A procedure is described for the selection of glucose uptake mutants based upon radiation suicide of Chinese hamster fibroblasts by 2-deoxy[3H]glucose. In one of these mutants, DS 7, the ability to transport either 2-deoxyglucose or 3-O-methylglucose was decreased to one-fifth to one-fourth. Besides this defect, DS 7 produces l/,4th the lactic acid produced by the parent when grown on 5 mM glucose. This block in aerobic glycolysis is due to a mutation that affects the expression of the phosphoglucose isomerase gene because no isomerase activity is detected in cell extracts of DS 7. This glycolytic block makes that cell line dependent exclusively on respiration for its energy requirement. Consequently, DS 7 survives well after removal of glucose but dies quickly in the presence of oligomycin. The parental line 0 23 (subclone of CCI 39) grows at low serum concentration, is anchorage-independent, and is tumorigenic in nude mice. The derived glycolytic mutant DS 7 has retained both the in vitro transformed phenotype (low serum dependence and loss of anchorage dependence) and the tumor-forming capability. The tumor cells derived from the injection of DS 7 cells have kept the original glycolytic defect. This finding suggests that the transformed properties (high hexose transport and aerobic glycolysis) that can be uncoupled from abnormal growth control are not necessary for the expression of the malignant phenotype in fibroblasts.So far, among the various properties that accompany viral or spontaneous transformation (for review, see refs. 1-4), it has been difficult to assign to any particular transformed property a primary role in the establishment and maintenance of the abnormal growth control. A set of surface and membrane changes-including low adhesion to substratum, rounded shape, increased agglutinability by plant lectins, altered cell locomotion, decreased cell alignment, and loss of microfilament bundles-has been dissociated from the mechanism that alters the control of division (5-9).Increases in hexose transport and in aerobic glycolysis are two other characteristics that one finds closely linked to transformation and increased proliferation in cells (10)(11)(12)(13)(14) The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U. S. C. §1734 solely to indicate this fact.

Insulin resistance syndromes are heterogeneous in either severity or mechanism. Many drugs have been shown to counteract various elements of insulin resistance. Some of them, by normalization of metabolic parameters, decrease insulin resistance induced by chronic hyperglycemia in diabetes. Insulin and, to some extent, sulfonylureas are in this group, but these drugs are not stricto sensu medication of insulin resistance. Some drugs sensitize peripheral tissues to the action of insulin. For instance, biguanides and thiazolidine-dione facilitate translocation to the membrane of glucose transporter in presence of insulin. Other compounds as vanadate or IGF-1 mimic some peripheral action of insulin. Finally, blockade of FFA oxidation by specific inhibitors (methylpalmoxyrate) can limit insulin resistance. In 1992, among these compounds, specific of insulin resistance, biguanides are mostly used. However, the efficacy of these drugs is moderate and limited to type 2 diabetes.

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To analyze the role of the cell energy metabolism in the expression of the malignant phenotype, we isolated fibroblast mutants with specific defects either in aerobic glycolysis or in respiration. From the anchorage-independent and tumorigenic subclone (023) of Chinese hamster lung fibroblasts, we selected two mutants. The first, DS7, is deficient in aerobic glycolysis and glucose transport as a consequence of a block in phosphoglucose isomerase activity. DS7 is strictly dependent upon respiration for cell viability. The second mutant, GSK3, is unable to oxidize glucose as a result of a defect in oxidative metabolism, therefore its energy for growth relies exclusively on aerobic glycolysis. When injected into nude mice, these two mutant cells have kept the capacity to form tumors. For both mutants we observed an increase in the latency of tumor formation and a decreased tumorigenicity only for the respiration defective cells. The tumoral cells analyzed after passaging in vivo have retained the respective phenotypes, glycolysis-and respiration-, of the injected cells. Finally, from the anchorage-dependent and non-tumorigenic Fisher rat fibroblast cell line, FR 3T3, we isolated mutants with a 6-fold derepressed aerobic glycolysis and high glucose transport rate. In spite of this transformed character, these mutants (GSR 16/24) have kept the normal growth characteristics of the parent FR 3T3 (anchorage dependency and non-tumorigenicity). These results indicate that only one of the two energy metabolisms of the mammalian cell -respiration or aerobic glycolysis -is enough for the expression of the malignant phenotype. Therefore, the high aerobic glycolysis of tumoral cells should be regarded as a non-essential character of tumoral growth.