Pioglitazone increases adiponectin and attenuates the appearance of diet-induced insulin resistance in high-fat-fed beagles.

This study investigated the efficacy of thiazolidinediones in mitigating diet-induced obesity and associated glucose intolerance in canines in vivo. We used a multitechnique approach and compared the results related to 1) fasting metabolites, hormones, and lipides; 2) oral glucose tolerance test (OGTT), and 3) hyperinsulinemic euglycemic (HIEG) clamps in 24 healthy dogs that were then fed a high-fat diet and assigned to a placebo group (n = 8) or received a daily dose of pioglitazone group (n = 16) for 56 days. The animals were studied before and after treatment, acting as their own controls, and we used a principal component analysis to combine the results obtained for the three different techniques. Both groups experienced weight gain, with 12% and 14% increases in the placebo and pioglitazone groups, respectively. The fasting level of free fatty acids was increased in both placebo (+17.5%) and pioglitazone groups (+7.7%), as were the insulin levels (+27% and 35%, respectively, in placebo and pioglitazone), but fasting glucose levels were reduced slightly in both (-2.7 and -2.9 mg/dL, respectively). Pioglitazone increased fasting adiponectin levels by 54% between day -1 and day 56. OGTTs revealed a significantly better glucose tolerance in the pioglitazone treatment group compared with the placebo group, as the level of insulin secreted during the OGTT was normalized. HIEG clamps demonstrated that, in the placebo group, glucose infusion rate and glucose utilization decreased in response to the diet, but this effect was prevented by pioglitazone. In conclusion, these findings show that pioglitazone is beneficial in preventing the consequences of dietary metabolic stress and overfeeding in canines.NEW & NOTEWORTHY This study validates the efficacy of the thiazolidinediones (TZD) drug pioglitazone in a fat-fed canine model. Using a novel principal component analysis integrating multimodal data (fasting metabolites, OGTT, and clamp results), we demonstrate that pioglitazone effectively reverses diet-induced glucose intolerance and significantly improves insulin sensitivity. Mechanistically, this improvement is driven by adiponectin action. These findings provide strong evidence supporting TZD use as a prophylactic tool for mitigating metabolic syndrome.