The global prevalence of diabetes mellitus was 537 million in 2021 and is projected to increase to 783 million by 2045. Diabetes progression is also associated with histone modifications. Previous studies have reported that Acalypha hispida leaves are rich in flavonoids and phenolic acids, which are associated with antihyperglycemic activity. Recently, we produced a nanoextract of A. hispida leaf that contains bioactive compounds with antidiabetic effects. However, there were no studies reported the antidiabetic efficacy of A. hispida extract and nanoextract. Hence, we aimed to evaluate the antidiabetic effects of A. hispida extract and nanoextract on pancreatic β‐cells, insulin secretion, glycogen content, and histone modifications in streptozotocin‐induced diabetic rats. Diabetic rats received oral doses of the extract (300 mg/kg bw) and nanoextract (30 and 60 mg/kg bw) daily for 28 days. Bodyweight, blood glucose levels, insulin levels, islets of Langerhans and pancreatic β‐cells, glycogen content, acetylation of lysine 9 on histone 3 (H3K9Ac) level, hematology, and lipid profile were assessed. Analyses of variance, principal component analysis (PCA), and partial least squares were performed. The nanoextract of A. hispida was successfully produced at a nanosize of 733 nm. The extract (300 mg/kg bw) and nanoextract (60 mg/kg bw) exhibited antidiabetic effects based on the following parameters: decreased blood glucose levels, increased pancreatic β‐cell number and density, increased insulin levels, decreased H3K9Ac level in the islets of Langerhans and liver, enhanced glycogen levels in the liver, and improved lipid metabolism. Moreover, PCA indicated that the nanoextract (60 mg/kg bw) showed the strongest antidiabetic effect based on these parameters. The increased β‐cell number and density led to decreased blood glucose levels. In conclusion, A. hispida extract and nanoextract have antidiabetic effects by restoring β‐cell number and density and decreasing H3K9 acetylation in the islets of Langerhans in streptozotocin‐induced diabetic rats.
