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 β- and α-cells. Previous studies have focused on the improvements in β-cell function, while the inhibition of α-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/m² 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).The incretin hormone glucagon-like peptide 1 (GLP-1), as well as GLP-1 analogues that are now being used for the treatment of patients with type 2 diabetes, potently suppresses α-cell secretion (1–4). Despite their hyperglycemia, patients with type 2 diabetes tend to have elevated fasting glucagon levels and exaggerated glucagon responses to meal ingestion (5). Since the hyperglucagonemia is thought to contribute to the hyperglycemia of these patients by increasing hepatic glucose production (HGP) (6), it follows that the glucagonostatic effect of GLP-1 may be as important clinically as its insulinotropic effect (7). Glucose-induced inhibition of α-cell secretion may be impaired in type 2 diabetic patients, but pharmacological amounts of GLP-1 have been shown to restore α-cell sensitivity to glucose (8,9), and we recently demonstrated that the glucagon-suppressive effect of GLP-1 was similar in patients with type 2 diabetes and healthy control subjects (10).Thus GLP-1 potently influences both β- and α-cell secretion in patients with type 2 diabetes, but the relative roles of these two effects in relation to the overall glucose-lowering action of GLP-1 are unclear. In the present studies, we sought to determine the importance of the glucagonostatic effect by measuring its contribution to changes in glucose turnover induced by the infusion of GLP-1 in pharmacological doses. We employed the pancreatic clamp technique (11) using somatostatin to block the endogenous secretion from the islets while substituting insulin and/or glucagon levels by infusions designed to mimic either basal levels and/or responses to a GLP-1 infusion rate (1 pmol/kg/min) known to normalize blood glucose in patients with type 2 diabetes (4). All examinations were done in the fasting state with plasma glucose (PG) clamped at individual fasting PG (FPG) levels. The amount of glucose infused to maintain the clamp was expected to accurately reflect the influence of the endocrine perturbations on glucose turnover (decreased hepatic glucose production and increased peripheral disposal).