The short half-life of glucagon-like peptide-1 in plasma does not reflect its long-lasting beneficial effects.
The incretin hormone glucagon-like peptide-1 (GLP-1) is capable of ameliorating glucose-dependent insulin secretion in subjects with diabetes. However, its very short half-life (1.5-5 min) in plasma represents a major limitation for its use in the clinical setting. The present study was designed to characterize the duration of the effect of GLP-1 in the Zucker diabetic fatty (ZDF) rat. ZDF rats were subjected to a 48 h infusion of human GLP-1 (30 pmol/kg per min), followed by an i.p. glucose tolerance test (IPGTT) (1 g/kg body weight), 2 h after removing the infusion pump. At 15 min from the beginning of the test, GLP-1-treated animals had lower plasma glucose levels (442+/-38 mg/dl) than saline-infused controls (583+/-63 mg/dl, P<0.01). This was reflected in the higher insulin levels attained in the GLP-1-treated animals (1999+/-163 vs 1250+/-51 pmol/l, GLP-1 vs saline respectively, P<0.01). Repetition of the IPGTT on day 3, 9 and 16 from the removal of the infusion pump revealed a surprising lasting 'memory' of the exposure to GLP-1. Indeed, the best insulin secretory response was observed approximately 1 week after discontinuation of the GLP-1 infusion, and lasted up to 3 weeks from the early exposure to GLP-1. Detection of fasting plasma levels of GLP-1 during the 3 weeks of the experiment showed a very rapid decline, consistent with the data reported by others. Our findings provide evidence for a long-lasting beneficial effect of GLP-1 that persists for weeks even when the circulating levels of GLP-1 are back to normal.
Hui
Hongxiang
H
Division of Endocrinology and Metabolism, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.
Farilla
Loredana
L
Merkel
Patricia
P
Perfetti
Riccardo
R
D000818:Animals; D001835:Body Weight; D005934:Glucagon / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D052216:Glucagon-Like Peptide 1; D005951:Glucose Tolerance Test; D006207:Half-Life; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D008297:Male; D010446:Peptide Fragments / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D011498:Protein Precursors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D051381:Rats; D013997:Time Factors
D007328:Insulin; D010446:Peptide Fragments; D011498:Protein Precursors; D052216:Glucagon-Like Peptide 1; D005934:Glucagon