GLP‐1 derivative liraglutide in rats with β‐cell deficiencies: influence of metabolic state on β‐cell mass dynamics

Abstract

1 Liraglutide is a long-acting GLP-1 derivative, designed for once daily administration in type II diabetic patients. To investigate the effects of liraglutide on glycemic control and b-cell mass in rat models of b-cell deficiencies, studies were performed in male Zucker diabetic fatty (ZDF) rats and in 60% pancreatectomized rats. 2 When liraglutide was dosed s.c. at 150 mg kg À1 b.i.d. for 6 weeks in ZDF rats 6 -8 weeks of age at study start, diabetes development was markedly attenuated. Blood glucose was approximately 12 mm lower compared to vehicle (Po0.0002), and plasma insulin was 2 -3-fold higher during a normal 24-h feeding period (Po0.001). Judged by pair feeding, approximately 53% of the antihyperglycemic effect observed on 24-h glucose profiles was mediated by a reduction in food intake, which persisted throughout the study and averaged 16% (Po0.02). 3 Histological analyses revealed that b-cell mass and proliferation were significantly lower in prediabetic animals still normoglycemic after 2 weeks treatment compared to vehicle-treated animals that had begun to develop diabetes. When the treatment period was 6 weeks, the liraglutide-treated animals were no longer completely normoglycemic and the b-cell mass was significantly increased compared to overtly diabetic vehicle-treated animals, while b-cell proliferation was unaffected. 4 In the experiments with 60% pancreatectomized rats, 8 days treatment with liraglutide resulted in a significantly lower glucose excursion in response to oral glucose compared to vehicle treatment. Again, part of the antihyperglycemic effect was due to reduced food intake. No effect of liraglutide on b-cell mass was observed in these virtually normoglycemic animals. 5 In conclusion, treatment with liraglutide has marked antihyperglycemic effects in rodent models of b-cell deficiencies, and the in vivo effect of liraglutide on b-cell mass may in part depend on the metabolic state of the animals.

Mechanisms of action of glucagon-like peptide 1 in the pancreas

“…No apparent changes in non-β cell islet mass as measured by a cocktail of antibodies against glucagon, somatostatin, and pancreatic polypeptide No significant increases in β cell volume or proliferation (Sturis et al, 2003) Zucker fa/fa 9 weeks old nondiabetic Ex-4, 3 μg/kg body weight twice a day for 6 weeks Decreased HbA1c in Ex-4 treated mice and par fed controls Hyperinsulinemic euglycemic clamp revealed improved insulin sensitivity in Ex-4 treated animals than in the par fed or the controls Animals treated with Ex-4 showed a decrease in β cell mass…”

The Physiology of Glucagon-like Peptide 1

“…Impressively, GLP-1 or exendin 4 administration for 5 days in the neonatal Goto-Kakisaki (GK) rat, a polygenetic and hypoinsulinemic model of type 2 diabetes, resulted in persistent improvement in glucose homeostasis and maintenance of beta-cell mass adult age (290). It is important to note that the trophic effects of GLP-1 agonists in rodents, like their insulinotropic properties, are coupled to the presence of hyperglycemia, and also to note that as GLP-1 alleviates hyperglycemia, which is in itself a very strong stimulus to beta-cell growth in rodents; this growth stimulus is reduced (272). Thus, in nondiabetic rats, the increase in beta-cell mass was transient and disappeared upon prolonged administration (6 wk) of a stable long-acting GLP-1 analog (20).…”

Effect of renal impairment on the pharmacokinetics of the GLP‐1 analogue liraglutide

“…In vitro receptor studies have shown liraglutide to be a potent and selective agonist on the cloned human GLP-1 receptor, and animal studies have shown it to be capable of lowering blood glucose, stimulating insulin secretion, reducing plasma glucagon levels, inhibiting appetite and gastric emptying, reducing body weight, and increasing b-cell volume or mass [22][23][24][25][26][27].…”