Stemming diabetes

Stemming diabetes

The much discussed stem cell research could mark a shift from insulin injections to injectable beta cell vials creating a certain permanency in the treatment of diabetes. However, lot of intricacies need to be dealt with prior to that. Vanessa Mahapatra finds out the promise these miraculous cells hold.

The nuances of stem cells have intrigued researchers for four decades now. If developed for diabetes, genetically manipulated stem cells could be the ultimate answer to the issue of auto-immunity and rejection, which is characteristic of pancreatic or islet cell transplants and to some extent even insulin replacement therapy. Furthermore, if administered at a premature stage of diabetes or at an early age, it can reverse all complications associated with it. “Stem cells entail a lot of hope for diabetic children as these potent cells can turn out to be a permanent cure for them,” believes Dr H B Chandalia, Diabetologist, Jaslok, Lilavati and Breach Candy Hospitals.

What’s in it?

The industry is abuzz with a conundrum of new drugs being churned out. However, there are some obvious gaps in the existing treatments that have led researchers to look to novel and absolute approaches, like stem cells. Stem cells have a greater role to play in diabetes treatment as it is (type I) an auto-immune disease. Some recent forms of treatment like islet cells transplant and pancreas transplant face immunity dilemmas wherein a diabetic rejects the insulin taken by the body. In such a case, it becomes mandatory for the patient to regularly consume immunosuppressants leaving very less chances of a normal lifestyle for the patient. “The treatments are cumbersome at the cost of time, effort and expense,” says Chandalia. Medical fraternity has since long felt a strong need to look for superior and more permanent solutions. Stem cells therapy seems to be the next ray of hope for most researchers now because of the promise it holds in terms of nullifying the basic problem behind the auto-immunity of type of diabetes. Stem cells could be fed into the body’s general insulin producing mechanism so as to culture, reproduce and differentiate into the desired beta cells in-vivo. This would render permanency to the solution, as the injected cells would produce insulin in a normal fashion. On the other hand, they could be cultured in- vitro and be administered to the patient as beta cells through the veins in the belly to be deposited in the liver or the pancreas where insulin production as per normal circumstances will ensue. Beta cells would act as a substitute to insulin itself and the solution would be a prolonged one yet not permanent. In such a case, the patient will have to be given regular doses of beta cells once in six to eight months, notifies Chandalia. He adds, “If beta cells are developed and cultured from stem cells, then one can produce an expanded supply of beta cells and for all you know, you can have vials with beta cells in them. So instead of administering insulin, we could have injections or vials with beta cells.”

A recent finding has provided the most sought for answer in diabetic stem cell research. Many researchers have reported that islet cells can be found intermingled with the pancreatic ductal cells during foetal development and that these stem cells give rise to new endocrine cells even as the foetus develops into an adult. This important discovery has opened several doors in stem cell research for diabetes. Firstly, since these cells could be found in a diabetic’s pancreatic ducts, they may eliminate the issue of autoimmunity and rejection. Secondly, they do not require any kind of stimulation to replicate into the desired beta cells. Chandalia says, “These are local cells which will only grow into beta cells. For instance, in bone marrow transplant, stem cells from bone marrow are transplanted into the body to grow into bone marrow cells and it is a permanent solution. So these localised stem cells have the potential of doing what you want them to do. Otherwise, if you pick up cells from elsewhere, you have to train the cell with different stimuli to differentiate into whatever cell type you want.”

Cracking the code

However, the ongoing research has led to a labyrinth with several blind ends that present a host of scientific challenges. Exact pathways that embryonic stem cells take to become pancreatic cells in humans are yet to be identified. “The initial experiments are to find out whether it is even possible to culture stem cells outside the body and see whether they can be developed into pancreatic cell types,” says Dr Hema Ramaswamy, Consultant, Belife Bio-Sciences. Until now, most of the assumptions and propositions are based on the research that has been conducted on animals. Scientists have identified specific growth inhibitors that induce mouse embryonic stem cells to adopt various characteristics of pancreatic islet cells in-vitro, including insulin production, glucose-dependent insulin release and formation of islet-like aggregates.

