It's well known that keeping blood glucose levels in check can help individuals avoid or manage diabetes, but new research led by biologists suggest that restricting blood glucose levels might also keep certain cancers at bay.

In a study published in the journal Cell Reports, researchers restricted circulating glucose in mice with lung cancer. Circulating glucose restriction was achieved by feeding the mice a ketogenic diet, which is very low in sugar, and by giving them a diabetes drug that prevents glucose in the blood from being reabsorbed by the kidneys.

"Both the ketogenic diet and the pharmacological restriction of blood glucose by themselves inhibited the further growth of squamous cell carcinoma tumors in mice with lung cancer," said the corresponding author of the multinational study. "While these interventions did not shrink the tumors, they did keep them from progressing, which suggests this type of cancer might be vulnerable to glucose restriction."

While many types of cancer cells are suspected to be heavily dependent on glucose -- or sugar -- as their energy supply, the authors have shown in previous laboratory studies that one specific type -- squamous cell carcinoma -- is remarkably more dependent than other cancer types, such as adenocarcinoma.

Authors identify exceptional glucose reliance among SCCs dictated by hyperactive GLUT1-mediated glucose influx. Mechanistically, squamous lineage transcription factors p63 and SOX2 transactivate the intronic enhancer cluster of SLC2A1. Elevated glucose influx fuels generation of NADPH and GSH, thereby heightening the anti-oxidative capacity in SCC tumors.

Systemic glucose restriction by ketogenic diet and inhibiting renal glucose reabsorption with SGLT2 inhibitor precipitate intratumoral oxidative stress and tumor growth inhibition. 

"The key finding of our new study in mice is that a ketogenic diet alone does have some tumor-growth inhibitory effect in squamous cell cancer," the author said. "When we combined this with the diabetes drug and chemotherapy, it was even more effective."

"Our results suggest that this approach is cancer-cell-type specific. We cannot generalize to all types of cancer," the author said.

The researchers also examined glucose levels in blood samples from 192 patients who had either lung or esophageal squamous cell cancer, as well as 120 patients with lung adenocarcinoma. The blood samples were taken at random parts of the day and classified into those containing glucose concentrations higher or lower than 120 mg/dL, which is one clinical measure of diabetes. None of the patients had been diagnosed with diabetes.

"Surprisingly, we found a robust correlation between higher blood-glucose concentration and worse survival among patients with squamous cell carcinoma," the author said. "We found no such correlation among the lung adenocarcinoma patients. This is an important observation that further implicates the potential efficacy of glucose restriction in attenuating squamous-cell cancer growth."

https://www.cell.com/cell-reports/fulltext/S2211-1247(19)30924-6

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