The University of New Mexico Best Student Essays

Diverse Approaches to Treating Type One Diabetes Mellitus: A Clinical Review of Various Treatments

Context: Several treatments explore the possibility of inhibiting or reversing type 1 diabetes. The extent to which these new treatments work in humans remains unknown.

Objective: To summarize evidence of various treatments for type 1 diabetes being explored today, compare their effectiveness and deficiencies, as well as suggesting future approaches.

Data Sources: All research articles available through the UNM Library database website.

Study Selection: All research articles containing the words “Type 1 diabetes,” “Treatment,” and “Cures.” Also, only research articles that contained the full text were eligible for use.

Data Extraction: All articles were read and information pertaining to treatments specifically for type 1 diabetes was extracted. Treatments were grouped into similar categories, explained, and discussed independently and collectively.

Data Synthesis: 14 articles were used, in which research on possible cures and treatments, as well as related experimentation, were discussed.

Conclusions: Current research data indicates the possibility of new treatments for type 1 diabetes. These procedures, however, have not surpassed mice or in vitro tests. For these reasons, all the reviewed experiments appear promising because they have only been successful in small-scale tests. It remains unknown how these treatments would affect humans, as well as the possible long-term risks associated with them. Moreover, it is not entirely understood how certain treatments work, which metabolic pathways they take, nor whether the efficacy of such treatment results directly from the observed reaction or through some other unknown means. Further experimentation is needed both at the small-scale and large-scale in order to evaluate these treatments as truly promising.

Key Words: Type 1 Diabetes, Cell Transplantation, Tyrosine Kinase Inhibitors, Multiple Daily Injections (MDI), Continuous Subcutaneous Insulin Infusion (CSII), NOD mice, Triple-Therapy Regime.

Introduction

The term “diabetes mellitus” refers to a group of diseases that affect how the body uses blood glucose, commonly called blood sugar. Glucose is vital to health because it is the main source of energy for the cells that make up muscles and tissues. It is the body’s main source of fuel. Having diabetes, no matter what type, means excess glucose in the blood, although the reasons may differ. Excess glucose can lead to serious health problems. Today’s most common treatments for type 1 diabetes include supplementation of insulin through injections or insulin pumps, which are sufficient enough to allow people with diabetes to live fairly normal lives. These approaches, however, merely alleviate its symptoms rather than treat the disease. More scientifically advanced, but also less common, are surgical procedures like islet and pancreas transplantation. Unfortunately, although both treatments target the cause of the disease—pancreatic cells failing to produce insulin—pancreas transplantation results in a fifty percent acceptance rate whereas islet cell transplantation requires two organ donors—something difficult to find.

This topic is highly important due to the increasing number of people, especially kids and adolescents, who develop type 1 diabetes at a very young age. Currently, the treatments seem to be very primitive—injecting the much-needed insulin to the body by means of multiple daily injections or insulin pumps. There needs to be a more substantial treatment that targets the heart of the problem—the insulin deficiency—instead of alleviating its symptoms. Diabetes is easily manageable, yet a simple lack of insulin can potentially result in death.

On a personal level, this topic is of high importance since my younger brother has type 1 diabetes, and I have seen him struggle and experience painful treatments for what seems like such a manageable disease. It appears that although he enjoys a very high level of freedom, the deficiency still prohibits him from living a “normal” childhood. A better treatment needs to be discovered—we’ve been treating this disease with a band-aid for decades.

In this article, I discuss the possible treatments and cures recently developed and tested for type 1 diabetes, their basic methodology and results, followed by a comparative analysis of each procedure and possible new pathways that could be explored. Although current pharmacologic approaches to the glycemic management of diabetes are improving steadily, they are still far from ideal. Nonetheless, current experimentation appears to bring us closer to finding a cure for this growing epidemic.

