Hyperglucagonemia correlates with plasma levels of non-branched-chain amino acids in patients with liver disease independent of type 2 diabetes

Abstract

Patients with type 2 diabetes (T2D) and patients with nonalcoholic fatty liver disease (NAFLD) frequently exhibit elevated plasma concentrations of glucagon (hyperglucagonemia). Hyperglucagonemia and α-cell hyperplasia may result from elevated levels of plasma amino acids when glucagon's action on hepatic amino acid metabolism is disrupted. We therefore measured plasma levels of glucagon and individual amino acids in patients with and without biopsy-verified NAFLD and with and without type T2D. Fasting levels of amino acids and glucagon in plasma were measured, using validated ELISAs and high-performance liquid chromatography, in obese, middle-aged individuals with I) normal glucose tolerance (NGT) and NAFLD, II) T2D and NAFLD, III) T2D without liver disease, and IV) NGT and no liver disease. Elevated levels of total amino acids were observed in participants with NAFLD and NGT compared with NGT controls (1,310 ± 235 µM vs. 937 ± 281 µM, P = 0.03) and in T2D and NAFLD compared with T2D without liver disease (1,354 ± 329 µM vs. 511 ± 235 µM, P < 0.0001). Particularly amino acids with known glucagonotropic effects (e.g., glutamine) were increased. Plasma levels of total amino acids correlated to plasma levels of glucagon also when adjusting for body mass index (BMI), glycated hemoglobin (Hb), and cholesterol levels (β = 0.013 ± 0.007, P = 0.024). Elevated plasma levels of total amino acids associate with hyperglucagonemia in NAFLD patients independently of glycemic control, BMI or cholesterol - supporting the potential importance of a "liver-α-cell axis" in which glucagon regulates hepatic amino acid metabolism. Fasting hyperglucagonemia as seen in T2D may therefore represent impaired hepatic glucagon action with increasing amino acids levels. NEW & NOTEWORTHY Hypersecretion of glucagon (hyperglucagonemia) has been suggested to be linked to type 2 diabetes. Here, we show that levels of amino acids correlate with levels of glucagon. Hyperglucagonemia may depend on hepatic steatosis rather than type 2 diabetes.

EJE PRIZE 2018: A gut feeling about glucagon

“…Similar to observations of fasting hyperglucagonaemia in obese normal glucose-tolerant subjects, our recent studies in patients with non-alcoholic fatty liver disease (with and without type 2 diabetes) show that fasting hyperglucagonaemia occurs independently of the diabetic state (38). Rather, fasting hyperglucagonaemia seems to relate to liver fat content and circulating amino acids (40), suggesting that liver-specific disruption of the liver-alpha cell axis represents an important determinant of fasting hyperglucagonaemia (Fig. 4).…”

“…Taken together, fasting hyperglucagonaemia seems to be independent of the diabetic state and rather related to obesity (31,105), steatosis-associated hepatic glucagon resistance (32,38) and ensuing reduced amino acid turnover (39,40). Reduced amino acid turnover ultimately results in hyperaminoacidaemia potentially stimulating glucagon secretion from pancreatic alpha cells (Fig.…”

“…In 2007, we reported the first human findings pointing to the gut and/or gut-derived factors as major determinants of the hyperglucagonaemia observed after nutrient ingestion in patients with type 2 diabetes (30), and a few years later, we observed that fasting hyperglucagonaemia is more tightly related to obesity than the diabetic state (31) and suggested that obesityassociated steatosis in the liver leads to hepatic glucagon resistance and compensatory glucagon secretion explaining fasting hyperglucagonaemia (32). These findings have spurred a range of clinical studies on the basis of which we have delineated the causality and aetiology of hyperglucagonaemia (11,34,36,37,38) and provided evidence to suggest (1) that fasting hyperglucagonaemia occurs due to steatosis-induced disruption of the newly discovered liver-alpha cell axis (32,33,34,35,36,37,38,39,40) and (2) that postprandial hyperglucagonaemia occurs on the basis of gut-derived glucagon secretion (41) and, possibly, contribution of glucagonotropic gut factors stimulating pancreatic glucagon secretion (18).…”

Evidence of a liver–alpha cell axis in humans: hepatic insulin resistance attenuates relationship between fasting plasma glucagon and glucagonotropic amino acids

“…Consistent with this proposed feedback loop, individuals with glucagon-producing tumours have decreased levels of plasma amino acids [11,31], and, conversely, individuals with glucagon receptor mutations [10,32,33] and mice with glucagon receptor deficiency [30,34] exhibit increased levels of plasma amino acids. Hyperglucagonaemia has also been reported in individuals with fatty liver disease independent of their glycaemic status [35], and this has recently been linked to an increased plasma pool of amino acids including alanine, but excluding the BCAAs isoleucine, leucine and valine [36].…”

“…The hypersecretion of glucagon from the pancreatic alpha cells may stem from an impairment of hepatic glucagon signalling (potentially caused by excessive food intake that may result in NAFLD and insulin resistance), which then, due to decreased glucagon-induced amino acid turnover, would result in hyperaminoacidaemia [36 ]. Finally, t he hyperaminoacidaemia, and in particular the increased plasma concentrations of the glucagon-stimulatory amino acids [27,28] alanine and tyrosine, may, as suggested by Solloway et al [7], result in hyperglucagonaemia, counteracting the NAFLDinduced impairment of glucagon-induced ureagenesis.…”