Nateglinide

Oral drug absorption involves drug permeation across the apical and basolateral membranes of enterocytes. Although transporters mediating the influx of anionic drugs in the apical membranes have been identified, transporters responsible for efflux in the basolateral membranes remain unclear. Monocarboxylate transporter 6 (MCT6/SLC16A5) has been reported to localize to the apical and basolateral membranes of human enterocytes and to transport organic anions such as bumetanide and nateglinide in the Xenopus oocyte expression system; however, its transport functions have not been elucidated in detail. In this study, we characterized the function of MCT6 expressed in HEK293T cells and explored fluorescent probes to more easily evaluate MCT6 function. The results illustrated that MCT6 interacts with CD147 to localize at the plasma membrane. When the uptake of various fluorescein derivatives was examined in NaCl-free uptake buffer (pH 5.5), the uptake of 5-carboxyfluorescein (5-CF) was significantly greater in MCT6 and CD147-expressing cells. MCT6-mediated 5-CF uptake was saturable with a K_m of 1.07 mM and inhibited by several substrates/inhibitors of organic anion transporters and extracellular Cl ion with an IC₅₀ of 53.7 mM. These results suggest that MCT6 is a chloride-sensitive organic anion transporter that can be characterized using 5-CF as a fluorescent probe.

Oral delivery of antidiabetic active components promises to free millions of people from daily suffering who require routine injections. However, oral insulin (Ins) and other short‐acting compounds such as nateglinide (NG) in harsh gastrointestinal tract still face great challenging, including low bioavailability, and rapid elimination. In this study, inspired by the self‐assembly of phenylalanine‐based peptides in nature, it is showed that NG a small phenylalanine derivative, assembles into left‐handed helical nanofibers in the presence of Ca2+. These helical NG nanofibers functioned as a coating layer on the surface of Ca2+‐linked alginate (Alg) microgels for the effective encapsulation of Ins. As expected, the sustained release and prolonged circulation of Ins and NG from the Ins‐loading Alg/NG microgels (Ins@Alg/NG) in the intestinal tract synergistically maintain a relatively normal blood glucose level in streptozotocin‐induced diabetic mice after oral administration of Ins@Alg/NG. This further confirms that Ins@Alg/NG ameliorated Ins resistance mainly through activating Insreceptor substrate 1 (IRS1), protein kinase B (AKT), and AMP‐activated protein kinase (AMPK), as well as by repressing glycogen synthase kinase‐3β (GSK‐3β). The strategy of using the assembly of NG as a coating achieves the oral delivery of insulin and showcases a potential for the treatment of diabetes.