In L6 Skeletal Muscle Cells, Glucose Induces Cytosolic Translocation of Protein Kinase C-α and Trans-activates the Insulin Receptor Kinase

Caruso, Martina; Miele, Claudia; Oriente, Francesco; Maitan, Alessandra; Bifulco, Giuseppe; Andreozzi, Francesco; Condorelli, Gerolama; Formisano, Pietro; Béguinot, Francesco

doi:10.1074/jbc.274.40.28637

Cited by 34 publications

(60 citation statements)

References 42 publications

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“…This kinase family has also been shown to be involved in the translocation of glucose transporters (GLUT) and=or regulation of glucose uptake in the heart 11 and skeletal muscle cells 16,17 and adipocytes. 18 Moreover, activation of PKC is suggested to be involved in the regulation of proteins controlling glucose oxidation 19 and glycogen metabolism.…”

Section: Introductionmentioning

confidence: 99%

Impaired glucose metabolism in the heart of obese Zucker rats after treatment with phorbol ester

et al. 2002

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OBJECTIVE:To investigate the influence of obesity on the regulation of myocardial glucose metabolism following protein kinase C (PKC) activation in obese (fa=fa) and lean (Fa=?) Zucker rats. DESIGN: Isolated hearts obtained from 17-week-old lean and obese Zucker rats were perfused with 200 nM phorbol 12-myristate 13-acetate (PMA) for different time periods prior to the evaluation of PKC and GLUT-4 translocation. For metabolic studies isolated hearts from 48 h starved Zucker rats were perfused with an erythrocytes-enriched buffer containing increased concentrations (10 -100 nM) of PMA. MEASUREMENTS: Immunodetectable PKC isozymes and GLUT-4 were determined by Western blots. Glucose oxidation and glycolysis were evaluated by measuring the myocardial release of 14 CO 2 and 3 H 2 O from [U-14 C]glucose and [5-3 H]glucose, respectively. RESULTS: PMA (200 nM) induced maximal translocation of ventricular PKCa from the cytosol to the membranes within 10 min. This translocation was 2-fold lower in the heart from obese rats when compared to lean rats. PMA also induced a significant translocation of ventricular GLUT-4 from the microsomal to the sarcolemmal fraction within 60 min in lean but not in obese rats. Rates of basal cardiac glucose oxidation and glycolysis in obese rats were approximately 2-fold lower than those of lean rats. Perfusion with increasing concentrations of PMA (10 -100 nM) led to a significant decrease of cardiac glucose oxidation in lean but not in obese rats. CONCLUSION: Our results show that in the heart of the genetically obese Zucker rat, the impairment in PKCa activation is in line with a diminished activation of GLUT-4 as well as with the lack of PMA effect on glucose oxidation.

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Section: Introductionmentioning

confidence: 99%

Impaired glucose metabolism in the heart of obese Zucker rats after treatment with phorbol ester

et al. 2002

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“…Hence, our previous work in muscle cells showed that glucose rapidly causes reverse translocation of PKC␣ from the plasma membrane to the cytoplasm. Reverse translocation of PKC␣ reduces PKC␣-IR association and IR Ser/Thr phosphorylation and acutely activates the insulin signaling system in these cells (42). A similar mechanism is unlikely to account for glucose effect on insulin mitogenic signaling in the JAr cells, however.…”

Section: Resultsmentioning

confidence: 94%

“…Firstly, in JAr cells, glucose may affect PKC activity. These Ser/Thr kinases phosphorylate several insulin signaling molecules and inhibit their subsequent tyrosine phosphorylation and function (42,43). Hence, our previous work in muscle cells showed that glucose rapidly causes reverse translocation of PKC␣ from the plasma membrane to the cytoplasm.…”

Section: Resultsmentioning

confidence: 99%

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Glucose Regulates Insulin Mitogenic Effect by Modulating SHP-2 Activation and Localization in JAr Cells

