Pharmacokinetic, insulinotropic, and glucagonostatic properties of GLP-1 [7–36 amide] after subcutaneous injection in healthy volunteers. Dose-response-relationships

✍ Scribed by R. Ritzel; C. Ørskov; J. J. Holst; M. A. Nauck

• Publisher: Springer
• Year: 1995
• Tongue: English
• Weight: 656 KB
• Volume: 38
• Category: Article
• ISSN: 0012-186X
• DOI: 10.1007/bf00401846

✦ Synopsis

Intravenous infusions of glucagon-like peptide 1 (GLP-1) [7-36 amide] are glucose-dependently insulinotropic and glucagonostatic and normalize plasma glucose concentrations in non-insulindependent diabetic patients. It was the aim of this study to investigate whether subcutaneous GLP-1 [7-36 amide] also has an influence on insulin and glucagon secretion, and which doses are required for significant effects. Therefore, eight healthy volunteers (24 + 2 years, body mass index [BMI] 21.9 + 2.3 kg/ m 2) were studied in the fasting state on five occasions in randomized order. Placebo (0.9 % NaC1 with 1% human serum albumin) or GLP-1 [7-36 amide] in doses of 0.15, 0.5, 1.5 or 4.5 nmol/kg body weight (volume i ml or, at the highest dose, 2 ml) was administered subcutaneously. An intravenous glucose bolus (0.33 g/kg body weight) was injected 30 min later. Blood was drawn for the measurement of glucose, insulin, C-peptide, GLP-1 [7-36 amide], and glucagon using specific radioimmunoassays. There were dose-related increments in GLP-1 [7-36 amide] concentrations (p < 0.0001). However, basal values were reached again after 90-120 min. Before glucose administration, insulin (p<0.0001) and C-peptide (p<0.0004) increased, whereas glucagon (p= 0.0018) and glucose (p < 0.0001) decreased in a dosedependent manner. After glucose stimulation, integrated increments in insulin (p = 0.0007) and C-peptide (p--0.02) were augmented and ka-values increased (p < 0.0001) in a dose-related fashion. The extent of reactive hypoglycaemia was related to the GLP-1 [7-36 amide] dose. With the highest GLP-1 [7-36 amide] dose, at the time of peak plasma concentrations, most volunteers felt unwell, and nausea and vomiting were observed in four subjects. In conclusion, subcutaneous is also able to stimulate insulin and inhibit glucagon secretion, thereby altering glucose assimilation. However, with unmodified GLP-1 [7-36 amide], the duration of action is short, and with high doses side effects are common. [Diabetologia (1995) 38: 720-725] Key words GLP-1 [7-36 amide], incretin, insulin, glucagon, pharmacokinetics Glucagon-like peptide i [7-36 amide] is an insulinotropic hormone probably secreted from enteroglucagon-producing L cells in the lower gut, i.e. the