Hypoglycemic, hypolipidemic and antioxidant effects of iridoid glycosides extracted from Corni fructus: possible involvement of the PI3K–Akt/PKB signaling pathway
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Iridoid glycosides (CIG) are the major component of Corni fructus. In this work, we researched the antioxidative, hypoglycemic and lowering blood lipids effects of CIG on diabetic mice induced by a high-fat diet (HFD) and streptozotocin (STZ). Furthermore, to investigate the molecular mechanism of action, the phosphorylation and protein expression of phosphoinositide 3-kinase (PI3K) and its downstream proteins, such as insulin receptor (INSR), protein kinase B (Akt/PKB) and glucose transporter 4 (GLUT4) have been detected. The results showed that CIG significantly improved oral glucose tolerance in diabetic mice. Biochemical indices also revealed that CIG had a positive effect on lipid metabolism and oxidative stress. In addition, CIG can significantly enhance the expression level of the PI3K-Akt/PKB pathway related proteins in skeletal muscle, which is the key pathway of insulin metabolism. These findings show that CIG can improve the hyperglycemia and hyperlipidemia of HFD-STZ-induced diabetic mice through the PI3K-Akt/PKB signaling pathway, and CIG might be a potential medicine or functional food for type 2 diabetes mellitus remedies.Keywords:
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The transport of glucose into cells and tissues is a highly regulated process, mediated by a family of facilitative glucose transporters (GLUTs). Insulin-stimulated glucose uptake is primarily mediated by the transporter isoform GLUT4, which is predominantly expressed in mature skeletal muscle and fat tissues. Our recent work suggests that two separate pathways are initiated in response to insulin: (i) to recruit transporters to the cell surface from intracellular pools and (ii) to increase the intrinsic activity of the transporters. These pathways are differentially inhibited by wortmannin, demonstrating that the two pathways do not operate in series. Conversely, inhibitors of p38 mitogen-activated protein kinase (MAPK) imply that p38 MAPK is involved only in the regulation of the pathway leading to the insulin-stimulated activation of GLUT4. This review discusses the evidence for the divergence of GLUT4 translocation and activity and proposed mechanisms for the regulation of GLUT4.Key words: glucose transporter 4 (GLUT4), glucose uptake, p38 MAPK, GLUT4 activity.
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It is well established that insulin stimulation of glucose uptake in skeletal muscle cells is mediated through translocation of GLUT4 from intracellular storage sites to the cell surface. However, the established skeletal muscle cell lines, with the exception of L6 myocytes, reportedly show minimal insulin-dependent glucose uptake and GLUT4 translocation. Using C(2)C(12) myocytes expressing exofacial-Myc-GLUT4-enhanced cyan fluorescent protein, we herein show that differentiated C(2)C(12) myotubes are equipped with basic GLUT4 translocation machinery that can be activated by insulin stimulation ( approximately 3-fold increase as assessed by anti-Myc antibody uptake and immunostaining assay). However, this insulin stimulation of GLUT4 translocation was difficult to demonstrate with a conventional 2-deoxyglucose uptake assay because of markedly elevated basal glucose uptake via other glucose transporter(s). Intriguingly, the basal glucose transport activity in C(2)C(12) myotubes appeared to be acutely suppressed within 5 min by preincubation with a pathophysiologically high level of extracellular glucose (25 mM). In contrast, this activity was augmented by acute glucose deprivation via an unidentified mechanism that is independent of GLUT4 translocation but is dependent on phosphatidylinositol 3-kinase activity. Taken together, these findings indicate that regulation of the facilitative glucose transport system in differentiated C(2)C(12) myotubes can be achieved through surprisingly acute glucose-dependent modulation of the activity of glucose transporter(s), which apparently contributes to obscuring the insulin augmentation of glucose uptake elicited by GLUT4 translocation. We herein also describe several methods of monitoring insulin-dependent glucose uptake in C(2)C(12) myotubes and propose this cell line to be a useful model for analyzing GLUT4 translocation in skeletal muscle.
