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

BACKGROUNDAmino acid (AA) concentrations are increased in prediabetes and diabetes. Since AAs 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.METHODSTo 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 AA mixture was infused together with insulin and glucagon (1.5 ng/kg/min 0-120 minutes; 3.0 ng/kg/min 120-240 minutes). Tracer-based measurement of hepatic leucine oxidation in response to rising glucagon concentrations and splanchnic balance (measured using arteriovenous differences across the liver) of the other AAs were the main outcomes measured.RESULTSThe 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 AAs and related metabolites differed among the groups. However, across-group differences of AA splanchnic balance in response to glucagon were unaffected by the presence of hepatic steatosis.CONCLUSIONThe action of glucagon on hepatic AA metabolism is unaffected by hepatic steatosis in humans.TRIAL REGISTRATIONClinical Trials.gov: NCT05500586.FUNDINGNIH National Institute of Diabetes and Digestive and Kidney Diseases DK116231, DK78646, DK116231, DK126206, and DK116231.