Hyperglycemia and cancer

The association between type 2 diabetes and some types of cancer might be mediated by glucose, the hallmark of diabetes, or by non-glycemic factors. Here we review evidence that hyperglycemia might itself promote cancer growth. Two considerations appear to support a causal role for hyperglycemia. The first derives from epidemiologic observations linking blood glucose levels to cancer risk, even within the non-diabetic range. The second lies in the observation that cancer cells are glucose-dependent and obtain their energy requirements from fermentation; in other words they perform anaerobic glycolysis in the presence of oxygen. It might therefore be anticipated that such cells would grow faster in a high glucose environment. To counterbalance this, it has recently been shown that the switch to an anaerobic pattern of glucose metabolism is advantageous for rapidly proliferating cells by enabling them to convert nutrients into biomass efficiently. Furthermore, glucose transport into cancer cells is already maximal at normal levels of circulating glucose, suggesting that such cells will gain no further advantage from hyperglycemia. In support of these pathophysiological observations, meta-analysis of clinical trials of glucose-lowering therapies in type 2 diabetes has shown no diminution of cancer risk.

Background

Hyperglycemia is the hallmark of diabetes, and it might therefore seem reasonable to anticipate that circulating glucose levels increase the risk of cancer development. If this were the case, hyperglycemia would be an important confounder of cancer risks associated with treatments such as exogenous insulin[1]

The ‘hyperglycemia hypothesis’ is supported by large inception cohort studies that demonstrate a strong relationship between elevated blood glucose and cancer incidence or mortality.[2][3][4][5]. The hyperglycaemia risk relationship appears to be consistent across all levels of blood glucose, even within the non-diabetic range.

The Warburg Effect

Otto Warburg
Otto Warburg
Otto Warburg demonstrated that cancer cells obtain their energy by glycolysis followed by lactic acid fermentation. Healthy cells normally fall back on this adaptation only in the absence of oxygen, i.e. during anaerobic metabolism, whereas cancer cells rely on fermentation rather than oxidation of glucose even when oxygen is plentiful. Anaerobic glycolysis is an inefficient way of burning glucose, gaining ~ 2 mol ATP/mol glucose, as against aerobic glycolysis which yields ~36 mol ATP. Warburg believed that this loss of efficiency represented a regression in evolutionary terms. As he said:

“Under these conditions, it is obvious – since ontogeny is the repetition of phylogeny – that the fermentation of body cells is the inheritance of undifferentiated ancestors that have lived in the past at the expense of fermentation energy”[6]

Far from representing loss of efficiency, it is now appreciated that a switch to anaerobic glycolysis is an adaptive change characteristic of rapidly proliferating cells, including fetal cells, which utilize the pentose phosphate pathway to convert nutrients into biomass (nucleotides, amino acids and lipids). Cancer-associated mutations favor this metabolic switch[7], achieved by expression of the fetal form (M2) of the glycolysis pathway enzyme pyruvate kinase, a metabolic adaptation that appears essential for cancer cell proliferation[8].

The Warburg Effect
The Warburg Effect
Cancer cells express non-insulin dependent glucose transporters such as GLUT-1 on their surface; these transporters achieve their maximum transport rate for glucose below 5 mmol/l. This rate of uptake can be so rapid with some large tumors as to induce hypoglycemia. It does however mean that tumor cells gain no metabolic advantage from a hyperglycemic environment[9].

A further implication is that cancer cells equipped with the insulin receptor gain advantage from the growth-promoting, but not the metabolic, effects of insulin.

Results from clinical trials

In support of these considerations derived from tumor pathology, evidence from a meta-analysis of cancer risk (i.e., both cancer incidence and mortality) from secondary outcomes reported in the major randomized controlled trials (RCTs) of intensified glycemic control and cardiovascular outcomes in type 2 diabetes does not support the causal hypothesis that lowering blood glucose will reduce the risk of cancer[10]. This makes it unlikely that hyperglycemia would be an important confounding factor in pharmacoepidemiologic studies of glucose-lowering drug exposure and cancer outcomes.

Summary

Since cancers are heterogeneous and insulin responsiveness is not universal, it is possible that proliferation may be enhanced by hyperglycemia in some tumors. The experimental and epidemiological evidence is however more consistent with the hyperinsulinemia hypothesis[11]

References

  1. ^ Gerstein HC. Does insulin therapy promote, reduce, or have a neutral effect on cancers? JAMA 2010;446–447

  2. ^ Jee SH et al. Fasting serum glucose level and cancer risk in Korean men and women. JAMA 2005;293:194–202

  3. ^ Stocks T et al. Blood glucose and risk of incident and fatal cancer in the metabolic syndrome and cancer project (me-can): analysis of six prospective cohorts. PLoS Med 2009;6:e1000201

  4. ^ Emerging Risk Factors Collaboration. Diabetes mellitus, fasting glucose, and risk of cause-specific death. N Engl J Med 2011;364:829–841

  5. ^ Pollak M. Do cancer cells care if their host is hungry? Cell Metab 2009;9:401–403

  6. ^ Warburg O. On the origin of cancer cells. Science 1956;123:309-12

  7. ^ Vander Heiden MG et al. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 2009;324:1029-33

  8. ^ ChristofkHR et al. The M2 splice form of pyruvate kinase is important for cancer metabolism and tumor growth. Nature 2009;

  9. ^ Tannock IF, Kopelyan I (1986) Influence of glucose concentration on growth and formation of necrosis in spheroids derived from a human bladder cancer cell line. Cancer Res 46:3105–3110

  10. ^ Johnson JA, Bowker SL. Intensive glycemic control and cancer risk in type 2 diabetes: a meta-analysis of major trials. Diabetologia 2011;54:25–31

  11. ^ Johnson JA, Pollak M. Insulin, glucose and the increased risk of cancer in patients with type 2 diabetes. Diabetologia 2010;53:2086–2088

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