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Physiology and pharmacology of diabetes therapies in the cat: insulin detemir, insulin glargine, exenatide and the incretin effect

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Title: Physiology and pharmacology of diabetes therapies in the cat: insulin detemir, insulin glargine, exenatide and the incretin effect
Author(s): Gilor, Chen
Director of Research: Graves, Thomas K.
Doctoral Committee Chair(s): Graves, Thomas K.
Doctoral Committee Member(s): Campbell, Karen L.; Dossin, Olivier; MacNeill, Amy L.; Swanson, Kelly S.
Department / Program: Vet Clinical Medicine
Discipline: VMS-Veterinary Clinical Medcne
Degree Granting Institution: University of Illinois at Urbana-Champaign
Degree: Ph.D.
Genre: Dissertation
Subject(s): Feline Isoglycemic clamp Pancreas Glucagon Insulin Gastric Inhibitory Peptide
Abstract: Diabetes mellitus is a common disease in cats. Most diabetic cats depend on insulin therapy to survive but traditional insulin formulations are associated with adverse effects and poor compliance. Novel insulin analogs and incretin-based therapies are more effective and have fewer side effects than traditional therapies. We studied some of these novel therapies in healthy cats. We used the isoglycemic clamp method to compare the pharmacodynamics of the synthetic insulin analogs, insulin detemir and insulin glargine. An analog-sensitive insulin ELISA was used at the same time to measure exogenous insulin concentrations. We also used the isoglycemic clamp method to study the pharmacodynamics of the GLP-1 mimetic, exenatide. An exenatide-specific ELISA was used for evaluation of exenatide pharmacokinetics. Finally, we studied the incretin effect in cats and compared the effect of glucose, lipids or amino acids on secretion of the incretin hormones glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1). The isoglycemic clamp method was used to compare the effects of the 3 treatments on insulin secretion. We found that insulin detemir and insulin glargine have similar pharmacodynamics in healthy cats. With durations of actions of approximately 12 hours and significant variability in their time-action profiles, their efficacy and safety as once-a-day drugs is questionable. We found that exenatide stimulates insulin secretion in cats in a glucose-dependent manner, but it did not increase glucose tolerability. Its absorption after subcutaneous injection was rapid, but so was its clearance from the blood. Therefore, the use of exenatide, in its current formulation for treatment of diabetes in cats, is questionable. Finally, we found that a glucose-stimulated incretin effect does occur in cats, it is probably mediated by GLP-1, and its magnitude is lower than reported in other species. This small incretin effect is probably related to the fact that GIP secretion was not stimulated by oral glucose. GIP secretion was strongly stimulated by oral amino acids and even more so, by oral lipids. GLP-1 secretion was stimulated to a similar degree by all three nutrients.
Issue Date: 2010-05-19
URI: http://hdl.handle.net/2142/16049
Rights Information: Copyright 2010 Chen Gilor
Date Available in IDEALS: 2010-05-19
Date Deposited: May 2010
 

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