Tatsuo Makino

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.

High incidence of synchronous cancer of the oral cavity and the upper gastrointestinal tract

A high incidence of synchronous esophageal or gastric carcinoma in preoperative patients with carcinoma of the oral cavity was reported. Esophageal carcinoma was found in seven out of 56 patients (12.5%) and gastric cancer in five patients (8.9%) by videoendoscopy aided with lugol staining in the esophagus and indigocarmine solution in the stomach, although all patients were completely asymptomatic for these lesions. All patients were male, regular drinkers and heavy smokers. The depth of invasion of such tumors was limited to either mucosa or submucosa. Those esophageal and gastric lesions beside the primary oral cancers were positive for p53 protein by immunohistochemistry. Careful preoperative evaluation of not only the esophagus but also the stomach should be a routine procedure in patients with carcinoma of the oral cavity.

Ileal duplication presenting as perforation: Report of a case

We describe herein the case of a 10-year-old boy in whom generalized peritonitis was caused by perforation of a tubular communicating ileal duplication cyst. Alimentary tract duplication cysts are rare congenital malformations, found primarily in children under the age of 15 years. The perforation was caused by heterotopic gastric mucosa within the duplication, giving rise to peptic ulceration in the adjacent intestinal mucosa. The presence of heterotopic gastric tissue is a primary cause of perforation that has been reported in as many as one third of patients with small intestine duplications; however, the detection of such ectopic tissue is timeconsuming, and there is no readily available method of diagnosing tubular duplications. Although very few patients present with peritonitis as the initial manifestation, the possibility should be borne in mind when diagnosing and planning therapy for such emergencies, particularly in children.

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.

Insulin resistance was connected with the alterations of substrate utilization in patients with cancer

To elucidate the contribution of insulin resistance to substrate utilization, insulin sensitivity and substrate oxidation were examined in 19 cancer patients and five normal controls using the euglycemic hyperinsulinemic glucose clamp technique combined with indirect calorimetry. Glucose uptake and storage were significantly decreased in cancer patients compared with that of controls. In cancer patients, both glucose storage and oxidation were positively correlated with metabolized glucose as measured by the M value in cancer patients. Decrease in glucose uptake was mainly a reflection of decreased glucose storage rather than glucose oxidation. Inversely fat oxidation was negatively correlated with both the M value and glucose oxidation in cancer patients. In cancer patients with insulin resistance, decreased glucose uptake was closely associated with a rapid decrease in glucose storage, an increase in fat oxidation and a mild decrease in glucose oxidation, suggesting that insulin resistance was connected with the alterations of substrate utilization which may induce host depletion.

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.

Alteration in immunoexpression of glucose transporter 2 in liver of tumour-bearing rats

To elucidate interactions between the glucose transport system and hepatic glucose production in the tumour‐bearing state, glycogen storage, expression of glucose transporter isoform 2 (Glut 2) and activities of glucose‐6‐phosphatase (G‐6‐Pase) and hexokinase were histochemically examined in hepatocytes of tumour‐bearing rats. Five male F344 rats, subcutaneously inoculated with methylcholanthrene(MCA)‐induced sarcoma cells were compared with five pair‐fed animals and four ad libitum fed controls. Glycogen storage was markedly decreased in liver cells of tumour‐bearing rats compared to in those of control animals. Glut 2 immunoreactivity was uniformly seen in the cellular membrane of hepatocytes from control animals. In rats bearing sarcoma, the staining intensity was significantly decreased, suggesting that Glut 2 with its bi‐directional transport capacity was down‐regulated in the tumour‐bearing state. Positive staining for hexokinase activity was located in the perivenous area in livers from control animals and was more diffusely located and more intense in livers from tumour‐bearing animals. G‐6‐Pase activity, limited to the peripheral area in livers from controls, extended to the intermediate area and had stronger reactivity in livers from tumour‐bearing animals. In the tumour‐bearing cachectic condition, glucose may be partially consumed by a futile cycle, hepatic metabolic zonation was disturbed, and the release of glucose from the liver may not be mediated by a facilitative glucose transporter‐2.

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.