Stem Cell Research Provides New Insights into Insulin Production

Insulin is a protein hormone made by the beta cells of the pancreatic islets. It signals to the liver, skeletal muscles, and fat tissue to take up glucose and store it as glycogen (a polymer of glucose), or to convert it into fat. Insulin also induces the uptake of amino acids by muscles and the liver to form protein. This makes insulin one of the most important anabolic (building) hormones in the body.

Without sufficient quantities of insulin, blood sugar levels soar, since cells do not have the signal to take up sugar. Large quantities of sugar are quite damaging to cells and tissues, and the accumulating damage causes blindness, kidney failure, heart failure, circulatory and peripheral nerve troubles and other ailments.

This pathological condition is known as diabetes mellitus, and treatment of it requires routine injections of insulin. In order to actually treat insulin, we must somehow replace the deleted or damaged beta cells. Stem care cell treatment can potentially do this, but the details are still being worked out.

Danish stem cell scientists have provided some insights into ways to convert stem cells into pancreatic beta cells. By examining pancreatic development in mice, Palle Serup and his research group discovered a new gene called “Mind Bomb-1” that plays a role in pancreatic beta cell formation.

Accord to Dr., Serup, “To get stem cells to develop into insulin-producing beta cells, it is necessary tp know what signaling mechanisms normally control the creation of beta cells during fetal development. This is what our new research results can contribute. When we know the signaling paths, we can copy then in test tubes and thus in time convert stem cells to beta cells.” Dr. Serup is a member of the Danish Stem Cell Center or DanStem at the University of Copenhagen.

In a collaboration with researchers at DanStem, the Danish Hagedorn Research Institute, and other international partners in Japan, Germany, South Korea and the United States, these new findings were published in the April edition of the Proceedings of the National Academy of Sciences.

Previous work has established that during the early hours of the development of the pancreas, a signaling pathway that utilizes the “Notch” protein prevents pancreatic cells from differentiating into endocrine (hormone-making) cells and promotes the continued growth and proliferation of a kind of generic, all-purpose pancreas precursor cell. These all-purpose pancreatic precursor cells are called multipotent progenitor cells or MPCs, and they express two genes: Nkx6-1, and Ptf1.

A bit later, Nkx6 and Ptf1a start to antagonize each other such that cells that express Nkx6 cannot express and Ptf1 and Ptf1-expressing cells cannot express Nkx6. This antagonism between these two genes segregates the developing pancreas into two domains. The bit that is furthest away from the ductal system expresses Ptf1a+ and form “acinar progenitors.” The acinar cells are the clusters that make all the digestive enzymes released by the pancreas the bicarbonate ions. The portion of the developing pancreas that is closet to the ductal system expresses Nkx6-1, and makes the pancreatic duct and β-cell progenitors (see Russ HA, Efrat S. Pediatr Endocrinol Rev. 2011 Dec;9(2):590-7).

This sounds simple, but there are still several gaps that have yet to be filled in. For example, the signals that regulate patterning of the incipient pancreas and cause the segregation of the cells from one end to the other. Also, what dictates the formation of β-cell progenitors as opposed to ductal cells is also presently unknown.

In this present article, Serup and his colleagues discovered that deleting Mind Bomb-1 activity from the developing pancreas preventing the segregation of MPCs into Nkx6-expressing and Ptf1a-expressing cells. Instead the Nkx6-1-expressing cells were replaced by Ptf1-expressing cells. This prevented the formation of beta cells.

Interestingly, Serup and his team found that once the Notch protein acts early during pancreatic development, it actually acts again to help establish the segregated pancreas with Nkx6-1-expressing cells at one end and Ptf1a-expressing cells at the other. This shows that Notch is not only necessary early on, but also later for beta cell formation.

According the Serup, “Our research contributes knowledge about the next step in development and the signaling involved in the communication between cells – an area that has not been extensively described. This new knowledge about the ability of the so-called “Notch” signaling first to inhibit and then to stimulate the creation of hormone-producing cells is crucially important to being able to control stem cells better when working with them in test tubes.”