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

Abstract

Summary 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, , 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 GLP-1 [7-36 amide] 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) ileum and colon/rectum [1,2]. , together with gastric inhibitory polypeptide (GIP) from the upper gut, acts as a physiological incretin hormone [3,4]. In pharmacological concentrations, exogenous GLP-1 [7-3~6 amide or 7-37] raised insulin and lowered glucagon concentrations also in noninsulin-dependent diabetic (NIDDM) patients [5,6]. By these mechanisms, plasma glucose was normalized by intravenous in NIDDM patients with secondary failure of sulphonylurea treatment within 3-4 h [7]. Therefore, it has been suggested to use GLP-1 [7-36 amide] or GLP-1 [7-37] (which has an identical action profile in rats [8] and

Mechanisms in bariatric surgery: Gut hormones, diabetes resolution, and weight loss

“…These results strongly support that the 2 hormones are involved in the inhibition of appetite and food intake after RYGB. It should be noted that the plasma concentrations of the 2 hormones observed after RYGB are actually greater than those that can be employed in studies of their effects on food intake in healthy individuals because of side effects [64] , [65] , indicating that the magnitude of their responses in the RYGB patients is consistent with a powerful effect on appetite and food intake. Clearly, these results do not exclude the possibility that other gut hormones may also play an important role.…”

Incretin mimetics as pharmacologic tools to elucidate and as a new drug strategy to treat traumatic brain injury

“…Like most endogenous peptides, however, GLP-1 is short-lived in the circulation following its release [92-94]. It is rapidly degraded by the effective protease dipeptidyl peptidase IV (DPP-IV), rendering it inert at the GLP-1R, and then cleared renally.…”

“…Although chiefly localized to pancreatic islets [81,82], GLP-1R expression also occurs on neurons throughout the brain and nervous system (primarily localized to dendrites [92]), which GLP-1 and analogues can readily enter after systemic administration [93-96]. Expanding upon our prior interest of GLP-1 and Ex-4 in T2DM, their insulinotropic and antiapoptotic actions [93,94,97,98], the structure-activity relation of their amino acid sequence [99-101], and their translation to clinic [102,75], we hypothesized that GLP-1R stimulation in brain would provide neurotrophic/protective activity as (i) GLP-1 has trophic action on β-cells [103-108], and (ii) the GLP-1R is coupled to the cAMP second messenger pathway, increases in which are well documented to be associated with neuroprotection [109,110] - a function very different from its prior known role in brain in the regulation of food intake and satiety [111,112].…”

From the Incretin Concept and the Discovery of GLP-1 to Today's Diabetes Therapy

“…Effects of single s.c. GLP-1 injections were extremely short lasting (the plasma half-life of the peptide in humans after iv. injection is around 2 min) (96). Oral administration was out of the question [and effects of buccal administration equally short-lasting (97)].…”