Beta-Cells Wanted! Looking For … Alpha-Cells.

Kyle M. Loh April 16, 2010 0

The devastating diseases of Type 1 and Type 2 diabetes are caused by perturbations in glucose metabolism homeostasis. Given the recent “diabetes epidemic” caused by increasing changes in Western lifestyle, the need for diabetes therapeutics is now more than ever. Here, we review novel and extraordinary potential therapies for diabetes that have been recently developed: reprogramming pancreatic cells to β-cells, differentiating stem cells into β-cells, and activating glucokinase.

Type 1 Diabetes is strongly believed to be caused by the autoimmune destruction of one’s own β-cells by one’s own immune system. β-cells are the only source of insulin (a hormone) in the human body — once they are destroyed, the body doesn’t have a source of insulin anymore. Decrease in blood insulin levels (hypoinsulinemia) leads to an inability for body cells to absorb the critical metabolic fuel glucose; this causes weakness and fatigue, and other, more serious symptoms, such as blindness, nerve damage, and even death. Currently, the treatment for Type 1 Diabetes is to periodically inject the patients with shots of insulin; this puts insulin into the bloodstream, the insulin that the destroyed β-cells would otherwise make. However, as one could imagine, this is a very transient and unsatisfactory treatment; because insulin doesn’t stay in the blood forever, diabetic patients must be injected with insulin once or more every day in order to maintain adequate insulin levels and glucose homeostasis.

Type 2 Diabetes is principally caused when body cells become “insulin resistant” — they can’t “hear” insulin too well anymore, and need higher levels of insulin in order to uptake glucose to feed themselves. Most drugs for Type 2 Diabetes (such as rosglitazone) are believed to act by reducing insulin resistance in these cells, thus allowing them to properly uptake glucose under normal insulin levels.

The first exciting recent finds for diabetes therapies was that other pancreatic cells can be “converted” (reprogrammed) into β-cells. When people are born, it’s thought that after development, they are given most of the β-cells that they’re going to have for the rest of their lives. There is evidence that shows that β-cells slowly replicate, but they don’t replicate too much. If you tamper with the set of β-cells you were born with, you’re in bad shape. Therefore, it was astonishing to find that you can make a lot of new β-cells — and not just through the replication of existing β-cells … but rather, that other pancreatic cell types can be directly turned into β-cells!

In 2008, Dr. Doug Melton (the Director of the Harvard Stem Cell Institute) published a Nature paper showing that when the genes MafA, Ngn3, and Pdx1 were experimentally overexpressed in pancreatic exocrine cells (cells that make digestive enzymes for your intestines), that the overexpression of these three genes could turn these exocrine cells into β-cells. This was a shocking result — the dogma that all scientists know is that stem cells make differentiated cells (which are good at doing certain body functions), and once these differentiated cells are made, they stay the way they are, efficiently doing a job for the body. It was unanticipated that differentiated cells can be turned into other differentiated cell types, especially since this was not accompanied by an intermediate re-conversion into a stem cell state. I had the pleasure of being able to read this manuscript prior to its publication during my internship in Dr. Melton’s laboratory.

Recently, in the beginning of April 2010, a group at the University of Geneva published in Nature that physiologically, cells normally directly reprogram to other cell types during the course of their jobs. The previous paper by Doug Melton’s laboratory had found that only under experimental conditions that exocrine cells could be reprogrammed to β-cells. This paper from Geneva showed that when β-cells are lost in the course of diabetes (in mice), that other pancreatic cells, known as α-cells, spontaneously reprogrammed themselves to β-cells in an attempt to restore β-cell numbers and to forestall diabetes. 

Together, these results provide a very interesting and novel strategy to treat Type 1 Diabetes. Don’t have enough β-cells? Don’t go through the trouble of transplanting more β-cells into these patients! Instead, just convert other cells in the patient’s pancreas into β-cells.

Alternatively, one could produce more β-cells in the laboratory to transplant them into the patient (a more difficult procedure, as it would probably involve a surgical procedure to transplant the β-cells into the diabetic patient). The idea underlying this approach is that in the laboratory, one can make human β-cells from stem cells. The process involves the differentiation of embryonic stem cells (stem cells that can make all cell types in the body) into β-cells.

