Protein and glutamine kinetics during counter-regulatory failure in type 1 diabetes

Background and aims: Healthy individuals counteract insulin-induced hypoglycaemia by increasing glutamine utilization but not proteolysis. Glucagon is important to this response because it increases glutamine uptake. In type 1 diabetes (T1DM) glucagon and epinephrine responses to hypoglycaemia are defective. We investigated whether glutamine and amino acid utilization during hypoglycaemia is altered in T1DM with defective counter-regulatory responses. Methods and results: Eight T1DM patients (duration of diabetes 14 4 years and therefore with presumed defective counter-regulatory response) and eight controls (CON) received a 3 h hypoglycaemic hyperinsulinaemic (0.65 mU/kg per min) clamp coupled to [6,6-H-2(2)]glucose, [1-C-13] leucine and [2-N-15]glutamine to trace the relative kinetics. Post-absorptive plasma glucose and glucose uptake were increased in T1DM (9.09 +/- 0.99 vs 5.01 +/- 0.22 mmol/l and 19.5 +/- 0.9 vs 12.6 +/- 0.8 mu mol/kg per min, p < 0.01). During the clamp T1DM but not CON required exogenous glucose (4.4 +/- 1.7 mu mol/kg per min) to maintain the hypoglycaemic plateau because the endogenous glucose production was significantly suppressed (p < 0.01). In T1DM the leucine and phenylatanine concentrations were less suppressed from basal (p < 0.05) despite a similar insulin suppression of proteolysis (-16 +/- 2 vs -20 +/- 4%, p = ns) indicating a defective stimulation of leucine metabolic clearance from basal (+18 +/- 3% vs +55 +/- 9%, p < 0.01). Glutamine concentration remained unchanged from basal (-7 +/- 3% vs -35 +/- 3%, p < 0.01) and the clearance of glutamine was markedly defective in T1DM (+6 +/- 2%) in comparison with controls (+22 +/- 4%; p = 0.02). Conclusions: In T1DM, the counter-regulatory failure to hypoglycaemia seems to be associated with a defective glutamine utilization. The failure to clear circulating amino acids, specifically glutamine, during hypoglycaemia may adversely affect gluconeogenesis. (C) 2008 Elsevier B.V. All rights reserved.