New insights into pancreatic cancer-induced paraneoplastic diabetes

Abstract

Up to 85% of patients with pancreatic cancer have diabetes or hyperglycaemia, which frequently manifests as early as 2-3 years before a diagnosis of pancreatic cancer. Conversely, patients with new-onset diabetes have a 5-8-fold increased risk of being diagnosed with pancreatic cancer within 1-3 years of developing diabetes. Emerging evidence now indicates that pancreatic cancer causes diabetes. As in type 2 diabetes, β-cell dysfunction and peripheral insulin resistance are seen in pancreatic cancer-induced diabetes. However, unlike in patients with type 2 diabetes, glucose control worsens in patients with pancreatic cancer in the face of ongoing, often profound, weight loss. Diabetes and weight loss, which precede cachexia onset by several months, are paraneoplastic phenomena induced by pancreatic cancer. Although the pathogenesis of these pancreatic cancer-induced metabolic alterations is only beginning to be understood, these are likely mechanisms to promote the survival and growth of pancreatic cancer in a hostile and highly desmoplastic microenvironment. Interestingly, these metabolic changes could enable early diagnosis of pancreatic cancer, if they can be distinguished from the ones that occur in patients with type 2 diabetes. One such possible biomarker is adrenomedullin, which is a potential mediator of β-cell dysfunction in pancreatic cancer-induced diabetes.

Conflict of interest statement

Competing interests

The authors declare no competing interests.

Figures

Figure 1

Bidirectional association between pancreatic cancer and diabetes. a | Risk of diabetes after diabetes diagnosis. The risk of pancreatic cancer is high with new-onset diabetes (5–8-fold) whereas the risk levels out at about 1.5-fold 4 years after diabetes diagnosis.b | Timecourse of paraneoplastic diabetes and weight loss in relation to pancreatic cancer diagnosis, onset of symptoms and cachexia.,

Figure 2

A model depicting the phases of weight loss in pancreatic cancer. Weight loss precedes any symptoms related to cancer or cachexia by several months. We propose that the weight loss, associated with diabetes and occurring prior to the onset of symptoms, is a paraneoplastic phenomenon induced by pancreatic cancer. Abbreviations: SAT, subcutaneous adipose tissue; VAT, visceral adipose tissue.

Figure 3

A model demonstrating pancreatic cancer and β-cell interactions resulting in the pathogenesis of paraneoplastic diabetes. Pancreatic cancer-derived products might directly affect β cells. Indirect effects resulting from the consequences of insulin resistance and adipose tissue interactions on β cells might also be important. Abbreviation: NEFA, non-esterified fatty acids.

Figure 4

A model demonstrating pancreatic cancer and adipose tissue interactions resulting in the pathogenesis of paraneoplastic diabetes and associated weight loss. Interactions between pancreatic cancer and adipose tissue might lead to adipose tissue inflammation resulting in a systemic cytokine response, altered adipokine secretion and lipolysis. Eventually, these factors cause peripheral insulin resistance and β-cell dysfunction. Abbreviation: NEFA, non-esterified fatty acids.

Figure 5

Significance of metabolic alterations in pancreatic cancer. Paraneoplastic diabetes and weight loss are induced by pancreatic cancer possibly to enhance survival, proliferation, tumour growth and carcinogenesis. Pancreatic cancer is highly desmoplastic with an extremely hostile microenvironment. The pancreatic cancer cell is metabolically reprogrammed for survival and proliferation in harsh conditions. Multiple cellular pathways have been identified that contribute to aerobic glycolysis and might lead to the release of tumour factors, which mediate systemic metabolic alterations. Diabetes and lipolysis might supply substrates for reprogrammed metabolic machinery resulting in enhanced survival of cancer cells and tumour growth whereas hyperglycaemia and hyperinsulinaemia might directly enhance proliferation and carcinogenicity.