Research into the connection between diabetes and pancreatic ductal adenocarcinoma (PDAC) indicates that new-onset hyperglycemia could offer earlier warning of PDAC development.

During a Monday morning symposium, Suresh T. Chari, MD, Professor of Medicine in the Department of Gastroenterology, Hepatology, and Nutrition at the University of Texas MD Anderson Cancer Center, Houston, reviewed findings included in an abstract he and his colleagues published last year. Registered meeting attendees can view the symposium, Trouble in the Neighborhood—Endocrine/Exocrine Interactions in Diabetes, at ADA2020.org through early September.

PDAC and other pancreatic cancers are so deadly because symptomatic diagnosis almost always takes place when the tumor is not resectable. But research shows metabolic phases of PDAC starting about two-and-a-half years before typical symptomatic diagnosis. The first phase involves an increase in fasting blood glucose 30 to 36 months before diagnosis, and the second phase involves decreases in body weight and lipids about 18 months before diagnosis.

Researchers have connected weight loss and the browning of subcutaneous adipose tissue (SAT). A study involving three patients with PDAC and three control patients showed a six-fold upregulation of mRNA levels of uncoupling protein 1 (UCP1), the signature marker protein for brown fat.

“UCP1 overexpression in SAT biopsy may be a biomarker for pancreatic cancer patients losing weight,” Dr. Chari said. “And the weight loss is very tightly connected to new-onset diabetes at this stage.”

Also during the symposium, Scott Oakes, MD, Professor and Vice Chair of Research in the Department of Pathology at the University of Chicago, discussed the genetics of inherited pancreatitis, noting that about half of patients with chronic pancreatitis develop diabetes.

The University of California, San Francisco, published a paper about a patient with chronic pancreatitis and diabetes in the 1960s, one of the first documented cases of familial pancreatitis. The genetic tools didn’t exist at the time to determine the cause, but the case led Dr. Oakes and colleague Mark Anderson, MD, PhD, to a genetic breakthrough years later.

Dr. Oakes’ group used whole exome sequencing and variant analysis, tracing the cause to a novel amino acid mutation, R90C, in chymotrypsin-like elastase 3B (CELA3B), which is only expressed in the pancreas.

“Our current data supports the hypothesis that this mutation causes upregulation of co-translational translocation of CELA3B, which upon secretion and activation by trypsin leads to uncontrolled proteolysis in the surrounding environment and recurrent pancreatitis,” Dr. Oakes said.

Teresa L. Mastracci, PhD, Senior Scientist at Indiana Biosciences Research Institute, discussed the role hypusine biosynthesis plays in exocrine pancreas development.

Changes in the hypusine biosynthesis pathway impact pancreas development, Dr. Mastracci said, and both exocrine and endocrine cells are differentially sensitive to hypusine biosynthesis alterations.

Dr. Mastracci said that deletion of the enzyme deoxyhypusine synthase (DHPS) in the exocrine pancreas led to reduced growth and premature death in mouse models. That absence also leads to altered mRNA translation and the synthesis of proteins critical for exocrine development and function. While DHPS is required for exocrine pancreas development, it’s dispensable for endocrine pancreas development, she said.

“When you put it all together, what’s really interesting is in that alterations in hypusine biosynthesis, we can definitely now link to impacting development in the embryo. What that says to us is that there could be an impact on disease,” Dr. Mastracci said.

Andy Norris, MD, PhD, Director of the Division of Pediatric Endocrinology and Diabetes and Associate Director of the FOE Diabetes Research Center at the University of Iowa, discussed research into cystic fibrosis (CF) and the pancreas, including cystic fibrosis-related diabetes. Dr. Norris’ research indicates that a single gene mutation in the pancreas that leads to a loss of cystic fibrosis transmembrane conductance regulator (CFTR) is expressed in ducts of the pancreas. This acute loss of CFTR from islet-associated ductal cells decreases glucose-stimulated insulin secretion.

According to this model, the pancreas becomes so diseased early in CF that it’s almost destroyed except for the duct cells. Then the islet cells return, as seen in animal models showing a decline in beta cells followed by an almost spontaneous recovery. The ductal cells may be playing a role, but how that happens remains under investigation, Dr. Norris said. In silico predictions indicate a ductal-islet paracrine signaling network.

“This suggests that perhaps ducts are important in the process of repopulating these islets. Of course, there are other possibilities, and we need to explore this,” Dr. Norris said.