Meal-derived glucagon responses are related to lower hepatic phosphate concentrations in obesity and type 2 diabetes

Aim: Type 2 diabetes (T2D) alters glucagon, glucagon-like peptide (GLP)-1, glucose-dependent insulinotropic polypeptide (GIP) and hepatic energy metabolism, yet the possible relationships remain unclear. Methods: In this observational study, lean insulin-sensitive control subjects (BMI: 23.2 ± 1.5 kg/m2), age-matched insulin-resistant obese subjects (BMI: 34.3 ± 1.7 kg/m2) and similarly obese elderly T2D patients (BMI: 32.0 ± 2.4 kg/m2) underwent mixed-meal tolerance tests (MMTTs), and assessment of hepatic ?ATP, inorganic phosphate (Pi) and lipids using 31P/1H magnetic resonance spectroscopy. Meal-induced secretion of glucagon and incretins was calculated from incremental areas under the concentration-time curves (iAUCs). Peripheral and adipose tissue insulin sensitivity were assessed from time courses of circulating glucose, insulin and free fatty acids. Results: MMTT-derived peripheral insulin sensitivity was lowest in T2D patients (P < 0.001), while glucagon concentrations were comparable across all three groups. At 260 min, GLP-1 was lower in T2D patients than in controls, whereas GIP was lowest in obese individuals. Fasting glucagon concentrations correlated positively with fasting (r = 0.60) and postprandial hepatocellular lipid levels (160 min: r = 0.51, 240 min: r = 0.59), and negatively with adipose tissue insulin sensitivity (r = -0.73). Higher meal-induced glucagon release (iAUC0-260 min) correlated with lower fasting (r = -0.62) and postprandial Pi levels (160 min: r = -0.43, 240 min: r = -0.42; all P < 0.05). Higher meal-induced release of GIP (iAUC0-260 min) correlated positively with fasting (r = 0.54) and postprandial serum triglyceride concentrations (iAUC0-260 min, r = 0.54; all P < 0.01). Conclusion: Correlations between fasting glucagon and hepatic lipids and between meal-induced glucagon and hepatic Pi suggest a role for glucagon in hepatic energy metabolism.