Associate editor: C.C.Y. PangPeroxisome proliferator-activated receptor gamma as a drug target in the pathogenesis of insulin resistance
Introduction
Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that belong to the nuclear hormone receptor superfamily. Their existence was originally postulated to explain the induction of peroxisome proliferation and associated enzymes by non-mutagenic, structurally diverse hypolipidemic agents that are collectively called peroxisome proliferators (Reddy & Rao, 1986). The cloning of a member of steroid hormone receptor superfamily in mouse liver, which induced peroxisome proliferation upon activation by peroxisome proliferators, strongly corroborates this hypothesis (Issemann & Green, 1990). Shortly thereafter, 3 structurally and functionally similar receptors, which are encoded by separate genes, were cloned in Xenopus. These receptors are named PPAR-alpha (NR1C1), PPAR-beta (also called delta, NR1C2), and PPAR-gamma (NR1C3) (Dreyer et al., 1992), although the latter 2 cousins do not share the peroxisome proliferating character.
PPARs are differentially expressed in a wide range of tissues and thus participate in a variety of cellular function in a number of tissues and organs. For example, PPAR-alpha RNA exists at the highest level in the liver, at moderate levels in the kidney and brown adipose tissue, while at a relatively lower level in the heart and intestine (Jones et al., 1995). PPAR-alpha is believed to play a critical role in the regulation of fatty acids metabolism (Berger & Moller, 2002). In contrast, PPAR-beta is ubiquitously expressed within the body, and in many instances at a much higher levels than either PPAR-alpha or PPAR-gamma (Braissant et al., 1996). Although less well characterized compared with the other 2 subtypes, PPAR-beta has been implicated to be involved in some disorders such as cancer, infertility, and dyslipidemia (Berger & Moller, 2002). PPAR-gamma, the most extensively studied receptor of the 3 subtypes, is predominantly detected in the adipose tissue and the large intestine, intermediately in the kidney, liver, and small intestine and with very limited extent in the muscle (Fajas et al., 1997). While PPAR-gamma has been shown to participate in a variety of normal physiological functions (e.g., adipocyte differentiation), it is also associated with several pathological conditions such as atherosclerosis and cancer (Rosen & Spiegelman, 2001). Accordingly, the 3 subtypes of PPARs mediate a variety of functions that seem to be dependent upon their divergent distribution in the system (Table 1).
Insulin resistance is defined as a state of reduced responsiveness to the normal concentrations of circulating insulin (Saltiel, 2000). It is associated with aging, sedentary lifestyle, as well as genetic predisposition (Zimmet et al., 2001). In addition, insulin resistance often exists together with central obesity, hypertension, polycystic ovarian syndrome, dyslipidemia, and atherosclerosis (Kahn, 1995). This constellation of abnormalities afflicts millions of North Americans.
Insulin resistance can progress to type-2 diabetes, which is characterized by variable degrees of insulin resistance, impaired insulin secretion, and increased glucose production (Powers, 2005). In contrast, some “insulin-resistant” individuals do not have type-2 diabetes. Indeed, these people do not have impaired insulin secretion or high levels of plasma glucose, which are characteristics of type-2 diabetes (Quinones et al., 2004a). However, it would appear that the system must produce large quantities of insulin to maintain the normal glucose plasma levels (Quinones et al., 2004b). In addition, insulin resistance often seems to precede the development of type-2 diabetes (Lillioja et al., 1988). Both longitudinal and cross-sectional studies have indicated that the earliest detectable abnormality in type-2 diabetes is the impairment of the ability of the body to respond to insulin, that is, resistance to the action of insulin (Lillioja et al., 1988, DeFronzo et al., 1992). Interestingly, an initial clinical study revealed that chronic administration of troglitazone (PPAR-gamma agonist) to pregnant women who manifested insulin resistance resulted in an improvement in whole-body insulin sensitivity and a reduction in the incidence of type-2 diabetes (Azen et al., 1998). Accordingly, insulin resistance appears to be a major risk factor for the development of type-2 diabetes and needs medical intervention as early as possible (Lillioja et al., 1993).
There is now substantiative evidence that implies that type-2 diabetes is associated with obesity, especially the accumulation of fat in the visceral abdominal part of the body (Wajchenberg, 2000). The risk of diabetes is reportedly increased by 7.3% upon each kilogram of weight gained (Koh-Banerjee et al., 2004). Furthermore, data from a prospective study have indicated that as little as 4% weight loss is associated with a reduction in the risk of type-2 diabetes (Wannamethee & Shaper, 1999). Increasing evidence supports the view that body weight control improves insulin sensitivity and reduces the risk for type-2 diabetes (Mayer-Davis & Costacou, 2001, Nilsson, 2005). Therefore, the pathogenesis of type-2 diabetes appears to be strongly associated with obesity (Shafrir, 1996). Taken together, insulin resistance is a symptom that manifests before and during type-2 diabetes, and the development of type-2 diabetes appears to be closely linked to the obesity.
