Type 2 diabetes (T2D) occurs when there is insufficient insulin release to control blood glucose, due to insulin resistance and impaired β-cell function. The GPR39 receptor is expressed in metabolic tissues including pancreatic β-cells and has been proposed as a T2D target. Specifically, GPR39 agonists might improve β-cell function leading to more adequate and sustained insulin release and glucose control. The present study aimed to test the hypothesis that GPR39 agonism would improve glucose stimulated insulin secretion in vivo. A high throughput screen, followed by a medicinal chemistry program, identified three novel potent Zn2+ modulated GPR39 agonists. These agonists were evaluated in acute rodent glucose tolerance tests. The results showed a lack of glucose lowering and insulinotropic effects not only in lean mice, but also in diet-induced obese (DIO) mice and Zucker fatty rats. It is concluded that Zn2+ modulated GPR39 agonists do not acutely stimulate insulin release in rodents.

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In the present study, we examined the concentration dependence of odor discrimination in turtle olfactory bulbar responses using the cross-adaptation technique. In the odorant pairs with diverse molecular structures, the degree of discrimination was unchanged or only slightly decreased with an increase in odorant concentrations, suggesting that odorants are well discriminated even at high concentrations. In the odorant pairs with closely related molecular structures, the degree of discrimination was decreased with an increase in odorant concentrations. An increase in the temperature of turtle olfactory epithelium also decreased the ability to discriminate these odorants. There was a good correlation between changes in the odor discriminating ability induced by an increase in odor concentrations and those induced by a temperature increase. The liposomes were made of lipids extracted from the turtle olfactory epithelia and changes of their membrane fluidity induced by adsorption of odorants were monitored with DPH. There was a good correlation between a decrease in odor discriminating ability and the membrane fluidity changes induced by odorants. We suggest that decreases in odor discriminating ability induced either by an increase in odor concentration or by a temperature increase are ultimately caused by changes in the membrane fluidity.

RNA interference (RNAi) is a powerful tool for the study of gene function in mammalian systems, including transgenic mice. Here, we report a gene knockdown system based on the human mir-187 precursor. We introduced small interfering RNA (siRNA) sequences against the mouse melanocortin-4 receptor (mMc4r) to alter the targeting of miR-187. The siRNA-expressing cassette was placed under the control of the cytomegalovirus (CMV) early enhancer/chicken β-actin promoter. In vitro, the construct efficiently knocked down the gene expression of a co-transfected mMc4r-expression vector in cultured mammalian cells. Using this construct, we generated a transgenic mouse line which exhibited partial but significant knockdown of mMc4r mRNA in various brain regions. Northern blot analysis detected transgenic expression of mMc4r siRNA in these regions. Furthermore, the transgenic mice fed a normal diet ate 9% more and were 30% heavier than wild-type sibs. They also developed hyperinsulinemia and fatty liver as do mMc4r knockout mice. We determined that this siRNA expression construct based on mir-187 is a practical and useful tool for gene functional studies in vitro as well as in vivo.