2-(2-(4-phenoxy-2-propylphenoxy)ethyl)indole-5-acetic-acid and Diabetes-Mellitus--Type-2

The use of the thiazolidinedione insulin sensitizers rosiglitazone and pioglitazone for the treatment of type 2 diabetes mellitus in recent years has proven to be effective in helping patients resume normal glycemic control. However, their use is often associated with undesirable side effects including peripheral edema, congestive heart failure and weight gain. Here, we report the identification and characterization of a novel selective PPARgamma modulator, SPPARgammaM5 ((2S)-2-(2-chloro-5-{[3-(4-chlorophenoxy)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl} phenoxy)propionic acid), which has notable insulin sensitizing properties and a superior tolerability profile to that of rosiglitazone. SPPARgammaM5 is a potent ligand of human PPARgamma with high selectivity versus PPARalpha or PPARdelta in receptor competitive binding assays. In cell-based transcriptional activation assays, SPPARgammaM5 was a potent partial agonist of human PPARgamma in comparison to the PPARgamma full agonist rosiglitazone. Compared to rosiglitazone or the PPARgamma full agonist COOH (2-(2-(4-phenoxy-2-propylphenoxy)ethyl)indole-5-acetic acid), SPPARgammaM5 induced an attenuated PPARgamma-regulated gene expression profile in fully differentiated 3T3-L1 adipocytes and white adipose tissue of chronically treated db/db mice. SPPARgammaM5 treatment also reduced the insulin resistance index by homeostasis model assessment (HOMA), suggesting an improvement in insulin resistance in these db/db mice. Treatment of obese Zucker rats with either rosiglitazone or SPPARgammaM5 resulted in an improvement in selected parameters that serve as surrogate indicators of insulin resistance and hyperlipidemia. However, unlike rosiglitazone, SPPARgammaM5 did not cause significant fluid retention or cardiac hypertrophy in these rats. Thus, compounds such as SPPARgammaM5 may offer beneficial effects on glycemic control with significantly attenuated adverse effects.

Topics: 3T3-L1 Cells; Acetates; Adipose Tissue, White; Animals; Cardiomegaly; Cardiovascular Diseases; Chlorocebus aethiops; COS Cells; Diabetes Mellitus, Type 2; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Partial Agonism; Gene Expression Profiling; Gene Expression Regulation; Hemodilution; Humans; Hypoglycemic Agents; Indoles; Insulin Resistance; Male; Mice; Mice, Inbred Strains; PPAR alpha; PPAR delta; PPAR gamma; Propionates; Protein Binding; Rats; Rats, Zucker; Rosiglitazone; Thiazolidinediones; Transcriptional Activation; Transfection; Water-Electrolyte Balance

We have previously reported that endothelium-dependent relaxation to acetylcholine is impaired in small mesenteric arteries from spontaneously diabetic (db/db) mice. The objective of the present study was to examine the effects of treatment of the db/db and the insulin-resistant ob/ob mice with the PPARgamma agonist 2-(2-(4-phenoxy-2-propylphenoxy)ethyl)indole-5-acetic acid (COOH). In the db/db model, an 8-week treatment with COOH (30 mg/kg/day) reduced plasma glucose from 48.0 +/- 2.5 (untreated) to 12.6 +/- 1.1 mM. In contrast, plasma glucose was not elevated in untreated ob/ob mice. Relaxation of small mesenteric arteries mediated by acetylcholine was impaired in the untreated db/db diabetic mice (51.7 +/- 7.4% maximal relaxation, n = 6) but not in the ob/ob mice (70.8 +/- 8.6% maximal relaxation, n = 3). This impairment was reversed with COOH treatment (86.9 +/- 0.4% maximal relaxation, n = 5). Malondialdehyde was elevated in plasma from diabetic db/db mice (13.9 +/- 1.1 versus 12.0 +/- 0.7 micromol/ml); however, when normalized to total cholesterol, no significant differences in the ratio of lipid peroxidation in plasma were identified. Western blot analysis and quantitative polymerase chain reaction for eNOS was performed on the isolated mesenteric vessels and revealed no differences in the relative levels of eNOS expression in diabetic and control animals; in addition, treatment with COOH had no significant effect on eNOS levels in either group. In summary, endothelial dysfunction and hyperglycemia were completely normalized in COOH-treated db/db mice. In contrast, nonhyperglycemic ob/ob mice exhibited normal vasodilatory responses to acetylcholine and, consequently, COOH treatment had no effect on endothelial function.

