Elevated glucagon levels are frequently observed in type 2 diabetes mellitus (T2DM), although the relationship between hyperglucagonemia and hepatic lipid accumulation remains incompletely understood. A metabolic study published in Diabetes Care evaluated associations between glucagon levels, hepatic lipid content (HLC), and metabolic dysfunction-associated steatotic liver disease (MASLD) in individuals with newly diagnosed T2DM and normal glucose tolerance (NGT).

The analysis included 50 individuals with newly diagnosed T2DM and 50 age-, sex-, and body mass index (BMI)-matched individuals with NGT. Participants underwent liquid mixed-meal tolerance testing, hyperinsulinemic-euglycemic clamps with stable isotope dilution, indirect calorimetry, and magnetic resonance spectroscopy and MRI assessments to evaluate HLC, insulin sensitivity, hepatic energy metabolism, and visceral adipose tissue (VAT) volume.

Findings

• Individuals with T2DM had approximately 65% higher HLC than those with NGT.
• Fasting glucagonemia was approximately 30% higher and postprandial glucagonemia approximately 75% higher in individuals with T2DM than in those with NGT.
• Multivariable analyses showed that MASLD, but not T2DM alone, was associated with higher fasting glucagonemia.
• Postprandial glucagonemia was associated with HLC only in T2DM, resulting in approximately 47% higher early postprandial glucagon levels among participants with both MASLD and T2DM.
• Associations between glucagon levels and HLC were independent of insulin sensitivity, VAT volume, amino acids, and NEFA concentrations.

Higher HLC and hyperglucagonemia were closely associated in early T2DM, particularly among individuals with concomitant MASLD. The findings suggest that hepatic glucagon resistance may contribute to hyperglucagonemia in early T2DM independent of insulin sensitivity or glucagonotropic metabolites.