Cell Transplantation for Diabetes

One of the most explored treatments today consists of cell transplantation. It is composed primarily of vascularized pancreas transplantations, cell islet transplantations, xenografting, and other less common approaches (1).

In vascularized pancreas transplantations, surgical transplantation of a whole or even half a pancreas can cure diabetes in most cases. However, diabetic renal failure can be experienced and transplanting a kidney as well as the pancreas becomes necessary. Moreover, this is a major surgical procedure with the possibility of pancreatic digestive enzymes leaking inside the body, endangering the patient’s life (1). Nonetheless, although results are improving steadily, the incidence of diabetes is far greater than the ability to find suitable organs.

Islet cell transplantation refers to the transplantation of isolated islets—regions of the pancreas that contain its endocrine cells—from a donor pancreas into the patient. Nevertheless, collection of islets requires digestion by enzymes as well as mechanical chopping (2). This creates a problem because islets can be damaged in the process. In the best circumstances, about one-third of the total number of islets in a fairly well-preserved state suitable for transplantation are collected through this procedure (1). Sadly, twice that number is required to release a patient from the need for insulin injections.

Xeno-islet grafting is the transplantation of islets from one species to another. Since pig islets are potentially available in large numbers and can be extracted in a similar manner to that used for human islets, this approach has been a popular one for scientists. Moreover, pig insulin differs from human insulin by only one amino acid, so it would make sense to use islets from pigs. Despite this fact, humans and pigs differ greatly in the proteins produced by their respective cells, which could result in reactions destructive to the immune system following transplantation (3). The best solution here would be to find highly successful immunosuppressant drugs that do not put the patient in danger; however, these remain undiscovered. Additionally, there is worry that porcine endogenous retrovirus might cause disease in the patient (1). Genetic engineering of these cells by removing and adding specific genes might one day make pig cell islets more like those in humans, however, it cannot be predicted when this will occur.

Other approaches include large-scale culturing of β (beta) cells, but so far there has been a severe deficit in the number of β cells that can be produced in culture; this number is excessively under the required number for successful islet transplantation. Transdifferentation of liver cells into islet cells has also been explored, since the liver and pancreas develop from the same embryological origin (4). In vivo cultural growth of embryonic pancreas rudiments is a similar approach that has achieved considerable success, but as with any other medical procedure dealing with embryonic cells, there is an ethical issue with using fetal tissue: few people believe that using a fetus to treat a patient with diabetes is justifiable (5).

The last approach is to engineer undifferentiated or differentiated cells to act as “surrogate” β cells. This can be accomplished in three different ways: through embryonic stem cells, adult stem cells, and the transfection of adult cells with the human insulin gene (1).

The use of embryonic stem cells could be very successful, since embryonic stem cells can turn into every cell type in the body. Recent work has shown promising results using embryonic stem cells from mice that have the insulin gene inserted into them. Nonetheless, translating this procedure to humans will be more difficult due to the embryonic stem cells’ difficulty to grow in vitro (5). Additionally, if such procedure were done successfully, then it would be crucial to eliminate all the undifferentiated embryonic stem cells from the culture because of the possibility of these cells growing into teratomata once inside the body (1).

Using adult stem cells would most likely involve a similar, if not identical, procedure to the one just mentioned. Adult stem cells have been found in certain adult tissues and in umbilical cord blood. These cells have been shown to differentiate again under the right cultural conditions, and in an experiment, transplanted animals have been shown to retain normal glucose levels for as many as five days without immunosuppressant treatment (6). Despite these results, three main questions remain: Could enough cells be obtained from the diabetic patient? Would the islets be useful for a significant amount of time? Are the culturing procedures and chemicals used safe? (7).

