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Typus
Verschleierung
Bearbeiter
Hindemith
Gesichtet
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Untersuchte Arbeit:
Seite: 16, Zeilen: 1ff (entire page)
Quelle: McCarthy and Elmendorf 2007
Seite(n): 381, 382, Zeilen: 381: l.col: 36ff; 382: l.col: 1ff
Impaired insulin signaling through downstream Akt2 and AS160 proteins has also been reported in skeletal muscle. Furthermore, the fatty acid metabolite ceramide causes insulin resistance that is coupled to impaired membrane recruitment and phosphorylation of Akt (72). Knowledge on mechanisms of such defects has remained underdeveloped. Increased IRS-1 serine phosphorylation may also help explain insulin resistance, as phosphorylated serine residues are thought to sterically hinder interactions with downstream PI3K. Dysregulated PKC activity in insulin resistance could increase serine phosphorylation (73) and PKC knockout mice are protected from insulin resistance (74).

Membrane and cytoskeletal defects are also a possible basis of insulin resistance. We now know that moderate increase in plasma membrane fluidity increase glucose transport . Furthermore, it has been shown that basal glucose transport is not fully active in fat cells and that it can be increased further by augmenting membrane fluidity. Consistent with membrane fluidity influencing insulin responsiveness, insulin-stimulated glucose transport is decreased when fluidity diminishes (75). Recent data suggest that the anti-diabetic drug metformin enhances insulin action by increasing membrane fluidity (76). Interestingly, the beneficial effects of chromium supplementation on insulin responsiveness may also be linked to membrane fluidity (77). With regards to cytoskeletal defects, recent study of various cell culture models of insulin resistance suggests that an underlying basis of reduced cellular insulin sensitivity may be perturbations in phosphoinositide-regulated cortical F-actin structure. In particular, PI -P2 control of cortical F-actin is disturbed by hyperinsulinaemic (78) and hyperendothelinaemic insulin-resistant conditions (79). Furthermore, isolated adipocytes from ethanol-induced insulin resistant Wistar rats (80) and skeletal muscle from obese insulin-resistant Zucker rats display altered actin polymerization. These findings agree with the necessity of an intact cytoskeleton for proper glucose regulation and suggest a membrane/cytoskeletal component of insulin resistance. Finally, some study has also revealed that insulin-resistant conditions are associated with defects in the SNARE pathway. As future research continues to expand our understanding of the signaling pathways of insulinregulated GLUT4 translocation and glucose transport, our ability to develop interventions to prevent, reverse, and ameliorate insulin resistance in obesity and type 2 diabetes will be favourably reached.


72. Teruel,T, Hernandez,R, Lorenzo,M: Ceramide mediates insulin resistance by tumor necrosis factor-alpha in brown adipocytes by maintaining Akt in an inactive dephosphorylated state. Diabetes 50:2563-2571, 2001

73. De Fea,K, Roth,RA: Protein kinase C modulation of insulin receptor substrate-1 tyrosine phosphorylation requires serine 612. Biochemistry 36:12939-12947, 1997

74. Kim,JK, Fillmore,JJ, Sunshine,MJ, Albrecht,B, Higashimori,T, Kim,DW, Liu,ZX, Soos,TJ, Cline,GW, O'Brien,WR, Littman,DR, Shulman,GI: PKC-theta knockout mice are protected from fat-induced insulin resistance. J.Clin.Invest 114:823-827, 2004

75. Czech,MP: Insulin action and the regulation of hexose transport. Diabetes 29:399-409, 1980

76. Wiernsperger,NF: Membrane physiology as a basis for the cellular effects of metformin in insulin resistance and diabetes. Diabetes Metab 25:110-127, 1999

77. Chen,G, Liu,P, Pattar,GR, Tackett,L, Bhonagiri,P, Strawbridge,AB, Elmendorf,JS: Chromium activates glucose transporter 4 trafficking and enhances insulinstimulated glucose transport in 3T3-L1 adipocytes via a cholesterol-dependent mechanism. Mol.Endocrinol. 20:857-870, 2006