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Glucose plays an important role in cardiac metabolism.It is the major energy source during myocardial ischemia.Trans-membrane glucose transport is the first rate-limited step for myocardial glucose metabolism,which is facilitated by glucose transports (GLUTs) and GLUT4 represents an important mechanism that governs the entry of glucose into the heart.The quality and quantity of GLUT4 play a decisive role in transmembrane glucose transport.To better retrieve myocardial metabolism and improve myocardial function under myocardial ischemia conditions,it is urgent to elucidate the regulatory mechanism of GLUT4 expression,the regulatory mechanism of GLUT4 translocation,the regulatory mechanism of GLUT4 intrinsic activity and glucose transport in cardiomyocytes.This review summarized the current state of knowledge regarding the regulation of GLUT4 functioning and glucose transport in cardiomyocytes.
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Glucose transport proteins, facilitative; Glucose transporter type 4; Myocytes, cardiac; Myocardial ischemia
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The transport of glucose across the plasma membrane of nonepithelial cells is mediated by a family of facilitative glucose transporters. One glucose transporter is insulin-responsive (GLUT4) and is found in muscle, heart, and fat cells, differentiated cells which are difficult to maintain and study in culture. Cultured dermal fibroblasts, on the other hand, also are insulin-responsive, can be easily maintained in culture, and retain the genetic complement of the donor. In this paper, we evaluate RNA isolated from cultured human fibroblasts for the expression of four different glucose transporters. Northern blot analysis indicated that human fibroblasts expressed the erythrocyte (GLUT1), the fetal skeletal muscle (GLUT3), and the insulin-responsive (GLUT4) glucose transporters, but not the liver glucose transporter (GLUT2). To confirm the presence of GLUT4 mRNA, cDNA was synthesized from human fibroblast RNA, amplified using primers specific for GLUT4 by the polymerase chain reaction, and sequenced. The sequence was identical to that of GLUT4 cDNA. These data indicate that cultured human fibroblasts express at least three genetically distinct facilitative glucose transporters.
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Skeletal muscle glucose transport and metabolism were studied in a line of transgenic mice overexpressing the human Glut4 facilitative glucose transporter. Skeletal muscle Glut4 protein levels were increased 2-4-fold in transgenic animals relative to their nontransgenic litter mates. Glut4 overexpression increased total transport activity (measured with 1 mm 2-deoxy-d-glucose) in the isolated extensor digitorum brevis muscle in the presence of insulin; this increase was due to 1) an increase in basal glucose transport (0.8 ± 0.1 versus 0.5 ± 0.1 μmol.ml−1.20 min−1 in transgenic and control mice, respectively) and 2) an increase in insulin-stimulated transport (1.5 ± 0.1 versus 0.8 ± 0.1 μmol.ml−1.20 min−1 above basal transport in transgenic and control mice, respectively). Glut4 overexpression also increased glucose transport stimulated by muscle contractions. In addition, glycolysis and glucose incorporation into glycogen were enhanced in muscle isolated from transgenic mice compared to controls. These data demonstrate that Glut4 overexpression in skeletal muscle increases insulin- and contraction-stimulated glucose transport activity and glucose metabolism. These findings are consistent with the role of Glut4 as the primary mediator of transport stimulated by insulin or contractions. Skeletal muscle glucose transport and metabolism were studied in a line of transgenic mice overexpressing the human Glut4 facilitative glucose transporter. Skeletal muscle Glut4 protein levels were increased 2-4-fold in transgenic animals relative to their nontransgenic litter mates. Glut4 overexpression increased total transport activity (measured with 1 mm 2-deoxy-d-glucose) in the isolated extensor digitorum brevis muscle in the presence of insulin; this increase was due to 1) an increase in basal glucose transport (0.8 ± 0.1 versus 0.5 ± 0.1 μmol.ml−1.20 min−1 in transgenic and control mice, respectively) and 2) an increase in insulin-stimulated transport (1.5 ± 0.1 versus 0.8 ± 0.1 μmol.ml−1.20 min−1 above basal transport in transgenic and control mice, respectively). Glut4 overexpression also increased glucose transport stimulated by muscle contractions. In addition, glycolysis and glucose incorporation into glycogen were enhanced in muscle isolated from transgenic mice compared to controls. These data demonstrate that Glut4 overexpression in skeletal muscle increases insulin- and contraction-stimulated glucose transport activity and glucose metabolism. These findings are consistent with the role of Glut4 as the primary mediator of transport stimulated by insulin or contractions. we thank Xiang-Jing Wang, Connie Skillington, Guofeng Zhou, and Dan Johnson for their excellent technical assitance.
