The glucagon-receptor antagonist MK-3577 reduces glucagon-stimulated plasma glucose and insulin concentrations in metabolically healthy overweight cats

• Published in: Domestic animal endocrinology 2024-10, Vol.89, p.106874, Article 106874
• Main Authors: Mott, J, Celly, C, Glock, R, Gilor, C
• Format: Article
• Language: English
• Subjects: Animals; Blood Glucose; Cat Diseases - drug therapy; Cats; Cross-Over Studies; Diabetes; Feline; Female; Glucagon - blood; Glucagon receptor antagonist; Glucagon stimulation; Insulin; Insulin - blood; Male; Overweight - veterinary; Quinolizines; Receptors, Glucagon - antagonists & inhibitors
• ISSN: 0739-7240; 1879-0054; 1879-0054
• DOI: 10.1016/j.domaniend.2024.106874

•MK-3577, a glucagon receptor antagonist has about a 15-hour half-life in cats.•MK-3577 treated cats exhibit blunted glucagon-induced rise of glucose and insulin.•MK-3577 lowers insulin requirement to maintain fasting euglycemia in treated cats. The role of glucagon disturbances in diabetes mellitus is increasingly recognized and, hence, glucagon antagonism might aid in treatment of hyperglycemia and other metabolic disturbances. The aim of this study was to assess the pharmacokinetics of the glucagon receptor antagonist MK-3577 and its effect on plasma glucose, insulin, and glucagon concentrations in healthy cats. In a cross-over placebo-controlled study, 5 purpose-bred cats were treated with either Placebo, MK-3577 (1 mg/kg), or MK-3577 (3 mg/kg). Glucose, insulin and glucagon concentrations were measured at 0, 15, 225, 240 min post-treatment administration. Glucagon (20 mcg/kg, IM) was administered at 240 min and glucose and insulin were measured at 255, 265, 275, 285 and 300 min. Plasma MK-3577 concentrations peaked at 4.2 and 3.2 hours after 1 and 3 mg/kg dosing with a half-life of 14.8h and 15.5h respectively. Baseline glucose, insulin and glucagon concentrations did not differ significantly between treatment groups. At a dose of 3 mg/kg, MK-3577 blunted the glucagon-stimulated rise of glucose (p=0.0089) and insulin (p=0.02). Similar trends were observed with MK-3577 at the 1 mg/kg dose but the effect was smaller, and not significant. In conclusion, the GRA MK-3577 has a pharmacokinetic profile suitable for diminishing the glucagon-induced rise of glucose and insulin in healthy cats.