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

Nicolai J Wewer Albrechtsen; Kristine Færch; Troels M Jensen; Daniel R Witte; Jens Pedersen; Yuvaraj Mahendran; Anna E Jonsson; Katrine D Galsgaard; Marie Winther-Sørensen; Signe S Torekov; Torsten Lauritzen; Oluf Pedersen; Filip K Knop; Torben Hansen; Marit E Jørgensen; Dorte Vistisen; Jens J Holst

doi:10.1007/s00125-017-4535-5

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

Nicolai J Wewer Albrechtsen, Kristine Færch, Troels M Jensen, Daniel R Witte, Jens Pedersen, Yuvaraj Mahendran, Anna E Jonsson, Katrine D Galsgaard, Marie Winther-Sørensen, Signe S Torekov, Torsten Lauritzen, Oluf Pedersen, Filip K Knop, Torben Hansen, Marit E Jørgensen, Dorte Vistisen, Jens J Holst

27 Citations (Scopus)

Abstract

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.

Original language	English
Journal	Diabetologia
Volume	61
Issue number	3
Pages (from-to)	671-680
ISSN	0012-186X
DOIs	https://doi.org/10.1007/s00125-017-4535-5
Publication status	Published - 1 Mar 2018

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Wewer Albrechtsen, N. J., Færch, K., Jensen, T. M., Witte, D. R., Pedersen, J., Mahendran, Y., Jonsson, A. E., Galsgaard, K. D., Winther-Sørensen, M., Torekov, S. S., Lauritzen, T., Pedersen, O., Knop, F. K., Hansen, T., Jørgensen, M. E., Vistisen, D., & Holst, J. J. (2018). Evidence of a liver-alpha cell axis in humans: hepatic insulin resistance attenuates relationship between fasting plasma glucagon and glucagonotropic amino acids. Diabetologia, 61(3), 671-680. https://doi.org/10.1007/s00125-017-4535-5

Evidence of a liver-alpha cell axis in humans : hepatic insulin resistance attenuates relationship between fasting plasma glucagon and glucagonotropic amino acids. / Wewer Albrechtsen, Nicolai J; Færch, Kristine; Jensen, Troels M et al.

In: Diabetologia, Vol. 61, No. 3, 01.03.2018, p. 671-680.

Research output: Contribution to journal › Journal article › Research › peer-review

Wewer Albrechtsen, NJ, Færch, K, Jensen, TM, Witte, DR, Pedersen, J, Mahendran, Y, Jonsson, AE, Galsgaard, KD , Winther-Sørensen, M , Torekov, SS, Lauritzen, T, Pedersen, O , Knop, FK , Hansen, T, Jørgensen, ME, Vistisen, D & Holst, JJ 2018, 'Evidence of a liver-alpha cell axis in humans: hepatic insulin resistance attenuates relationship between fasting plasma glucagon and glucagonotropic amino acids', Diabetologia, vol. 61, no. 3, pp. 671-680. https://doi.org/10.1007/s00125-017-4535-5

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

abstract = "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.",

author = "{Wewer Albrechtsen}, {Nicolai J} and Kristine F{\ae}rch and Jensen, {Troels M} and Witte, {Daniel R} and Jens Pedersen and Yuvaraj Mahendran and Jonsson, {Anna E} and Galsgaard, {Katrine D} and Marie Winther-S{\o}rensen and Torekov, {Signe S} and Torsten Lauritzen and Oluf Pedersen and Knop, {Filip K} and Torben Hansen and J{\o}rgensen, {Marit E} and Dorte Vistisen and Holst, {Jens J}",

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doi = "10.1007/s00125-017-4535-5",

language = "English",

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journal = "Diabetologia",

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T1 - Evidence of a liver-alpha cell axis in humans

T2 - hepatic insulin resistance attenuates relationship between fasting plasma glucagon and glucagonotropic amino acids

AU - Wewer Albrechtsen, Nicolai J

AU - Færch, Kristine

AU - Jensen, Troels M

AU - Witte, Daniel R

AU - Pedersen, Jens

AU - Mahendran, Yuvaraj

AU - Jonsson, Anna E

AU - Galsgaard, Katrine D

AU - Winther-Sørensen, Marie

AU - Torekov, Signe S

AU - Lauritzen, Torsten

AU - Pedersen, Oluf

AU - Knop, Filip K

AU - Hansen, Torben

AU - Jørgensen, Marit E

AU - Vistisen, Dorte

AU - Holst, Jens J

PY - 2018/3/1

Y1 - 2018/3/1

N2 - 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.

AB - 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.

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DO - 10.1007/s00125-017-4535-5

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C2 - 29305624

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JO - Diabetologia

JF - Diabetologia

IS - 3

ER -

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

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