ArticleDiabetologia2018
Evidence of a liver-alpha cell axis in humans: hepatic insulin resistance attenuates relationship between fasting plasma glucagon and glucagonotropic amino acids.
Article in Diabetologia, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 68 papers, 1 of them a synthesis that pooled it.
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Who cites it
68 citing papers in PubMed, 1 synthesis or guideline pooled it, 116 citations in OpenAlex.
- The relationship between glucose and the liver-alpha cell axis - A systematic review.Frontiers in endocrinology · 2022Pooled it
- Trial
- Hepatic steatosis and postprandial hyperglucagonemia in early type 2 diabetes: Revisiting the liver-α-cell axis.Journal of diabetes investigation · 2026Article
- Loss of Slc39a5 in α-cells impairs glucose metabolism by chronically increasing glucagon.Journal of advanced research · 2026Article
- Central leptin resistance precedes obesity and drives early endocrine dysfunction.The Journal of physiology · 2026Article
- Comment on Huttasch et al. Increased Early Postprandial Glucagon Concentrations in Humans With Newly Diagnosed Type 2 Diabetes and Steatotic Liver Disease.Diabetes care · 2026Article
- Oral glucose absorption is enhanced in early metabolic dysfunction-associated steatotic liver disease.Diabetologia · 2026Article
- Pancreatic islet α cell function and proliferation require the arginine transporter SLC7A2.The Journal of clinical investigation · 2026Article
- Chronic attenuation of brain leptin signalling is associated with early metabolic dysfunction in lean rats.The Journal of physiology · 2026Article
- Increased Early Postprandial Glucagon Concentrations in Humans With Newly Diagnosed Type 2 Diabetes and Steatotic Liver Disease.Diabetes care · 2026Article
- Is glucagon action altered in steatotic liver disease?The Journal of clinical investigation · 2026Article
- Differential association of hyperglucagonemia with C-peptide levels in diabetic ketosis/ketoacidosis and hyperosmolar hyperglycemic state.Diabetology international · 2026Article
- Dynamic multi-omics profiling of islet and gut hormonal secretion and peripheral crosstalk in response to various nutrient loads.Cell reports. Medicine · 2025Article
- Islet hormones at the intersection of glucose and amino acid metabolism.Nature reviews. Endocrinology · 2025Review
- The neglected PCK1/glucagon (inter)action in nutrient homeostasis beyond gluconeogenesis: Disease pathogenesis and treatment.Molecular metabolism · 2025Review
- Pancreatic endocrine and exocrine signaling and crosstalk in physiological and pathological status.Signal transduction and targeted therapy · 2025Review
- Variable glucagon metabolic actions in diverse mouse models of obesity and type 2 diabetes.Molecular metabolism · 2024Article
- Lipid metabolism in MASLD and MASH: From mechanism to the clinic.JHEP reports : innovation in hepatology · 2024Review
- Dissociation between liver fat content and fasting metabolic markers of selective hepatic insulin resistance in humans.European journal of endocrinology · 2024Article
- Advances in basic research on glucagon and alpha cells.Diabetology international · 2024Review
8 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
17 authors at 3 institutions in 1 country.
Funding
Abstract
aims/hypothesisThe secretion of glucagon is controlled by blood glucose and inappropriate secretion of glucagon contributes to hyperglycaemia in diabetes. Besides its role in glucose regulation, glucagon regulates amino acid metabolism in hepatocytes by increasing ureagenesis. Disruption of this mechanism causes hyperaminoacidaemia, which in turn increases glucagon secretion. We hypothesised that hepatic insulin resistance (secondary to hepatic steatosis) via defective glucagon signalling/glucagon resistance would lead to impaired ureagenesis and, hence, increased plasma concentrations of glucagonotropic amino acids and, subsequently, glucagon.
methodsTo examine the association between glucagon and amino acids, and to explore whether this relationship was modified by hepatic insulin resistance, we studied a well-characterised cohort of 1408 individuals with normal and impaired glucose regulation. In this cohort, we have previously reported insulin resistance to be accompanied by increased plasma concentrations of glucagon. We now measure plasma levels of amino acids in the same cohort. HOMA-IR was calculated as a marker of hepatic insulin resistance.
resultsFasting levels of glucagonotropic amino acids and glucagon were significantly and inversely associated in linear regression models (persisting after adjustment for age, sex and BMI). Increasing levels of hepatic, but not peripheral insulin resistance (p > 0.166) attenuated the association between glucagon and circulating levels of alanine, glutamine and tyrosine, and was significantly associated with hyperaminoacidaemia and hyperglucagonaemia. A doubling of the calculated glucagon-alanine index was significantly associated with a 30% increase in hepatic insulin resistance, a 7% increase in plasma alanine aminotransferase levels, and a 14% increase in plasma γ-glutamyltransferase levels. CONCLUSIONS/
interpretationThis cross-sectional study supports the existence of a liver-alpha cell axis in humans: glucagon regulates plasma levels of amino acids, which in turn feedback to regulate the secretion of glucagon. With hepatic insulin resistance, reflecting hepatic steatosis, the feedback cycle is disrupted, leading to hyperaminoacidaemia and hyperglucagonaemia. The glucagon-alanine index is suggested as a relevant marker for hepatic glucagon signalling.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.