ABSTRACT-To determine whether insulin resistance is responsible for the development of hypertension, we examined whether blood pressure changes in an insulin-resistant animal that was given a fructose solu tion as their drinking water. Wistar Kyoto rats that drank a 10% fructose solution for 10 weeks showed significant increases not only in plasma triglyceride and insulin levels but also in systolic blood pressure. The decrease in blood glucose in response to the intraperitoneal injection of insulin (0.2-1.0 U/kg) was slight in these fructose-drinking rats. To confirm whether insulin resistance contributes to the observed hyperten sion, we examined the effect of pioglitazone, an insulin sensitizer, on blood pressure in rats given a 10% fructose solution. When pioglitazone was administered to the rats at a dose of 10 mg/kg/day for 4 weeks from 12 weeks of age, plasma triglyceride and insulin levels and systolic blood pressure decreased, and blood glucose reduction in response to insulin was normalized. These results suggest that insulin resistance is responsible for the development of hypertension in fructose-drinking rats. It is well-known that non-insulin dependent diabetes mellitus patients frequently develop hypertension (1-4), and essential hypertension has often been associated with obesity and/or glucose intolerance (5 8). Therefore, hypertension and non-insulin dependent diabetes mellitus seem to share the common physiological characteristic of insulin resistance. Hyperinsulinemia caused by the insulin resistance has been thought to enhance sodium reabsorp tion from the kidneys (9, 10) and to activate the sym pathetic nervous system (11, 12), resulting in an increase in blood pressure.Fructose has been reported to induce insulin resistance in the liver (13). To determine whether insulin resistance is responsible for the development of hypertension, we examined whether blood pressure changes in an insulin resistant animal that was given a fructose solution as their drinking water.Pioglitazone is an insulin sensitizer that improves insu lin sensitivity of peripheral tissues and the liver and low ers the plasma glucose and insulin levels in animal models of diabetes (14,15). To confirm whether insulin resistance contributes to the observed hypertension, we examined the effect of pioglitazone on blood pressure in rats given a 10010 fructose solution. MATERIALS AND METHODS AnimalsMale Wistar Kyoto (WKY) rats were bred in the laboratory animal unit of our division and weaned at 4 weeks of age. These rats were maintained on a standard chow diet (CE-2; Clea Japan Inc., Tokyo) and water ad libitum. Throughout the experiment, these rats were housed in metal cages under controlled temperature (23 ± l C) and humidity (55_L5076), with a 12-hr light /dark cycle. Fructose induced insulin resistance in WKY ratsAt 6 weeks of age, these rats were divided into two groups. One group continued to receive the diet and water, and the other was given the diet and a 10% fruc tose solution for 6 weeks. Body weight, plasma compo ne...

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Transfection of human fibroblast growth factor 9 (FGF-9) cDNA into mouse BALB/c 3T3 clone A31 cells led to morphological transformation of the cells and foci formation 4 weeks later. Isolated transformants had a higher saturation density than parental A31 cells, could grow in soft agar, and secreted FGF-9 into the culture supernatant. The introduction of FGF-9 N33 cDNA, which encodes a truncated protein that has 33 N-terminal amino acids deleted and has the same mitogenic potency as FGF-9, failed to lead to foci formation. Although FGF-9 is a secretory protein, it does not have a typical secretory signal sequence, and the secreted protein retains the full sequence coded in the cDNA except for the initiating methionine. The produced FGF-9 N33 was not secreted and remained within the cell. It is possible that FGF-9 has an uncleavable signal sequence within the first 33 N-terminal amino acids. All of the phenotypes acquired by transformation could be arrested by treatment with a neutralizing anti-human FGF-9 monoclonal antibody (MAb) 150-59. Additionally, transformants formed tumors in nude mice. Injection of MAb 150-59 suppressed tumor formation in nude mice and caused existing tumors to regress. Our results suggest that the cellular transformation mediated by FGF-9 is produced by autocrine stimulation. We have detected FGF-9 production in the human tumor cell lines glioma NMC-G1, from which FGF-9 was originally purified, and stomach carcinoma AZ-521. The growth of NMC-G1 was not affected by MAb 150-59, but that of AZ-521 was arrested by MAb 150-59 in the presence of heparin. Moreover, the growth of the AZ-521 cell tumor in nude mice could be partially arrested by antibody treatment. The possibility of a participation of FGF-9 in the formation of human tumors is suggested. Int. J.

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Transfection of human fibroblast growth factor 9 (FGF-9) cDNA into mouse BALB/c 3T3 clone A31 cells led to morphological transformation of the cells and foci formation 4 weeks later. Isolated transformants had a higher saturation density than parental A31 cells, could grow in soft agar, and secreted FGF-9 into the culture supernatant. The introduction of FGF-9 N33 cDNA, which encodes a truncated protein that has 33 N-terminal amino acids deleted and has the same mitogenic potency as FGF-9, failed to lead to foci formation. Although FGF-9 is a secretory protein, it does not have a typical secretory signal sequence, and the secreted protein retains the full sequence coded in the cDNA except for the initiating methionine. The produced FGF-9 N33 was not secreted and remained within the cell. It is possible that FGF-9 has an uncleavable signal sequence within the first 33 N-terminal amino acids. All of the phenotypes acquired by transformation could be arrested by treatment with a neutralizing anti-human FGF-9 monoclonal antibody (MAb) 150-59. Additionally, transformants formed tumors in nude mice. Injection of MAb 150-59 suppressed tumor formation in nude mice and caused existing tumors to regress. Our results suggest that the cellular transformation mediated by FGF-9 is produced by autocrine stimulation. We have detected FGF-9 production in the human tumor cell lines glioma NMC-G1, from which FGF-9 was originally purified, and stomach carcinoma AZ-521. The growth of NMC-G1 was not affected by MAb 150-59, but that of AZ-521 was arrested by MAb 150-59 in the presence of heparin. Moreover, the growth of the AZ-521 cell tumor in nude mice could be partially arrested by antibody treatment. The possibility of a participation of FGF-9 in the formation of human tumors is suggested. Int. J.