日本外科代謝栄養学会

Glucose Transporter

　mammalian cellには二つの糖輸送機構が存在する：Na+‐glucose co‐transporter及びfacilitative glucose transporter（GLUTs）。前者は糖輸送にATPを必要とし、主として小腸の吸収上皮に存在する。後者は濃度依存性に血管と細胞間との糖輸送をつかさどるもので、これまでに７種のisoformが確認されている。GLUT１は赤血球に認められ糖との親和性が高くbasic glucose transporterと見なされる。GLUT２は主として肝臓に依存、両方向性の糖輸送に関わる。GLUT３は脳、神経組織に認められる。GLUT４はインスリン反応性組織（脂肪、骨格筋）に認められインスリン反応性糖輸送蛋白として知られている。インスリン刺激により細胞内から細胞膜へ移動し作用する。TranslocationにはIRS−１の燐酸化が刺激となることがインスリン非依存性糖尿病で確認されている。GLUT５はfructose transporterであることが最近の研究で明らかとなり、GLUT familyからは除外して考えられることが多い。GLUT６は翻訳されず、GLUT７はmicrosomal glucose transporterであることも判明している。
　Positron emission tomography（PET）が臨床に応用されるに至り腫瘍での糖取り込みのメカニズムが注目されている。また臨床的にはある種のGLUT、殊にGLUT１の発現量と予後の間に関連があることが乳癌、大腸癌、胃癌、膵臓癌等で示されている。

参考文献抄録

１）癌細胞への糖取り込みのメカニズム　−glucose transporter発現の意義−

　癌細胞は正常細胞に比較し、糖の取り込みが亢進しているため、glucose eaterと呼ばれる。しかし癌細胞への糖取り込みの細胞レベルでのメカニズムはいまだ明らかではない。本検討ではヒト由来の胃癌細胞株（MKN２８、MKN４５、STSA）を用いて、GLUTの発現とglucose uptakeとの関連を検討し癌細胞におけるGLUTの発現の意義をあきらかにすることを目的とし施行した。RT‐PCRによりGLUT１及びGLUT４mRNAは全ての細胞株で確認された。GLUT４蛋白の発現はMKN４５やSTSAよりMKN２８でより著明に認められた（IHC）。Insulin刺激によりMKN２８細胞ではglucose uptakeがbasal conditionsに比較して２０％増加した（０.６０±０.０５fmol／cell／min（after insulin stimulation）、０.５３±０.０７fmol／cell／３min（basal））が、MKN４５とSTSA細胞では認められなかった。MKN４５を用いてincubation buffer中のNaCl存在の有無でglucose uptakeを比較したところ、差は全く認められなかった。Antisense GLUT１をMKN４５に挿入した株ではglucose uptakeのほぼ８０％が抑制された。このように胃癌細胞株では糖取り込みはNa＋‐ATP‐dependent transporterによるところはほとんど無く、ほぼ全ての糖取り込みがfacilitative glucose transporterに依存する。なかでもその大部分はGLUT１を介して行われ、GLUT４強発現株でもinsulin刺激に依存するglucose uptakeはたかだか２０％に過ぎない。ゆえに癌細胞内糖代謝をtargetとする場合GLUT１の抑制が癌治療と結びつく可能性が示唆された。

野口芳一，吉川貴己，斎藤　綾ほか：外科と代謝・栄養，33：121，1999

２）Overexpression of glucose transporter１and increased FDG uptake in pancreatic carcinoma

