PPARγ Partial Agonists Research Articles

Halofenate Is a Selective Peroxisome Proliferator–Activated Receptor γ Modulator With Antidiabetic Activity

Halofenate has been shown previously to lower triglycerides in dyslipidemic subjects. In addition, significant decreases in fasting plasma glucose were observed but only in type 2 diabetic patients. We hypothesized that halofenate might be an insulin sensitizer, and we present data to suggest that halofenate is a selective peroxisome proliferator-activated receptor (PPAR)-gamma modulator (SPPARgammaM). We demonstrate that the circulating form of halofenate, halofenic acid (HA), binds to and selectively modulates PPAR-gamma. Reporter assays show that HA is a partial PPAR-gamma agonist, which can antagonize the activity of the full agonist rosiglitazone. The data suggest that the partial agonism of HA may be explained in part by effective displacement of corepressors (N-CoR and SMRT) coupled with inefficient recruitment of coactivators (p300, CBP, and TRAP 220). In human preadipocytes, HA displays weak adipogenic activity and antagonizes rosiglitazone-mediated adipogenic differentiation. Moreover, in 3T3-L1 adipocytes, HA selectively modulates the expression of multiple PPAR-gamma-responsive genes. Studies in the diabetic ob/ob mouse demonstrate halofenate's acute antidiabetic properties. Longer-term studies in the obese Zucker (fa/fa) rat demonstrate halofenate's comparable insulin sensitization to rosiglitazone in the absence of body weight increases. Our data establish halofenate as a novel SPPARgammaM with promising therapeutic utility with the potential for less weight gain.

A screening platform for identification of anti-diabetic compounds in plants used in traditional complementary medicine

Diabetes is a major health problem due to a massive growth in the number of type 2 diabetes patients. Type 2 diabetes is characterized by insulin resistance, and hence, treatment with thiazolidinedione (TZD) insulin sensitizing drugs is often prescribed. TZDs bind to and activate the nuclear receptor Peroxisome Proliferator-Activated Receptor (PPAR)γ, a master regulator of fat cell formation. TZDs significantly improve insulin sensitivity and restore glycemic control, but unfortunately, the use of TZDs is accompanied by a number of side effects such as weight gain due to fat accumulation. Some of the side effects result from the use of full PPARγ agonists that recruit a “non-desirable“ complement of so-called co-activators to PPARγ, and it appears that certain partial PPARγ agonists may recruit a more “beneficial“ complement of co-activators. Many types of Traditional Complementary Medicine (TCM) have been used against conditions resembling type 2 diabetes and the aims of the present work were (i) to establish a platform for systematic screening of selected classes of TCM for compounds that function as partial PPARγ agonists without promoting fat cell differentiation and (ii) to investigate the possibilities for improving the content of potential anti-diabetic compounds in plants by cultivation and breeding. American ginseng is known for its anti-diabetic effects. By using the platform we have performed a systematic screening of several types of ginseng extracts and purified ginsenosides and demonstrated that they have characteristics that warrant further investigations of their effects on glucose (and lipid) homeostasis. We have furthermore shown that the content of ginsenosides can be improved by selection and breeding. Also herbs such as thyme and oregano, not normally considered as “anti-diabetic“ plants contain bioactive compounds that activate PPARγ in vitro, and hence may affect glucose homeostasis.

Structure-Based Drug Design of a Novel Family of PPARγ Partial Agonists: Virtual Screening, X-ray Crystallography, and in Vitro/in Vivo Biological Activities

Peroxisome proliferator-activated receptor gamma (PPARgamma) is well-known as the receptor of thiazolidinedione antidiabetic drugs. In this paper, we present a successful example of employing structure-based virtual screening, a method that combines shape-based database search with a docking study and analogue search, to discover a novel family of PPARgamma agonists based upon pyrazol-5-ylbenzenesulfonamide. Two analogues in the family show high affinity for, and specificity to, PPARgamma and act as partial agonists. They also demonstrate glucose-lowering efficacy in vivo. A structural biology study reveals that they both adopt a distinct binding mode and have no H-bonding interactions with PPARgamma. The absence of H-bonding interaction with the protein provides an explanation why both function as partial agonists since most full agonists form conserved H-bonds with the activation function helix (AF-2 helix) which, in turn, enhances the recruitment of coactivators. Moreover, the structural biology and computer docking studies reveal the specificity of the compounds for PPARgamma could be due to the restricted access to the binding pocket of other PPAR subtypes, i.e., PPARalpha and PPARdelta, and steric hindrance upon the ligand binding.

