The Liver-Alpha Cell Axis in Health and in Disease

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.