Hepatic steatosis in humans is associated with preserved glucagon action on amino acid metabolism

Hannah E. Christie; Sneha Mohan; Aoife M. Egan; Federica Boscolo; Chiara Dalla Man; Scott M. Thompson; Michael Jundt; Chad J. Fleming; James C. Andrews; Kent R. Bailey; Michael D. Jensen; K. Sree Nair; Adrian Vella

doi:10.1172/JCI200913

Hepatic steatosis in humans is associated with preserved glucagon action on amino acid metabolism

Hannah E. Christie,¹ Sneha Mohan,¹ Aoife M. Egan,¹ Federica Boscolo,² Chiara Dalla Man,² Scott M. Thompson,³ Michael Jundt,³ Chad J. Fleming,³ James C. Andrews,³ Kent R. Bailey,⁴ Michael D. Jensen,¹ K. Sree Nair,¹ and Adrian Vella¹

Published December 23, 2025 - More info

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Abstract

BACKGROUND. Amino acid (AA) concentrations are increased in prediabetes and diabetes. Since AA stimulate glucagon secretion which should then increase hepatic AA catabolism, it has been hypothesized that hepatic resistance (associated with hepatic fat content) to glucagon’s actions on AA metabolism leads to hyperglucagonemia and hyperglycemia.

METHODS. To test this hypothesis, we therefore studied lean and obese individuals, the latter group with and without hepatic steatosis as defined by Proton Density Fat Fraction (PDFF) > 5%. After an overnight fast, femoral vein, femoral artery, and hepatic vein catheters were placed. [3-3H] glucose and L-[1-13C,15N]-leucine were used to measure glucose turnover and leucine oxidation respectively. During a hyperglycemic clamp, an amino acid mixture was infused together with insulin and glucagon (1.5 ng/kg/min 0 – 120 min; 3.0 ng/kg/min 120 – 240 min). Tracer-based measurement of hepatic leucine oxidation in response to rising glucagon concentrations and splanchnic balance (measured using arterio-venous differences across the liver), of the other AA were the main outcomes measured.

RESULTS. The presence of hepatic steatosis did not alter hepatic glucose metabolism and leucine oxidation in response to insulin and rising concentrations of glucagon. Splanchnic balance of a few amino acids, and related metabolites differed amongst the groups. However, across-group differences of AA splanchnic balance in response to glucagon were unaffected by the presence of hepatic steatosis.

CONCLUSION. The action of glucagon on hepatic amino acid metabolism is unaffected by hepatic steatosis in humans.

TRIAL REGISTRATION. This study was registered at Clinical Trials.Gov: NCT05500586.

FUNDING. This work was funding by the NIH.

Hepatic steatosis in humans is associated with preserved glucagon action on amino acid metabolism

Hannah E. Christie,¹ Sneha Mohan,¹ Aoife M. Egan,¹ Federica Boscolo,² Chiara Dalla Man,² Scott M. Thompson,³ Michael Jundt,³ Chad J. Fleming,³ James C. Andrews,³ Kent R. Bailey,⁴ Michael D. Jensen,¹ K. Sree Nair,¹ and Adrian Vella¹

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Hepatic steatosis in humans is associated with preserved glucagon action on amino acid metabolism

Hannah E. Christie,1 Sneha Mohan,1 Aoife M. Egan,1 Federica Boscolo,2 Chiara Dalla Man,2 Scott M. Thompson,3 Michael Jundt,3 Chad J. Fleming,3 James C. Andrews,3 Kent R. Bailey,4 Michael D. Jensen,1 K. Sree Nair,1 and Adrian Vella1

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Hannah E. Christie,¹ Sneha Mohan,¹ Aoife M. Egan,¹ Federica Boscolo,² Chiara Dalla Man,² Scott M. Thompson,³ Michael Jundt,³ Chad J. Fleming,³ James C. Andrews,³ Kent R. Bailey,⁴ Michael D. Jensen,¹ K. Sree Nair,¹ and Adrian Vella¹