Increased Early Postprandial Glucagon Concentrations in Humans With Newly Diagnosed Type 2 Diabetes and Steatotic Liver Disease

OBJECTIVE: Glucagon-based polyagonists improve metabolic dysfunction-associated steatotic liver disease (MASLD), which could result from glucagon-stimulated hepatic lipid oxidation. Nevertheless, people with long-standing type 2 diabetes (T2D) exhibit a paradoxical rise in both hepatic lipid content (HLC) and glucagon levels, which has been related to disturbed hepatic metabolism generating glucagonotropic metabolites such as amino acids and nonesterified fatty acids (NEFAs). We examined these relationships in individuals with normal glucose tolerance (NGT) and newly diagnosed T2D. RESEARCH DESIGN AND METHODS: Fifty individuals with newly diagnosed T2D and 50 age-, sex-, BMI-matched individuals with NGT underwent liquid mixed-meal tolerance tests to measure glucagon and metabolites, hyperinsulinemic-euglycemic clamps with stable isotope dilution, indirect calorimetry to assess insulin sensitivity and lipid oxidation, and 1H/31P magnetic resonance spectroscopy and MRI to quantify HLC, ATP, and visceral adipose tissue (VAT) volume. RESULTS: Individuals with T2D had an ∼65% higher HLC as well as higher fasting and postprandial glucagonemia (∼30% and ∼75%) than those with NGT. Multivariable linear regression analyses revealed that the presence of MASLD, but not T2D, was associated with higher fasting glucagonemia. Interestingly, postprandial glucagon was related to HLC only in T2D, leading to ∼47% higher early postprandial glucagonemia in individuals with combined MASLD and T2D. These differential associations were independent of insulin sensitivity or VAT volume, and neither were mediated by amino acids or NEFAs. CONCLUSIONS: Hyperglucagonemia in the face of higher HLC in early T2D is not due to differences in insulin sensitivity or glucagonotropic metabolites but could suggest hepatic glucagon resistance.