Liver fat may disrupt post-meal glucagon control in early type 2 diabetes

By Vijay Kumar MalesuReviewed by Susha Cheriyedath, M.Sc.May 10 2026

A new study suggests that fatty liver disease may help explain why glucagon regulation becomes abnormal early in type 2 diabetes, pointing to a complex liver-pancreas connection that could shape future metabolic research.

Study: Increased Early Postprandial Glucagon Concentrations in Humans With Newly Diagnosed Type 2 Diabetes and Steatotic Liver Disease. Image Credit: Yunus Nugraha / Shutterstock

In a recent study published in the journal Diabetes Care, a group of researchers examined whether liver fat content is linked to fasting and post-meal glucagon levels in newly diagnosed type 2 diabetes (T2D) and metabolic dysfunction-associated steatotic liver disease (MASLD).

Liver Fat, Diabetes, and Glucagon Background

More than 800 million people worldwide are estimated to live with diabetes, and many also develop fatty liver disease, a condition now called MASLD. Fatty liver has been associated with increased levels of insulin resistance, long-term inflammation, and a higher risk of cardiovascular disease. However, another key hormone associated with diabetes is glucagon. It increases blood glucose when it drops excessively low. In people with normal glucose regulation, glucagon is typically suppressed after nutrient intake, whereas this regulation may be impaired in diabetes.

Scientists have proposed that liver fat may interfere with normal glucagon signaling, yet the exact relationship remains unclear. More research will be needed to understand these early metabolic changes.

German Diabetes Study Design and Measures

Researchers analyzed 100 adults enrolled in the German Diabetes Study. This included 50 participants newly diagnosed with T2D and 50 with normal glucose tolerance (NGT), matched to the T2D group for age, sex, and body mass index (BMI). Following an overnight fast, participants performed numerous metabolic tests.

Changes in glucose, insulin, glucagon, amino acids, non-esterified fatty acids (NEFAs), and C-peptide were recorded for three hours after eating using the liquid mixed meal tolerance test. Insulin sensitivity was determined using hyperinsulinemic-euglycemic clamps and stable isotope dilution methods. These methods are recognized as the ‘gold standard’ in evaluating glucose metabolism. Resting energy expenditure and substrate oxidation were measured using indirect calorimetry.

Researchers measured hepatic lipid content (HLC), liver energy, and visceral adipose tissue using magnetic resonance spectroscopy and magnetic resonance imaging (MRI). Associations between HLC, glucagon concentrations, insulin resistance, and plasma levels of amino acids and fatty acids were evaluated using sex-, age-, and BMI-adjusted statistical analyses. They also conducted mediation analyses to determine whether amino acids or NEFAs could explain the association between liver fat and glucagon.

Postprandial Glucagon Findings in T2D and MASLD

Participants with newly diagnosed T2D showed metabolic abnormalities compared with individuals with NGT. Liver fat content was approximately 65% higher in the T2D group, while fasting glucagon concentrations were about 30% higher.

Early postprandial glucagon responses after the mixed meal were nearly 75% higher in T2D participants, demonstrating that abnormal glucagon regulation appears very early during diabetes development. These participants also had lower whole-body insulin sensitivity and higher hepatic and adipose tissue insulin resistance.

The study revealed that MASLD was more strongly associated with elevated fasting glucagon levels than diabetes alone, as fasting glucagon levels in MASLD patients were about 29% higher than those without MASLD, regardless of diabetes status. However, the most important observation that was made was the postprandial glucagon response.

The researchers found a positive correlation between liver fat and postprandial glucagon levels only among participants with T2D, not among those with NGT. It was also observed that individuals with both T2D and MASLD had postprandial glucagon levels approximately 47% higher than those without MASLD.

Additionally, these associations remained significant even after accounting for insulin sensitivity and visceral fat volume. As such, excess liver fat may be associated with abnormalities in glucagon signaling in people with T2D, independent of body fat or insulin sensitivity. Similar results were observed in the sensitivity analyses when glucose-lowering medication users were excluded, thereby increasing confidence in the results.

Amino Acids, NEFAs, and Energy Metabolism

The researchers also evaluated the connection between abnormal glucagon responses and specific amino acids, particularly alanine, as well as NEFAs. Compared with those without MASLD, fasting alanine levels were higher in those with MASLD, but neither alanine nor NEFAs contributed to the relationship between liver fat and glucagon levels.

In addition, total amino acids or branched-chain amino acids (BCAAs) could not provide an explanation for these findings. These results challenge the notion that alanine, BCAAs, or NEFAs alone account for elevated glucagon levels in this setting.

Another notable finding of this study was the absence of a consistently observable relationship between glucagon concentrations and overall energy metabolism. With appropriate statistical adjustments, no significant relationship was observed between plasma glucagon levels and glucose oxidation, lipid oxidation, or hepatic adenosine triphosphate (ATP) availability.

Thus, the findings may be consistent with altered hepatic glucagon signaling, although the study cannot prove a specific hepatic glucagon-resistance mechanism.

Implications for Glucagon-Based Diabetes Research

The study showed that glucagon concentrations are already abnormally elevated in the early stages of T2D and are closely linked to MASLD. Increased liver fat accumulation was associated with a higher post-meal glucagon response in T2D, compared with those without diabetes, after controlling for insulin sensitivity and abdominal fat.

Further, neither amino acids nor NEFAs contributed to this relationship, indicating a possible disruption of glucagon signaling in the liver. However, because the study was cross-sectional and some subgroup analyses of MASLD were exploratory, the findings should be interpreted as hypothesis-generating rather than causal.

These findings highlight the complex relationship between fatty liver disease and diabetes and may inform future research on glucagon-based therapies aimed at improving both glucose control and liver health.