The Liver–α-Cell Axis in Health and in Disease

Abstract

Glucagon and insulin are the main regulators of blood glucose. While the actions of insulin are extensively mapped, less is known about glucagon. Besides glucagon's role in glucose homeostasis, there are additional links between the pancreatic alpha cells and the hepatocytes, often collectively referred to as the liver-alpha cell axis, which may be of importance for health and disease. Thus, glucagon receptor antagonism (pharmacological or genetic), which disrupts the liver-alpha cell axis, not only results in lower fasting glucose, but also in reduced amino acid turnover, and dyslipidemia. Here, we review the actions of glucagon on glucose homeostasis, amino acid catabolism, and lipid metabolism in the context of the liver-alpha cell axis. The concept of glucagon resistance is also discussed, and we argue that the various elements of the liver-alpha cell axis may be differentially affected in metabolic diseases such as diabetes, obesity, and non-alcoholic fatty liver disease (NAFLD). This conceptual rethinking of glucagon biology may explain why patients with type 2 diabetes have hyperglucagonemia and how NAFLD disrupts the liver-alpha cell axis, compromising the normal glucagon-mediated enhancement of substrate-induced amino acid turnover and possibly fatty acid beta-oxidation. Glucagon-induced glucose production may, in contrast to amino acid catabolism, however not be affected by NAFLD explaining the diabetogenic effect of NAFLD-associated hyperglucagonemia. Consideration of the liver-alpha cell axis is essential to understand the complex pathophysiology underlying diabetes and other metabolic diseases.

Opposing effects of chronic glucagon receptor agonism and antagonism on amino acids, hepatic gene expression, and alpha cells

“…We show that these changes are likely mediated by transcriptional changes in liver genes encoding proteins involved in amino acid metabolism, amino acid transport, and ureagenesis, and a non-transcriptional change in the enzymatic activity of the rate-limiting urea cycle enzyme CPS-1. Importantly, tying hepatic, plasma, and pancreatic changes together, while providing molecular insight into how chronic glucagon excess also causes substantial hepatic and pancreatic changes, we show that both chronic activation and inhibition of glucagon receptor signaling result in pronounced changes in the liver-alpha cell axis ( Richter et al., 2022 ), thus furthering our understanding of this axis.…”

Sustained glucagon receptor antagonism in insulin-deficient high-fat-fed mice

“…Thus, carbohydrate oxidation drives RER to a value closer to 1.0, with fatty acid oxidation reducing this towards 0.7 (Rosenkilde et al 2010;Purdom et al 2018). Hyperaminoacidaemia has also been reported following inhibition of GCGR signalling and assessment of plasma amino acids levels would have been interesting in this regard (Richter et al 2022). Although, the impact of the high fat (45%) background diet, enduring insulin deficiency and small GCGR antagonist-induced changes in food intake and body weight need to be considered in terms of overall effects on carbohydrate metabolism.…”

Rethinking the Paradoxical Increase in Endogenous Glucose Production in Response to Metformin: Should We Retain the Glucagon Antagonistic Effect of the Drug?

“…The authors also reported increased lactate concentrations and reduced pH levels in portal vein but not in peripheral veins suggesting increased intestinal glycolytic glucose utilization and increased glucose cycling [26]. Similar to Penicaud, Hitier [20], authors followed by a stable isotope investigation to trace glucose kinetics; where they reported increased doubly labeled glucose-1,6-13 C after oral ingestion of mono-labeled glucose-1-13 C. Importantly, these findings suggest breakdown of mono-labeled glucose-1- 13 C to lactate and its conversion back to glucose-1,6-13 C in the aldolase reaction, consistent with increased glucose cycling. However, the findings from this study do not appear to support blunted postprandial glucose cycling [26].…”

“…In fact, proofs that metformin may counteract glucagon effects came from the study that demonstrated concomitantly an increase in EGP [12]. Surprisingly, this occurred in concomitance to increased gluconeogenic amino acids (AAs) levels, which may suggest a liver-alpha cell crosstalk [12,13].…”