Activation of peroxisome proliferator-activated receptors (PPARs) have been implicated in the treatment of metabolic disorders with different mechanisms; PPAR␣ agonists promote fatty acid oxidation and reduce hyperlipidemia, whereas PPAR␥ agonists regulate lipid redistribution from visceral fat to subcutaneous fat and enhance insulin sensitivity. To achieve combined benefits from activated PPARs on lipid metabolism and insulin sensitivity, a number of PPAR␣/␥ dual agonists have been developed. However, several adverse effects such as weight gain and organ failure of PPAR␣/␥ dual agonists have been reported. By use of virtual ligand screening, we identified and characterized a novel PPAR␣/␥ dual agonist, (R)-1-(4-(2-(5-methyl-2-p-tolyloxazol-4-yl)ethoxy)benzyl)piperidine-2-carboxylic acid (CG301360), exhibiting the improvement in insulin sensitivity and lipid metabolism. CG301360 selectively stimulated transcriptional activities of PPAR␣ and PPAR␥ and induced expression of their target genes in a PPAR␣-and PPAR␥-dependent manner. In cultured cells, CG301360 enhanced fatty acid oxidation and glucose uptake and it reduced pro-inflammatory gene expression. In db/db mice, CG301360 also restored insulin sensitivity and lipid homeostasis. Collectively, these data suggest that CG301360 would be a novel PPAR␣/␥ agonist, which might be a potential lead compound to develop against insulin resistance and hyperlipidemia.

BackgroundWe examined the change in the levels of incretin hormone and effects of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) on insulin secretion in women with previous gestational diabetes (pGDM).MethodsA 75-g oral glucose tolerance test (OGTT) was conducted on 34 women with pGDM. In addition, 11 women with normal glucose tolerance, matched for age, height and weight, were also tested. The insulin, GIP, GLP-1, and glucagon concentrations were measured, and their anthropometric and biochemical markers were also measured.ResultsAmong 34 women with pGDM, 18 had normal glucose tolerance, 13 had impaired glucose tolerance (IGT) and 1 had diabetes. No significant differences were found in GLP-1 concentration between the pGDM and control group. However, a significantly high level of glucagon was present in the pGDM group at 30 minutes into the OGTT. The GIP concentration was elevated at 30 minutes and 60 minutes in the pGDM group. With the exception of the 30-minute timepoint, women with IGT had significantly high blood glucose from 0 to 120 minutes. However, there was no significant difference in insulin or GLP-1 concentration. The GIP level was significantly high from 0 to 90 minutes in patients diagnosed with IGT.ConclusionGLP-1 secretion does not differ between pGDM patients and normal women. GIP was elevated, but that does not seem to induce in increase in insulin secretion. Therefore, we conclude that other factors such as heredity and environment play important roles in the development of type 2 diabetes.