Evidence Suggesting That Pancreatic Cancer Causes Diabetes

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The majority of diabetes associated with pancreatic cancer is diagnosed either concomitantly with the cancer or during the two years before the cancer is found [6]; 71% of the glucose intolerance found in pancreatic cancer patients is unknown before the cancer is diagnosed [5]. These suggest that recently-developed glucose intolerance or diabetes may be a consequence of pancreatic cancer and that recent onset of glucose intolerance or diabetes may be an early sign of pancreatic cancer. Several studies have demonstrated that diabetes in pancreatic cancer patients is characterized by peripheral insulin resistance [4,5,7]. Insulin resistance is also found in non-diabetic or glucose intolerant pancreatic cancer patients, though to a lesser degree [7]. Insulin sensitivity and overall diabetic state in pancreatic cancer patients who undergo tumor resection are markedly improved three months after the surgery [7].

These data suggest that pancreatic tumors are causally related to the insulin resistance and diabetes seen in pancreatic cancer patients. In their study of sera from patients with pancreatic cancer and culture media conditioned by human pancreatic cancer cells, Basso et al. found a 2030 MW peptide that they considered to be a putative pancreatic cancer associated diabetogenic factor [8].

A number of investigators have studied insulin resistance at the organ, tissue, and cellular levels in pancreatic cancer [7-13]. Studies of the initial steps in the insulin signaling cascade in human skeletal muscles showed no significant differences in insulin receptor binding, tyrosine kinase activity, and insulin receptor substrate-1 content between pancreatic cancer patients and healthy controls [9]. However, phosphatidylinositol 3-kinase (PI3-K) activity and glucose transport, which are located downstream to the initial insulin signaling steps, were impaired in pancreatic cancer patients [10]. In addition, glycogen synthase activity was reduced in skeletal muscles of humans and rodents with pancreatic carcinoma [9,11] and in isolated rat skeletal muscles exposed to human pancreatic tumor extracts in vitro [7]. These data show that the insulin signaling cascade in skeletal muscle is impaired at multiple steps by pancreatic cancer.

An Italian group has performed a series of studies to investigate the effects of pancreatic cancer cells on hepatic insulin sensitivity. When mice were treated with culture medium conditioned by the human pancreatic cancer cell line Mia PaCa2, blood glucose was elevated compared to the control value seen in mice treated with unconditioned medium [12]. In addition, isolated rat hepatocytes showed impaired glycolysis when incubated in culture media conditioned by four human pancreatic cancer cell lines [13].

Islet dysfunction is another etiological component underlying the diabetes associated with pancreatic cancer. Because the islet mass destroyed by the tumor is only a small proportion of the whole islet mass, the islet dysfunction is unlikely to be the result of decreased total islet volume. In fact, endocrine pancreatic function can be maintained even with a larger loss of pancreatic islets [14]. Reduced insulin release is seen in pancreatic cancer patients in response to classic stimuli [5,15,16]. Insulin release was also reduced when isolated rat pancreatic islets were incubated in culture media conditioned by the human pancreatic cancer cell lines Panc-1 and HPAF or co-cultured with Panc-1 and HPAF cells [17,18]. Studies of chemically-induced pancreatic cancer in hamsters found that glucose-stimulated insulin release was impaired in vivo [19] but not in isolated perfused pancreata [20]. Ishikawa et al. found an increase in proinsulin relative to insulin in pancreatic cancer patients [21], suggesting that the maturation of proinsulin may also be affected by the tumor.

Islet hormone profiles are changed in the circulation of pancreatic cancer patients, suggesting that secretion by different types of islet cells is disrupted by pancreatic cancer [22]. Changes in islet hormone concentrations in the circulation can also be seen in hamsters after induction of pancreatic cancer [23]. Human pancreatic islets adjacent to pancreatic carcinoma show morphological abnormalities characterized by abnormal co-localization of islet hormones in islet cells [24].