Metabolic effects of sustained activation of the GLP-1 receptor alone and in combination with background GIP receptor antagonism in high fat-fed mice.
OBJECTIVE
Enzyme-resistant glucagon-like peptide-1 (GLP-1) receptor agonists and GIP receptor antagonists have been proposed to have therapeutic potential for the treatment of type 2 diabetes. Such benefits are based on actions mediated primarily through stimulation of insulin secretion or alleviation of insulin resistance respectively. This study examined the long-term actions of the stable GLP-1 receptor agonist (D-Ala(8))GLP-1 and the GIP receptor antagonist (Pro(3))GIP alone and in combination in high fat-fed mice.


METHODS
Mice on high-fat diet for 155 days were injected once daily with (D-Ala(8))GLP-1 or (Pro(3))GIP (25 nmol/kg body weight) for 24 days. In the following 24-day period, half of the (Pro(3))GIP-treated mice were administered an additional dose of (D-Ala(8))GLP-1 (25 nmol/kg body weight), while the remaining mice continued their original treatment regimes.


RESULTS
Daily intraperitoneal injections of (D-Ala(8))GLP-1 or (Pro(3))GIP restored glycaemic control to normal levels and significantly (p < 0.05) improved glucose tolerance compared with high-fat controls by day 24. Food intake and body weights were not affected. On day 48, all treatment groups displayed significantly improved glucose tolerance (p < 0.05) and insulin sensitivity (p < 0.001) compared with high-fat controls on day 48. HDL cholesterol levels were significantly increased in mice treated with (D-Ala(8))GLP-1 alone (p < 0.05) or in combination with (Pro(3))GIP (p < 0.01) compared with normal chow-fed controls.


CONCLUSIONS
These results illustrate efficacy of (Pro(3))GIP and (D-Ala(8))GLP-1 for treatment of glucose intolerance and insulin resistance caused by high-fat feeding. Combination therapy appeared to have little benefit over either treatment alone.
Irwin
N
N
School of Biomedical Sciences, University of Ulster, Northern Ireland, UK. n.irwin@ulster.ac.uk
McClean
P L
PL
Hunter
K
K
Flatt
P R
PR
D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D004041:Dietary Fats / Q000008:administration & dosage; D004359:Drug Therapy, Combination; D005260:Female; D005749:Gastric Inhibitory Polypeptide / Q000008:administration & dosage / Q000494:pharmacology*; D052216:Glucagon-Like Peptide 1 / Q000008:administration & dosage / Q000494:pharmacology*; D000067757:Glucagon-Like Peptide-1 Receptor; D018149:Glucose Intolerance / Q000378:metabolism; D007274:Injections, Intraperitoneal; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000502:physiology; D051379:Mice; D011964:Receptors, Gastrointestinal Hormone / Q000037:antagonists & inhibitors; D018027:Receptors, Glucagon / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016896:Treatment Outcome
D001786:Blood Glucose; D004041:Dietary Fats; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D007328:Insulin; D011964:Receptors, Gastrointestinal Hormone; D018027:Receptors, Glucagon; D005749:Gastric Inhibitory Polypeptide; D052216:Glucagon-Like Peptide 1; C041086:gastric inhibitory polypeptide receptor