Introduction and Objective: Pre-diabetes is characterized by abnormal postprandial suppression of glucagon and circulating amino acid (AA) concentrations. It is unknown if hyperglucagonemia arises from a defective α-cell response to AA or from abnormal metabolism resulting in elevated AA. Methods: Lean (BMI: 23 ± 0.5 Kg/M2, n = 10) and obese (BMI 31 ± 0.5 Kg/M2, n = 20) subjects underwent hepatic MRI to quantify fat content using Proton Density Fat Fraction (PDFF). They were then studied on two occasions in random order after an overnight fast using a graded glucose infusion. On one occasion saline was infused (Saline Day) and on the other an AA mixture [Clinisol (15%, 0.003ml/kg/min); Baxter, Healthcare, Deerfield, IL - AA day]. The glucagon secretion rate (GSR) was derived from peripheral glucagon concentrations using a mathematical model, which also provided G50 - the change in glucose required to reduce GSR by 50% - for each subject. AA and their metabolites (n = 42) were measured by mass spectrometry at 0, 120 and 240 mins. Results: On both occasions, experimental conditions produced a progressive rise in insulin secretion and an inverse-exponential suppression of glucagon. AA infusion did not change G50 (1.4 ± 0.2 vs. 1.3 ± 0.3 mmol/L, AA vs. saline respectively, p = 0.20) in lean subjects. This was not the case in the obese group (2.3 ± 0.4 vs. 1.3 ± 0.2 mmol/L, p = 0.02). On the AA day G50 correlated with alanine (R2 = 0.34) and cysteine (R2 = 0.25) concentrations. Concentrations of alanine (R2 = 0.38), α-aminoadipic acid (R2 = 0.14) and lysine (R2 = 0.34) positively correlated with PDFF irrespective of changing insulin and glucagon concentrations throughout both study days. Conclusion: These experiments demonstrate that α-cell function is modulated by circulating AA. Increased PDFF is associated with increased AA concentrations, but these differences are present regardless of islet hormone concentrations at 0, 120 and 240 mins.
361-OR: The Alpha-Cell Response to Hyperglycemia Is Modulated by Circulating Amino Acid Concentrations in the Presence of Obesity and Hepatic Fat
BOSCOLO, FEDERICA;DALLA MAN, CHIARA;
2025
Abstract
Introduction and Objective: Pre-diabetes is characterized by abnormal postprandial suppression of glucagon and circulating amino acid (AA) concentrations. It is unknown if hyperglucagonemia arises from a defective α-cell response to AA or from abnormal metabolism resulting in elevated AA. Methods: Lean (BMI: 23 ± 0.5 Kg/M2, n = 10) and obese (BMI 31 ± 0.5 Kg/M2, n = 20) subjects underwent hepatic MRI to quantify fat content using Proton Density Fat Fraction (PDFF). They were then studied on two occasions in random order after an overnight fast using a graded glucose infusion. On one occasion saline was infused (Saline Day) and on the other an AA mixture [Clinisol (15%, 0.003ml/kg/min); Baxter, Healthcare, Deerfield, IL - AA day]. The glucagon secretion rate (GSR) was derived from peripheral glucagon concentrations using a mathematical model, which also provided G50 - the change in glucose required to reduce GSR by 50% - for each subject. AA and their metabolites (n = 42) were measured by mass spectrometry at 0, 120 and 240 mins. Results: On both occasions, experimental conditions produced a progressive rise in insulin secretion and an inverse-exponential suppression of glucagon. AA infusion did not change G50 (1.4 ± 0.2 vs. 1.3 ± 0.3 mmol/L, AA vs. saline respectively, p = 0.20) in lean subjects. This was not the case in the obese group (2.3 ± 0.4 vs. 1.3 ± 0.2 mmol/L, p = 0.02). On the AA day G50 correlated with alanine (R2 = 0.34) and cysteine (R2 = 0.25) concentrations. Concentrations of alanine (R2 = 0.38), α-aminoadipic acid (R2 = 0.14) and lysine (R2 = 0.34) positively correlated with PDFF irrespective of changing insulin and glucagon concentrations throughout both study days. Conclusion: These experiments demonstrate that α-cell function is modulated by circulating AA. Increased PDFF is associated with increased AA concentrations, but these differences are present regardless of islet hormone concentrations at 0, 120 and 240 mins.
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