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Title:Pharmacokinetics and effect of pioglitazone in obese, insulin-resistant cats
Author(s):Clark, Melissa
Director of Research:Ferguson, Duncan C.
Doctoral Committee Chair(s):Ferguson, Duncan C.
Doctoral Committee Member(s):Hoenig, Margarethe; Lavergne, Sidonie N.; Dirikolu, Levent
Department / Program:Comparative Biosciences
Discipline:VMS - Comparative Biosciences
Degree Granting Institution:University of Illinois at Urbana-Champaign
Insulin sensitivity
Abstract:Pioglitazone is a thiazolidinedione (TZD) insulin sensitizer approved for use in human type 2 diabetes mellitus. In addition to improving glycemic control, lipid profiles, and pancreatic β-cell function in diabetics, pioglitazone decreases hepatic triglyceride content in humans with non-alcoholic fatty liver disease. Cats, like humans, are predisposed by obesity to a form of diabetes characterized by peripheral insulin resistance and insulin secretory defects. They are also prone to a syndrome of severe hepatic triglyceride accumulation (hepatic lipidosis) during periods of decreased food intake. Therapeutic options for both diabetes and hepatic lipidosis in cats are limited, and additional treatment choices would be beneficial. The primary goal of this dissertation was to evaluate the effects of pioglitazone on insulin sensitivity in obese, insulin-resistant cats, to assess its potential for use in cats with diabetes mellitus. A secondary goal was to explore a technique for noninvasive measurement of liver fat in cats, to facilitate further study of pioglitazone or other agents in feline hepatic lipidosis. First, pharmacokinetic parameters for pioglitazone were determined in lean and obese cats, and data were used to design an oral dosing regimen for further study. Second, 1 and 3 mg/kg dosages of oral pioglitazone (ActosTM) were administered to 12 obese, insulin-resistant cats in a placebo-controlled 3-way crossover design. Effects on insulin sensitivity were measured using intravenous glucose tolerance testing; additionally, indirect calorimetry was used to detect any species-specific effects of pioglitazone on substrate oxidation or energy expenditure. Third, 1H magnetic resonance spectroscopy (1H MRS) was performed to determine hepatic fat content in the 12 obese cats and in 6 lean cats using a modification of established human methods, and fat content in liver samples from a separate group of 4 lean and 5 obese cats was also determined by chemical triglyceride assay. Oral pioglitazone was rapidly absorbed in cats, with a median bioavailability of 55% and a median half-life of 3 h. After 6 weeks of daily dosing, 3 mg/kg pioglitazone significantly increased insulin sensitivity, reduced insulin area under the curve during IVGTT, and lowered serum triglyceride and cholesterol concentrations in the obese cats. No changes in substrate oxidation or energy expenditure were observed. Pioglitazone concentrations after chronic dosing suggested dose-dependent absorption characteristics for this drug in cats. In the 12 obese and 6 lean cats, median liver fat percentages determined by 1H MRS (6.8% and 1.3% for the obese and lean cats, respectively), were similar to chemical assay values from the 5 obese and 4 lean cats (median liver fat 6% and 1.7%, respectively). Data obtained from these studies demonstrate a positive effect of 3 mg/kg pioglitazone on insulin sensitivity and lipid metabolism in obese cats, and suggest that further evaluation of the drug in cats with diabetes mellitus or other metabolic disorders is warranted. As well, they provide a foundation for continued development of 1H MRS techniques to quantify the effects of therapeutic interventions on liver fat in cats.
Issue Date:2013-05-24
Rights Information:Copyright 2013 Melissa H. Clark
Date Available in IDEALS:2013-05-24
Date Deposited:2013-05

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