OBJECTIVE— Acute activation of G protein–coupled receptor 40 (GPR40) by free fatty acids (FFAs) or synthetic GPR40 agonists enhances insulin secretion. However, it is still a matter of debate whether activation of GPR40 would be beneficial for the treatment of type 2 diabetes, since chronic exposure to FFAs impairs islet function. We sought to evaluate the specific role of GPR40 in islets and its potential as a therapeutic target using compounds that specifically activate GPR40. RESEARCH DESIGN AND METHODS— We developed a series of GPR40-selective small-molecule agonists and studied their acute and chronic effects on glucose-dependent insulin secretion (GDIS) in isolated islets, as well as effects on blood glucose levels during intraperitoneal glucose tolerance tests in wild-type and GPR40 knockout mice (GPR40 −/− ). RESULTS— Small-molecule GPR40 agonists significantly enhanced GDIS in isolated islets and improved glucose tolerance in wild-type mice but not in GPR40 −/− mice. While a 72-h exposure to FFAs in tissue culture significantly impaired GDIS in islets from both wild-type and GPR40 −/− mice, similar exposure to the GPR40 agonist did not impair GDIS in islets from wild-type mice. Furthermore, the GPR40 agonist enhanced insulin secretion in perfused pancreata from neonatal streptozotocin-induced diabetic rats and improved glucose levels in mice with high-fat diet–induced obesity acutely and chronically. CONCLUSIONS— GPR40 does not mediate the chronic toxic effects of FFAs on islet function. Pharmacological activation of GPR40 may potentiate GDIS in humans and be beneficial for overall glucose control in patients with type 2 diabetes.

The predominant form of 5alpha-reductase (5aR) in human scalp is 5aR1. None the less, clinical studies have shown that finasteride, a selective inhibitor of 5aR2, decreases scalp dihydrotestosterone and promotes hair growth in men with androgenetic alopecia. Immunolocalization studies were thus carried out to examine 5aR isozyme distribution within scalp and, in particular, to determine whether 5aR2 might be associated with hair follicles. 5aR2 was localized using both a rabbit polyclonal and a mouse monoclonal antibody. 5aR1 was detected with a mouse monoclonal antibody. The specificity of these reagents was demonstrated both by immunofluorescence and Western blot analyses of COS cells overexpressing human 5aR1 or 5aR2. When cryosections of scalp from men with androgenetic alopecia were stained with antibody against 5aR2, using immunoperoxidase avidin-biotin complex methodology, immunostaining was observed in the inner layer of the outer root sheath and, in more proximal regions of the follicle, in the inner root sheath. Staining was also prominent in the infundibular region of the follicle, with less intense staining extending throughout the granular layer of the epidermis. Some staining was also seen in sebaceous ducts. Similar results were obtained with both the polyclonal and monoclonal 5aR2 antibodies. In contrast, in scalp cryosections stained with antibody to 5aR1, no immunostaining was observed within hair follicles. Intense staining for the type 1 isozyme was, however, detected within sebaceous glands. Our immunolocalization data suggest that the results seen in clinical trials of men with male pattern hair loss treated with finasteride may be due, at least in part, to local inhibition of 5aR2 within the hair follicle.

Despite their proven antidiabetic efficacy, widespread use of peroxisome proliferator-activated receptor (PPAR)␥ agonists has been limited by adverse cardiovascular effects. To overcome this shortcoming, selective PPAR␥ modulators (SPPAR␥Ms) have been identified that have antidiabetic efficacy comparable with full agonists with improved tolerability in preclinical species. The results of structural studies support the proposition that SPPAR␥Ms interact with PPAR␥ differently from full agonists, thereby providing a physical basis for their novel activities. Herein, we describe a novel PPAR␥ ligand, SPPAR␥M2. This compound was a partial agonist in a cell-based transcriptional activity assay, with diminished adipogenic activity and an attenuated gene signature in cultured human adipocytes. X-ray cocrystallography studies demonstrated that, unlike rosiglitazone, SPPAR␥M2 did not interact with the Tyr473 residue located within helix 12 of the ligand binding domain (LBD). Instead, SPPAR␥M2 was found to bind to and activate human PPAR␥ in which the Tyr473 residue had been mutated to alanine (hPPAR␥Y473A), with potencies similar to those observed with the wild-type receptor (hPPAR␥WT). In additional studies, we found that the intrinsic binding and functional potencies of structurally distinct SPPAR␥Ms were not diminished by the Y473A mutation, whereas those of various thiazolidinedione (TZD) and non-TZD PPAR␥ full agonists were reduced in a correlative manner. These results directly demonstrate the important role of Tyr473 in mediating the interaction of full agonists but not SPPAR␥Ms with the PPAR␥ LBD, thereby providing a precise molecular determinant for their differing pharmacologies.The peroxisome proliferator-activated receptors (PPARs) ␥, ␦, and ␣ compose a nuclear receptor subfamily that modulates the transcription of a large compendium of genes encoding proteins that regulate lipid metabolism, cell differentiation, and signal transduction in a ligand-dependent manner (Berger and Moller, 2002). PPAR␥ has been shown to be a master regulator of adipogenesis and nutrient metabolism in adipocytes where it is highly expressed. Thiazolidinedione (TZD) PPAR␥ full agonists have demonstrated clinical efficacy for the treatment of type 2 diabetes mellitus (T2DM) patients . However, the use of these insulin-sensitizing agents has been restricted because of their association with several adverse effects, including

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A novel series of selective ligands for the human glucocorticoid receptor (hGR) are described. Preliminary structure-activity relationships were focused on substitution at C-1 and indicated a preference for 3-, 4-, and 5-substituted aromatic and benzylic groups. The resulting analogues, e.g., 18 and 34, exhibited excellent affinity for hGR (IC(50) 1.9 nM and 2.8 nM, respectively) and an interesting partial agonist profile in functional assays of transactivation (tyrosine aminotransferase, TAT, and glutamine synthetase, GS) and transrepression (IL-6). The most potent compounds described in this study were the tertiary alcohol derivatives 21 and 25. These candidates showed highly efficacious IL-6 inhibition versus dexamethasone. The thiophenyl analogue 25 was evaluated in vivo in the mouse LPS challenge model and showed an ED(50) = 4.0 mg/kg, compared to 0.5 mg/kg for prednisolone in the same assay.