New Treatment Strategies for Patients with Hypertension and Insulin Resistance

The metabolic syndrome is characterized by the clustering of insulin resistance, dyslipidemia, and hypertension and is associated with increased risk of cardiovascular disease and type 2 diabetes mellitus. However, older antihypertensive agents such as thiazide diuretics and β-blockers have potentially adverse effects on glucose and lipid metabolism and may even the exacerbate the metabolic syndrome and increase risk of type 2 diabetes. Recent clinical trials have suggested that antihypertensive agents that inhibit the renin-angiotensin system may reduce risk for new-onset type 2 diabetes, but only a few of these studies were placebo controlled, and in most cases, the absolute antidiabetic effects were relatively modest. Evidence is accumulating that telmisartan, in addition to blocking the angiotensin II type 1 receptor, activates the peroxisome proliferator-activated receptor (PPAR)–γ a well-known target for treatment of the metabolic syndrome and diabetes. By contrast, other angiotensin-receptor blockers are largely devoid of activity on PPAR-γ. Telmisartan is a partial agonist of PPAR-γ and has a superior tolerability profile without causing the fluid retention and edema associated with full agonists of PPAR-γ such as pioglitazone and rosiglitazone. Recent studies have indicated that in addition to antidiabetic properties, PPAR-γ activators may also provide protection against atherosclerosis and coronary events. Thus, the ability of telmisartan both to activate PPAR-γ and to block the angiotensin receptor may provide added value not only in the treatment of the metabolic syndrome and prevention of type 2 diabetes but also in prevention and treatment of atherosclerotic cardiovascular disease.

Differential Recognition of LPA and Rosiglitazone by PPARγ 1

The ether analog of lysophosphatidic acid AGP is a high-affinity partial agonist of PPARγ . Binding studies showed that AGP and Rosiglitazone (Rosi) both specifically bind to PPARγ and compete with each other. However, AGP only displaced 40% of bound Rosi. Activation of PPARγ-dependent reporter gene expression showed similar potency, yet AGP-mediated activation was only 40% that of Rosi. A complex between AGP and PPARγ was generated using molecular modeling based on a PPARγ crystal structure. AGP interacting residues were compared with Rosi interacting residues identified within the Rosi-PPARγ co-crystal complex. These comparisons showed that the two ligands occupy partially overlapping positions but make different hydrogen bonding and ion-pairing interactions. Site-specific mutants of PPARγ were prepared to examine their contribution to binding of individual ligands. The H323A and H449A mutants showed reduced binding of Rosi but maintained binding of AGP. In contrast, the R288A mutant showed reduced AGP binding but maintained Rosi binding. Y473A abolished binding and activation by Rosi and AGP. These observations indicate that AGP is a high-affinity ligand of PPARγ but that it binds via interactions distinct from those involved in Rosi binding. This work was supported by grants from USPHS & AHA.

Synthesis and Biological Activities of Novel Aryl Indole‐2‐carboxylic Acid Analogues as PPARγ Partial Agonists.

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Regulation of Peroxisome Proliferator–Activated Receptor γ Activity by Losartan Metabolites