There appears to be a connection between PPAR-gamma activation and insulin sensitization. Pharmacological evidence seems to support the view that stimulation of PPAR-gamma alleviates insulin resistance. The most extensively employed insulin-sensitizing drugs, thiazolidinedione derivatives (TZDs), have been found to possess a high affinity for PPAR-gamma (Lehmann et al., 1995). In addition, the binding affinity of the TZDs to PPAR-gamma seems to closely correlate with the potency of their insulin-sensitizing actions (Berger et al., 1996, Willson et al., 1996). Therefore, it has been suggested that the insulin-sensitizing effect of TZDs is mediated via the stimulation of PPAR-gamma. As well, non-TZD-related PPAR-gamma agonists, namely, the oxyiminoacetic acid derivatives have also been demonstrated to have strong anti-diabetic activity (Imoto et al., 2002). Therefore, the evidence implies that PPAR-gamma activation but not other properties of these chemicals mediate the anti-diabetic effects in the insulin-resistant states. In addition, in a mouse model of insulin resistance, retinoid X receptor (RXR) agonists also ameliorate the typical symptoms of insulin resistance (Keller et al., 1993). RXR has been shown to act synergistically with PPAR-gamma (Keller et al., 1993), and RXR agonists are capable of increasing the activity of both types of receptors (Issemann et al., 1993, Mukherjee et al., 1997). This is further evidence to suggest that the activation of PPAR-gamma may mediate anti-diabetic action. Based on these facts, it is thus logical to assume that TZDs, oxyiminoacetic acid derivatives, and RXR ligands are able to mitigate insulin resistance by activating PPAR-gamma. On the other hand, alteration in PPAR-gamma activity appears to influence insulin sensitivity. An individual with a PPAR-gamma gene mutation (proline→alanine) appeared to be at a lesser risk of developing insulin resistance and type-2 diabetes (Altshuler et al., 2000). Moreover, a change of the phosphorylation state of PPAR-gamma magnifies the activity of PPAR-gamma and selectively enhances insulin sensitivity (Rangwala et al., 2003). However, dominant-negative mutations in human PPAR-gamma have been demonstrated to be associated with severe insulin resistance (Barroso et al., 1999). The evidence appears to support the view that alteration of PPAR-gamma activity modifies the pathophysiology of insulin resistance. Therefore, it seems that PPAR-gamma should be a promising drug target for the treatment of insulin resistance.
PPAR-gamma, as a nuclear receptor, becomes activated upon ligand binding. The activation of the receptor either increases or decreases the target gene transcription (Mangelsdorf et al., 1995). The alteration of gene transcription results in the up-regulation of the insulin-sensitizing factors and down-regulation of the insulin-resistant factors. It is suggested that the initiation of obesity-related insulin resistance occurs mainly by 2 mechanisms (Rangwala & Lazar, 2004): (a) interruption of lipid homeostasis leading to an increase of plasma fatty acids concentration that is normally suppressed via the activation of PPAR-gamma, and (b) the activation of factors such as cytokines depressed by PPAR-gamma that also cause insulin resistance (Pittas et al., 2004). Therefore, it is logical to suggest that activation of PPAR-gamma may partially reverse the state of insulin resistance (Roden, 2004). Indeed, activation of PPAR-gamma by TZDs has been reported to ameliorate insulin resistance (Berger et al., 1996, Willson et al., 1996). It appears that PPAR-gamma is a reasonably viable drug target in the treatment of the insulin resistance.
Section snippets
Classification and structure
Like thyroid hormone, retinoic acid, and vitamin D receptors, PPARs have been categorized as class II nuclear receptors (Mangelsdorf et al., 1995). The nuclear receptors in this class share some common properties such as heterodimerizing with RXR and binding to direct repeat sequences of nucleotides (Mangelsdorf et al., 1995). The class II nuclear receptors such as PPAR-gamma are composed of 6 structural regions (A–F) in 4 functional domains (Fig. 1) (Mangelsdorf et al., 1995). The variable NH2
Insulin
Insulin is a polypeptide that contains 2 chains of amino acids linked by disulfide bridges. It is synthesized in the rough endoplasmic reticulum of the beta cells of the islets of Langerhan of the pancreas and then packaged in membrane-bound granules (William, 2005). In healthy people, insulin secretion is stimulated after ingestion of the food containing glucose. Circulating insulin increases the storage of glucose, fatty acids, and amino acids in skeletal muscle via suppression of endogenous
Pathogenesis of insulin resistance
In patients with insulin resistance, IRS phosphorylation, PI 3-kinase activity, and GLUT-4 activity are impaired (Krook et al., 2004). Elevated free fatty acids (FFA), adipose cell-secreted factors most notably tumor necrosis alpha (TNF-alpha), and several other proteins expressed in fat tissue are thought to be factors responsible for the genesis of obesity-related insulin resistance (Rangwala & Lazar, 2004). Moreover, it has been shown that FFA rather than TNF-alpha may play a critical role
Therapeutic implications
Currently non-pharmacological interventions to improve obesity-related insulin resistance include healthy diet, weight reduction, and increased physical activity (Leung et al., 2004). These strategies have been shown to be beneficial based on data from clinical trials (Leung et al., 2004). However, the most appropriate and beneficial therapy for patients who are insulin resistant still relies mainly on the use of oral anti-diabetic medications (Meriden, 2004). At present, the drugs used in
Summary
PPAR-gamma, a ligand-activated transcription factor, becomes activated upon ligand binding. The activation of the receptor either increases or decreases the target gene transcription. These genes have been shown to encode proteins or peptides that participate in the pathogenesis of insulin resistance. Insulin resistance is defined as a state of reduced responsiveness to normal circulating concentrations of insulin. The disease often exists together with central obesity, hypertension, polycystic
Acknowledgments
Research in our laboratory is supported from grants from Natural Sciences and Engineering Research Council of Canada and Heart and Stroke Foundation of New Brunswick. The authors wish to thank Professor Sudesh Vasdev for the helpful discussion during the preparation of this manuscript.
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