Effect of linagliptin, alone and in combination with voglibose or exendin-4, on glucose control in male ZDF rats

• Published in: European journal of pharmacology Vol. 729; pp. 59 - 66
• Main Authors: Jones, Robert B., Vickers, Steven P., Cheetham, Sharon C., Headland, Katie R., Mark, Michael, Klein, Thomas
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 15-04-2014
• Subjects: Animals; Blood Glucose - drug effects; Blood Glucose - metabolism; Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - drug therapy; Drug Therapy, Combination; Exendin-4; GLP-1; Glucose control; Hypoglycemic Agents - administration & dosage; Inositol - administration & dosage; Inositol - analogs & derivatives; Linagliptin; Male; Peptides - administration & dosage; Purines - administration & dosage; Quinazolines - administration & dosage; Rats; Rats, Zucker; Treatment Outcome; Type 2 diabetes; Venoms - administration & dosage; Voglibose; Type 2 diabetes; GLP-1; Linagliptin (PubChem CID:10096344); AUCB2; DPP-4; Voglibose; Voglibose (PubChem CID: 444020); B1; Exendin-4; Glucose control; B2; Exendin-4 (PubChem CID: 16157882); Linagliptin; ZDF
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2014.02.004

The effects of the dipeptidyl peptidase-4 (DPP-4) inhibitor, linagliptin, alone and in combination with voglibose or exendin-4, on glycaemic control and body weight were assessed in an animal model of type 2 diabetes. Voglibose is an α-glucosidase inhibitor but also increases glucagon-like peptide 1 (GLP-1). Exendin-4 is a GLP-1 receptor agonist. Male Zucker Diabetic Fatty (ZDF) rats were dosed for 3 days, fasted overnight and a sucrose/glucose tolerance test was performed. Linagliptin (1mg/kg po) improved glucose tolerance by increasing plasma GLP-1 (active) and insulin secretion, whilst having no effect on body weight. Voglibose (1 and 10mg/kg po) reduced body weight, improved glycaemic control, reduced plasma insulin and increased total but not active GLP-1. The combination of linagliptin and voglibose significantly reduced body weight, improved glycaemic control and reduced plasma insulin compared to linagliptin alone. Furthermore, linagliptin plus voglibose produced a marked increase in GLP-1 (active) at 5min post-sucrose, compared to linagliptin, possibly because linagliptin prevented the degradation of GLP-1 secreted in response to voglibose. Exendin-4 (10μg/kg sc) significantly reduced body weight, improved glucose tolerance but reduced GLP-1 (active). The combination of linagliptin and exendin-4 significantly reduced body weight and improved glycaemic control but had no effect on plasma GLP-1. Overall it did not markedly improve glycaemic control compared to the individual drugs. The improved glucose control, reduced body weight and markedly increased plasma GLP-1 levels in animals given linagliptin with voglibose, suggests that this combination may be particularly beneficial in the treatment of type 2 diabetes.