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.

In this observational study, lean insulin-sensitive control subjects (BMI: 23.2±1.5kg/m²), age-matched insulin-resistant obese subjects (BMI: 34.3±1.7kg/m²) and similarly obese elderly T2D patients (BMI: 32.0±2.4kg/m²) underwent mixed-meal tolerance tests (MMTTs), and assessment of hepatic γATP, inorganic phosphate (P_i) 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.

MMTT-derived peripheral insulin sensitivity was lowest in T2D patients (P<0.001), while glucagon concentrations were comparable across all three groups. At 260min, 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 (160min: r=0.51, 240min: r=0.59), and negatively with adipose tissue insulin sensitivity (r=−0.73). Higher meal-induced glucagon release (iAUC_{0–260 min}) correlated with lower fasting (r=−0.62) and postprandial P_i levels (160min: r=−0.43, 240min: r=−0.42; all P<0.05). Higher meal-induced release of GIP (iAUC_{0–260 min}) correlated positively with fasting (r=0.54) and postprandial serum triglyceride concentrations (iAUC_{0–260 min}, r=0.54; all P<0.01).

Correlations between fasting glucagon and hepatic lipids and between meal-induced glucagon and hepatic P_i suggest a role for glucagon in hepatic energy metabolism.