Scientists from Singapore have high hopes for stem cells in the treatment of all types of diabetes. However, more research is needed to control their differentiation and insulin production.

According to the World Health Organization (WHO), one in eleven persons on our planet suffers from diabetes. The disease was the direct cause of 1.6 million deaths in 2016, according to the latest publicly available data. Since then, who has identified diabetes as one of four priority noncommunicable diseases (beside with cancer, respiratory and cardiovascular diseases) that should be considered by global health authorities.

Despite the fact that diabetes is a simple disease, in fact, it manifests itself in numerous forms. Type I diabetes (T1D) occurs due to an autoimmune reaction that destroys insulin producing cells called beta cells located in the pancreas. Type II diabetes (T2D) occurs because cells no longer respond to insulin. Less known is monogenic diabetes – a rare form of diabetes caused by mutations in one of the genes.

“Over time, however, pancreatic beta cell failure and beta cell death is a common denominator for all types of diabetes”, – said Adrian Teo, a Principal Investigator at A*STAR’s Institute of Molecular and Cell Biology (IMCB), lead author of an article published in iScience. “Obesity is a major contributing factor to diabetes in the West, the main contributing factor in Asia is generally pancreatic beta cell failure. Although current diabetes medication can help to control blood glucose levels for extended periods of time, they do not cure or even improve pancreatic beta cell health.”

Based on this, the Teo team intends to use the powerful potential of stem cells to fight diabetes. Unlike most body cells, stem cells have the ability to self-renew and can differentiate into various types of cells, including pancreatic beta cells. Therefore, stem cells could potentially be used to replace non-functioning pancreatic beta cells in diabetic patients, restore their ability to produce insulin and regulate glucose levels.

Many of the world’s research uses stem cells from embryos. However, Teo rejected this source, which was controversial from an ethical point of view. He plans to receive blood cells and fibroblasts (a type of skin cell) from patients with diabetes, and then reprogram them into induced pluripotent stem cells (iPSCs).

In the future, the research team plans to edit the genes to correct diabetes-related mutations or gene variations in the obtained iPSCs before they differentiate into pancreatic beta cells and are transplanted back to the patient.

“This method potentially allows for the creation of a near-unlimited supply of pancreatic beta cells for cell replacement therapy”, – said Blaise Su Jun Low, a final year Ph.D. student in Teo’s lab. “Because patients will be transplanted with their own cells, graft rejection is less likely to occur.”

In addition to cell replacement therapy, iPSCs can also help shed light on the underlying molecular mechanisms of diabetes. For example, the Teo research team uses iPSCs from patients diagnosed with MODY diabetes (a subtype of monogenic diabetes) to understand how certain gene networks control the development of the pancreas and liver. Both organs are crucial for normal glucose metabolism.

MODY diabetes (Maturity Onset Diabetes of the Young) is a group of diseases caused by mutations in one of the genes involved in glucose regulation. MODY diabetes is often hereditary. It is diagnosed in 2-5% of cases of the total number of people with different types of diabetes. Diagnosis of various types of MODY based only on the clinical picture is impossible.

The general experimental scheme developed by the Teo’s group is as follows: at the initial stage, the researchers stimulate the differentiation of iPSCs obtained from MODY patients into the anterior intestinal endoderm and human pancreatic progenitors –  the parts of the human embryo that eventually develop into the pancreas and liver and then into beta-like pancreatic cells. The team then compares their gene expression pattern with samples, obtained from healthy donors.

This approach allowed the Teo team to find that mutations in a gene called HNF4A lead to a decrease in the total expression of genes that determine the development of the pancreas and liver in patients with MODY 1. It is important to note, Teo says, that this discovery would not have been possible using mouse models because mice with one mutant copy of HNF4A do not develop diabetes, unlike humans.

“Currently, there are more than 14 forms of MODY, each caused by mutations in a different gene (e.g. HNF4A, HNF1A, PAX4 and INS)”, – Teo explained. “Interestingly, gene variants found in many of these MODY genes are associated with T2D, the most common form of diabetes that affects approximately 90 percent of the diabetic population.” The findings from MODY patients may therefore be relevant to the pathophysiology of T2D as well, Teo added.

In addition, using iPSCs as a platform for genetic screening, researchers can more correctly divide patients into different treatment groups, as well as identify new drug targets. This would eliminate the universal solution for all patients. Medications will be prescribed based on major genetic defects unique to each diabetic.

The use of human iPSCs for genetic screening and the search for diabetes drugs is already being carried out in many laboratories around the world. However, therapy involving replacing nonfunctional pancreatic beta cells with human induced pluripotent  stem cells has yet to go some way before it can be approved for use in clinics.

Teo says that the function of pancreatic beta cells derived from iPSCs has not yet been fully confirmed.

“They need to function just like bona fide human pancreatic beta cells or islets”, – he warned. “Otherwise the glucose levels of the individual will not be properly regulated, posing health risks.”