The Metabolic Action of PPARs
Oral abstract presentations
Sunday, June 06, 2004
8:00 am – 10:00 am
Chair: Dr Joseph L Evans
Reviewed by Joelle Escoffery, PhD
Abstract 134-OR: Muraglitazar, a Novel Non-TZD Dual PPARα/γ Agonist, Improves Metabolic Abnormalities in Obese, Severely Diabetic db/db Mice
Presenter: Dr Narayanan Hariharan
Muraglitazar (BMS-298585), a non-TZD, dual PPARα/γ agonist, is in development for the treatment of type 2 diabetes and its associated dyslipidemia. In the first study, 6 db/db mice were treated with 10 mg/kg/day of either muraglitazar or rosiglitazone for 2 weeks. Muraglitazar was more effective than rosiglitazone in lowering fasting plasma glucose (FPG) and urea, and significantly reducing free fatty acids (FFAs). Muraglitazar was also associated with a correction in corticosterone and adiponectin levels, which improve insulin sensitivity.
In a second study, db/db mice were treated with muraglitazar 0.1 – 30 mg/kg/day for 4 weeks. Muraglitazar significantly reduced FPG, insulin, and HOMA levels. It was also associated with a correction in corticosterone and adiponectin levels.
In conclusion, muraglitazar improves glucose tolerance, insulin sensitivity, and insulin content in the pancreas.
Abstract 135-OR: Selective Induction of Vascular Permeability and PKC Activation in Adipose Tissue by Rosiglitazone: Novel Mechanism for PPARγ Agonist’s Effect on Edema and Weight Gain
Presenter: Dr Konstantinos Sotiropoulos
Being PPARγ agonists, use of Thiazolidinediones (TZDs) are associated with an increase in vascular permeability and the activation of PKCβ. They have also been reported to increase the expression of vascular endothelial growth factor (VEGF). In this study, the effects of 4 weeks of treatment with rosiglitazone on these factors were assessed. Lean, fatty and diabetic fatty Zucker rats, and PKCβ knock-out and control mice were used.
After 2 weeks, there was an increase in vascular permeability and VEGF in adipose tissue and the retina in rodents treated with rosiglitazone. For the remaining 2 weeks of the study, some rodents added ruboxistaurin, a PKCβ inhibitor, to their treatment regimen, while the rest continued monotherapy with rosiglitazone.
At 4 weeks, rodents treated with both ruboxistaurin and rosiglitazone had normalized vascular permeability in adipose tissue and the retina, significantly decreased weight gain, and decreased whole body fat, and water content, when compared to those treated with rosiglitazone alone. Furthermore, rosiglitazone monotherapy was associated with increased PKCβ activity in adipose; this effect was inhibited by ruboxistaurin in the combination therapy group. To add to this point, rosiglitazone monotherapy was unable to increase weight gain or vascular permeability in the PKCβ knock-out mice vs. control.
Therefore, it was concluded that TZDs may cause edema and weight gain through a mechanism including PKCβ activation, vascular permeability, and selective adipose fluid retention. Hence, a PKCβ inhibitor, such as ruboxistaurin, could be used to prevent edema and reduce weight gain during TZD treatment.
Abstract 136-OR: Effects of PPARα/γ Therapy on Glucose/Lipid Metabolism, Hepatic Fat and Plasma Adiponectin in Type 2 Diabetes
Presenter: Dr Mandeep Bajaj
In this study, the effects of pioglitazone (40 mg/day) and fenofibrate (200 mg/day) alone and in combination were examined in 14 T2D patients for a total of 6 months. For 3 months, patients were given either pioglitazone, a PPARα or fenofibrate, a PPARγ. At that time, an addition of the other agent was made for the remaining 3 months of the study.
After the first 3 months, Pioglitazone monotherapy was associated with a significant reduction in FPG and HbA1c, an increase in insulin sensitivity and HDL-C, a significant increase in adiponectin, and a decrease in plasma triglycerides, FFAs, glucose concentration, and hepatic fat. Fenofibrate monotherapy was associated with a significant reduction in plasma triglycerides, while maintaining all other parameters, including adiponectin levels.
