Tumour-associated hypoglycaemia in a murine cachexia model

Abstract

SummaryAnimals bearing a cachexia-inducing tumour, the MAC16 adenocarcinoma, showed a progressive decrease in blood glucose levels with increasing weight loss, while animals bearing a histologically similar tumour, the MAC13 adenocarcinoma, showed no change in either body weight or blood glucose levels with growth of the tumour. The effect of the MAC16 tumour on blood glucose levels appeared to be unrelated to food intake, glucose consumption by the tumour, or to the production of increased levels of IGF-I and IGF-II mRNA by the tumour cells. The relationship between the induction of cachexia and alteration in blood glucose levels remains unknown.A high rate of glucose consumption under both anaerobic and aerobic conditions is a characteristic feature of both experimental (Weber et al., 1961;Weber, 1977) and human tumours (Nolop et al., 1987). Alterations in glucose metabolism in tumour cells are associated with an increased intracellular concentration of glucose, which is tightly coupled with an over-expression of facilitative glucose transporter genes (Yamamoto et al., 1990), an increased transcription of the hexokinase gene (Johansson et al., 1985), as well as alterations in isoenzyme profiles of the enzymes involved in glycolysis (Weber et al., 1961). The enhanced glucose transport is not insulin-dependent, since hypoglycaemia often develops in both tumour-bearing animals (Bibby et al., 1987) and cancer patients (Heber et al., 1985) with normal or even decreased blood insulin levels. The architecture of solid tumours also plays an important role in determining the metabolic substrate for energy production. Large solid tumours tend to have a poor blood supply, and consequently become hypoxic, in which case glucose will become the predominant metabolic substrate, since the Embden-Meyerhof pathway is the only means of ATP production in the absence of oxygen.We have recently reported studies on glucose utilisation by tumour and host tissues in NMRI mice bearing the MAC16 colon adenocarcinoma, which is capable of inducing cachexia in recipient animals (Mulligan & Tisdale, 1991). Glucose consumption by the tumour was second only to brain and the increased demand for glucose was met by a decrease in glucose utilisation by host organs and in particular the brain. This study further investigates changes in blood glucose levels and the possible role of insulin-like growth factors (IGF) in the MAC16 model. Since antibodies to both mouse IGFI and IGFII were not readily available, we have chosen to measure their production in the MAC16 tumour indirectly, through the study of gene expression. Materials and methodsPure strain NMRI mice were bred in our own colony and were fed on a rat and mouse breeding diet (Pilsbury, Birmingham, UK) and water ad libitum. Fragments (1 x 2 mm) of either the MAC16 or MAC13 tumour were implanted into the flank of male NMRI mice (starting weight 28 g) by means of a trocar as described (Bibby et al., 1987

Induction of cachexia in mice by a product isolated from the urine of cachectic cancer patients

“…This suggests that the two substances are identical. Intravenous injection of this substance in mice causes a state of cachexia similar to that observed after administration of the murine material (Todorov et al, 1996a) in mice bearing the MAC16 tumour in that (a) weight loss occurs without a reduction in food and water intake (Beck and Tisdale, 1987) and thus is not due to toxicity of the material, (b) weight loss can be attenuated by prior administration of the monoclonal antibody, (c) there is marked hypoglycaemia (McDevitt and Tisdale, 1992) and (d) there is a decreased level of plasma triglycerides; in the last respect the effect is unlike that of TNF-a, which causes an increase (Mahony et al, 1988). This observation, together with the finding of decreased plasma levels of 3-hydroxybutyrate, suggests that energy expenditure may be increased.…”

Effect of a cachectic factor on carbohydrate metabolism and attenuation by eicosapentaenoic acid

“…Hypoglycaemia has previously been reported with both human (Nolop et al, 1987) and experimental tumours such as the MAC16 adenocarcinoma (McDevitt and Tisdale, 1992) and appears to be unrelated to food intake, glucose consumption by the tumour or insulin-like growth factors (either IFG-I or IGF-II) produced by tumours. Insulin levels have been found to be low in cases of tumour-associated hypoglycaemia (Bibby et al, 1987) and the production of an insulin-like factor by the tumour was suggested as the cause of the enhanced peripheral glucose uptake.…”

Effect of a tumour-derived lipid-mobilising factor on glucose and lipid metabolism in vivo

“…Many of the effects of LMF in mice are similar to those produced by the MAC16 tumour. Thus both produce hypoglycaemia (McDevitt and Tisdale, 1992), lipid depletion (Beck and Tisdale, 1987) and an increased 14 CO 2 production from […”

“…Despite fat mobilisation there was a decrease in blood glucose levels. Hypoglycaemia occurs in mice bearing a cachexia-inducing tumour (MAC16), although the mechanism by which this occurs is not known (McDevitt and Tisdale, 1992).The purpose of the present study was to investigate the effect of LMF on glucose and lipid metabolism in vivo in order to quantitate the effect on energy utilisation. …”

“…Despite fat mobilisation there was a decrease in blood glucose levels. Hypoglycaemia occurs in mice bearing a cachexia-inducing tumour (MAC16), although the mechanism by which this occurs is not known (McDevitt and Tisdale, 1992).…”