Finally, transfecting adult cells with the human insulin gene has provided what appears to be encouraging experimental results using adult liver cells. This approach can use non-viral electroporition to introduce the insulin gene plasmid into cells in vitro or in vivo (6). Viral vectors could be used which are more effective, but these introduce the probability of oncogenes being introduced into the cells. Early clinical trials have led to modest clinical improvement, but there have been three major disasters as well: one in which the adeno virus proliferated with fatal consequences, and the other two cases in which the lente virus used unmasked nuclear oncogenes leading to leukemia (8). Despite this background, cultural techniques alone may not be sufficient and vector help may be needed. For this reason, current work using a modified herpes I virus as a vector for the human insulin gene is underway. There has been no evidence of disease in the six patients treated (with a follow-up of five years). Some of the theoretical advantages of using this virus are: Although the virus enters the nucleus, it does not integrate with the host DNA and is therefore not likely to unmask oncogenes; it functions separately from the host DNA as an episome; most patients have already had contact with the herpes I virus, which normally resides in an inactive state in neurological tissue; immune reaction against the virus is relatively mild; and finally, effective antiviral treatment against the herpes virus is widely available (1).

Experiments are currently trying to determine which cell or tissue is most appropriate for viral infection as well as whether the cells should be infected in vitro then inserted into the patient, or if the virus should be injected directly into the patient. Also, the lifespan of gene activity in the virus as well as the factors that may limit its proteins synthesis need to be understood in more depth (1). Large scale cell treatment of diabetes using these types of cell transplantation may still be far from being accomplished, but the mutual work of scientists in these discussed procedures may eventually lead to successful treatment in humans.

Intensive Insulin Therapy

Intensive insulin therapy refers to the two most common diabetic treatments for type 1 diabetes today – multiple daily injections (MDI) and continuous subcutaneous insulin infusion (CSII). According to data between 2002 and March of 2008, there exists evidence indicating that compared to MDI, CSII reduces HbA1c in adults with type 1 diabetes. The impact on hypoglycemia, however, is unclear (9). The extent of glycemic control achieved was determined by using the final HbA1c, a number used to calculate the amount of glycated hemoglobin in red blood cells when glucose is present—the higher the number, the higher the amount of glycated hemoglobin and the greater the risk of developing diabetes.

Results indicate that, in the fifteen trials used for the meta analysis, in patients with type 1 diabetes, CSII is associated with a slightly lower HbA1c, although the clinical significance behind this remains uncertain. No significant difference between hypoglycemia risk in adolescents and adults exists. Conversely, children with type 1 diabetes enrolled in parallel trials had a higher risk of minor hypoglycemia when treated with CSII. Use of insulin analogs in the MDI groups did not significantly alter hypoglycemia results either. Moreover, there was no association between HbA1c achieved and the magnitude of the benefit on glycemic control or on the risk of hypoglycemia (10).

Overall, there is a very small improvement on HbA1c using CSII over MDI, and they are not dramatically different in terms of efficacy and safety. There are, however, benefits as well as disadvantages when using both, which need to be considered; satisfaction of treatment, quality of life, cost, and burden of both treatments needs to be taken into consideration.

The use of insulin pumps poses significant challenges at different age groups, with each group requiring different levels of skill and training. Paying close attention to the varying needs of different age populations may safely bring the potential benefits of intensive insulin therapy to all patients with diabetes. Nonetheless, hypoglycemia is the main limitation to the efficacy of intensive insulin therapy in patients with diabetes.

As for the future, insulin pumps will continue to improve and be available to a larger number of patients. Currently, the most technologically advanced CSIIs are composed of an insulin pump and a wireless glucose sensor monitor that measures glucose levels in the blood in real time. The monitor sends this information to the pump, which in turn injects the patient with the appropriate dose of insulin, or warns the patients that his/her glucose levels are low. Personally I have seen my little brother enjoy a more “normal” life being under CSII, although it appears that his glucose levels are not as stable as they were when he was using MDI; this might simply be that he forgets about it, and it is not the pump at fault.

