March 9th, 2015
A short overview of the connections between diabetes and pancreatic cancer

Up to 85% of pancreatic cancer patients also develop diabetes or hypoglycaemia and patients with new-onset diabetes run a 5-8 fold increased risk of being diagnosed with pancreatic cancer. The connection between diabetes and pancreatic cancer has been known and investigated since the late 19th century, but still no clear picture has emerged explaining the relationship in detail. This is mainly due to the bidirectional nature of the diseases. Pancreatic cancer causes diabetes, so called paraneoplastic diabetes, and at the same time diabetes increases the likelihood of development of pancreatic cancer over the long term.

Interestingly, symptoms of paraneoplastic diabetes occur many months, sometimes years, before cancer symptoms appear. These include both beta cell dysfunction and peripheral insulin resistance. Thus, diabetes may be diagnosed well before the tumour is radiologically detectable. In pancreatic cancer the majority of diabetes cases are new onset (<3 years since diagnosis) and diagnosis is typically accompanied by weight loss, not the common diabetic symptoms of metabolic syndrome and weight gain. Nevertheless, these features are insufficient to distinguish paraneoplastic from non-cancer induced diabetes.

A proposed model of the induction of diabetes through pancreatic cancer suggests that early non-detectable cancer causes adipose tissue inflammation via an, as of yet, unknown molecular mechanism. In the model, inflammatory cytokines induce lipolysis in adipocytes, which induce the initial weight loss. Toxic by-products of lipolysis then cause peripheral insulin resistance and beta cell dysfunction. An alternative model suggests that tumour secreted molecules induce beta cell disruption directly. This notion is supported by in vitro experiments, which show that pancreatic cancer cell lines secrete diabetogenic substances that increase insulin resistance in cultured hepatocytes. Similarly, injection of pancreatic cancer cell line supernatant has been shown to induce hyperglycaemia in in vivo experiments on mice. The identity of these toxic molecules are still unknown. Furthermore, some studies indicate that risk for developing pancreatic cancer may be modified by diabetes medication, increasing or decreasing cancer risk depending on medication type.

Identification of biomarkers specific for diabetes induced by early non-detectable PC should lead to earlier detection of the cancer and, consequently, increased long-term survival. Up until now, only single and small groups of biomarkers have been used to identify specific factors responsible for cancer inducing diabetes. Despite these efforts, no biomarkers sensitive enough for successful screening of pancreatic cancer have been found. A microarray approach with screening of large sets of antigens may prove superior by identifying more complex patterns of biomarkers and a signature highly specific for diabetes induced by early non-detectable pancreatic cancer.

Andreas Holmér,PhD,  Immunovia, Sweden

References

Sah RP, Nagpal SJ, Mukhopadhyay D, Chari ST. New insights into pancreatic cancer-induced paraneoplastic diabetes. Nat Rev Gastroenterol Hepatol. 2013;10(7):423-33.

Muniraj T, Chari ST. Diabetes and pancreatic cancer. Minerva Gastroenterol Dietol. 2012;58(4):331-45.

Pannala R, Basu A, Petersen GM, Chari ST. New-onset diabetes: a potential clue to the early diagnosis of pancreatic cancer. Lancet Oncol. 2009;10(1):88-95.