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...

Stearoyl-CoA desaturase 1 (SCD1) deficiency protects mice from diet-induced obesity and insulin resistance. To understand the tissue-specific role of SCD1 in energy homeostasis, we have generated mice with an adipose-specific knockout of Scd1 (AKO), and report here that SCD1 deficiency increases GLUT1 expression in adipose tissue of AKO mice, but not global SCD1 knockout (GKO) mice. In 3T3-L1 adipocytes treated with a SCD inhibitor, basal glucose uptake and the cellular expression of GLUT1 were significantly increased while GLUT4 expression remained unchanged. Consistently, adipose-specific SCD1 knockout (AKO) mice had significantly elevated GLUT1 expression, but not GLUT4, in white adipose tissue compared to Lox counterparts. Concurrently, adiponectin expression was significantly diminished, whereas TNF-α expression was elevated. In contrast, in adipose tissue of GKO mice, GLUT4 and adiponectin expression were significantly elevated with lowered TNF-α expression and little change in GLUT1 expression, suggesting a differential responsiveness of adipose tissue to globalor adipose-specific SCD1 deletion. Taken together, these results indicate that adipose-specific deletion of SCD1 induces GLUT1 up-regulation in adipose tissue, associated with decreased adiponectin and increased TNF-α production, and suggest that GLUT1 may play a critical role in controlling glucose homeostasis of adipose tissue in adipose-specific SCD1-deficient conditions.

Fibroin, the protein of silk, and hydrolyzed fibroin have recently been described to enhance insulin sensitivity and glucose metabolism in 3T3-L1 adipocytes. Here, we report that a series of synthetic peptides derived from the fibroin sequence have enhancing effects on glucose transport in normal and insulin-resistant 3T3-L1 cells. We observed that, among several enzymatic hydrolysates of fibroin, the chymotryptic and peptic hydrolysates were significantly more effective than others in augmenting insulin-stimulated glucose uptake in both cells. We synthesized several peptides of repetitive sequences in fibroin. Treatment with synthesized hexapeptides enhanced insulin-stimulated glucose uptake more than tri-, tetra-or pentapeptides. Among those, the effect of Gly-Ala-Gly-Ala-Gly-Tyr (GAGAGY) was most robust, and especially its activity of blocking off the chronic-insulin-induced loss of insulin-stimulated uptake was remarkable. Data reveal that the residues of tyrosine situated at the ends of the peptides play a critical role for exerting their activities. We demonstrate that the insulin-sensitizing effect of GAGAGY is due to enhancement of phosphoinositide 3-kinase (PI 3-K) signaling pathway. The GAGAGY-induced insulin-stimulated glucose uptake was sensitive to inhibition of PI 3-K by wortmannin. Phosphorylation of Akt was also elevated in GAGAGY-treated cells. Furthermore, GAGAGY significantly increased insulin-induced glucose transporter 4 (GLUT4) translocation without affecting the synthesis of GLUT4. Our findings suggest that fibroin-derived peptides such as GAGAGY could be considered as novel insulin-sensitizing agents with an activity of blocking the development of insulin resistance.

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Abstract-In this paper, we advocate addressing the communication overhead problem between OpenFlow controllers and OpenFlow switches due to table-miss in a flow table. It may cause the communication overhead between controllers and switches because a switch has to send packet-in message to a controller for processing table-missed flows. We propose a simple flow entry management scheme for reducing the controller overhead by increasing the flow entry matching ratio. By using an LRU caching algorithm, a switch can keep the flow entries in a flow table as many as possible, and then the flow entry matching ratio can be increased.