Following the second 3-month period, the addition of fenofibrate to pioglitazone was associated with a further reduction in plasma triglycerides and a slight trend towards increased HDL. No other parameters were affected. The addition of pioglitazone to fenofibrate increased insulin sensitivity and adiponectin levels, while maintaining all other parameters.
Therefore, it was concluded that combination PPARα/γ therapy is associated with a further decrease in plasma triglycerides compared to PPARγ monotherapy, but has no further effect on FFAs or glucose metabolism.
Abstract 137-OR: Peroxisome Proliferator-Activated Receptor-γ (PPARγ) Activation Protects Human Islets from Human Islet Amyloid Polypeptide Induced Apoptosis
Presenter: Dr Chia-Yu Lin
Type 2 diabetes is associated with a deficit in β-cell mass, which is due to increased β-cell apoptosis and islet amyloid, derived from islet amyloid polypeptide (IAPP). Human IAPP (hIAPP) forms toxic oligomers, causing β-cell apoptosis in T2D. The purpose of this study was to determine whether hIAPP directly induces islet cell death and if activation of endogenous PPARγ by rosiglitazone can prevent hIAPP-induced cell death. Human pancreatic islets were used in this experiment.
hIAPP (0, 5, or 40 μM) was applied to human islets, which were then treated with rosiglitazone (0, 5, or 50 μM) for 48 hours. Increased apoptosis was detected with the hIAPP-treated islets at 5 and 40 μM compared to the control group. Rosiglitazone at 5 and 50 μM prevented apoptosis induced by hIAPP at 5 and 40 μM, respectively (P < 0.0001). Rosiglitazone did not cause any toxicity.
In conclusion, rosiglitazone treatment protects human islets from hIAPP-induced cytotoxicity, which may be one of the mechanisms of increased β-cell apoptosis in humans with T2D. It is suggested that the inhibition of β-cell apoptosis may be one of the mechanisms by which activation of the PPARγ receptor can prevent development of T2D.
Abstract 138-OR: Glucose Lowering Effects of Multiple Dose Administration of Muraglitazar (BMS-298585), a Novel PPARα/γ Dual Agonist, in Type 2 Diabetic Patients
Presenter: Dr Richard Gregg
In the present study, patients with type 2 diabetes were randomized to receive either muraglitazar 1.5, 5, 20, or 50 mg/day, pioglitazone 45 mg/day, or placebo for 28 days. The anticipated clinical dose range of muraglitazar will be 1.5 – 20 mg/day.
Treatment with muraglitazar was associated with improved 24-hour mean glucose concentrations. At the 5 mg dose, glucose concentration was slightly more improved than pioglitazone; all other doses were comparable to pioglitazone 45 mg/day. All doses of muraglitazar were more effective than pioglitazone 45 mg/day at reducing total serum cholesterol, triglycerides, and LDL-C, while increasing HDL-C; results peaking at 20 mg/day. The average levels of HbA1c observed with muraglitazar treatment were 7.5 – 8. Muraglitazar was well-tolerated at each dose, with 2 cases of subcutaneous edema and an average of 8-10 kg of weight gain observed in the 50 mg dosage group. No significant differences were noted in hematocrit vs. pioglitazone. There was no dose-response comparison made with pioglitazone in this study.
Abstract 139-OR: Efficacy of Naveglitazar (LY519818), a Novel Non-TZD, PPARγ-dominant α/γ Dual Agonist
Presenter: Dr Melvin Prince
The purpose of this 12-week study was to assess the efficacy of naveglitazar in reducing FPG and HbA1c. Patients with type 2 diabetes (N=151), controlled with diet and exercise alone or metformin or sulfonylurea monotherapy, were randomized to either placebo, naveglitazar 0.04, 0.2, 0.8, or 1.2 mg/day, or rosiglitazone 8 mg/day.
When compared to placebo, each dose of naveglitazar significantly reduced FPG. In the 0.8 and 1.2 mg dosage groups, HbA1c and triglycerides were significantly reduced, while HDL-C was significantly increased. These similar trends, though positive, were not significant for rosiglitazone. There was an overall improvement in LDL-C and total serum cholesterol seen with naveglitazar, though not significant. Weight gain did not differ significantly across all treatment groups, though the greatest increase was seen with rosiglitazone.
In conclusion, naveglitazar demonstrated comparable to superior efficacy when compared to rosiglitazone in a 12 week, Phase II study.
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