Introduction and Objective: Obesity and prediabetes are characterized by abnormal glucagon response to glucose and amino acids (AA). Elevated AA concentrations, seen in these states, are associated with increased risk of type 2 diabetes. The relative contributions of AA, glucose and insulin to glucagon secretion is unknown.Methods: Lean (BMI: 23 ± 0.5 kg/m2, n = 10) and obese (BMI 31 ± 0.6 kg/m2, n = 16) subjects were 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%. AA and their metabolites (n = 42) were measured by mass spectrometry at 0, 120 and 240 mins.Results: During both study days, we observed a progressive rise in insulin and an inverse-exponential suppression of glucagon. AA infusion produced elevation of 15 AA compared to the saline day. We had previously observed that AA stimulation of glucagon secretion led to impaired suppression by hyperglycemia in obese subjects, resulting in an increased G50 that correlated with body weight (R2 = 0.15, p = 9.9 x 10-3). Examination of the relationship of G50 with AA concentrations suggests that when adjusted for weight, arginine and histidine concentrations are correlated with rise of G50 (R2 = 0.45, p = 2.6 x 10-5). Neither glucose nor insulin concentrations observed at peak AA concentrations altered this relationship.Conclusion: Circulating concentrations of arginine and histidine modulate α-cell function. This effect is more marked as weight increases and occurs independent of changes to glucose and insulin concentrations.
S. Mohan: None. F. Boscolo: None. H.E. Christie: None. A. Egan: None. C. Dalla Man: Other – Webinar provider; Ended; Sanofi. Other – Joint research project; Current; Sanofi-Aventis Deutschland GmbH. A. Vella: Advisory Panel; Ended; Boehringer Ingelheim International GmbH. Advisory Panel; Current; Rezolute. Research Support; Current; Dexcom, Inc. Advisory Panel; Current; Neurotronic, Amylx.
National Institutes of Health (DK116723)
Source link
Leave a Reply