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

Autor: Wewer Albrechtsen NJ; Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark.; NNF Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Færch K; Steno Diabetes Center Copenhagen, Gentofte, Denmark., Jensen TM; Steno Diabetes Center Copenhagen, Gentofte, Denmark., Witte DR; The Danish Diabetes Academy, Odense, Denmark.; Department of Public Health, Section of General Practice, Aarhus University, Aarhus, Denmark., Pedersen J; Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark.; NNF Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Mahendran Y; NNF Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Jonsson AE; NNF Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Galsgaard KD; Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark.; NNF Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Winther-Sørensen M; Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark.; NNF Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Torekov SS; Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark.; NNF Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Lauritzen T; Department of Public Health, Section of General Practice, Aarhus University, Aarhus, Denmark., Pedersen O; NNF Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Knop FK; NNF Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.; Center for Diabetes Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark.; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Hansen T; NNF Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Jørgensen ME; Steno Diabetes Center Copenhagen, Gentofte, Denmark.; National Institute of Public Health, Southern Denmark University, Odense, Denmark., Vistisen D; Steno Diabetes Center Copenhagen, Gentofte, Denmark., Holst JJ; Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark. jjholst@sund.ku.dk.; NNF Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. jjholst@sund.ku.dk.
Jazyk: angličtina
Zdroj: Diabetologia [Diabetologia] 2018 Mar; Vol. 61 (3), pp. 671-680. Date of Electronic Publication: 2018 Jan 05.
DOI: 10.1007/s00125-017-4535-5
Abstrakt: Aims/hypothesis: The 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.
Methods: To 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.
Results: Fasting 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/interpretation: This 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.
Databáze: MEDLINE
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