Cell types outside the pancreas make insulin, too, study shows

Researchers at Yale and the Weizmann Institute of Science have found the first evidence that the human fetus can spontaneously produce insulin outside the pancreas — in the small intestine, specifically — a startling discovery that stands in contrast to the longheld belief that insulin production is unique to the pancreas.

While other researchers had previously been able to manipulate the proteins that regulate insulin secretion — thereby getting other cells to produce insulin — there have been no previous reports of other cells (outside of the pancreas) making insulin on their own.

Insulin is known to be produced by pancreatic cells to regulate glucose levels in the blood. It is also a growth factor. Destruction of insulin-producing cells in the pancreas causes Type 1 diabetes, while Type 2 is triggered by insulin resistance. The possibility that other cells are able to produce insulin can open up new avenues for diabetes treatment, researchers say. It also suggests that insulin might be involved in intestinal growth in the fetus.

The findings are published in the December issue of Nature Medicine.

For the study, researchers analyzed single cell data on both fetal tissue and neonatal tissue. When they first noted insulin-producing cells in the gut, they were surprised.

“It was completely serendipitous,” said Dr. Liza Konnikova, an assistant professor in pediatrics and obstetrics, gynecology and reproductive sciences at Yale School of Medicine, a member of the Human and Translational Immunology Program, and co-senior author of the study. “The more we looked into it, we realized that insulin was originating from within the small intestine. We were able to show that both the RNA and the protein are made in the small intestinal cells. Moreover, signaling for insulin production is also intact in these cells.”

For the study, the researchers wanted to see what the transcriptional or RNA differences were between the fetus, which is not exposed to an abundant microbiome and is continuously developing, and newborns, who are exposed to an abundant microbiome. Looking at how immune and epithelial development are different between the fetuses and newborns highlighted not only the existence of intestinal insulin-producing cells, but also their complete expression signature. This could provide avenues through which this dormant ability might be awakened in adults.

“Cells in the intestinal tract are a wonderful potential source of insulin because they are continuously renewed from intestinal stem cells,” said co-lead author Shalev Itzkovitz, associate professor at the Weizmann Institute of Science, a research institution based in Israel. “This could be an advantage in Type 1 diabetes, where insulin-producing cells are under attack from our immune system.”

Other authors on the study included Dhana Llivichuzhca-Loja and Blake McCourt from the Yale School of Medicine.