Furthermore, scientists are looking at factors that cause the beta cells to be wiped out within the human body and hence, working towards the prevention of apoptosis and auto-immunity. Researchers believe that identification of these factors would lead to the development of a counter mechanism that would sustain beta cells within the endocrine system. The answer lies in engineered cells, which can be made invisible to the body’s defence mechanism. “We are trying to develop stem cells which would be genetically engineered, so they are immunologically silent. These cannot be recognised by the immune mechanism,” notifies Chandalia. In such a case the possibility the immuno-suppressants intake would be nullified. He adds, “Ultimately you need to grow the cells. Therefore, you need to identify one of the factors that would make them grow, multiply, remain healthy, be responsive to sugar and secrete the required amount of insulin.”

Nonetheless, the stimulation of cells is a very sensitive issue as, an external growth factor if carried a little further can amount to teratogenesis or cancer formation, informs Chandalia. The multiplication of cells could also rouse the formation of teratomas, tumours that are caused by very early and uncontrolled differentiation of cells. Clinical trials on animals have reported cases of embryonic stem cells forming teratomas. Scientists have inferred that even in humans there could be a distinct danger of tumour formation by uncontrolled proliferation. Furthermore, it has been observed that cells derived from foetuses are pluripotent and naturally have tumour forming potential. “Stem cells injected into the blood stream could possibly get lost in some other tissue and start producing teratomas,” comments Ramaswamy, further adding, “It is a boon that embryonic stem cells can divide without any limits and keep producing different types of tissues but at the same time, it is a curse because they may lodge somewhere else into the body and turn into tumours.”

Through animal trials, it has been observed that the interaction of a beta cell with the other cells in the cluster (islet of langerhans) has to be taken into account in order to study its reaction. Thus, researchers are looking at establishing the response of beta cells vis-à-vis other islet cells. Some studies indicate that isolated beta cells, those cultured in the absence of other islet cell types, alpha and delta cells, are less responsive to changes in glucose concentration than intact islet clusters.

Apart from this, the identification of cell lines is another area of study. Chandalia explains, “You have to pickup a line of cells from these stem cells, that line which can produce beta cells. Otherwise you may take 100 cells but may be only one of them becomes a beta cell. So you have to either identify a cell line that will specifically differentiate into beta cells or find a stimulus to enable the differentiation,” he adds. Once the cell line is identified, it has to be extracted, cultured in a laboratory and replicated to generate an expanded supply.

Whats in the market?
Diabetes treatment has been on the verge of evolution over the past decade. So far, diabetes treatment has been a combination of diet, exercise and oral medication, usually a sulfonylurea (drugs that stimulate the pancreas to make more insulin) or biguanide (agents that decrease the amount of glucose produced by the liver like Metformin) to keep blood sugar levels at the normal level for type II diabetics. The treatment of type I diabetes almost always involves the daily injection of insulin, usually a combination of short-acting insulin such as regular or Lispro or Asparat insulin and longer acting insulin such as NPH, lente, glargine, detemir, or ultralente insulins. The methods of insulin delivery include insulin pens, insulin jet injectors and insulin pumps.

Final destination

From beta cell vials to beta cell injections to stem cell replacement surgery, there are multiple options that can be invested upon. Chandalia points out, “At the moment, we are still grappling with two ideas—beta cells through stem cells or stem cells directly put in the liver or anywhere in the body where they can replicate,” answers Chandalia.

Nevertheless, both the theories are suppositions that subject to trial. Whether these therapies would furthermore eliminate or reverse the damages done to a diabetic’s body is still a guessing game. “If you are diabetic for 20 years, you have already developed some tissue damage. Some of these may reverse and some of these may not. But in a child who develops diabetes and is transplanted with stem cells in a year or two, maybe completely cured,” remarks Chandalia. These statements can only be observed and established after proper human trials. Ramaswamy informs that scientists are employing the trial and error method for identifying growth factors but there are no valid, conclusive reports so far. She further adds that, “A lot of work is being done on animal stem cells but how much of it would translate into human trials is something one has to wait and see.”

Ultimately, only authentic clinical trials can answer all the questions that this potentially rich area of research arises. “The opportunities are many but tremendous effort is required to develop something substantial,” notes Chandalia, adding that the progress is very slow. In India, Reliance Life Sciences and the Indian Council of Medical Research are working in the field of stem cells but no research is being done specifically for diabetes.

Although much basic research remains to be done, genetically engineered stem cells appear to have great therapeutic potential over other forms of medications, in that they avoid issues of immune rejection. Moreover, if administered at an early stage or at a young age, they could permanently cure diabetes ushering in a lifestyle free from customary needle pricks.