Topics: Acetates; Adrenergic alpha-Agonists; Animals; Blood Glucose; Blotting, Western; Cholesterol; Diabetes Mellitus; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Endothelium, Vascular; Hypoglycemic Agents; Indoles; Lipid Peroxidation; Male; Malondialdehyde; Mesenteric Arteries; Mice; Mice, Inbred C57BL; Mice, Knockout; Nitric Oxide Synthase Type III; Phenylephrine; PPAR gamma; Receptors, Cell Surface; Receptors, Leptin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

The Type 2 diabetic db/db mouse experiences vascular dysfunction typified by changes in the contraction and relaxation profiles of small mesenteric arteries (SMAs). Contractions of SMAs from the db/db mouse to the alpha1-adrenoceptor agonist phenylephrine (PE) were significantly enhanced, and acetylcholine (ACh)-induced relaxations were significantly depressed. Drug treatment of db/db mice with a nonthiazolidinedione peroxisome prolifetor-activated receptor-gamma agonist and insulin sensitizing agent 2-[2-(4-phenoxy-2-propylphenoxy)ethyl]indole-5-acetic acid (COOH) completely prevented the changes in endothelium-dependent relaxation, but, with the discontinuation of therapy, endothelial dysfunction returned. Dysfunctional SMAs were found to specifically upregulate the expression of a 35-kDa isoform of sarcolemmal membrane-associated protein (SLMAP), which is a component of the excitation-contraction coupling apparatus and implicated in the regulation of membrane function in muscle cells. Real-time PCR revealed high SLMAP mRNA levels in the db/db microvasculature, which were markedly downregulated during COOH treatment but elevated again when drug therapy was discontinued. These data reveal that the microvasculature in db/db mice undergoes significant changes in vascular function with the endothelial component of vascular dysfunction specifically correlating with the overexpression of SLMAP. Thus changes in SLMAP expression may be an important indicator for microvascular disease associated with Type 2 diabetes.

Topics: Acetates; Animals; Diabetes Mellitus, Type 2; Endothelium, Vascular; Gene Expression Regulation; Indoles; Male; Membrane Proteins; Mice; Mice, Mutant Strains; PPAR gamma; RNA, Messenger; Vasodilation

Hearts from insulin-resistant type 2 diabetic db/db mice exhibit features of a diabetic cardiomyopathy with altered metabolism of exogenous substrates and reduced contractile performance. Therefore, the effect of chronic oral administration of 2-(2-(4-phenoxy-2-propylphenoxy)ethyl)indole-5-acetic acid (COOH), a novel ligand for peroxisome proliferator-activated receptor-gamma that produces insulin sensitization, to db/db mice (30 mg/kg for 6 wk) on cardiac function was assessed. COOH treatment reduced blood glucose from 27 mM in untreated db/db mice to a normal level of 10 mM. Insulin-stimulated glucose uptake was enhanced in cardiomyocytes from COOH-treated db/db hearts. Working perfused hearts from COOH-treated db/db mice demonstrated metabolic changes with enhanced glucose oxidation and decreased palmitate oxidation. However, COOH treatment did not improve contractile performance assessed with ex vivo perfused hearts and in vivo by echocardiography. The reduced outward K+ currents in diabetic cardiomyocytes were still attenuated after COOH. Metabolic changes in COOH-treated db/db hearts are most likely indirect, secondary to changes in supply of exogenous substrates in vivo and insulin sensitization.

Topics: Acetates; Administration, Oral; Animals; Blood Glucose; Cardiomyopathies; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Echocardiography; Heart; Indoles; Male; Mice; Mice, Inbred C57BL; Myocardial Contraction; Myocardium; Receptors, Cell Surface; Receptors, Cytoplasmic and Nuclear; Receptors, Leptin; Transcription Factors; Treatment Outcome