Synergistic effect of the human GLP-1 analogue liraglutide and a dual PPARalpha/gamma agonist on glycaemic control in Zucker diabetic fatty rats.
OBJECTIVE
Combination therapies are increasingly common in the clinical management of type 2 diabetes. We investigated to what extent combined treatment with the human glucagon-like peptide-1 (GLP-1) analogue liraglutide and the dual PPARalpha/gamma agonist ragaglitazar would improve glycaemic control in overtly diabetic Zucker diabetic fatty (ZDF) rats.


METHODS
Ninety overtly diabetic male ZDF rats were stratified into groups with matched haemoglobin A1c (HbA1c) (9.0+/-0.1%). Liraglutide (15 and 50 microg/kg subcutaneously twice daily), ragaglitazar (1 and 3 mg/kg perorally once daily) and their vehicles were studied as monotherapy and in combination in a 3x3 factorial design.


RESULTS
After 4-week treatment, synergistic effects on HbA1c, non-fasting morning blood glucose (BG) and/or 24-h BG profiles were observed with three of the four combinations. The relationship between plasma insulin and BG in combination-treated animals approached that of historical lean ZDF rats representing normal glucose homeostasis, suggesting that insulin secretion and insulin sensitivity were markedly improved. Increased insulin immunostaining in islets further supports the improved beta-cell function and/or insulin sensitivity in combination-treated animals. The synergistic effect on glycaemic control was found without a similar synergistic increase in beta-cell mass in the combination groups.


CONCLUSIONS
Our data demonstrate that combination treatment with a human GLP-1 analogue and a dual PPARalpha/gamma agonist through distinct mechanism of actions synergistically improves glycaemic control in the ZDF rat.
Brand
C L
CL
Research and Development, Novo Nordisk A/S, Maaloev, Denmark.
Galsgaard
E D
ED
Tornehave
D
D
Rømer
J
J
Gotfredsen
C F
CF
Wassermann
K
K
Knudsen
L B
LB
Vølund
A
A
Sturis
J
J
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D003920:Diabetes Mellitus / Q000188:drug therapy*; D004195:Disease Models, Animal; D004357:Drug Synergism; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006442:Glycated Hemoglobin / Q000032:analysis; D018398:Homeodomain Proteins / Q000032:analysis; D006706:Homeostasis / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007150:Immunohistochemistry; D007328:Insulin / Q000097:blood; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000276:immunology; D000069450:Liraglutide; D010078:Oxazines / Q000627:therapeutic use*; D010666:Phenylpropionates / Q000627:therapeutic use*; D051381:Rats; D011924:Rats, Zucker; D015534:Trans-Activators / Q000032:analysis
D001786:Blood Glucose; D052216:Glucagon-Like Peptide 1; D006442:Glycated Hemoglobin; D018398:Homeodomain Proteins; D007004:Hypoglycemic Agents; D007328:Insulin; D000069450:Liraglutide; D010078:Oxazines; D010666:Phenylpropionates; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; C432703:ragaglitazar