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

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_0-260min) 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_0-260min) correlated positively with fasting (r=0.54) and postprandial serum triglyceride concentrations (iAUC_0-260min, 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.