Role of glucose and ketone bodies in the metabolic control of experimental brain cancer

Abstract

Brain tumours lack metabolic versatility and are dependent largely on glucose for energy. This contrasts with normal brain tissue that can derive energy from both glucose and ketone bodies. We examined for the first time the potential efficacy of dietary therapies that reduce plasma glucose and elevate ketone bodies in the CT-2A syngeneic malignant mouse astrocytoma. C57BL/6J mice were fed either a standard diet unrestricted (SD-UR), a ketogenic diet unrestricted (KD-UR), the SD restricted to 40% (SD-R), or the KD restricted to 40% of the control standard diet (KD-R). Body weights, tumour weights, plasma glucose, beta-hydroxybutyrate (beta-OHB), and insulin-like growth factor 1 (IGF-1) were measured 13 days after tumour implantation. CT-2A growth was rapid in both the SD-UR and KD-UR groups, but was significantly reduced in both the SD-R and KD-R groups by about 80%. The results indicate that plasma glucose predicts CT-2A growth and that growth is dependent more on the amount than on the origin of dietary calories. Also, restriction of either diet significantly reduced the plasma levels of IGF-1, a biomarker for angiogenesis and tumour progression. Owing to a dependence on plasma glucose, IGF-1 was also predictive of CT-2A growth. Ketone bodies are proposed to reduce stromal inflammatory activities, while providing normal brain cells with a nonglycolytic high-energy substrate. Our results in a mouse astrocytoma suggest that malignant brain tumours are potentially manageable with dietary therapies that reduce glucose and elevate ketone bodies.

Figure 1

Energy intake (A) and body weights (B) in male C57BL/6J mice bearing the intracerebral CT-2A brain tumour. Tumours were implanted on day 0 and dietary treatment was started on day 1. Values are expressed as means with 95% confidence intervals, and n=the number of tumour bearing mice examined in each group.

Figure 2

Influence of diet on the intracerebral growth of the CT-2A brain tumour. Dietary treatment was initiated 1 day after tumour implantation and was continued for 13 days as shown in Figure 1. Tumour weights were measured in C57BL/6J mice receiving either the standard diet (SD) or ketogenic diet (KD) under either unrestricted (UR) or restricted (R) feeding. Values are expressed as means with 95% CIs, and n=the number of mice examined in each group. The dry weights of the tumours in R groups were significantly lower than those in the UR groups at P<0.01.

Figure 3

Linear regression analysis of plasma glucose and CT-2A-tumour growth in mice from both the SD and KD dietary groups combined (n=34). These analyses included the values for plasma glucose and tumour growth of individual mice from both the UR- and R-fed groups. The linear regression was highly significant at ^*P<0.001.

Figure 4

Linear regression analysis of plasma glucose and IGF-1 levels (A), and plasma IGF-1 levels and CT-2A-tumour growth (B) in mice fed with both the SD and KD (n=23). These analyses included the values for plasma glucose and β-OHB levels of individual mice from both the UR- and R-fed groups. The linear regressions were highly significant at P<0.01.