Review articleThiazolidinediones as antidiabetic agents: A critical review
Graphical abstract
Introduction
Diabetes mellitus (DM) is a metabolic disorder, characterized by hyperglycemia and related problems caused due to deficiency in insulin secretion, insulin action or both in combination. Type 1 diabetes mellitus (T1DM) is associated with lack of insulin, either completely or partially, due to autoimmune-mediated destruction of pancreatic β-cells, whereas type 2 diabetes mellitus (T2DM) is correlated with erratic degrees of insulin resistance, imbalanced insulin secretion, moderate to severe beta-cell apoptosis and increased hepatic glucose production [1]. The hormonal balance of insulin and glucagon sustain glucose homeostasis by controlling its concentration in the blood. An increase in the blood glucose level triggers insulin mediated signaling to lower the raised levels by increasing glucose uptake in the skeletal muscle, adipocytes and kidneys along with the promotion of its utilization and storage in the liver. When the blood glucose level decreases, glucagon acts to promote glucose production and release in the liver and by increasing lipolysis from adipose tissue. Glucose homeostasis can also be influenced by compounds that target glucose regulating processes in the pancreas, liver, skeletal muscles and adipocytes [2]. The conventional pharmaceutical agents used in the treatment of DM include insulin and oral antidiabetic agents such as sulphonylureas, biguanides, thiazolidinediones (TZDs) and γ-glucosidase inhibitors [3].
Section snippets
Historical aspects of TZDs
In early 1975, Japanese based Takeda laboratories synthesized 71 analogues of Clofibrate, in an attempt to discover more potent fibrate hypolipidemic drugs and tested them for their hypolipidemic activity [4]. Interestingly some of these compounds displayed hypoglycemic effects in diabetic mice (Fig. 1). In the year 1982, through extensive studies on structure-activity relationship, the first TZD, Ciglitazone, was discovered with promising lipid and glucose lowering effects in animal models.
Advantages of TZDs
The primary purpose of TZDs is to control hyperglycemia in T2DM patients by lowering the fasting blood glucose levels to normal levels (<100 mg/dL) and reducing the concentration of HbA1c, the glycosylated form of hemoglobin. Higher levels of HbA1c indicate long-term exposure to elevated levels of blood glucose. This is in contrast to an instant measure of glucose, which indicates a “snapshot” of blood sugar levels. Both Rosiglitazone and Pioglitazone act similar in improving glucose levels,
Mechanism of action of TZDs
The molecular mechanisms of biological responses of TZDs are reported to be mediated through the modulation of PPARs [17]. These nuclear receptors identified in mouse in the year 1990 [18], are reported to be activated upon exposure to peroxisome proliferators, such as hypolipidemic drugs, herbicides and industrial plasticizers. In 1992, three isotypes of PPARs, namely, PPAR-α (NR1C1), PPAR-β/δ (NR1C2) and PPAR-γ (NR1C3) in xenopus were reported [19]. PPARs are transcription factors that can be
PPAR based ligands
The structural similarity of PPAR-α, -γ and -δ, particularly in their ligand-binding domains, has rationalized the development/exploration of several synthetic/natural dual- or pan-PPAR agonists. Several reviews have also been reported based on various structural aspects of PPAR receptor [31], [32], [33], [34]. Molecules that display balanced activation (dual agonists) have been hypothesized to provide a better balance between efficacy and side effects when compared to single agonists or dual
TZDs as agents for T2DM
The TZDs which are withdrawn from the clinical use were developed at the time when not much scientific data were available on the structure and the transcriptional mechanisms of PPARs. Recent advances in the understanding of the structure and function of PPARs have led to newer and more rationalized approaches to develop agents of this class. Recent reviews on TZDs as antidiabetic agents have led to a better understanding of the different aspects of their medicinal chemistry [40], [41], [42].
Summary and future perspectives
TZDs are an important class of drugs that act by increasing the transactivation activity of PPARs, as a result of which, they reduce hepatic glucose production, increase peripheral utilization of glucose and lipid metabolism. These actions, therefore, reduce the preload and after load on β-cells and lipid homeostasis. As a result, the effect of endogenous insulin improves so as to maintain the level of blood glucose. Unfortunately, the clinically used TZDs, Troglitazone, Pioglitazone and
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