The glucagonostatic and insulinotropic effects of glucagon-like peptide 1 contribute equally to its glucose-lowering action

Abstract

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.

Research design and 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).

FIG. 1.

Plasma levels of glucose (A), GLP-1 (B), glucagon (C), insulin (D), and C-peptide (E) during day 1 (●), day 2 (▲), day 3 (■), day 4 (△), and day 5 (○). Data shown are means ± SEM. NS indicates P > 0.5.

FIG. 2.

Glucose demand (g) for each day: day 1: GLP-1(insulin stimulation, glucagon inhibition); day 2: GLP-1, somatostatin, basal insulin, basal glucagon; day 3: somatostatin, basal insulin; day 4: somatostatin, “stimulated” insulin (mimicking day 1-insulin response), basal glucagon; day 5: somatostatin, “stimulated” insulin (mimicking day 1-insulin response). Data shown are means ± SEM. A: Glucose demands on each day shown in grams infused (g); means ± SEM. B: Glucose demand calculated from each interval of 30 min on each day. Data shown in grams (g); means ± SEM. NS indicates P > 0.5, *P < 0.5, ***P < 0.001.