Two active metabolites of the angiotensin type 1 (AT 1 ) receptor blocker losartan have been described previously, EXP3174 and EXP3179. Whereas EXP3174 is the main antihypertensive AT 1 receptor–blocking metabolite, the role of EXP3179 is widely unknown. Recently, a subgroup of AT 1 receptor blockers has been identified as ligands for the peroxisome proliferator–activated receptor γ (PPAR-γ). Here we characterize the PPAR-γ–activating properties of the 2 active losartan metabolites. PPAR-γ activity was measured with a chimeric Gal4-DNA–binding domain–hPPARγ-ligand–binding domain (LBD) fusion protein on a Gal4-dependent luciferase reporter system. EXP3179 prominently induced the activation of the PPAR-γ–LBD reaching a maximum at 100 μmol/L with a 7.1±1-fold induction ( P <0.05 versus vehicle-treated cells). Maximum PPAR-γ–LBD activation by EXP3179 reached 51% of the maximum response induced by the full PPAR-γ agonist pioglitazone, identifying EXP3179 as a partial PPAR-γ agonist. EXP3174 did not induce PPAR-γ–LBD activation. EC 50 values were calculated for PPAR-γ–LBD activity (pioglitazone EC 50 : 0.88 μmol/L; EXP3179 EC 50 : 17.1 μmol/L; losartan EC 50 : >50 μmol/L). Consistent with the activation of PPAR-γ, EXP3179 potently induced 3T3-L1 adipocyte differentiation, a typical PPAR-γ–dependent cell function, and markedly stimulated PPAR-γ target gene expression. EXP3174 failed to regulate differentiation or PPAR-γ target gene expression. The present study characterizes the active losartan metabolite EXP3179 as a partial PPAR-γ agonist. PPAR-γ activation by EXP3179 may help us to understand the beneficial metabolic effects of losartan observed in clinical trials.

Synthesis and biological activities of novel aryl indole-2-carboxylic acid analogs as PPARγ partial agonists

A series of novel aryl indole-2-carboxylic acids has been identified as potent selective PPARγ modulators. Their chemical synthesis and in vitro activities are discussed. Compound 5 was selected for in vivo testing in the db/ db mouse model of type 2 diabetes and resulted in reduction of hyperglycemia at comparable plasma exposure when compared to rosiglitazone.

Netoglitazone is a PPAR-gamma ligand with selective effects on bone and fat

Thiazolidinediones are effective anti-diabetic drugs that improve insulin sensitivity through the activation of the nuclear receptor and adipocyte-specific transcription factor, peroxisome proliferator-activated receptor gamma (PPAR-γ). Recent evidence suggests that PPAR-γ also controls bone cell development and bone homeostasis. In mice, PPAR-γ insufficiency results in increased bone mass, whereas administration of the specific PPAR-γ agonist rosiglitazone leads to bone loss and increased bone marrow adiposity. Although the pro-adipocytic and anti-osteoblastic activities of PPAR-γ can be separated in vitro using ligands with distinct chemical structures, little evidence exists supporting this functional separation in vivo. Netoglitazone (MCC-555, RWJ-241947) is a thiazolidinedione, which acts as either a full or partial PPAR-γ agonist, or antagonist, in a cell type specific manner. In this study, the pro-adipocytic and anti-osteoblastic activities of netoglitazone were evaluated in vitro, using both U-33/γ2 cells as a model of marrow mesenchymal cell differentiation under the control of PPAR-γ2 and primary bone marrow cultures, and in vivo in C57BL/6 mice. In vitro, netoglitazone induced adipocyte and inhibited osteoblast formation in a PPAR-γ2-dependent manner; however, it was 100-fold less effective than rosiglitazone. In vivo, the administration of netoglitazone at an effective hyperglycemic dose (10 μg/g body weight/day) did not result in trabecular bone loss. Bone quality parameters such as bone mineral density and bone microarchitecture were not affected in netoglitazone-treated animals. The observed lack of an in vivo effect of netoglitazone on bone was entirely consistent with its low anti-osteoblastic activity in vitro. In contrast to the observed in vitro effects, netoglitazone in vivo effectively induced marrow adipocyte formation and induced changes in the weights of extramedullary fat depots. Consistent with these cell type-specific effects, expression of the adipocyte-specific gene marker FABP4/aP2 was increased, whereas the expression of osteoblast-specific gene markers, Runx2, Dlx5, osteocalcin, and collagen were not affected by netoglitazone. In conclusion, netoglitazone is a member of a new class of PPAR-γ ligands with distinct anti-diabetic, anti-osteoblastic, and pro-adipocytic activities in vivo.

