCPR, and AUC CPR values, respectively. ΔIRG0-30min was positively correlated with peak/baseline of Glu (r = 0.188, P = 0.034). IRG levels at 60, 90, and 120 minutes were positively correlated with age (r = 0.496, P < 0.001), diabetes duration (r = 0.362, P < 0.001), and blood urea nitrogen (r = 0.316, P < 0.001). Participants using SGLT2 inhibitors showed an exaggerated glucagon response compared to non-users. Conclusion: IRG response to arginine challenge is positively associated with responses of insulin and glucose, age, disease duration, and blood urea nitrogen levels in people with type 2 diabetes. These findings provide insight into glucose-insulin-glucagon interactions following amino acid ingestion. Disclosure: Y. Kaikoi: None. M. Okumura: None. H. Goto: None. Y. Nakano: None. Y. Takeshita: None. T. Takamura: Research Support; Kowa Company, Ltd, Taisho Pharmaceutical Holdings Co., Ltd.