Fetal Gut May Have Insulin-Producing Cells That Shut Off at Birth

Marlene Busko

December 27, 2021

In addition to pancreatic beta cells that secrete insulin, researchers have found that fetal cells in the gut secrete insulin proteins, but neonatal cells do not, suggesting that this ability is turned off at birth.

The study findings are "plausible, because the pancreas and the small intestine originate from the same tissue in the growing fetus at about the fifth week of gestation," said senior study author Shalev Itzkovitz, PhD, principal investigator, Weizmann Institute of Science, in Rehovot, Israel, in a news story in The Jerusalem Post.

The study by Adi Egozi, a PhD student at the Weizmann Institute of Science and colleagues in Israel and in the United States, was recently published in Nature Medicine.

The researchers speculated that if they could get cells in adults to secrete insulin proteins, this might lead to a new way to treat diabetes, but this research is very preliminary.

"We found insulin-producing cells in fetuses, yet not in neonates," Itzkovitz summarized in an email to Medscape Medical News.

"It would be exciting to uncover situations where the insulin-producing cells naturally re-appear, eg, in diabetes, gastric bypass, or other perturbations," and to "identify molecules that could awaken the beta-like state we discovered,” Itzkovitz added.

The study findings "highlight a potential extra-pancreatic source of beta cells and expose its molecular blueprint," the researchers summarize.

"The dream is to have a drug that could re-awaken the fetal insulin-expressing program," Itzkovitz said.

"Even though the insulin-producing cells are a minority, the gut surface is huge, and their numbers add up," he noted. In addition, "gut cells are constantly replaced via divisions of stem cells."

"This means that the impact of autoimmune attack in type 1 diabetes might be less pronounced on intestinal insulin-producing cells," according to Itzkovitz.

"Surprising" Insulin Expression in Certain Fetal Gut Cells

Although the intestine is fully formed in the second trimester of pregnancy, it does not yet work in the same way as after birth.

Cells that are responsible for nutrient absorption after birth, Itzkovitz explained, do not really need to function during fetal life when all the food arrives from the mother through the placenta.

"We therefore hypothesized," he said, "that fetal intestinal cells might have hidden functions that may diverge from those in the adult gut."

To investigate this, the researchers obtained intestinal tissue from four fetuses from terminated pregnancies and from two neonates who were having surgery.

They dissociated intestinal tissues from fetuses and neonates into tens of thousands of single cells and performed single-cell RNA sequencing, which reveals the amounts of mRNA of all genes.

"This enabled characterizing the identities of all cells in the human gut, from immune cells, through stromal cells to epithelial cells," said Itzkovitz.

"When comparing the differences in gene expression between distinct cell types in fetuses and neonates," he said, "we were surprised to discover highly elevated levels of expression of the insulin gene in a subset of [fetal] hormone-producing enteroendocrine cells."

"These cells expressed both the mRNAs and proteins of insulin as well as major components of the glucose sensing and insulin secretion machinery seen in pancreatic beta cells," he continued.

"Moreover, under the microscope they exhibited the distinctive mRNA-protein polarization of pancreatic beta cells."

"We therefore concluded that a subset of enteroendocrine cells in the human fetal gut may operate in insulin secretion," and "this program disappeared after birth," Itzkovitz reiterated.

The authors were supported by the Wolfson Family Charitable Trust, the Edmond de Rothschild Foundations, the Fannie Sherr Fund, the Dr Beth Rom-Rymer Stem Cell Research Fund, the Minerva Stiftung, the Israel Science Foundation, the Broad Institute‐Israel Science Foundation, the European Research Council, the Chan Zuckerberg Initiative, the network of Pancreatic Organ Donors with Diabetes, the Bert L. and N. Kuggie Vallee Foundation, and the Howard Hughes Medical Institute. One author received support from the University of Pittsburgh, Yale University, the Binational Science Foundation, and the National Institute of Health (NIH). No NIH funds were used for the fetal work. The authors declare that they have no conflict of interest disclosures.

Nat Med. Published online December 9, 2021. Abstract

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