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Insulin responsiveness in skeletal muscle is determined by glucose transporter (Glut4) protein level
Glucose transport in skeletal muscle is mediated by two distinct transporter isoforms, designated muscle/adipose glucose transporter (Glut4) and erythrocyte/HepG2/brain glucose transporter (Glut1), which differ in both abundance and membrane distribution. The present study was designed to investigate whether differences in insulin responsiveness of red and white muscle might be due to differential expression of the glucose transporter isoforms. Glucose transport, as well as Glut1 and Glut4 protein and mRNA levels, were determined in red and white portions of the quadriceps and gastrocnemius muscles of male Sprague-Dawley rats (body wt. approx. 250 g). Maximal glucose transport (in response to 100 nM-insulin) in the perfused hindlimb was 3.6 times greater in red than in white muscle. Red muscle contained approx. 5 times more total Glut4 protein and 2 times more Glut4 mRNA than white muscle, but there were no differences in the Glut1 protein or mRNA levels between the fibre types. Our data indicate that differences in responsiveness of glucose transport in specific skeletal muscle fibre types may be dependent upon the amount of Glut4 protein. Because this protein plays such an integral part in glucose transport in skeletal muscle, any impairment in its expression may play a role in insulin resistance.
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The glucose transporter isoform CLUT4 is predominantly responsible for insulin-mediated glucose transport in muscle and adipose tissue. The activation of glucose transport is associated with the translocation of GLUT4-containing vesicles from an intracellular pool to the plasma membrane. Much has been learned in the past decade about the changes in the expression of this transporter in insulin-responsive tissues in diabetes mellitus and other insulin-resistant; states. The development of transgenic mice that overexpress CLUT4 or GLUT1 in muscle, adipose tissue, or both has also underscored the importance of the glucose transporters in glucose homeostasis. Data regarding which signaling steps are involved in the activation of glucose transport are just emerging, and even less is known about the molecular and cellular mechanisms governing translocation and recycling of GLUT4 vesicles. Another area of recent interest is the molecular basis of GLUT4 targeting to its intracellular vesicle.
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Abstract A family of facilitative glucose transporters or GLUTs mediates glucose uptake by cells and tissues. The glucose transporter isoform GLUT4, which is the predominant isoform expressed in mature muscle and fat tissues, is primarily responsible for the increase in glucose uptake in response to insulin stimulation. Recent work in our laboratory suggests that there are two divergent responses initiated by insulin stimulation. The first response involves the recruitment of GLUT4 transporters from intracellular reserves and their subsequent insertion into the plasma membrane. The second pathway results in an increase in the intrinsic activity of the transporters. This review will discuss evidence supporting the divergence of the two pathways regulating glucose uptake and, in particular, evidence for the increased intrinsic activity of GLUT4 in response to insulin stimulation. Inhibitors of p38 mitogen‐activated protein kinase (MAPK) affected only the arm leading to the insulin‐stimulated activation of GLUT4. This implicates p38 MAPK involvement in the regulation of this pathway. There is further evidence that p38 MAPK is itself recruited to the plasma membrane. The role of the phosphorylation state of the glucose transporter in response to insulin stimulation has been studied and indicates that, contrary to what might be predicted, there is actually a decrease in its phosphorylation at the plasma membrane in response to insulin. The relationship of this change to glucose uptake remains to be established. Other possible mechanisms regulating GLUT4 activity include binding of (+) or (−) modulators of its function.
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