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

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

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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Blood Glucose / drug effects
  • Blood Glucose / metabolism*
  • Female
  • Glucagon-Like Peptide 1 / administration & dosage
  • Glucagon-Like Peptide 1 / analogs & derivatives*
  • Glucagon-Like Peptide 1 / metabolism
  • Glucagon-Like Peptide-1 Receptor
  • Glucose Clamp Technique
  • Glucose Tolerance Test
  • Humans
  • Hypoglycemic Agents / administration & dosage
  • Hypoglycemic Agents / metabolism*
  • Infusions, Parenteral
  • Insulin / blood*
  • Liver / drug effects
  • Liver / metabolism*
  • Male
  • Middle Aged
  • Obesity / metabolism*
  • Peptide Fragments / administration & dosage
  • Peptide Fragments / metabolism*
  • Peptide Fragments / pharmacology
  • Peptides / administration & dosage
  • Peptides / metabolism*
  • Receptors, Glucagon / drug effects
  • Receptors, Glucagon / metabolism*
  • Time Factors

Substances

  • Blood Glucose
  • GLP1R protein, human
  • Glucagon-Like Peptide-1 Receptor
  • Hypoglycemic Agents
  • Insulin
  • Peptide Fragments
  • Peptides
  • Receptors, Glucagon
  • glucagon-like peptide-1 (9-36)-amide
  • glucagon-like peptide 1 (7-36)amide
  • exendin (9-39)
  • Glucagon-Like Peptide 1