A Peroxisome Proliferator-Activated Receptor α/γ Dual Agonist with a Unique in Vitro Profile and Potent Glucose and Lipid Effects in Rodent Models of Type 2 Diabetes and Dyslipidemia

LSN862 is a novel peroxisome proliferator-activated receptor (PPAR)alpha/gamma dual agonist with a unique in vitro profile that shows improvements on glucose and lipid levels in rodent models of type 2 diabetes and dyslipidemia. Data from in vitro binding, cotransfection, and cofactor recruitment assays characterize LSN862 as a high-affinity PPARgamma partial agonist with relatively less but significant PPARalpha agonist activity. Using these same assays, rosiglitazone was characterized as a high-affinity PPARgamma full agonist with no PPARalpha activity. When administered to Zucker diabetic fatty rats, LSN862 displayed significant glucose and triglyceride lowering and a significantly greater increase in adiponectin levels compared with rosiglitazone. Expression of genes involved in metabolic pathways in the liver and in two fat depots from compound-treated Zucker diabetic fatty rats was evaluated. Only LSN862 significantly elevated mRNA levels of pyruvate dehydrogenase kinase isozyme 4 and bifunctional enzyme in the liver and lipoprotein lipase in both fat depots. In contrast, both LSN862 and rosiglitazone decreased phosphoenol pyruvate carboxykinase in the liver and increased malic enzyme mRNA levels in the fat. In addition, LSN862 was examined in a second rodent model of type 2 diabetes, db/db mice. In this study, LSN862 demonstrated statistically better antidiabetic efficacy compared with rosiglitazone with an equivalent side effect profile. LSN862, rosiglitazone, and fenofibrate were each evaluated in the humanized apoA1 transgenic mouse. At the highest dose administered, LSN862 and fenofibrate reduced very low-density lipoprotein cholesterol, whereas, rosiglitazone increased very low-density lipoprotein cholesterol. LSN862, fenofibrate, and rosiglitazone produced maximal increases in high-density lipoprotein cholesterol of 65, 54, and 30%, respectively. These findings show that PPARgamma full agonist activity is not necessary to achieve potent and efficacious insulin-sensitizing benefits and demonstrate the therapeutic advantages of a PPARalpha/gamma dual agonist.

Differential effects of peroxisome proliferator activated receptor-γ (PPARγ) ligands in proximal tubular cells: Thiazolidinediones are partial PPARγ agonists

Background. Peroxisome proliferator activated receptors (PPARs) are ligand-activated transcription factors with multiple effects on target cell function. PPAR gamma activity is regulated by extracellular signal-regulated protein kinase (ERK), mitogen-activated protein (MAP) kinase, and PPAR gamma ligands have varying effects on activity of ERK. Different PPAR gamma ligands have been shown to have both protective and detrimental effects in the kidney. Since transcriptional activation by different PPAR agonists is ligand- and depot-specific PPAR gamma, we have examined the effects of different agonists on PPAR activity in the proximal tubule. Opossum kidney cells were used in all experiments, transiently transfected with a PPAR response element luciferase reporter and subject to stimulation with various PPAR ligands. The role of ERK and phosphorylation in PPAR gamma activation were studied, as were the effects of PPAR agonists on ERK activation and cell proliferation. Transcriptional activity of PPAR was not stimulated by PPAR alpha agonists, and only very modestly stimulated by a PPAR beta agonist. The PPAR gamma agonists 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), ciglitazone, and troglitazone stimulated significant transcriptional activation and phosphorylation of PPAR gamma. These effects were more marked with 15d-PGJ(2). Thiazolidinediones attenuated 15d-PGJ(2) evoked PPAR gamma activation and phosphorylation. ERK activity positively regulated PPAR activation. Only 15d-PGJ(2) stimulated ERK activity and cell proliferation, and these effects were also inhibited by thiazolidinediones. PPAR gamma agonists exert differential effects in proximal tubule cells with thiazolidinediones behaving as partial agonists.

A non-thiazolidinedione partial peroxisome proliferator-activated receptor γ ligand inhibits vascular smooth muscle cell growth

