The glucagonostatic and insulinotropic effects of glucagon-like peptide 1 contribute equally to its glucose-lowering action.
OBJECTIVE
Glucagon-like peptide 1 (GLP-1) exerts beneficial antidiabetic actions via effects on pancreatic beta- and alpha-cells. Previous studies have focused on the improvements in beta-cell function, while the inhibition of alpha-cell secretion has received less attention. The aim of this research was to quantify the glucagonostatic contribution to the glucose-lowering effect of GLP-1 infusions in patients with type 2 diabetes.


METHODS
Ten male patients with well-regulated type 2 diabetes (A1C 6.9 +/- 0.8%, age 56 +/- 10 years, BMI 31 +/- 3 kg/m(2) [means +/- SD]) were subjected to five 120-min glucose clamps at fasting plasma glucose (FPG) levels. On day 1, GLP-1 was infused to stimulate endogenous insulin release and suppress endogenous glucagon. On days 2-5, pancreatic endocrine clamps were performed using somatostatin infusions of somatostatin and/or selective replacement of insulin and glucagon; day 2, GLP-1 plus basal insulin and glucagon (no glucagon suppression or insulin stimulation); day 3, basal insulin only (glucagon deficiency); day 4, basal glucagon and stimulated insulin; and day 5, stimulated insulin. The basal plasma glucagon levels were chosen to simulate portal glucagon levels.


RESULTS
Peptide infusions produced the desired hormone levels. The amount of glucose required to clamp FPG was 24.5 +/- 4.1 (day 1), 0.3 +/- 0.2 (day 2), 10.6 +/- 1.1 (day 3), 11.5 +/- 2.7 (day 4), and 24.5 +/- 2.6 g (day 5) (day 2 was lower than days 3 and 4, which were both similar and lower than days 1 and 5).


CONCLUSIONS
We concluded that insulin stimulation (day 4) and glucagon inhibition (day 3) contribute equally to the effect of GLP-1 on glucose turnover in patients with type 2 diabetes, and these changes explain the glucose-lowering effect of GLP-1 (day 5 vs. day 1).
Department of Biomedical Sciences, The Panum Institute, University of Copenhagen, Copenhagen, Denmark.
Kristine J
KJ
Hare
Tina
T
Vilsbøll
Meena
M
Asmar
Carolyn F
CF
Deacon
Filip K
FK
Knop
Jens J
JJ
Holst
D000328:Adult; D000704:Analysis of Variance; D019540:Area Under Curve; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000188:drug therapy*; D005934:Glucagon / Q000097:blood* / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000627:therapeutic use*; D015309:Glucose Clamp Technique; D006801:Humans; D007328:Insulin / Q000097:blood* / Q000378:metabolism; D000078790:Insulin Secretion; D008297:Male; D008875:Middle Aged; D013997:Time Factors; D016896:Treatment Outcome
D001786:Blood Glucose; D007328:Insulin; D052216:Glucagon-Like Peptide 1; D005934:Glucagon