Tohoku University clarifies a mechanism regulating the number of insulin cells — Increase during pregnancy and a decrease after being phagocytosed

A research group led by Associate Professor Junta Imai, Assistant Professor Akira Endo, and Professor Hideki Katagiri of the Tohoku University Graduate School of Medicine has announced the discovery that beta (β) cells (insulin producing pancreatic cells), which increase in number during pregnancy, are phagocytosed by macrophages and return to their original number after parturition (the act of giving birth). Evaluation of the islets of Langerhans in the pancreas of mice before and after parturition revealed that the number of macrophages increased after parturition, and the suppression of these macrophages resulted in the manifestation of hypoglycemia (low blood sugar level).

Additionally, the researchers identified the substances released by β cells to attract macrophages immediately after parturition. Macrophages phagocytosing β cells were also successfully captured under the microscope. The results are expected to lead to the clarification of the mechanism through which normal blood glucose levels are maintained as well as the development of methods to prevent and treat diabetes. The results were published in the September 15, 2023 issue of the international journal Developmental Cell.

Localized in the islets of Langerhans in the pancreas, β cells produce insulin, a hormone that lowers the blood glucose level. Diabetes is caused by a decrease in these β cells. It is well known that insulin resistance, accompanied by increased β cell proliferation, occurs in pregnant women and that these cells rapidly return to their original number after parturition. This is thought to increase glucose level in the blood and facilitate its supply to the fetus. However, it was unclear how the number of β cells returned to normal after parturition.

Previously, the research group reported that obesity produces neural signals that stimulate β cell proliferation. In this study, the researchers aimed to clarify the mechanism by which the number of β cells is regulated before and after pregnancy. First, they examined the number of β cells in the islets of Langerhans in the pancreas in a mouse model of pregnancy. It was confirmed that the cell number was doubled on the 17th day of pregnancy compared with that in non-pregnant mice, but it gradually decreased after parturition, returning to the original number 10 days after delivery. Because the gestation of mice is 20 days, the 17th day is in the late gestation.

The researchers observed islets of Langerhans in the pancreas before and after parturition and found that macrophages were proliferating significantly in these pancreatic islets after the 5th day of delivery. Since macrophages engulf bacteria, foreign substances and dead cells that invade the body and then digest them in the process of phagocytosis, the possibility that macrophages are involved in β cell loss was investigated. After parturition, treatment to inhibit the increase in macrophage numbers in the islets of Langerhans in the pancreas preventedβ cell loss and led to hypoglycemia.

The researchers also confirmed that the inhibition of macrophage phagocytic activity after parturition prevented the β cell loss. Additionally, microscopic observation of the islets of Langerhans after parturition revealed that β cells were phagocytosed by macrophages. Macrophages have been shown to reduce β cells through phagocytosis after parturition.

In the search for the substances involved in this increase in macrophages in the islets of Langerhans in the pancreas, a significant increase in the cytokine CXCL10 was observed in the β cells immediately after parturition (day 2 after delivery). It was also confirmed that the released CXCL10 attracts macrophages to the islets of Langerhans and increases their number in the pancreas. Conversely, the inhibition of CXCL10 function suppressed the decrease in β cells after parturition.

Through this, the research group has revealed the existence of a mechanism that maintains normal blood glucose levels by reducing the number of β cells in several successive and elaborate processes according to body conditions.

Imai said, "Diabetes is caused by a decrease in β cells. The mechanism we found this time works when insulin becomes more effective after parturition and the number of β cells needs to be reduced. However, if it works when the number need not be reduced, then possibility of developing diabetes may arise. If we can identify the link, we believe that it will lead to the development of interventions for the prevention and treatment of diabetes."

Journal Information
Publication: Developmental Cell
Title: Phagocytosis by macrophages promotes pancreatic β cell mass reduction after parturition in mice
DOI: 10.1016/j.devcel.2023.08.002