Many of you may have read the very interesting news about β-cell regeneration that was reported by the JDRF recently. For those of you who haven’t, and for those of you who wanted to know more about what exactly the reported α-to-β cell conversion was, here are some more details on the study, based on my reading of the paper published in Nature. A disclaimer: I am not a trained biologist (yet; this disease appears to be turning me into one), so if I get anything wrong, please let me know.
Before we dive into what the researchers at the University of Geneva found, it is important to understand a few of the basics about the pancreas, and its cellular landscape.
The pancreas, whether human or mouse, is composed of two types of tissue: exocrene, which is responsible for creating certain digestive enzymes, and endocrene, which is made up of clusters of cells that look like dense islands (and are therefore named the isles of Langerhans).
This study, like most diabetes research, is mainly concerned with the set of cells that form the islands in the endocrine tissue. There are four types of cells that make up most of the mass and functional power of the islands:
- δ-cells (delta-cells), which produce the regulatory hormone somatostatin,
- PP cells, which produce the regulatory protein pancreatic polypeptide,
- α-cells (alpha-cells), which produce the hormone glucagon, and
- β-cells (beta-cells), which produce the hormone insulin.
The last two cells here– α-cells and β-cells– are particularly important to the study of diabetes, as both play an integral role in the body’s management of glucose levels. β-cells, which produce insulin, are the very cells that are destroyed by the immune system in Type 1 diabetes, rendering the diabetic unable to produce insulin. α-cells, meanwhile, produce glucagon, which is the hormone that the body releases when other regulatory cells sense that glucose levels are low. Glucagon instructs the liver to convert and release stored glucose into the bloodstream.
In Type 1 diabetics, the isles of Langerhans in the pancreas have little or no β-cells. For reasons still unclear, the immune system has marked the β-cells as unwanted intruders, and has killed them off, leaving behind the other three cell types.
As a result, a cure for Type 1 diabetes has to solve two problems:
- How do we get the immune system to stop attacking the β-cells? This question is being addressed by a number of studies, including the recent nanoparticle approach.
- How do we get β-cells back into the pancreas, producing insulin?
This second question of regenerating β-cells has been addressed from a number of angles over the years– implantation and stem-cells being two of the most promising– but no one has yet found a full and successful answer. The University of Geneva study, though, offers a new potential pathway to answering question 2.
The Set Up
The researchers wanted to look at part 2 of the problem of Type 1 diabetes– regenerating β-cells– without complicating their study with having to address part 1 simultaneously. If they worked with diabetic mice, they would have to stop the aggression of the immune system before they could really look at what was happening to the β-cells. So, instead of looking at diabetic mice, they decided to look at normal mice in which the researchers themselves killed off the β-cells; this would allow them to closely control how many β-cells existed, and how many could be generated under various different conditions.
The researchers, therefore, genetically engineered mice with special diphtheria toxin receptor gene. Mice are normally relatively resistant to diphtheria, but this gene was specially designed to build a receptor for the toxin only in β-cells in the mouse pancreas. In other words, when a mouse was injected with diphtheria toxin, most of its body would resist and be left unharmed, but the pancreatic β-cells would react to the toxin and die off.
As a result, the researchers had a unique version of Type 1 diabetic mice, in which there was no insulin production, but, should new β-cells be created, there was also no angry immune-system threatening to kill the new cells. Immediately after diphtheria was injected, the mice had all the symptoms of diabetes, including high blood glucose levels and ketoacidosis; if left untreated and without insulin, the mice died. In order to keep the mice alive for the longer-term experiments (up to ten months), the scientists injected insulin into the mice whenever their blood glucose rose above a sustainable level.