Once daily injection of exendin-4 to diabetic mice achieves long-term beneficial effects on blood glucose concentrations

Glucagon-like peptide-1 is the main hormonal mediator of the enteroinsular axis. Recently, it has additionally received considerable attention as a po ssible new treatment for Type II (non-insulin-dependent) diabetes mellitus. Its major disadvantage is that its duration of action is too short to achi eve good 24-h metabolic control. Exendin-4, which is produced in the saliva ry glands of Gila monster lizards, is structurally similar to glucagon-like peptide-1 and shares several useful biological properties with glucagon-li ke peptide-1. It binds the glucagon-like peptide-1 receptor, stimulates ins ulin release and increases the cAMP production in beta cells. We report tha t exendin-4 is a more potent insulinotropic agent when given intravenously to rats than is glucagonlike peptide-1 (ED50 0.19 nmol/kg for glucagon-like peptide-1 vs 0.0143 nmol/kg for exendin-4) and causes a greater elevation in cAMP concentrations in isolated islets. Of even greater interest we foun d that when given intraperitoneally only once daily to diabetic mice it had a prolonged effect of lowering blood glucose. After 1 week of treatment bl ood glucoses were 5.0 +/- 2.6 mmol/l compared to diabetic concentrations of 13.2 +/- 2.5 mmol/l. After 13 weeks of daily treatment HbA(1c) was 8.8 +/- 0.4% in non-treated diabetic animals compared with 4.7 +/- 0.25% in treate d diabetic animals. Blood glucoses also were lower (p < 0.005) and insulin concentrations higher (p < 0.02) in the treated animals. Exendin-4 could th erefore be preferable to glucagon-like peptide-1 as a long-term treatment o f Type II diabetes.