Sustained antidiabetic effects of a berberine-containing Chinese herbal medicine through regulation of hepatic gene expression.

Diabetes and obesity are complex diseases associated with insulin resistance and fatty liver. The latter is characterized by dysregulation of the Akt, AMP-activated protein kinase (AMPK), and IGF-I pathways and expression of microRNAs (miRNAs). In China, multicomponent traditional Chinese medicine (TCM) has been used to treat diabetes for centuries. In this study, we used a three-herb, berberine-containing TCM to treat male Zucker diabetic fatty rats. TCM showed sustained glucose-lowering effects for 1 week after a single-dose treatment. Two-week treatment attenuated insulin resistance and fatty degeneration, with hepatocyte regeneration lasting for 1 month posttreatment. These beneficial effects persisted for 1 year after 1-month treatment. Two-week treatment with TCM was associated with activation of AMPK, Akt, and insulin-like growth factor-binding protein (IGFBP)1 pathways, with downregulation of miR29-b and expression of a gene network implicated in cell cycle, intermediary, and NADPH metabolism with normalization of CYP7a1 and IGFBP1 expression. These concerted changes in mRNA, miRNA, and proteins may explain the sustained effects of TCM in favor of cell survival, increased glucose uptake, and lipid oxidation/catabolism with improved insulin sensitivity and liver regeneration. These novel findings suggest that multicomponent TCM may be a useful tool to unravel genome regulation and expression in complex diseases.

Up-regulated pancreatic tissue microRNA-375 associates with human type 2 diabetes through beta-cell deficit and islet amyloid deposition.

OBJECTIVES: The aim of this study was to examine correlations of the islet-specific microRNA-375 expression to islet amyloid formation and pancreatic islet damage in human type 2 diabetes. METHODS: Autopsy pancreas samples from 40 type 2 diabetic and 15 nondiabetic patients were used to detect microRNA-375 expression using real-time quantitative polymerase chain reaction. Serial paraffin sections of the corresponding type 2 diabetic and nondiabetic cases were stained by immunofluorescence to evaluate for amylin expression, amyloid formation, and proportions of alpha and beta cells. RESULTS: Pancreatic microRNA-375 expression was increased in type 2 diabetic patients comparing with the nondiabetic patients (median, 4.02 for the diabetic patients vs 0.92 for the nondiabetic patients; P = 0.0001). The median was 6.14 for the diabetic patients with islet amyloid and 3.51 for islet amyloid-free diabetic patients. The expression level of microRNA-375 correlated positively with the frequency and the severity of islet amyloid formation and negatively with proportions of islet beta-cells and amylin-positive area, and islet mitochondria density. CONCLUSIONS: Up-regulated microRNA-375 is associated with type 2 diabetes and pancreatic islet amyloid formation and beta-cell deficit. microRNA-375 may serve as a biomarker for known and novel pathways in the pathogenesis of type 2 diabetes related to islet amyloid deposition and beta-cell dysfunction.