Nomura K

Insulin resistance in patients with cancer: relationships with tumor site, tumor stage, body-weight loss, acute-phase response, and energy expenditure.

We examined peripheral insulin sensitivity in 32 patients with cancer (17 with stomach cancer, 7 with colorectal cancer, and 8 with lung cancer) and 6 normal control subjects by the euglycemic hyperinsulinemic glucose clamp technique. The relationships between insulin resistance and tumor factors (type and stage), malnutrition, and inflammatory reaction were evaluated. Insulin sensitivity often was reduced in patients with cancer; however, the amount of glucose metabolized was not related to tumor site or stage. The decreased glucose uptake was negatively correlated with the acute-phase response but was not correlated with body-weight loss, serum albumin, or resting energy expenditure. Our results suggest that insulin resistance in cancer patients was not induced by malnutrition. Although the qualitative presence of tumor might be the major factor inducing insulin resistance, other factors such as inflammatory reactions might be involved in the development of insulin resistance.

Long-term effect of radical gastrectomy on nutrition and immunity

The long-term effects of gastrectomy on the nutritional and immunologic status were prospectively studied in 79 gastric cancer patients who underwent curative gastrectomy and were followed by us after operation for an average of 5 years and 3 months. The percent of actual weight to pre-illness normal weight was lower than 95% in 80% of all study patients. Retinol binding protein, prealbumin, and albumin were lower than normal in 17%, 26%, and 26% of the patients, respectively. The mean values of the percent normal weight, retinol binding protein, and prealbumin were significantly lower in the totally gastrectomized patients than in the subtotally gastrectomized ones (P<0.01). The procedures of reconstruction did not affect the nutritional status except for the prealbumin level which was significantly decreased in Roux-en-Y cases than in interposed cases of totally gastrectomized patients. Cell-mediated immunological alterations after gastrectomy were observed in 31%, 37%, and 71% of all patients for OKT3 subpopulation, OKT4/OKT8 ratio, and blastogenesis by phytohemagglutinin, respectively. A multivariate analysis revealed that the long-term immunity of the gastrectomized patients after operation was not affected by the levels of albumin and rapid turnover proteins but by the splenectomy and weight loss they underwent.

The possible role of TNF-α and IL-2 in inducing tumor-associated metabolic alterations

This study was conducted to investigate the role of tumor necrosis factor-α (TNF-α) and interleukin-2 (IL-2) in inducing cancer cachexia, and the results were compared with those obtained from our previous study on Fisher 344 rats with methylcholanthrene-induced sarcoma. Three groups of male Fisher 344 rats received one of the following regimens: 4×104 IU of human recombinant TNF-α per rat per day subcutaneously (sc) for 5 consecutive days (n=5), 3.5×105 U human recombinant IL-2 per rat per day sc for 14 consecutive days (n=5), or normal saline (n=5). The activities of both phosphoenolpyruvate carboxykinase (PEPCK) and malic enzyme (ME) were increased slightly in the IL-2 group. Furthermore, LPL activity was significantly increased in the adipose tissue of the TNF group and in the cardiac muscle of the IL-2 group, but not in that of the TNF group. These results show that there is a significant difference between the metabolic alterations seen in the tumor-bearing state and those induced by either TNF-α or IL-2 alone. Thus, it is unlikely that IL-2 or TNF-α is the sole mediator of cancer cachexia in this tumor and rat model.

Stimulation of Decreased Lipoprotein Lipase Activity in the Tumor-Bearing State by the Antihyperlipidemic Drug Bezafibrate

The activity of lipoprotein lipase (LPL), a key regulatory enzyme for triglyceride (TG) clearance from plasma, is reported to decrease as the tumor burden increases in tumor-bearing animals and patients with lung cancer; therefore, it is believed to play a key role in inducing cancer cachexia. We attempted to reverse cancer cachexia by stimulating LPL activity with an antihypertriglyceridemic drug, bezafibrate. Bezafibrate, which reduces circulating TG levels by stimulating tissue LPL activity, has been used clinically in patients with hypertriglyceridemia. Bezafibrate was administered subcutaneously to 24 rats at a dose of 30 mg/kg per day from the 8th day after tumor inoculation with methylcholanthrene-induced sarcoma until they were killed on either the 25th or 33rd day, at the precachectic and cachectic stages, respectively. The animals were divided into the following three groups: treated tumor-bearing rats (treated TBR group), untreated TBRs (untreated TBR group), and a control (CTR) group. LPL activities in both the adipose tissue and cardiac muscle were measured by the method of Nilsson-Ehle and Schotz. Both TG and nonesterified fatty acid (NEFA) became elevated as the size of the tumor increased in the TBRs; however, this increment was quantitatively less in the treated TBR group than in the untreated TBR group. The administration of bezafibrate resulted in preservation of the epididymal fat pad mass at the cachectic stage. A significant decrease in LPL activity in the epididymal fat was observed in the untreated TBR group at the cachectic stage, but this was prevented in the treated TBR group, the values being 2.97±1.37 U/whole tissue in the untreated TBR group, 4.03±1.11 in the treated TBR group, and 10.15±6.61 in the CTR group. Thus, tumor growth in the treated TBR group at the cachectic stage was significantly suppressed compared with that of the untreated TBR group. These results suggest that the decreased LPL activity that occurs in the tumor-bearing state can be stimulated by the antihyperlipidemic drug bezafibrate, which may modulate some of the tumor-induced metabolic alterations leading to cancer cachexia.