Bifulco¹,

Carlo²,

Caruso³

et al. 2002

Journal of Biological Chemistry

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The glucose effect on cell growth has been investigated in the JAr human choriocarcinoma cells. When JAr cells were cultured in the presence of 6 mM glucose (LG), proliferation and thymidine incorporation were induced by serum, epidermal growth factor, and insulinlike growth factor 1 but not by insulin. In contrast, at 25 mM glucose (HG), proliferation and thymidine incorporation were stimulated by insulin, serum, epidermal growth factor, and insulin-like growth factor 1 to a comparable extent, whereas basal levels were 25% lower than those in LG. HG culturing also enhanced insulinstimulated insulin receptor and insulin receptor substrate 1 (IRS1) tyrosine phosphorylations while decreasing basal phosphorylations. These actions of glucose were accompanied by an increase in cellular tyrosine phosphatase activity. The activity of SHP-2 in HGtreated JAr cells was 400% of that measured in LGtreated cells. SHP-2 co-precipitation with IRS1 was also increased in HG-treated cells. SHP-2 was mainly cytosolic in LG-treated cells. However, HG culturing largely redistributed SHP-2 to the internal membrane compartment, where tyrosine-phosphorylated IRS1 predominantly localizes. Further exposure to insulin rescued SHP-2 cytosolic localization, thereby preventing its interaction with IRS1. Antisense inhibition of SHP-2 reverted the effect of HG on basal and insulin-stimulated insulin receptor and IRS1 phosphorylation as well as that on thymidine incorporation. Thus, in JAr cells, glucose modulates insulin mitogenic action by modulating SHP-2 activity and intracellular localization.

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“…Further studies have shown that PED stabilises phospholipase D (PLD) [26] and induces activation of classical protein kinase C (PKC) isoforms, including PKCα and PKCβ [23,27]. The induction of classical PKCs, in turn, inhibits insulin signalling, at least in skeletal muscle, adipose and liver cells [28][29][30][31]. Nevertheless, the role of PED in diabetic complications is not known.…”

Section: Introductionmentioning

confidence: 99%

Overproduction of phosphoprotein enriched in diabetes (PED) induces mesangial expansion and upregulates protein kinase C-β activity and TGF-β1 expression

et al. 2009

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Aims/hypothesis Overproduction of phosphoprotein enriched in diabetes (PED, also known as phosphoprotein enriched in astrocytes-15 ) is a common feature of type 2 diabetes and impairs insulin action in cultured cells and in mice. Nevertheless, the potential role of PED in diabetic complications is still unknown. MethodsWe studied the effect of PED overproduction and depletion on kidney function in animal and cellular models. Results Transgenic mice overexpressing PED (PEDTg) featured age-dependent increases of plasma creatinine levels and urinary volume, accompanied by expansion of the mesangial area, compared with wild-type littermates. Serum and kidney levels of TGF-β1 were also higher in 6-and 9-month-old PEDTg. Overexpression of PED in human kidney 2 cells significantly increased TGF-β1 levels, SMAD family members (SMAD)2/3 phosphorylation and fibronectin production. Opposite results were obtained following genetic silencing of PED in human kidney 2 cells by antisense oligonucleotides. Inhibition of phospholipase D and protein kinase C-β by 2-butanol and LY373196 respectively reduced TGF-β1, SMAD2/3 phosphorylation and fibronectin production. Moreover, inhibition of TGF-β1 receptor activity and SMAD2/3 production by SB431542 and antisense oligonucleotides respectively reduced fibronectin secretion by about 50%. TGF-β1 circulating levels were significantly reduced in Ped knockout mice and positively correlated with PED content in peripheral blood leucocytes of type 2 diabetic patients. Conclusions/interpretation These data indicate that PED regulates fibronectin production via phospholipase D/protein kinase C-β and TGF-β1/SMAD pathways in kidney cells. Raised PED levels may therefore contribute to the abnormal accumulation of extracellular matrix and renal dysfunction in diabetes.

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In L6 Skeletal Muscle Cells, Glucose Induces Cytosolic Translocation of Protein Kinase C-α and Trans-activates the Insulin Receptor Kinase

Cited by 34 publications

References 42 publications

Impaired glucose metabolism in the heart of obese Zucker rats after treatment with phorbol ester

Impaired glucose metabolism in the heart of obese Zucker rats after treatment with phorbol ester

Glucose Regulates Insulin Mitogenic Effect by Modulating SHP-2 Activation and Localization in JAr Cells

Overproduction of phosphoprotein enriched in diabetes (PED) induces mesangial expansion and upregulates protein kinase C-β activity and TGF-β1 expression

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