Search

Increased plasma levels of glucagon (hyperglucagonemia) promote diabetes development but are also observed in patients with metabolic dysfunction–associated steatotic liver disease (MASLD). This may reflect hepatic glucagon resistance toward amino acid catabolism. A clinical test for measuring glucagon resistance has not been validated. We evaluated our glucagon sensitivity (GLUSENTIC) test, which consists of 2 study days: a glucagon injection and measurements of plasma amino acids and an infusion of mixed amino acids and subsequent calculation of the GLUSENTIC index (primary outcome measure) from measurements of glucagon and amino acids. To distinguish glucagon-dependent from insulin-dependent actions on amino acid metabolism, we also studied patients with type 1 diabetes (T1D). The δ-decline in total amino acids was 49% lower in MASLD following exogenous glucagon (P = 0.01), and the calculated GLUSENTIC index was 34% lower in MASLD (P < 0.0001) but not T1D (P > 0.99). In contrast, glucagon-induced glucose increments were similar in control participants and participants with MASLD (P = 0.41). The GLUSENTIC test and index may be used to measure glucagon resistance in individuals with obesity and MASLD. Article Highlights: Patients with metabolic dysfunction–associated steatotic liver disease have an increased risk of developing diabetes due to altered insulin and glucagon signaling. While standardized methods exist to assess and identify insulin resistance, this is not the case for glucagon resistance. We aimed to determine the clinical applicability of an experimental test for assessing glucagon sensitivity (GLUSENTIC) and found that glucagon resistance may be captured by the GLUSENTIC test and index. Individuals with obesity and metabolic dysfunction–associated steatotic liver disease have glucagon resistance, as characterized by the impaired effects of glucagon on amino acid metabolism. The GLUSENTIC test may be applied in the clinical evaluation of glucagon resistance. [ABSTRACT FROM AUTHOR]

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 α-cells and the hepatocytes, often collectively referred to as the liver-α-cell axis, that may be of importance for health and disease. Thus, glucagon receptor antagonism (pharmacological or genetic), which disrupts the liver-α-cell axis, results not only 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-α-cell axis. The concept of glucagon resistance is also discussed, and we argue that the various elements of the liver-α-cell axis may be differentially affected in metabolic diseases such as diabetes, obesity, and nonalcoholic 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-α-cell axis, compromising the normal glucagon-mediated enhancement of substrate-induced amino acid turnover and possibly fatty acid β-oxidation. In contrast to amino acid catabolism, glucagon-induced glucose production may not be affected by NAFLD, explaining the diabetogenic effect of NAFLD-associated hyperglucagonemia. Consideration of the liver-α-cell axis is essential to understanding the complex pathophysiology underlying diabetes and other metabolic diseases. [ABSTRACT FROM AUTHOR]