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Obesity (Silver Spring). 2008 Jul;16(7):1501-9. doi: 10.1038/oby.2008.229. Epub 2008 Apr 17.

GLP-1 (9-36) amide, cleavage product of GLP-1 (7-36) amide, is a glucoregulatory peptide.

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  • 1Department of Surgery, Johns Hopkins University, School of Medicine, Baltimore, Maryland, USA. delahi1@jhmi.edu

Abstract

OBJECTIVE:

Glucagon-like peptide-1 (GLP-1) (7-36) amide is a glucoregulatory hormone with insulinotropic and insulinomimetic actions. We determined whether the insulinomimetic effects of GLP-1 are mediated through its principal metabolite, GLP-1 (9-36) amide (GLP-1m).

METHODS AND PROCEDURES:

Glucose turnover during two, 2-h, euglycemic clamps was measured in 12 lean and 12 obese (BMI <25 or >30 kg/m(2)) male and female subject volunteers with normal oral glucose tolerance test. Saline or GLP-1m were infused from 0 to 60 min in each study. Additionally, seven lean and six obese subjects underwent a third clamp in which the GLP-1 receptor (GLP-1R) antagonist, exendin (9-39) amide was infused from -60 to 60 min with GLP-1m from 0 to 60 min.

RESULTS:

No glucose infusion was required in lean subjects to sustain euglycemia (glucose clamp) during saline or GLP-1m infusions. However, in obese subjects glucose infusion was necessary during GLP-1m infusion alone in order to compensate for a marked (>50%) inhibition of hepatic glucose production (HGP). Plasma insulin levels remained constant in lean subjects but rose significantly in obese subjects after termination of the peptide infusions. During GLP-1R blockade, infusion of glucose was immediately required upon starting GLP-1m infusions in all subjects due to a more dramatic reduction in HGP, as well as a delayed and modest insulinotropic response.

DISCUSSION:

We conclude that GLP-1m potently inhibits HGP and is a weak insulinotropic agent. These properties are particularly apparent and pronounced in obese but only become apparent in lean subjects during GLP-1 (7-36) receptor blockade. These previously unrecognized antidiabetogenic actions of GLP-1m may have therapeutic usefulness.

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