Coronarin A modulated hepatic glycogen synthesis and gluconeogenesis via inhibiting mTORC1/S6K1 signaling and ameliorated glucose homeostasis of diabetic mice.

Promotion of hepatic glycogen synthesis and inhibition of hepatic glucose production are effective strategies for controlling hyperglycemia in type 2 diabetes mellitus (T2DM), but agents with both properties were limited. Herein we report coronarin A, a natural compound isolated from rhizomes of Hedychium gardnerianum, which simultaneously stimulates glycogen synthesis and suppresses gluconeogenesis in rat primary hepatocytes. We showed that coronarin A (3, 10 µM) dose-dependently stimulated glycogen synthesis accompanied by increased Akt and GSK3ß phosphorylation in rat primary hepatocytes. Pretreatment with Akt inhibitor MK-2206 (2 µM) or PI3K inhibitor LY294002 (10 µM) blocked coronarin A-induced glycogen synthesis. Meanwhile, coronarin A (10 µM) significantly suppressed gluconeogenesis accompanied by increased phosphorylation of MEK, ERK1/2, ß-catenin and increased the gene expression of TCF7L2 in rat primary hepatocytes. Pretreatment with ß-catenin inhibitor IWR-1-endo (10 µM) or ERK inhibitor SCH772984 (1 µM) abolished the coronarin A-suppressed gluconeogenesis. More importantly, we revealed that coronarin A activated PI3K/Akt/GSK3ß and ERK/Wnt/ß-catenin signaling via regulation of a key upstream molecule IRS1. Coronarin A (10, 30 µM) decreased the phosphorylation of mTOR and S6K1, the downstream target of mTORC1, which further inhibited the serine phosphorylation of IRS1, and subsequently increased the tyrosine phosphorylation of IRS1. In type 2 diabetic ob/ob mice, chronic administration of coronarin A significantly reduced the non-fasting and fasting blood glucose levels and improved glucose tolerance, accompanied by the inhibited hepatic mTOR/S6K1 signaling and activated IRS1 along with enhanced PI3K/Akt/GSK3ß and ERK/Wnt/ß-catenin pathways. These results demonstrate the anti-hyperglycemic effect of coronarin A with a novel mechanism by inhibiting mTORC1/S6K1 to increase IRS1 activity, and highlighted coronarin A as a valuable lead compound for the treatment of T2DM.

Association between diurnal temperature range and respiratory tract infections.

OBJECTIVE: This study aimed to assess the association between emergency-room visits for respiratory tract infection (RTI) with diurnal temperature range (DTR), a weather parameter closely associated with urbanization and global climate change. METHODS: We conducted a semiparametric time-series analysis to estimate the percentage increase in emergency-room visits for RTI associated with changes in DTR after adjustment for daily weather conditions (temperature and relative humidity) and outdoor air pollution. RESULTS: DTR was significantly associated with daily emergency-room visits for RTI. An increase of 1 °C in the current-day (L0) and in the 2-day moving average (L01) DTR corresponded to a 0.94% [95% confidence interval (CI), 0.34%-1.55%] and 2.08% (95% CI, 1.24%-2.93%) increase in emergency-room visits for RTI, respectively. CONCLUSION: DTR was associated with increased risk of RTI. More studies are needed to understand the impact of DTR on respiratory health.