Determinants of Fasting Hyperglucagonemia in Patients with Type 2 Diabetes and Nondiabetic Control Subjects

Fasting hyperglucagonemia can be detrimental to glucose metabolism in patients with type 2 diabetes (T2D) and may contribute to metabolic disturbances in obese and/or prediabetic subjects. However, the mechanisms underlying fasting hyperglucagonemia remain elusive.

We evaluated the interrelationship between fasting hyperglucagonemia and demographic and biochemical parameters in 106 patients with T2D (31% female, age: 57 ± 9 years [mean ± standard deviation; body mass index (BMI): 30.1 ± 4.4 kg/m²; fasting plasma glucose (FPG): 9.61 ± 2.39 mM; hemoglobin A1c (HbA1c): 57.1 ± 13.1 mmol/mol] and 163 nondiabetic control subjects (29% female; age: 45 ± 17 years; BMI: 25.8 ± 4.1 kg/m²; FPG: 5.2 ± 0.4 mM; and HbA1c: 35.4 ± 3.8 mmol/mol). Multiple linear regression analysis was applied using a stepwise approach with fasting plasma glucagon as dependent parameter and BMI, waist-to-hip ratio (WHR), blood pressure, hemoglobin A1c, FPG, and insulin concentrations as independent parameters.

Fasting plasma glucagon concentrations were significantly higher among patients with T2D (13.5 ± 6.3 vs. 8.5 ± 3.8 mM, P < 0.001) together with HbA1c (P < 0.001), FPG (P < 0.001), and insulin (84.9 ± 56.4 vs. 57.7 ± 35.3 mM, P < 0.001). When adjusted for T2D, HbA1c and insulin were significantly positive determinants for fasting plasma glucagon concentrations. Furthermore, WHR comprised a significant positive determinant.

We confirm that fasting plasma glucagon concentrations are abnormally high in patients with T2D, and show that fasting plasma glucagon concentrations are influenced by WHR (in addition to glycemic control and fasting plasma insulin concentrations), which may point to visceral fat deposition as an important determinant of increased fasting plasma glucagon concentrations.