INTRODUCTION:

Diabetes mellitus is associated with impaired glucose metabolism that leads to an increase in blood glucose levels and free radicals production.¹Metabolic disorders (excessive free radicals generation and diabetes) are closely related. Insulin resistance, a key feature of type II diabetes, is thought as a physiological response to intense oxidative metabolism. Too much dietary intake (free fatty acids) results in enhanced oxidation and leads to the generation of free radicals. This triggers inflammatory response as a protection from further damage and dampens metabolism by

1. Reducing insulin action (local phosphorylation of insulin signaling molecules).

2. Diminishing fatty acid oxidation (reducing the activation of adenosine monophosphate activated protein kinase, increasing malonyl CoA levels and hindering fatty acid entry into the mitochondria).

3. Drop off in mitochondria function and number as mitochondrial deoxyribonucleic acid is unprotected and susceptible to free radicals.²

Auto-oxidation of glucose results in formation of glycoxidation products which generates reactive oxygen radicals. The reduced sugar on the other hand reacts with the free amino acid of proteins, lipids and nucleic acid to form Schiff’s bases that ultimately forms advanced glycation end products.³

PRECINCTS OF CONTEMPORARY AGENTS:

Treatment of diabetes has been focused on sulfonylureas to augment insulin secretion, Metformin to reduce hepatic glucose production, Acarbose to decrease the rate of glucose absorption from gut and glitazones to sensitize the insulin.⁴ Unfortunately, none of the present drugs used in management of Diabetes are unimpeachable. Sulfonylureas result in hypoglycemia, Metformin increases the risk of lactic acidosis while Acarbose causes flatulence and bloating. Rosiglitazone as compared to other oral antidiabetic drugs is correlated with an increased rate of cardiovascular events by 20 % in diabetic patients while thiazolidinedione drug class as a whole is not associated with an increased cardiovascular risk.⁵ Fracture risk is known to increase due to Pioglitazone and Rosiglitazone.⁶ Thiazolidinediones increase bone marrow adiposity and decrease bone formation due to the agonistic activity to peroxisome proliferator activated receptor γ in bone by promoting the differentiation of precursor cell into adipocytes instead of osteoblasts.⁷

NEED FOR ASSORTED ACTIVITIES OF ANTIDIABETIC AGENTS:

The primary goals for treating metabolic syndrome are prevention of type 2 diabetes and cardiovascular events.⁸ As compared to sulfonylureas, glycemic control using Metformin is reported to have an superior impact on the parameters of free radicals oxidation. Metformin is more effective in decreasing glycalated hemoglobin, lipid peroxidation, malonic dialdehyde levels in the serum and increasing superoxide dismutase and glutathione peroxidase in erythrocytes.⁹

Glitazones ameliorate endothelial dysfunction in patients with diabetes, lowers inflammatory markers and reactive oxygen species. Indeed, glitazones lower C-reactive protein by 30 % within a week of treatment.¹⁰

2,4-THIAZOLIDINEDIONE AS ANTIOXIDANT AGENTS:

Drug discovery entered a new era with report of an antidiabetic agent possessing thiazolidinedione ring. 5-[4-(2-methyl-2-phenylpropoxy)benzyl]thiazolidine-2,4-dione (I) was found to have potent hypoglycemic activity in genetically obese and diabetic mice, yellow KK.¹¹

2,4-thiazolidinedione structure is common in a variety of agents and difference in side chain modifications influence their pharmacological actions. Thiazolidinediones are believed to mediate their effects via a variety of targets: peroxisome proliferator activated receptor (PPAR), protein tyrosine phosphate 1B (PTP 1B), mitochondria. Their therapeutic attestation as antidiabetic, antioxidant, anti-inflammatory, antibacterial, antiobesityagents point toward biodynamic nature of 2,4-thiazolidinedione.

Hossain et al. have synthesized a series of 5-arylidene-2,4-thiazolidinediones and its geranyloxy or prenyloxy derivatives (II) and studied for their radical scavenging activity using 1,1-diphenyl-2-picrylhydrazyl assay.¹²

Jeong et al. synthesized multi-substituted benzylidenethiazolidine-2,4-diones by Knoevenagel condensation of di- or tri-substituted 4-hydroxy benzaldehydes [or 1-(3,5-di-tert-butyl-4-hydroxyphenyl) ethanone] (III) with thiazolidine-2,4-dione and evaluated them for antioxidant activities.¹³

CONCLUSION:

Thiazolidinediones have been cited as the most costly oral antidiabetic medications.¹⁴Limiting glucose lowering efficacy (20% maximum decrease in fasting plasma glucose at the maximum recommended dose) and side effect profile (chiefly weight and fluid retention) confines the use of currently available thiazolidinediones.¹⁵

Therefore, novel thiazolidinediones compounds which have superior glucose lowering efficacy coupled with antioxidant activity are needed. This will help in the development of thiazolidinediones derivatives possessing a broad spectrum of activities as to counter major components of metabolic syndrome.

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Received on 11.12.2011 Accepted on 20.12.2011

Asian J. Pharm. Ana. 1(4): Oct. - Dec. 2011; Page 71-73