Cancer remains a frightening diagnosis. But for a growing number of cancers, we feel comfortable talking about remission or long-term survival; it is not the automatic death sentence of 30 or 40 years ago. Once initial treatment is completed, be it surgery, chemotherapy or radiation, patients settle into a routine of follow-up, but for many, cancer remains the focus. That is problematic because other medical problems can develop which may do more to reduce one’s life expectancy or quality of life than cancer. That brings us to a study of the onset of diabetes after a cancer diagnosis – spoiler alert, the risk increases.
The Study
The study mines the data within the national patient database of South Korea, a single payer and therefore widely inclusive system. It looked for associations between the initial diagnosis of cancer and the subsequent discovery of diabetes in a sample of about 500,000. Diagnostic information was obtained from administrative coding and drug prescriptions.
- 15,130 participants developed cancers
- 26,610 participants developed diabetes. Of these patients, 3% already carried a diagnosis of cancer and represented “excess cases” – diabetes that would not have occurred if not for the patient having cancer.
- These “excess cases” occurred predominantly in the first two years after a cancer diagnosis.
- Some cancers were more likely to be associated with new-onset diabetes, the highest risk (a fivefold increase) was pancreatic cancer [1]
Now the 3% value was expressed as the incidence per thousand per years, so I am not sure that statistical analysis is not blinding us to what is essentially a random finding. But that having being said, why would there be a linkage between the two disease?
Linking cancer to diabetes – creating a narrative
The most straightforward explanation is that the diagnosis of cancer results in more detailed surveillance and that glucose dysregulation would be identified sooner – the “Hawthorne effect.” The second explanation is that diabetes is a complication or iatrogenic injury from cancer treatment. This is easily explained by the adjunctive use of steroids for the side effects of chemotherapy or to reduce swelling from brain or spinal cord involvement, and steroids are known to elevated glucose levels. A third explanation is that both cancer and diabetes share some risk factors, like obesity.
For me, a more intriguing, but as yet unsubstantiated notion is whether the known perturbations of our metabolism and energy kinetics resulting from cancer are not linked in some way to the development of diabetes. A simple example would be that the stress of cancer and its treatment exhausts marginal islet cells resulting in a decreased release of insulin in response to an unchanged glucose load – that we act more insulin “resistant.” Some chemical mediators, including those associated with the muscle wasting (cachexia) of advanced cancer, are also associated with insulin “resistance.”
Could the apparent increased incidence of diabetes reflect alterations in cellular glucose metabolism? Glucose usually is efficiently transformed into energy by mitochondria that utilize the oxygen we breathe. When less oxygen is available the conversion of glucose to energy occurs through a less efficient pathway. It has been known for some time that cancer cells can preferentially metabolize glucose through these less efficient pathways even in the presence of adequate oxygen – this is called the “Warburg effect.” Is it possible that some subset of the cancers being considered had energy kinetics more aligned with this “Warburg effect?” Is it possible that a subtle change in the use of energy tipped the balance and that this is manifested as glucose dysregulation?
I recognize that this is conjecture, but it is what makes understanding the underlying biology of disease alternatingly frustrating and fascinating.
[1] That should be of little surprise as the pancreas contains the islet cells responsible for insulin production and deeply involved in glucose regulation. Cellular dysfunction of the pancreas has to, at some point, involve insulin production.
Source: Incidence of Diabetes after Cancer Development: A Korean National Cohort Study JAMA Oncology DOI: 10.1001/jamaoncol.2018.1684
