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


RESULTS
Eight T1DM patients (duration of diabetes 14+/-4 years and therefore with presumed defective counter-regulatory response) and eight controls (CON) received a 3h hypoglycaemic hyperinsulinaemic (0.65mU/kg per min) clamp coupled to [6,6-(2)H(2)]glucose, [1-(13)C]leucine and [2-(15)N]glutamine to trace the relative kinetics. Post-absorptive plasma glucose and glucose uptake were increased in T1DM (9.09+/-0.99 vs 5.01+/-0.22mmol/l and 19.5+/-0.9 vs 12.6+/-0.8micromol/kg per min, p<0.01). During the clamp T1DM but not CON required exogenous glucose (4.4+/-1.7micromol/kg per min) to maintain the hypoglycaemic plateau because the endogenous glucose production was significantly suppressed (p<0.01). In T1DM the leucine and phenylalanine 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.
Battezzati
A
A
San Raffaele Scientific Institute, Clinical Research Unit II, Department of Medicine, Milan, Italy.
Benedini
S
S
Sereni
L P
LP
DeTaddeo
F
F
Maffi
P
P
Secchi
A
A
Luzi
L
L
D000328:Adult; D001786:Blood Glucose / Q000378:metabolism; D016022:Case-Control Studies; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism* / Q000503:physiopathology; D004837:Epinephrine / Q000097:blood; D005260:Female; D005934:Glucagon / Q000097:blood / Q000378:metabolism; D005943:Gluconeogenesis / Q000502:physiology; D005947:Glucose / Q000493:pharmacokinetics*; D015309:Glucose Clamp Technique; D005973:Glutamine / Q000378:metabolism / Q000493:pharmacokinetics*; D006801:Humans; D007003:Hypoglycemia / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D007930:Leucine / Q000378:metabolism / Q000493:pharmacokinetics*; D008297:Male; D008657:Metabolic Clearance Rate
D001786:Blood Glucose; D007328:Insulin; D005973:Glutamine; D005934:Glucagon; D007930:Leucine; D005947:Glucose; D004837:Epinephrine