The Insulinotropic and Antihyperglycemic Effect of Hypericum Perforatum L. Extract Based on Changes in AMPK Expression and PKCε Concentration in Diabetic Rats

Ethnopharmacological relevance: Hypericum perforatum&nbsp;L., commonly known as St. John's Wort (SJW), represents one of the best-known and most thoroughly researched medicinal plant species. The ethnobotanical usage and bioactivities related to&nbsp;H. perforatum&nbsp;include treatment of skin diseases, wounds and burns, gastrointestinal problems, urogenital diseases, and psychiatric disorders, particularly depression. In the last decade, many studies focused on the&nbsp;bioactive constituents responsible for the&nbsp;antihyperglycemic and antidiabetic activity of SJW extracts. However,&nbsp;the mechanism by which&nbsp;H. perforatum &nbsp;extract exhibits these properties is still unclear.&nbsp;Hence, the current study was designed to gain insight into the underlying biochemical and molecular mechanisms by which wildly growing&nbsp;H. perforatum &nbsp;exerts its antihyperglycemic and antidiabetic activities.&nbsp;<br><br>Material and methods:&nbsp;Plant material of&nbsp;H. perforatum was harvested from a natural population in the Republic of North Macedonia during full flowering season. Methanol (80% v/v) was used to extract bioactive components from HH powder.The dissolved HH dry extract (in 0.3% CMC) was given daily as a single treatment (200 mg/kg bw) during 14 days both in healthy and streptozotocin-induced diabetic rats. As a positive control, we applied glibenclamide.&nbsp;The activity of &nbsp;key enzymes involved in carbohydrate methabolisam in the liver were assessed, along with substrate concentration, as well as AMPK&nbsp;mRNA levels, PKCε concentration, plasma insulin level and pancreatic PARP activity.<br><br>Results:&nbsp;Compared to diabetic rats, treatment of diabetic rats with HH extract resulted with decreased activity of hepatic enzymes glucose-6-phospatase and fructose-1,6-bisphosphatase, increased liver glycogen and&nbsp;glucose-6-phosphate&nbsp;content, which resulted with reduced blood glucose concentration up to normoglycaemia. Non-significant changes were observed in the activity of hexokinase, glycogen phosphorylase and glucose-6-phospahte dehydrogenase. HH-treatment also caused an increase in plasma insulin concentration and&nbsp;increase in&nbsp;pancreatic PARP activity. Finally, HH&nbsp;treatment of diabetic rats showed significant increase in AMPK expression and decrease of&nbsp;PKCε concentration.<br><br>Conclusion:&nbsp;We present&nbsp;in vivo&nbsp;evidence that HH extract exert insulinotropic effects and regulate endogenous glucose production mostly by suppressing liver gluconeogenesis. The HH-treatment did not effected glycogenolysys and glycolysis. Finally, we confirm the antihyperglycemic and antidiabetic effect of HH-extract and the mechanism of this effect involves amelioration of AMPK and PKCε changes in the liver