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Pancreatic cancer has a pancreatopathy distinct from type 2 diabetes



Patients with pancreatic cancer have a particular form of endocrine pancreatopathy distinct from that of type 2 diabetes mellitus (T2DM), with increased islet size but normal insulin to glucagon ratios and lower levels of islet amyloid.

“The endocrinopathies associated with type 2 diabetes mellitus and pancreatic cancer are distinct, the former represented by an increase in glucagon and the latter characterized by a reduction in islet size,” said Sajan Nagpal, MD, of the Mayo Clinic in Rochester, Minn., at Digestive Disease Week 2018®. “These data lend insight to a unique pathophysiology of diabetes that results from pancreatic cancer.”

Prior to presenting his results, Dr. Nagpal pointed out an interesting relationship between pancreatic cancer and diabetes.

“Pancreatic cancer and diabetes have a very unique, two-way relationship. While long-standing diabetes [LSDM] increases the risk of developing pancreatic cancer by 1.5-2 times over a person’s lifetime, pancreatic cancer itself causes a paraneoplastic form of diabetes. A person with a new diagnosis of diabetes mellitus has a five to eight times increased risk of being diagnosed with pancreatic cancer as compared to the general population within 3 years.“

This form of diabetes is referred to as pancreatic cancer–induced new onset diabetes (PC-NOD).

Dr. Nagpal and his team conducted a study that included 46 patients: 16 patients with pancreatic cancer (5 with LSDM, 5 NOD, and 6 without diabetes mellitus), 15 patients with T2DM (9 LSDM, 6 NOD), and 15 controls matched for age and body mass index. NOD was defined as a diabetes mellitus diagnosis less than 3 years from the date of autopsy or pancreatic cancer diagnosis. All pancreatic specimens were resected from pancreatic cancer patients or obtained as autopsy specimens. Researchers performed islet morphometric studies utilizing immunofluorescence analysis with specific insulin and glucagon antibodies.

The results of the study showed that patients with pancreatic cancer had islet sizes that were about a third smaller than those in the patients with T2DM and the healthy controls (P = .005). This held true for both LSDM and NOD pancreatic cancer patients, compared with the T2DM and healthy control groups. Researchers also found that insulin to glucagon (I:G) ratios were preserved in pancreatic cancer patients, whereas they were lower in patients with T2DM because of a higher percentage of glucagon in the islets (P = .08). Additionally, islet amyloid was much higher in T2DM patients (66.7%) versus patients with diabetes associated with pancreatic cancer (55.6%) and healthy controls (13.3%; P = .01).

There were several limitations to this study, including the small number of patients in each group and how pancreatic islet characteristics can vary based on their location. Finally, ductal obstruction can cause changes to islet morphology.

Along with the pathological changes found by Dr. Nagpal and his research team, PC-NOD and T2DM also have unique clinical profiles. As patients with pancreatic cancer approach their diagnosis, they begin to lose weight. This begins about 1 year before the patient’s diagnosis of pancreatic cancer. Conversely, these patients have worsening fasting glucose levels despite the fact that they are losing weight. The paradoxical relationship between weight loss and hyperglycemia are what distinguishes PC-NOD from T2DM, according to Dr. Nagpal. In patients with PC-NOD, worsening hyperglycemia happens over a periods of months, compared with the gradual increase over the course of years seen in T2DM.

The differences between these diseases may be caused by differences in their pancreatopathy.

When discussing the pancreatopathy associated with T2DM, Dr. Nagpal pointed out that there is a decrease in the I:G ratio, compared with those seen in patients without diabetes. The prevailing theory is that this decrease in the I:G ratio is caused by beta-cell apoptosis and transdifferentiation to alpha-cells. T2DM patients also have increased amyloid deposits, the result of increased islet amyloid polypeptide.

”Pancreatic cancer provides subtle metabolic clues, such as worsening glucose tolerance and weight loss, that can serve as potential targets for its early detection.”

According to Dr. Nagpal, more research is needed on pathogenesis of PC-NOD. Identification of biomarkers for screening may be possible in patients with new onset diabetes.

Dr. Nagpal had no financial conflicts of interest to report.

SOURCE: Nagpal S et al. DDW 2018, Abstract 392.

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