Long-term total parenteral nutrition and osteoporosis : report of a case

A patient who had been supported with total parenteral nutrition (TPN) for over 8 years is herein presented, with emphasis on the changes observed in calcium metabolism. The patient was a 31-year-old female, who had undergone a subtotal jejunal and ileal resection for superior mesenteric artery occlusion. TPN was started soon after the surgery. She had been on TPN support for 105 months. Back pain developed at 97 months after the initiation of TPN. During her course, the serum calcium levels were judged to be within the normal ranges, while the 1α, 25(OH)2Vit.D declined. Intermittent hypercalciuria was occasionally observed. Both the serum level of calcium and urinary calcium loss correlated closely to the amount of calcium infused, but they were not influenced by the amount of vitamin D (ergocalciferol) received. The serum level of parathormone and calcitonin were also within the normal ranges. The patients vertebral bone, which was obtained at autopsy, revealed histopathological changes characteristic of osteoporosis. Based on the above, we conclude that a careful monitoring of the amount of calcium infused is called for to prevent bone disease in patients on long-term parenteral nutrition.

Insulin Resistance and the Alterations of Glucose Transporter-4 in Adipose Cells From Cachectic Tumor-Bearing Rats

BACKGROUND Insulin resistance may play an important role in cancer cachexia; however, its mechanisms remain to be clarified. METHODS Cellular mechanisms of insulin resistance in tumor-bearing rats (TBR) were investigated in isolated adipose cells by measuring 3-O-[14C]methyl glucose transport activity and glucose transporter-4 (GLUT4) protein in low-density microsomes at a basal state and in the plasma membrane at an insulin-stimulated state. RESULTS The insulin-stimulated glucose transport activity in adipose cells from TBR was significantly lower than that of control rats (CTR) (0.51 +/- 0.25 and 2.27 +/- 0.11 fmol/cell/min, respectively). The amount of GLUT4 in low-density microsomes at a basal state and in plasma membrane at an insulin-stimulated state was less in TBR than in CTR. CONCLUSIONS These data suggest that the insulin resistance seen in the adipose cells of these tumor-bearing rats was caused in part by both a decreased amount of GLUT4 protein in a basal state and a decreased translocation of GLUT4 in response to insulin stimulation.

Role of insulin resistance in decreasing lipoprotein lipase activity in tumor-bearing rats

The role of insulin resistance in the tumor-induced decrease in tissue lipoprotein lipase (LPL) activity was studied in vivo and vitro in methylcholanthrene-induced sarcoma-bearing rats. Intraperitoneal (ip) injection of 2 U of regular insulin resulted in high-adipose LPL activity in control rats (CTR) of 122.0±42.4 U/mg tissue, but it had little effect on tumor-bearing rats (TBR), which showed a value of only 9.6±5.5 U/mg tissue (P=0.002). When adjusted for serum insulin concentrations, adipose LPL activity remained significantly different between the TBR and CTR at 0.19±0.17 and 0.78±0.29 U/mg tissue, respectively (P=0.02). Following the in vitro incubation with either 1.44 g/l glucose of 1×10−8 U insulin of adipose tissue fragments obtained from the TBR and the CTR, measurable LPL activity was maintained in the tissue from the CTR for 2h but not in that from the TBR. These results suggest that the decreased LPL activities seen in the tumor-bearing state may be mediated by insulin resistance.

The effects of a biological response modifier, OK-432, on tumor-induced alterations in the host metabolism

The effects of multicytokine inducer, OK-432, on tumor-induced metabolic alterations were studied by assessing three key regulatory enzymes of gluconeogenesis, de novo fatty acid synthesis and the triglyceride clearance pathways. Two Klinish Einheit (KE) of OK-432 was subcutaneously injected on alternate days, for 10 days, into Fischer 344 rats with or without methylcholanthrene-induced sarcoma. At the time of sacrifice, the tumors accounted for approximately 23% of their total body weight. The injections of OK-432 did not affect the amount of food intake in either the tumor bearers or the controls. The tissue lipoprotein lipase activities in the epididymal fat pads of the tumor bearers were significantly decreased compared with the controls (P<0.01). Phosphoenolpyruvate carboxykinase activity in the liver was significantly increased (P<0.01), while malic enzyme activity tended to be decreased in the tumor bearers compared with the controls. However, there were no significant differences in those activities depending on the OK-432 injections, even though OK-432 induced tumor necrosis factor (TNF) and increased cytotoxic activities in the mesenteric lymph nodes as well as in the spleen. Thus, although the role of monokines in inducing cancer cachexia is not yet clearly understood, OK-432 was not able to revert the tumor-induced metabolic alterations which lead to tissue wasting and cancer cachexia.