Glucose uptake in insulin-sensitive tissues, which is dependent on the activity of glucose transporters (GLUTs), is a major regulatory process in the homeostatic control of blood glucose levels. GLUT1 is ubiquitously expressed for fulfilling basal glucose uptake, whereas GLUT4 is expressed in the insulin sensitive tissues in which glucose uptake is acutely stimulated by insulin.1) The regulatory mechanisms for the activity of glucose transporters have been extensively studied. It has been known that, at least two distinct signaling pathways are implicated in insulin-stimulated GLUT4 translocation and glucose uptake. One pathway results from the tyrosine phosphorylation of insulin receptor substrate (IRS) protein, leading to the activation of phosphatidylinositol 3-kinase (PI 3-K), and a second pathway occurs through the tyrosine phosphorylation of Clb, followed by the activation of TC10.2) Recent evidence has demonstrated that atypical protein kinase C (PKCz/l) is known to be a convergent target of the insulin-stimulated PI 3-K and TC10 pathways.
3)Related to GLUT1, it has been reported that activation of extracellular signal-regulated kinase (ERK) up-regulates GLUT1 expression, resulting in augmentation of basal glucose uptake in the absence of acute insulin stimulation. 4,5) In addition, an enhancement of GLUT1-mediated glucose transport is reportedly associated with an stimulation of AMP-activated protein kinase (AMPK).
6,7)Berberine, an isoquinoline alkaloid isolated from some Chinese medicinal herbs such as Coptidis Rhizoma and Cortex Phellodendri, has been used for the treatment of diarrhea an other gastrointestinal infections as an antibacterial drug in Chinese medicine. 8) Recently, it has been reported that berberine reduces serum cholesterol, triglycerides, and LDLcholesterol in hypercholesterolemic patients, with being suggested as a novel cholesterol-lowing drug.9) Recent studies have also shown that berberine has antihyperglycemic effects.10-12) However, elucidations of berberine action are not in agreement between research groups. One suggested an insulin-independent effect, 10) whereas others showed an insulin-secretion stimulating 11) or insulin-sensitizing effects.
13)Although the mechanism underlying the berberine effect is not known in detail, it might involve the activation of AMPK. Lee et al. suggested that berberine has beneficial effects in diabetes and obesity in part via activation of AMPK.14)Presently, we found that berberine displays an enhancing effect on GLUT1-mediated glucose transport in 3T3-L1 adipocytes. To explore a yet unidentified mechanism, we analyzed related signal transduction pathways that are activated by berberine.
MATERIALS AND METHODS
MaterialsAntibodies against IR, IRS-1, phospho-IRS-1 (Ser636/639), PKCz/l, phospho-PKCz/l (Thr410/403), p38, phospho-p38 (Thr180/Tyr182), ERK1/2, phospho-ERK1/2 (Thr202/Tyr204), AMPK, and phospho-AMPK (Thr172) were purchased from Cell Signaling Technology (Beverly, MA, U.S.A.). Anti-GLUT1 and anti-GLUT4 antibodies were purchased from San...