　Increased glycolysis is a characteristic metabolic feature of a malignant transformed phenotype.In cultured cells transformed by viruses or activated oncogenes,enhanced glycolytic metabolism is mediated by the overexpression of glucose transporter １ （Glut−１） and key regulatory glycolytic enzymes.Whether increased glucose metabolism in solid human malignant tumors is related to the overexpression of key regulatory proteins of glucose metabolism is presently unknown.We thus studied the expression of Glut−１ and glucose uptake,assessed with ２−fluorodeoxyglucose （FDG） and PET in human pancreatic carcinoma（PC） and chronic mass‐forming pancreatitis （MFP）.METHODS:Glucose uptake was measured in the fasting state with FDG and PET in １２ patients with PC and １５ patients with MFP.The standardized uptake value （SUV） of FDG was determined as a global quantitative measure of tissue glucose utilization in cancer tissue or MFP.The expression of Glut−１ and Glut−４ was analyzed from operatively removed cancer or MFP tissue by Northern analysis or semiquantitative reverse transcriptase‐polymerase chain reaction.The count ratio of Glut−１ to Glut−４ transcripts was used as an indicator of selective Glut−１ up‐regulation.RESULTS:The SUVs of FDG in patients with cancer and MFP were ２．９８＋／−１．２３ and １．２５＋／−０．５１ （p＜０．０１）,respectively.Northern analysis showed intense Glut−１ expression in four of five patients with cancer but not in any of the five patients with MFP that were tested.In PC,Glut−１ and Glut−４ transcripts were found in five of five three of １０ patients,respectively,using reverse transcriptase‐polymerase chain reaction,whereas in MFP,Glut−１ was detected in one of five and Glut−４ was detected in all five patients.The Glut−１−to‐ Glut−４ transcript rations were ６．１７＋／−１．２７　in patients with cancer and ０．４２＋／−０．１２ in patients with MFP.The mean Glut−１ concentration in eight patients with cancer was １．７１nmol of Glut−１ mRNA／μg of mRNA （range,０．０４４６−９．４３） and ０．１５ （range,０−１．５５）（p＜０．０５） in １３ patients with MFP.The concomitant enhancement of glucose utilization and selective overexpression of Glut−１ mRNA in pancreatic cancer but not in MFP suggested constitutive activation of Glut−１gene or decreased degradation of Glut−１ mRNA in human pancreatic cancer.These findings may imply a potential for the early detection of pancreatic cancer with FDG and PET and identify new targets for anticancer therapy.

Reske SN,Grillenberger KG,Glatting G,et al:J Nucl Med 38:1344−438,1997

３）Expression of facilitative glucose transporter isoforms in lung carcinomas:its relation to histologic type,differentiation grade,and tumor stage

　Expression of facilitative glucose transporter（GLUT）isoforms was studied immunohistochemically in lung carcinomas.GLUT１ was expressed in ４５ （７４％） of ６１ lung carcinoma,including １９ （１００％） of １９ squamous cell carcinomas.No GLUT１ staining was seen in normal lung epithelium surrounding the tumors.In squamous cell carcinomas and small cell carcinomas,GLUT１ immunostaining was stronger in the central area of tumor cell nests corresponding to the hypoperfused region.Focal staining was seen in １４ （５８％） of ２４adenocarcinomas,and positive staining was correlated to lesser differentiation,larger tumor size,and positive lymph node metastasis.Glut２ was detected in normal airway epithelium,but no positive staining was seen in lung carcinomas.GLUT３ and GLUT４ were not positively stained in normal lung epithelium,but a few lung carcinoma samples showed positive reaction （９ of ６１ in GLUT３;４ of ６１ in GLUT４）.GLUT４ immunoexpression was seen in regenerating alveolar and bronchiolar epithelia around and in cancer tissues.GLUT５ expression was not detected in normal and tumor tissues.RT‐PCR for GLUT１,GLUT３,and GLUT４ confirmed the expression revealed by immunohistochemical analysis.Overexpression of GLUT could enhance uptake of glucose into lung carcinoma cells,and the increased glucose flux could be involve in cell biologic activities.

Ito T,Noguchi Y,Satoh S,et al:Modern Pathol 11:437−43,1998

４）Inhibition of IRS−１ phosphorylation and the alterations of GLUT４ in isolated from cachectic tumor‐bearing rats

　Cellular and molecular mechanisms of insulin resistance in isolated adipocytes from methylcholanthrene‐induced sarcoma‐bearing rats were investigated by measuring３−O−［１４ C］methyl glucose transport activity,glucose transporter−４（GLUT４） protein in both plasma membrane and low‐density microsomes,and insulin‐stimulated tyrosine phosphorylation of the insulin receptor （IR） and insulin receptor substrate−１（IRS−１） Compared to both pair‐fed and freely fed controls,tumor‐bearing rats （TBR） had a decreased insulin‐stimulated glucose transport activity with a lower Vmax and a higher EC５０.GLUT４ protein in low‐density microsomes from adipocytes maintained at the basal state was less in TBR than in controls.In insulin‐stimulated adipocytes,GLUT４ protein in plasma membranes was also less inn tumor‐bearing rats than in controls.Insulin‐induced tyrosine phosphorylation of IRS−１ was less in TBR than controls,but that or the IR was similar among the three groups.These data suggest that the insulin resistance seen in adipose cells of these tumor‐bearing rats was caused in part by a decreased amount of GLUT４ protein in both basal and insulin‐stimulated states resulting from the selective inhibition of insulin‐stimulated phosphorylation of IRS−１.

Yoshikawa T,Noguchi Y,Satoh S:Biochem Biophy Res Comm 256:676−81,1999

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日本外科代謝栄養学会