78. Chen,G, Raman,P, Bhonagiri,P, Strawbridge,AB, Pattar,GR, Elmendorf,JS: Protective effect of phosphatidylinositol 4,5-bisphosphate against cortical filamentous actin loss and insulin resistance induced by sustained exposure of 3T3-L1 adipocytes to insulin. J.Biol.Chem. 279:39705-39709, 2004

79. Strawbridge,AB, Elmendorf,JS: Endothelin-1 impairs glucose transporter trafficking via a membrane-based mechanism. J.Cell Biochem. 97:849-856, 2006

80. Sebastian,BM, Nagy,LE: Decreased insulin-dependent glucose transport by chronic ethanol feeding is associated with dysregulation of the Cbl/TC10 pathway in rat adipocytes. Am.J.Physiol Endocrinol.Metab 289:E1077-E1084, 2005

Impaired insulin signaling through downstream Akt2 and AS160 proteins has also been reported in skeletal muscle51,120. Furthermore, the fatty acid metabolite ceramide causes insulin resistance that is coupled to impaired membrane recruitment and phosphorylation of Akt121. Knowledge on mechanisms of such defects has remained underdeveloped. [...] Increased IRS-1 serine phosphorylation may also help explain insulin resistance, as phosphorylated serine residues are thought to sterically hinder interactions with downstream PI3K. Dysregulated PKC activity in insulin resistance could increase serine phosphorylation124, and PKC knockout mice are protected from insulin resistance125.

Membrane and cytoskeletal defects are also a possible basis of insulin resistance. We now know that moderate increases in plasma membrane fluidity increase glucose transport126-128. Furthermore, it has been shown that basal glucose transport is not fully active in fat cells and that it can be increased further by augmenting membrane fluidity126. Consistent with membrane fluidity influencing insulin responsiveness, insulin-stimulated glucose transport is decreased when fluidity diminishes127. Recent data suggest that the anti-diabetic drug metformin enhances insulin action by increasing membrane fluidity129,130. Interestingly, the beneficial effects of chromium supplementation on insulin responsiveness may also be linked to membrane fluidity131-133. With regards to cytoskeletal defects, recent study of various cell culture models of insulin resistance suggests that an underlying basis of reduced cellular insulin sensitivity may be perturbations in phosphoinositide-regulated cortical F-actin structure. In particular, PI 4,5-P2 control of cortical F-actin is disturbed by hyperinsulinaemic134 and hyperendothelinaemic135,136 insulin-resistant conditions and reversal of these changes by experimental manipulation of PI 4,5-P2 corresponds with a restoration in insulin sensitivity. Furthermore, isolated adipocytes from ethanol-induced insulinresistant Wistar rats82 and skeletal muscle from obese insulin resistant Zucker rats137 display altered actin polymerization. These findings agree with the necessity of an intact cytoskeleton for proper glucose regulation and suggest a membrane/cytoskeletal

[page 382]

component of insulin resistance. Finally, some study has also revealed that insulin-resistant conditions are associated with defects in the SNARE machinery138. As future research continues to expand our understanding of the signaling pathways of insulinregulated GLUT4 translocation and glucose transport, our ability to develop interventions to prevent, reverse, and ameliorate insulin resistance in obesity and type 2 diabetes will be favourably impacted.


51. Karlsson HK, Zierath JR, Kane S, Krook A, Lienhard GE, Wallberg-Henriksson H. Insulin-stimulated phosphorylation of the Akt substrate AS160 is impaired in skeletal muscle of type 2 diabetic subjects. Diabetes 2005; 54 : 1692-7.

82. Sebastian BM, Nagy LE. Decreased insulin-dependent glucose transport by chronic ethanol feeding is associated with dysregulation of the Cbl/TC10 pathway in rat adipocytes. Am J Physiol Endocrinol Metab 2005; 289 : E1077-84.