Several peroxisome proliferator-activated receptor γ (PPARγ) agonists of the thiazolidinedione class inhibit vascular smooth muscle cell proliferation. It is not known whether the antiproliferative activity of PPARγ agonists is limited to the thiazolidinedione class and/or is directly mediated through PPARγ-dependent transactivation of target genes. We report here that a novel non-thiazolidinedione partial PPARγ agonist (nTZDpa) attenuates rat aortic vascular smooth muscle cell proliferation. In a transfection assay for PPARγ transcriptional activation, the non-thiazolidinedione partial PPARγ agonist elicited ∼25% of the maximal efficacy of the full PPARγ agonist rosiglitazone. In the presence of the non-thiazolidinedione partial PPARγ agonist, the transcriptional activity of the full agonist, rosiglitazone, was blunted, indicating that the non-thiazolidinedione partial PPARγ agonist inhibits rosiglitazone-induced PPARγ activity. The non-thiazolidinedione partial PPARγ agonist (0.1–10 μM) inhibited vascular smooth muscle cell growth which was accompanied by an inhibition of retinoblastoma protein phosphorylation. Mitogen-induced downregulation of the cyclin-dependent kinase (CDK) inhibitor p27 kip1, and induction of the G1 cyclins cyclin D1, cyclin A, and cyclin E were also attenuated by the non-thiazolidinedione partial PPARγ agonist. Maximal antiproliferative activity of the non-thiazolidinedione partial PPARγ agonist required functional PPARγ as adenovirus-mediated overexpression of a dominant-negative PPARγ mutant partially reversed its inhibition of vascular smooth muscle cell growth. In contrast, overexpression of dominant-negative PPARγ did not reverse the inhibitory effect of the non-thiazolidinedione partial PPARγ agonist on cyclin D1. As the full PPARγ agonist rosiglitazone exhibited no effect on cyclin D1, inhibition of that G1 cyclin by the non-thiazolidinedione partial PPARγ agonist likely occurred through a PPARγ-independent mechanism. These data demonstrate that a non-thiazolidinedione partial PPARγ agonist may constitute a novel therapeutic for proliferative vascular diseases and could provide additional evidence for the important role of PPARγ in regulating vascular smooth muscle cell proliferation.

Pro-inflammatory mechanisms of a non-steroidal anti-inflammatory drug

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used as analgesic and anti-inflammatory therapeutic agents. They work by inhibiting the cyclooxygenase enzymes, thereby blocking the production of inflammatory prostaglandins. NSAIDs have also been used as chemoprotective agents for cancer, although the mechanism by which they achieve this chemoprotective effect is thought to be independent of cyclooxygenase inhibition. Adamson et al. [1xDiclofenac antagonizes peroxisome proliferator-activated receptor γ signalling. Adamson, D.J.A. et al. Mol. Pharmacol. 2001; 61: 7–12Crossref | Scopus (60)See all References][1] now identify the peroxisome proliferator activated receptor γ (PPAR-γ) as a possible target for the analgesic diclofenac, and highlight some therapeutic implications for type 2 diabetes and cancer treatment.The authors used a spectrophotometric assay to measure the displacement of the PPAR-γ agonist cis-parinaric acid (CPA) to measure the binding affinity of NSAIDs with PPAR-γ. The NSAID diclofenac was shown to have fourfold greater affinity for PPAR-γ than the putative endogenous ligand, which indicates that a single oral dose of diclofenac would produce sufficiently high serum concentrations to allow interaction with PPAR-γ. PPAR-γ is a member of the nuclear hormone receptor family and in conjunction with retinoid X receptors regulates the transcription of various genes involved in lipid metabolism. It is an important therapeutic target for the treatment of diabetes and has recently been identified as a target for anticancer agents. The effect on PPAR-γ-mediated gene regulation by diclofenac was measured using a transactivation assay. Diclofenac was found to be a partial agonist of PPAR-γ, producing a twofold activation of gene expression (compared with a 6.6-fold activation elicited by the PPAR-γ agonist rosiglitazone). When added in combination with rosiglitazone, diclofenac lowered reporter gene activation by sub-saturating levels, but not saturating levels, of rosiglitazone, the expected effects of a competitive partial agonist. In physiological tests, diclofenac was also shown to inhibit adipocyte differentiation induced by PPAR-γ and released a PPAR-γ-dependent cancer cell line from growth arrest induced by rosiglitazone.Many NSAIDs are freely available and widely used for the treatment of pain. Therefore, it is important to understand the mechanisms by which these compounds mediate their effects and how they might interact with other treatments. By inhibiting the effects of rosiglitazone, diclofenac would probably result in poor glucose control for diabetics taking a treatment of thiazolidnedione. The authors also suggest that diclofenac might inhibit endogenous PPAR-γ signalling. If this is the case, diclofenac would be expected to block the anti-inflammatory effects of PPAR-γ, and in support of this theory there is evidence suggesting that some NSAIDs have pro-inflammatory responses. Finally, the authors point out that because PPAR-γ has also become a possible target for cancer chemoprotective agents, not all NSAIDs would necessarily be beneficial in this area.

