Insulinotropic Hormone Glucagon-Like Peptide-1-(7-37) Appears Not to Augment Insulin-Mediated Glucose Uptake in Young Men during Euglycemia

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Abstract
Glucagon-like peptide-1 (GLP-1) is an intestinal insulinotropic hor- mone that augments insulin secretion in response to meals and lowers blood glucose levels in both type 1 and type 2 diabetic subjects. It has been proposed that a substantial component of the glucose-lowering effects of GLP-1 occurs via insulin-independent mechanisms. How- ever, the interpretations of the studies have been controversial. This study was conducted to examine whether glucagon-like peptide (GLP-1) has an insulin-like effect during euglycemia. Nine young lean men (age, 25 6 1.4 yr; body mass index, 24.0 6 0.7 kg/m2) volunteered to participate in two euglycemic clamp studies (n 5 18 clamps) for 120 min. The initial clamp was performed with a primed continuous infusion of GLP-1 at a final rate of 1.5 pmol/kgzmin from 0 - 60 min. At 60 min, the GLP-1 infusion was terminated, and euglycemia was maintained from 60 -120 min. After the GLP-1 study, each individ- ual's plasma insulin level was measured. A second study was per- formed that was identical to the first, with the infusion of regular insulin in place of GLP-1. Insulin infusion rates were designed in each individual to simulate plasma insulin levels produced during the GLP-1 infusion. The rate of disappearance of glucose was calculated for each subject. Basal plasma insulin levels were similar between studies and averaged 49 6 5 pmol/L. Basal GLP-1 levels were also similar (6.0 6 1.0 pmol/L). In response to the GLP-1 infusion, although basal plasma glucose levels were clamped, significant increases in insulin occurred in all subjects (P , 0.001). With the nearly identical plasma insulin levels during the two studies (30 - 60 min levels: GLP-1 study, 151 6 48; insulin study, 146 6 31 pmol/L), the rate of disappearance of glucose progressively in- creased in response to both GLP-1 and insulin infusions, but was not significantly different between the studies. The design of the study necessitated conducting the GLP-1 study first, which may have been accompanied by a greater stress than the second study. We, therefore, measured cortisol levels. Basal cortisol (and ACTH) levels were not different. However, cortisol levels significantly increased during the GLP-1 infusions, and this was preceded by an increase in ACTH levels. Somatostatin levels were not different either basally or during the clamps. We conclude that in the eu- glycemic state, an acute infusion of GLP-1 does not have insulin- like effects in lean nondiabetic men. Intravenous administration of GLP-1 activates hypothalamic neuroendocrine neurons. (J Clin Endocrinol Metab 83: 2399 -2404, 1998)

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