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/m²) 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.