The effect of obesity on the alpha cell response to amino acids in the presence of hyperglycaemia

Background and aims: Type 2 diabetes mellitus (T2DM) and pre-diabetes are characterized by abnormal post-prandial suppression of glucagon. Elevated circulating concentrations of some amino acids (AA) are markers of insulin resistance and of increased progression of pre-diabetes to T2DM. α-cells respond to elevated AA with increased glucagon secretion which in turn should stimulate hepatic AA catabolism. At present it is unknown if hyperglucagonemia represents an innate defect in α-cell responsiveness to AA. We sought to quantify the extent to which glucose-induced glucagon suppression is altered by AA. We also sought to ascertain whether this is an early change in the pathogenesis of pre-diabetes. Materials and methods: Subjects were studied on two occasions in random order after an overnight fast. On each day, a graded glucose infusion was used in conjunction with a saline infusion (Saline Day) or an AA mixture (Clinisol (15%, 0.003ml/kg/min; 51% essential AA, 18% branched-chain AA, 9% aromatic AA; Baxter, Healthcare, Deerfield, IL - AA day). The glucagon secretion rate (GSR) was derived by deconvolution from peripheral glucagon concentrations and G50 - the change in glucose required to reduce GSR by 50% - was calculated for each subject. Data are reported as mean ± standard error of the mean (SEM) with significant results indicated by p-value <0.05. Results: Participants studied to date (51.6 ± 3.6 years), were categorized based on body fat percentage as lean (<30%) and overweight or obese (≥35%). The relationship of GSR to glucose concentration is demonstrated in Figure 1. Lean participants (average body fat percentage = 27 ± 2%, BMI = 24 ± 2 kg/m2) showed no significant change in G50 in the presence and absence of AA respectively (1.7 ± 0.8 vs. 1.6 ± 0.7 mmol/L, p = 0.3). However, individuals with obesity (average body fat percentage = 43.6 ± 2.8%, BMI = 31 ± 1 kg/m2) showed significantly higher G50 when infused with AA compared to saline (2.2 ± 0.5 vs. 1.5 ± 0.4 mmol/L, p = 0.04). Conclusion: Obesity is associated with an increase in G50 in the presence of AA suggesting that obesity impairs α-cell suppression by hyperglycemia providing a potential explanation for glucagon elevation in obesity and T2DM.