120. Brozinick JT, Jr., Roberts BR, Dohm GL. Defective signaling through Akt-2 and -3 but not Akt-1 in insulinresistant human skeletal muscle: potential role in insulin resistance. Diabetes 2003; 52 : 935-41.

121.Teruel T, Hernandez R, Lorenzo M. Ceramide mediates insulin resistance by tumor necrosis factor-alpha in brown adipocytes by maintaining Akt in an inactive dephosphorylated state. Diabetes 2001; 50 : 2563-71.

124.De Fea K, Roth RA. Protein kinase C modulation of insulin receptor substrate-1 tyrosine phosphorylation requires serine 612. Biochemistry 1997; 36 : 12939-47.

125. Kim JK, Fillmore JJ, Sunshine MJ, Albrecht B, Higashimori T, Kim DW, et al. PKC-theta knockout mice are protected from fat-induced insulin resistance. J Clin Invest 2004; 114 : 823-7.

126.Czech MP. Insulin action and the regulation of hexose transport. Diabetes 1980; 29 : 399-409.

127. Pilch PF, Thompson PA, Czech MP. Coordinate modulation of D-glucose transport activity and bilayer fluidity in plasma membranes derived from control and insulin-treated adipocytes. Proc Natl Acad Sci USA 1980; 77 : 915-8.

128. Whitesell RR, Regen DM, Beth AH, Pelletier DK, Abumrad NA. Activation energy of the slowest step in the glucose carrier cycle: break at 23 degrees C and correlation with membrane lipid fluidity. Biochemistry 1989; 28 : 5618-25.

129. Muller S, Denet S, Candiloros H, Barrois R, Wiernsperger N, Donner M, et al. Action of metformin on erythrocyte membrane fluidity in vitro and in vivo. Eur J Pharmacol 1997; 337 : 103-10.

130.Wiernsperger NF. Membrane physiology as a basis for the cellular effects of metformin in insulin resistance and diabetes. Diabetes Metab 1999; 25 : 110-27.

131.Evans GW, Bowman TD. Chromium picolinate increases membrane fluidity and rate of insulin internalization. J Inorg Biochem 1992; 46 : 243-50.

132. Chen G, Liu P, Pattar GR, Tackett L, Bhonagiri P, Strawbridge AB, et al. Chromium activates GLUT4 trafficking and enhances insulin-stimulated glucose transport in 3T3-L1 adipocytes via a cholesterol-dependent mechanism. Mol Endocrinol 2006; 20 : 857-70.

133. Pattar GR, Tackett L, Liu P, Elmendorf JS. Chromium picolinate positively influences the glucose transporter system via affecting cholesterol homeostasis in adipocytes cultured under hyperglycemic diabetic conditions. Mutat Res 2006; 610 : 93-100.

134. Chen G, Raman P, Bhonagiri P, Strawbridge AB, Pattar GR, Elmendorf JS. Protective effect of phosphatidylinositol 4,5-bisphosphate against cortical filamentous actin loss and insulin resistance induced by sustained exposure of 3T3-L1 adipocytes to insulin. J Biol Chem 2004; 279 : 39705-9.

135. Strawbridge AB, Elmendorf JS. Phosphatidylinositol 4,5-bisphosphate reverses endothelin-1-induced insulin resistance via an actin-dependent mechanism. Diabetes 2005; 54 : 1698-705.

136. Strawbridge AB, Elmendorf JS. Endothelin-1 impairs glucose transporter trafficking via a membrane-based mechanism. J Cell Biochem 2006; 97 : 849-56.

137. McCarthy AM, Spisak KO, Brozinick JT, Jr., Elmendorf JS. Phosphatidylinositol 4,5-bisphosphate and cortical Factin abnormalities in insulin resistant skeletal muscle. Diabetes 2005; 54 : A319.

138.Chen G, Liu P, Thurmond DC, Elmendorf JS. Glucosamine-induced insulin resistance is coupled to Olinked glycosylation of Munc18c. FEBS Lett 2003; 534 : 54-60.

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(Hindemith), LieschenMueller

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