From 2005 to 2008, the therapeutics corporation Novocell published a really paradigm-shifting set of papers in Nature Biotechnology showing a process where embryonic stem cells could be differentiated into β-cells through a logical, stepwise process. They showed that when these β-cells were transplanted into immunosuppressed diabetic mice, they could sufficiently restore β-cell numbers such that these mices’ diabetes was ameliorated. This shows that making β-cells in the lab for diabetic patients is an interesting therapeutic strategy … but immunosuppressing a human patient to accept these β-cells is obviously a big complication. Also, for Type 1 Diabetes patients, you can’t immunosuppress them for every single day for the rest of their lives. Once the immunosuppression is lifted, these patients’ autoimmune response will simply destroy the grafted β-cells like it destroyed the patient’s original β-cells. So there are still some challenges.

One of the biggest challenges in making β-cells from stem cells is the relative inefficiency of the process — in the original report, it was found that embryonic stem cells can be differentiated to β-cells in the laboratory at an efficiency of 0.7%! An idea is to use drugs (chemical compounds) to try to increase the efficiency of this process, in order to yield larger numbers of β-cells to transplant them into potential human patients. Shuibing Chen, from Dr. Melton’s laboratory, found that the efficiency of this β-cell differentiation process can be increased ten-fold if the cells are treated with a chemical compound, Indolactam V (this was published in Nature Chemical Biology). Gosia Borowiak, also from Dr. Melton’s lab, found the efficiency can be increased by four times again if another chemical compound (IDE1) is added; this result was published in Cell Stem Cell. Altogether, these findings show that β-cells can be produced in the lab with appreciable efficiency, though many challenges still remain in transplanting human diabetics with these β-cells.

The final series of findings involved Type 2 Diabetes. A unique subset of distinct forms of Type 2 Diabetes, known as “Maturity Onset of Diabetes in the Young” (MODY), is actually inherited and is caused by inherited genetic lesions of certain genes. MODY can be caused by a mutation in the glucokinase (Gck) gene. As biochemistry students know, glucokinase is the enzyme that mediates the first step of glucose metabolism. Ablating glucokinase activity means that β-cells can’t process glucose anymore — and thus, they don’t know how much glucose is around them and how much insulin to secrete. Consequently, mutations in Gck lead to inheritable Type 2 Diabetes in children.

A recent publication in the New England Journal of Medicine described a novel Gck mutation where the glucokinase enzyme, instead of becoming inactivated, becomes hyperactive. As anticipated, β-cells with this mutation thought there was glucose around them day and night and pumped out insulin all the time. Ironically, these abnormally high levels of insulin (hyperinsulinemia) were the exact opposite of what diabetics suffer from, which is abnormally low levels of blood insulin (hypoinsulinemia).

The interesting facet of this study was that glucokinase hyperactivity doesn’t just make β-cells churn out insulin all the time … it makes β-cells replicate as well! In the normal adult pancreas, β-cells hardly replicate at all. But in patients with glucokinase hyperactivity, 9% of β-cells were replicating! While this doesn’t seem like a lot, consider that over several weeks, months, or years, this means that these patients will end up with a TON more β-cells than normal humans.

This suggests that inducing β-cell replication by activating glucokinase is a great two-pronged strategy to treat diabetes: both by triggering them to secrete large amounts of insulin (due to percieved glucose) and also by making β-cells replicate! Probably the best part of this strategy is that drugs that activate glucokinase have already been developed. Roche, a pharmaceutical company, has developed a drug (RO-28-1675), that allosterically activates glucokinase. They published in Science that this glucokinase activator ameliorates diabetes in mice. It will be interesting to see if the same (or similar) drugs can similarly treat diabetes in human patients.

Here, we have reviewed three novel therapeutic strategies to combat the increasing threat of diabetes. Two strategies (direct reprogramming and stem cell differentiation) make new β-cells to replace lost β-cells. The third strategy (activating glucokinase) causes existing β-cells to pump out more glucose and to replicate. These therapeutic methods show promise to finally ameliorate diabetes in human patients.

Kyle M. Loh is a Rutgers senior who has been accepted to Stanford University School of Medicine. Correspondence should be addressed to: kyle.m.loh@gmail.com. Referenced scientific publications available upon request.

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