Dataset Information

Effects of pioglitazone on insulin sensitivity and serum lipids in obese cats.

ABSTRACT:

Background

Pioglitazone is a thiazolidinedione (TZD) insulin sensitizer approved for use in human type 2 diabetes mellitus. Therapeutic options for diabetes in cats are limited.

Objective

To evaluate the effects of pioglitazone in obese cats, which are predisposed to insulin resistance, to assess its potential for future use in feline diabetes mellitus.

Animals

A total of 12 obese purpose-bred research cats (6 neutered males and 6 spayed females, 5-7 years of age, weighing 5.4-9.8 kg).

Methods

Randomized, placebo-controlled 3-way crossover study. Oral placebo or pioglitazone (Actos™; 1 or 3 mg/kg) was administered daily for 7-week periods, with IV glucose tolerance testing before and after each period.

Results

Three mg/kg pioglitazone significantly improved insulin sensitivity (geometric mean [95% CI] 0.90 [0.64-1.28] to 2.03 [1.49-2.78] min?¹pmol?¹L; P = .0014 versus change with placebo), reduced insulin area under the curve during IVGTT (geometric mean [range] 27 [9-64] to 18 [6-54] min?nmol/L; P = .0031 versus change with placebo), and lowered serum triglyceride (geometric mean [range] 71 [29-271] to 48 [27-75] mg/dL; P = .047 versus change with placebo) and cholesterol (geometric mean [range] 187 [133-294] to 162 [107-249] mg/dL; P = .0042 versus change with placebo) concentrations in the obese cats. No adverse effects attributable to pioglitazone were evident in the otherwise healthy obese cats at this dosage and duration.

Conclusions and clinical importance

Results of this study support a positive effect of 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 might be warranted.

SUBMITTER: Clark M

PROVIDER: S-EPMC4895531 | biostudies-literature | 2014 Jan-Feb

REPOSITORIES: biostudies-literature

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Publications

Effects of pioglitazone on insulin sensitivity and serum lipids in obese cats.

Clark M M Thomaseth K K Dirikolu L L Ferguson D C DC Hoenig M M

Journal of veterinary internal medicine 20140101 1

<h4>Background</h4>Pioglitazone is a thiazolidinedione (TZD) insulin sensitizer approved for use in human type 2 diabetes mellitus. Therapeutic options for diabetes in cats are limited.<h4>Objective</h4>To evaluate the effects of pioglitazone in obese cats, which are predisposed to insulin resistance, to assess its potential for future use in feline diabetes mellitus.<h4>Animals</h4>A total of 12 obese purpose-bred research cats (6 neutered males and 6 spayed females, 5-7 years of age, weighing ...[more]

PMID: 24592408

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Project description:To gain further insight into the role of adipocyte mitochondria in systemic lipid metabolism, inflammation and insulin sensitivity in humans and to provide a better understanding of the mechanisms of action of the peroxisome proliferator-activated receptor gamma agonist pioglitazone. Mitochondrial DNA (mtDNA) copy number, mitochondrial distribution, mitochondrial and overall cellular protein abundances as well as intrinsic mitochondrial function of subcutaneous adipocytes were assessed by real-time quantitative PCR, MitoTracker staining, global proteomics analyses and NADH cytochrome c reductase activity in insulin-sensitive, normal-glucose-tolerant (NGT) individuals and age, gender, adiposity-matched insulin-resistant individuals with abnormal glucose tolerant (AGT) before and after 3 months of pioglitazone treatment. mtDNA copy number/adipocyte and mtDNA copy number/adipocyte volume were ~55% and ~4-fold lower in AGT than in NGT, respectively, and correlated positively with the M-value of euglycemic clamps and high-density lipoprotein, and negatively with fasting plasma triglyceride, tumor necrosis factor-α and interleukin-6 levels in the entire cohort. mtDNA copy number/adipocyte volume also correlated positively with plasma adiponectin. Pioglitazone, which improved insulin sensitivity, plasma lipids and inflammation, increased the mitochondrial copy number, and led to a redistribution of mitochondria from a punctate to a more reticular pattern as observed in NGT. This was accompanied by disproportionately increased abundances of mitochondrial proteins, including those involved in fat oxidation and triglyceride synthesis. Pioglitazone also increased the abundance of collagen VI and decreased the abundance of cytoskeletal proteins. NADH cytochrome c reductase activity of isolated adipocyte mitochondria was similar in AGT and NGT and unaltered by pioglitazone. Adipocyte mitochondria are deficient in insulin-resistant individuals and correlate with systemic lipid metabolism, inflammation and insulin sensitivity. Pioglitazone induces mitochondrial biogenesis and reorganization as well as the synthesis of mitochondrial proteins including those critical for lipid metabolism. It also alters extracellular matrix and cytoskeletal proteins. The intrinsic function of adipocyte mitochondria appears unaffected in insulin resistance and by pioglitazone.International Journal of Obesity advance online publication, 31 October 2017; doi:10.1038/ijo.2017.192.

Project description:BackgroundWeight loss in obese individuals aims to reduce the risk of type 2 diabetes by improving glycemic control. Yet, significant intersubject variability is observed and the outcomes remain poorly predictable.ObjectiveThe aim of the study was to predict whether an individual will show improvements in insulin sensitivity above or below the median population change at 6 mo after a low-calorie-diet (LCD) intervention.DesignWith the use of plasma lipidomics and metabolomics for 433 subjects from the Diet, Obesity, and Genes (DiOGenes) Study, we attempted to predict good or poor Matsuda index improvements 6 mo after an 8-wk LCD intervention (800 kcal/d). Three independent analysis groups were defined: "training" (n = 119) for model construction, "testing" (n = 162) for model comparison, and "validation" (n = 152) to validate the final model.ResultsInitial modeling with baseline clinical variables (body mass index, Matsuda index, total lipid concentrations, sex, age) showed limited performance [area under the curve (AUC) on the "testing dataset" = 0.69; 95% CI: 0.61, 0.77]. Significantly better performance was achieved with an omics model based on 27 variables (AUC = 0.77; 95% CI: 0.70, 0.85; P = 0.0297). This model could be greatly simplified while keeping the same performance. The simplified model relied on baseline Matsuda index, proline, and phosphatidylcholine 0-34:1. It successfully replicated on the validation set (AUC = 0.75; 95% CI: 0.67, 0.83) with the following characteristics: specificity = 0.73, sensitivity = 0.68, negative predictive value = 0.60, and positive predictive value = 0.80. Marginally lower performance was obtained when replacing the Matsuda index with homeostasis model assessment of insulin resistance (AUC = 0.72; 95% CI: 0.64, 0.80; P = 0.08).ConclusionsOur study proposes a model to predict insulin sensitivity improvements, 6 mo after LCD completion in a large population of overweight or obese nondiabetic subjects. It relies on baseline information from 3 variables, accessible from blood samples. This model may help clinicians assessing the large variability in dietary interventions and predict outcomes before an intervention. This trial was registered at www.clinicaltrials.gov as NCT00390637.

Dataset Information

Effects of pioglitazone on insulin sensitivity and serum lipids in obese cats.

Background

Objective

Animals

Methods

Results

Conclusions and clinical importance

Publications

Effects of pioglitazone on insulin sensitivity and serum lipids in obese cats.

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