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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.

Key Points

  • Compelling evidence now indicates that pancreatic cancer causes paraneoplastic diabetes

  • As in type 2 diabetes, β-cell dysfunction and peripheral insulin resistance occur in pancreatic cancer-induced diabetes; however, unlike type 2 diabetes, weight loss occurs alongside worsening diabetes in pancreatic cancer

  • Paraneoplastic diabetes and weight loss manifest many months prior to the onset of cachexia or clinical presentation of pancreatic cancer

  • Differential responses of visceral and subcutaneous adipose tissue compartments in pancreatic cancer might underlie the development of insulin resistance and paradoxical weight loss

  • These metabolic alterations might be induced by pancreatic cancer for enhanced survival and tumour growth in an otherwise hostile microenvironment

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Figure 1: Bidirectional association between pancreatic cancer and diabetes.
Figure 2: A model depicting the phases of weight loss in pancreatic cancer.
Figure 3: A model demonstrating pancreatic cancer and β-cell interactions resulting in the pathogenesis of paraneoplastic diabetes.
Figure 4: A model demonstrating pancreatic cancer and adipose tissue interactions resulting in the pathogenesis of paraneoplastic diabetes and associated weight loss.
Figure 5: Significance of metabolic alterations in pancreatic cancer.

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Acknowledgements

D. Mukhopadhyay was supported by funding from NIH (R01 CA150190) and the Mayo Clinic Pancreas Cancer SPORE (P50 CA 102701). S. T. Chari was supported by grants from the NIH (R01 CA 100685) and the Mayo Clinic Pancreas Cancer SPORE (P50 CA 102701).

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All authors researched data for the article and reviewed and/or edited the manuscript before submission. R. P. Sah, D. Mukhopadhyay and S. T. Chari substantially contributed to the discussion of content. R. P. Sah, S. J. S. Nagpal and S. T. Chari wrote the Review.

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Correspondence to Suresh T. Chari.

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Sah, R., Nagpal, S., Mukhopadhyay, D. et al. New insights into pancreatic cancer-induced paraneoplastic diabetes. Nat Rev Gastroenterol Hepatol 10, 423–433 (2013). https://doi.org/10.1038/nrgastro.2013.49

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