Pro-inflammatory mechanisms of a nonsteroidal anti-inflammatory drug

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used as analgesic and anti-inflammatory therapeutic agents. They work by inhibiting the cyclo-oxygenase enzymes, so blocking the production of inflammatory prostaglandins. NSAIDs have also been used as chemoprotective agents for cancer, although the mechanism by which they achieve this is thought to be independent of cyclo-oxygenase inhibition. Adamson et al. [1xDiclofenac antagonizes peroxisome proliferator-activated receptor-γ signalling. Adamson, D.J.A. et al. Mol. Pharm. 2001; 61: 7–12Crossref | Scopus (56)See all References][1] now identify the peroxisome proliferator-activated receptor-γ (PPARγ) as a possible target for the analgesic diclofenac, and highlight some therapeutic implications for type 2 diabetes and cancer treatment.The authors used a spectrophotometric assay to measure the displacement of the PPARγ agonist, cis-parinaric acid (CPA), to measure the binding affinity of NSAIDs with the PPARγ receptor. The NSAID, diclofenac, was shown to have fourfold greater affinity for the PPARγ receptor than did the putative endogenous ligand, and a single oral dose of diclofenac would produce sufficiently high serum concentrations to allow interaction with PPARγ. PPARγ is a member of the nuclear hormone receptor family and, in conjunction with retinoid X receptors, regulates the transcription of various genes involved in lipid metabolism. It is an important therapeutic target for the treatment of diabetes and has recently been identified as a target for anticancer agents. The effect on PPARγ-mediated gene regulation by diclofenac was measured using a transactivation assay. Diclofenac was found to be a partial agonist of PPARγ, producing a twofold activation of gene expression (compared with a 6.6-fold activation for the PPARγ agonist rosiglitazone). When added in combination with rosiglitazone, diclofenac lowered reporter gene activation by subsaturating levels of rosiglitazone but not saturating levels, the expected effects of a competitive partial agonist. In physiological tests, diclofenac was also shown to inhibit adipocyte differentiation induced by PPARγ, and released a PPARγ-dependant cancer cell line from growth arrest induced by rosiglitazone.Many NSAIDs are freely available and widely used for the treatment of pain. It is important therefore to understand the mechanisms by which these compounds bring about their effects and how they might interact with other treatments. By inhibiting the effects of rosiglitazone, diclofenac would probably result in poor glucose control for diabetics taking a treatment of thiazolidnedione. The authors also suggest that diclofenac might inhibit endogenous PPARγ signalling. If this is the case, then it would be expected to block the anti-inflammatory effects of PPARγ, and in support of this, there is evidence suggesting that some NSAIDs have pro-inflammatory responses. Finally, the authors point out that, as PPARγ has also become a possible target for cancer chemoprotective agents, not all NSAIDs would necessarily be beneficial in this area.

Sinuses in and About the Withers and Their Treatment

Peroxisome Proliferator-Activated Receptors (PPARs) are ligand-dependent transcription factors that control various functions in human organism, including the control of glucose and lipid metabolism. PPARγ is a target of TZD agonists, clinically used to improve insulin sensitivity whereas fibrates, PPARα ligands, lower serum triglyceride levels. We report here the structural studies of GL479, a synthetic dual PPARα/γ agonist, designed by a combination of clofibric acid skeleton and a phenyldiazenyl moiety, as bioisosteric replacement of stilbene group, in complex with both PPARα and PPARγ receptors. GL479 was previously reported as a partial agonist of PPARγ and a full agonist of PPARα with high affinity for both PPARs. Our structural studies reveal different binding modes of GL479 to PPARα and PPARγ, which may explain the distinct activation behaviors observed for each receptor. In both cases the ligand interacts with a Tyr located at helix 12 (H12), resulting in the receptor active conformation. In the complex with PPARα, GL479 occupies the same region of the ligand-binding pocket (LBP) observed for other full agonists, whereas GL479 bound to PPARγ displays a new binding mode. Our results indicate a novel region of PPARs LBP that may be explored for the design of partial agonists as well dual PPARα/γ agonists that combine, simultaneously, the therapeutic effects of the treatment of insulin resistance and dyslipidemia.