Insulin-producing cells in the fetal gut discovered by US-Israeli scientists

The beta cells dispersed throughout the pancreas have an exclusive “license” to make insulin in the human body. However, because beta cells can become sparse or defective in persons with diabetes, researchers have been looking for alternative cells that can be coaxed into producing the crucial glucose-regulating hormone.

Researchers from the Weizmann Institute of Science and Yale School of Medicine discovered insulin-producing cells in an unexpected area, the fetal gut. This discovery could lead to new directions in the development of diabetes medicines in the future. Their findings were published today in Nature Medicine.

Many of the fetus’s cells are undecided about their future fates while it grows in the womb, keeping their identities variable for a time. This is especially true of cells in the embryonic gut: the intestine is already fully developed in the second trimester, but it doesn’t need to absorb food or resist infection while still in the womb.

Prof. Shalev Itzkovitz of the Weizmann Institute of Science’s Molecular Cell Biology Department collaborated with pediatrician Prof. Liza Konnikova of Yale School of Medicine to learn about unexpected responsibilities that embryonic intestine cells could take on, such as insulin manufacturing.

Both teams used single-cell RNA sequencing to generate an atlas of embryonic intestine cells for the study. This method simultaneously builds profiles of complete gene expression in thousands of individual cells.

The researchers then compared these patterns to those seen in babies’ intestines. The Hormone-producing cells were given specific attention. Those cells that makeup just approximately 1% of total intestinal cells are incredibly important because they release hormones that regulate the body’s metabolism.

Indeed, the comparison analysis discovered K/L fetal cells in the small intestine that were expressing the insulin gene. This gene was previously only known to be expressed in pancreatic beta cells. The K/L type of cells was also seen in newborn small intestines, however, unlike fetal intestinal cells, these did not express insulin.

The newly discovered cells were given the name FIKL, which stands for fetal and insulin. Although these cells only make up around 2% of the hormone-producing cells in the fetal intestine or 0.0002% of all intestinal cells, they are present in relatively large quantities due to the human gut’s vast lining. (An adult’s gut lining is about the size of a badminton court when stretched flat.)

FIKL cells were discovered to contain a full molecular program that might support the hormone’s function, including genes for glucose sensing and assuring insulin release from the cell, in addition to the insulin-making gene. Furthermore, the FIKL cells were discovered to produce a considerable amount of insulin.

Their insulin gene, like that of beta cells, was extraordinarily active, producing tens of thousands of copies of messenger RNA molecules at a time, much exceeding the human genome’s average of roughly ten copies per gene at any given moment.

When the scientists imaged the RNA and other components within the cells, they discovered yet another parallel with beta cells: Both beta and FIKL cells were set up in the same way, with the messenger RNA of insulin facing the cell’s center and the hormone itself accumulating on the cell’s outward-facing side, allowing for easier release.

“These analogies with pancreatic beta cells make sense,” Itzkovitz says, “since the pancreas and small intestine both originate from the same tissue in the growing baby around the fifth week of gestation.”

It’s unclear why the fetal gut contains insulin-producing cells. The study’s cells originated from a repository of fetal tissues, and the mothers’ health status was unknown. Because the mother’s insulin and glucose levels might change during pregnancy, it’s likely that the insulin program was activated in response to the mother’s gestational diabetes, to assist the baby in dealing with high glucose levels in the mother’s blood. The gut-produced insulin may also have a local effect, supporting the rapid expansion of the intestine.

It’s also uncertain what turns off the insulin-making program during birth. However, according to Itzkovitz, the most important question is if it can be turned back on.

“Perhaps this dormant program for generating insulin in persons with diabetes can be activated one day,” Itzkovitz says. “If that’s the case, intestinal lining cells might be a great supply of insulin because they’re constantly replenished — this would be especially beneficial to people with Type 1 diabetes, whose insulin-producing cells are regularly destroyed by the immune system.”

Beta cells are frequently destroyed in people with Type 2 diabetes as a result of the stress of dealing with high glucose levels. Until far, research on replacing lost beta cells with stem cells or engineering cells other than beta cells to produce insulin has primarily focused on stem cells or engineering cells other than beta cells to manufacture insulin.

“We realized that the advantage of FIKL cells is that they naturally possess a functioning program for generating insulin,” Konnikova explains. “If we can figure out how to control this program with cues, we might be able to switch it on and off as needed one day.”

Among the participants in the research are Yale School of Medicine’s Dhana Llivichuzhca-Loja and Blake McCourt; Weizmann’s Molecular Cell Biology Department’s Dr. Keren Bahar Halpern and Dr. Lydia Farack; and the University of Pittsburgh’s Xiaojing An, Fujing Wang, and Dr. Kong Chen.