Age-Dependent Development of Metabolic Derangement and Effects of Intervention with Pioglitazone in Zucker Diabetic Fatty Rats

Abstract

Zucker diabetic fatty (ZDF) rats are a standard animal model for the study of type 2 diabetes and for pharmacological characterization of insulin-sensitizing drugs. To analyze the agedependent development of their metabolic derangements and the associated changes in their responses to treatment with the insulin sensitizer pioglitazone, groups of 7, 10.5, or 15.5-weekold ZDF rats were treated orally with vehicle or pioglitazone (12 mg/kg/day). Metabolic parameters including circulating concentrations of glucose, insulin, lipids, and adiponectin as well as body weight, tissue glycogen content, and the activity of p70S6 kinase in skeletal muscle were determined. Blood glucose of ZDF rats rose steeply from 5.9 Ϯ 0.4 to 23.7 Ϯ 0.5 mM between 7 and 13 weeks of age and then reached a new steady state, which was associated with increased tissue glycogen content (in 15-week-old ZDF rats versus lean littermates: skeletal muscle, 18.0 Ϯ 0.9 versus 10.5 Ϯ 1.4 mol/g; liver, 181 Ϯ 6 versus 109 Ϯ 14 mol/g; both p Ͻ 0.001). Early intervention with pioglitazone at 7 weeks of age fully prevented the development of hyperglycemia (blood glucose, 6.4 Ϯ 0.4 versus 18.7 Ϯ 1.5 mM after 5.5 weeks of treatment), which was accompanied by a 40% (p ϭ 0.01) reduction of the activity of p70S6 kinase in skeletal muscles. These beneficial effects of pioglitazone were progressively lost, if treatment was initiated at later stages of disease development. Thus, ZDF rats are suitable for preclinical characterization of insulin-sensitizing thiazolidinediones in many aspects, but several important differences versus human type 2 diabetes exist and are to be considered in the use of this animal model.

Childhood Obesity and Environmental Chemicals

“…Pioglitazone exposures beginning in late puberty nearly doubled fat‐pad weight in these rats, while causing a more modest increase in fat‐pad mass in older rats 165. These effects on adiposity may have been mediated by increased food intake among rats exposed to pioglitazone 165. Similarly, pubertal exposure to rosiglitazone increased brown and white adipose tissue mass of rats 166.…”

“…Animal studies favor a positive association between TZDs and obesity. Body‐weight gain was substantially greater in rats that were exposed to pioglitazone in late puberty compared with unexposed rats 165. Pioglitazone exposures beginning in late puberty nearly doubled fat‐pad weight in these rats, while causing a more modest increase in fat‐pad mass in older rats 165.…”

“…Body‐weight gain was substantially greater in rats that were exposed to pioglitazone in late puberty compared with unexposed rats 165. Pioglitazone exposures beginning in late puberty nearly doubled fat‐pad weight in these rats, while causing a more modest increase in fat‐pad mass in older rats 165. These effects on adiposity may have been mediated by increased food intake among rats exposed to pioglitazone 165.…”

Repeated Electroacupuncture in Obese Zucker Diabetic Fatty Rats: Adiponectin and Leptin in Serum and Adipose Tissue

“…Drugs such as thiazolidinediones (TZDs, e.g., pioglitazone) are effective in preventing hyperglycemia or restoring normoglycemia in Zucker diabetic fatty (ZDF) rats if the treatment is started at a young age of <9 weeks [1]. The antidiabetic action of TZDs requires adiponectin, with plasma adiponectin levels being raised through TZD effects on synthesis and secretion by white adipose tissue [2,3].…”

The effects of amino acids on glucose metabolism of isolated rat skeletal muscle are independent of insulin and the mTOR/S6K pathway

“…In human muscle, high fatty acids lower intracellular glucose 6-phosphate, indicating inhibitory action on the level of glucose transport/phosporylation (20). More stringent regulation of glucose utilization on the level of transport/ phosporylation in human than in rodent muscle could also explain why muscle glycogen stores are decreased in type 2 diabetic patients but increased in comparable rodent models (11,22). 5 and present study) vs. inhibition on the level of glucose transport and a decrease in glucose 6-phosphate in human muscle (presumably mediated by mTOR and S6K) (9,15,25).…”