In Vivo and Ex Vivo Evaluation of 1,3-Thiazolidine-2,4-Dione Derivatives as Euglycemic Agents

Abstract

Thiazolidinediones (TZDs), used to treat type 2 diabetes mellitus, act as full agonists of the peroxisome proliferator-activated receptor gamma. Unfortunately, they produce adverse effects, including weight gain, hepatic toxicity, and heart failure. Our group previously reported the design, synthesis, in silico evaluation, and acute oral toxicity test of two TZD derivatives, compounds 40 (C40) and 81 (C81), characterized as category 5 and 4, respectively, under the Globally Harmonized System. The aim of this study was to determine whether C40, C81, and a new compound, C4, act as euglycemic and antioxidant agents in male Wistar rats with streptozotocin-induced diabetes. The animals were randomly divided into six groups (n = 7): the control, those with diabetes and untreated, and those with diabetes and treated with pioglitazone, C40, C81, or C4 (daily for 21 days). At the end of the experiment, tissue samples were collected to quantify the level of glucose, insulin, triglycerides, total cholesterol, and liver enzymes, as well as enzymatic and nonenzymatic antioxidant activity. C4, without a hypoglycemic effect, displayed the best antioxidant activity. Whereas C81 could only attenuate the elevated level of blood glucose, C40 generated euglycemia by the end of the treatment. All compounds produced a significant decrease in triglycerides.

Figure 1

(a) The fasting blood glucose level was evaluated in all groups (n = 7). ^∗p ≤ 0.05 vs. T2DM. (b) Body weight of the animals subjected to the different treatments (n = 7). ^∗p ≤ 0.05 vs. T2DM. (c) The glucose tolerance test from 0 to 300 min. Compared to the untreated diabetic rats, the animals treated with derivatives C40, C81, and C4 displayed a lower level of blood glucose at the end of the experiment (n = 7). ^∗p ≤ 0.05 vs. T2DM+Pio (diabetic rats treated with pioglitazone). T2DM, untreated diabetic rats.

Figure 2

Metabolic parameters of the different groups (n = 7): (a) glucose (mg/dL), (b) insulin (ng/mL), (c) triglycerides (mg/dL), (d) cholesterol (mg/dL), (e) ALT (U/L), (f) AST (U/L), and (g) ALP (U/L). ^∗p ≤ 0.01 vs. the untreated diabetic group (T2DM). Pio: pioglitazone.

Figure 3

Enzymatic and nonenzymatic antioxidant activity in the different groups (n = 7): (a) SOD (U/mL), (b) CAT (nmol/min/mL), (c) GSH (μM/g of wet tissue), and (d) TBARS (μmol/μg of wet tissue). ^∗p ≤ 0.01 vs. T2DM (the untreated diabetic rats). Pio: pioglitazone.