Scientists Develop Method to Alter Pancreatic Cells into Insulin Producing Cells

A research team from Stanford University School of Medicine has discovered that blocking the effects of two key genes could induce alpha cells of the pancreas to become efficient insulin producing cells. This study conducted by Dr. Harini Chakravarthy was published in the journal Cell Metabolism and was based on studies on human pancreases of diabetic cadaver donors. These alpha cells, of small percentage of these cadaver pancreas samples, were found to switch naturally to cells that produced insulin. This natural flexibility was utilized to devise methods to induce alpha cells into insulin producing cells, providing a new therapeutic strategy for diabetes. Professor of developmental biology and medicine, Dr. Seung Kim, who is the senior author of the study, said that it was important to evaluate all the possible methods of obtaining functional cells that produce insulin. The professor believes that this is an exciting step in the quest for a therapy for diabetes as the current study has identified a method of converting the alpha cells into indistinguishable beta cells.

Dr. Andrew Rakeman who is the Director of discovery research at an organization that funds research on type 1 diabetes, JDRF, said that the differentiation of alpha cells into insulin-producing beta cells is a therapeutic approach that can be used to regain the function of beta cells and eliminating type 1 diabetes. The director further stated that Dr. Chakravarthy and colleagues have taken an important step in terms of identifying the therapeutic potential of converting alpha cells into insulin producing beta cells.

Blood Glucose Levels and Food

Islets are clusters of cells, with every islet consisting of nearly 3,000 to 4,000 cells. In adult pancreas, there are 1 million islets, constituting only 1 to 2 % of the organ. There are two main types cells within each islet - alpha cells and the beta cells, which work together to regulate blood sugar.

The alpha cells and the beta cells of the pancreas play an important role in maintaining blood glucose levels. When the glucose levels are high, the beta cells are induced to secrete insulin which removes the excess glucose form the blood and stores it for later use. However, when the blood glucose levels drop, the alpha cells are induced to release glucagon, which in turn will induce the release of the glucose stored.

In certain individuals, the immune cells destroy the beta cells, resulting in diabetes. The insulin producing beta cells may cease to function in the pancreas of a diabetic, but 98% of the cells in the organ functions normally and produces digestive enzymes.

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Studies have shown that alpha cells could also be dysfunctional in both type 1 and type 2 diabetes. As Dr. Kim states, dysfunctional alpha cells could be stimulating an increased secretion of glucagon, which could lead to the increase in glucose in the blood. There are many alpha cells in the body and, if there are some that are initiating the secretion of additional glucagon, then converting a few of these alpha cells into insulin producing beta cells will be beneficial.

Natural Progression to Beta Cells

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Previous studies conducted on mice showed that when beta cells were completely destroyed, one percentage of the alpha cells behaved like beta cells, however, the process of conversion was very slow. The Swiss based laboratory which conducted the study on mice was also involved in the current study. The earlier study, though, lacked an understanding of the mechanisms that were involved in the conversion of alpha cells into beta cells. The current study was able to unearth master regulators that were involved.

Targeting Proteins

The research team studied two main candidate proteins

• ARX – Important in the process of development of alpha cells.
• DNMT1- Aid alpha cells in remaining alpha cells using chemical tags present on its DNA.

The current study was conducted on mice that were unable to synthesize either of these proteins. A chemical was added to the drinking water of study mice to generate strains of mice that were unable to produce both DNMT1 as well as ARX. The study findings showed that

• In the absence of the two proteins, there was rapid conversion of alpha cells into beta cells
• The conversion to beta cells occurred within 7 weeks of preventing the synthesis of the two proteins.

The results of the study were confirmed by collaborating with Stanford’s professor of bioengineering and of applied physics, Dr. Stephen Quake, who co-authored the study. This aided in understanding the expression pattern of the genes of the former alpha cells. Another similar collaborative part of the study was with scientists from the University of Illinois, which aided in identifying electrophysiological characteristics of the cells and their response to glucose. These studies showed that there was remarkable similarity between the converted alpha cells and native beta cells.

Human Cell Studies

Human pancreatic tissue obtained from cadaver donors, both diabetic and nondiabetic, was studied and it was found that

• Tissue samples collected within a year or two of death of children with type 1 diabetes showed the presence of bi-hormonal cells.
• The bi-hormonal cells could produce both insulin and glucagon. The scientists believe that these bi-hormonal cells could be the intermediate cells, when they were in the process of converting to beta cells.
• There was no expression of the genes ARX and DNMT1 in the samples of human alpha cells from diabetic donors.

According to the senior scientist of the study, Dr. Kim, these changes could be occurring in type 1 diabetes patients, but the use of targeted therapy could block the genes in the pancreas of such people, elevating the level of conversion of alpha cells into beta cells.

References:

1. What are Islet Cells? - (https://www.diabetesresearch.org/islet-cells)

Source-Medindia