Blockage or Deficiency of Activating Receptors Found in Human Ligands on Pancreatic β Cells

The possibility of a new therapeutic treatment based on the blockage or deficiency of NKp46, an activating receptor found in mice and human ligands on pancreatic β cells is currently being researched. Experimental results showed that even though the function of natural killer (NK) cells is still unknown (11), mice that had NKp46 deficiencies had less development of type 1 diabetes induced by injection of a low dose of streptozotocin. By injecting non-obese diabetic mice with NKp46 either at an early stage of insulitis or the prediabetic stage, diabetic development was stopped almost completely. A medical treatment that blocks NKp46—possibly in the form of a vaccine—could be given during the “honeymoon” period and slow down or stop the destruction of β cells (12).

Researchers have found that although their function remains unknown, natural killer (NK) cells infiltrate the islets of the human pancreas (11). Moreover, the proportion of the NK cells, their numbers and the timing of their entry into the pancreas correlate with the severity of type 1 diabetes in NOD mice. Additionally, depletion of these NK cells inhibits the development of type 1 diabetes in these mice (12).

Injecting the mice with NKp46 proteins prevent type 1 diabetes when injected early; treatment initiated when mice are six weeks old successfully prevented diabetes for up to thirty-six weeks compared to the control group, in which eighty-nine percent of mice became diabetic. Additionally, a late injection of these NKp46 proteins during the late prediabetic stage reversed type 1 diabetes in NOD mice. Once injected at eleven to twelve weeks of age, NOD mice create antibodies against the injected proteins and remained free of disease six weeks after treatment ceased (at twenty weeks of age), suggesting that NKp46 therapy might be used to prevent the development of diabetes at the late prediabetic stage (12).

Based on these results, two possible pharmacological treatments exist to prevent disease: the first is a passive vaccination in which patients would be injected with anti-NKp46 to block NKp46 function. Still, even though this would bypass the need for the body to create NKp46 antibodies, the process would be time consuming, as rapid generation of antibodies for the injected anti-NKp46 would follow. The second option is to inject patients with NKp46 protein to the body, which would generate long-lasting NKp46 antibodies. Unfortunately, antibody generation takes time, and extra amounts of NKp46 in the system could potentially speed up the onset of the disease (12).

Short-Term “Triple-Therapy” Regimen

Exploring the possibility of a short-term “triple-therapy” regimen to cure type 1 diabetes in non-obese diabetic (NOD) mice has found promising results. This treatment halts auto-immune destruction of insulin-producing β cells and restores both euglycemia and immune tolerance to β cells. A fourteen or twenty-eight day dosage of the triple treatment restored an enduring euglycemic state in fifty-five of the sixty treated NOD mice. Even so, this does not lead to an increase in insulin or β cell mass, showing that relief from insulin resistance is essential in the restoration of glycemia induced by a successful therapy (13).

Injecting NOD mice with a triple-therapy regimen (RPM IL-2.1g mutIL15.1g) resulted in an achievement of euglycemia within five to seven weeks of treatment and maintained throughout a follow-up period of more than 300 days. Moreover, this triple therapy halts auto-immunity and induces specific immune tolerance to β cells in NOD mice with new-onset type 1 diabetes (13).

Using the treatment also allowed for inhibition of insulin resistance in NOD mice, and restored in vivo insulin signaling as well. Using RT-PCR, a “targeted transcriptional profile for specific inflammation-associated gene expression within muscle and fat—key tissues for insulin-driven disposal of glucose—significantly reduced inflammation within pancreatic lymph nodes, and euglycemic levels were restored much faster” (13). This is due to inflammation within insulin-sensitive tissue obstructing insulin responsiveness and insulin signaling.

The results indicate that relief from insulin resistance is a critical factor in the restoration of euglycemia induced by therapy. Furthermore, unless insulin-induced resistance and faulty insulin signaling are restored, immune system-targeted therapies like this one will most likely fail.

Receptor Tyrosine Kinase Inhibitors

A separate study demonstrated that treating NOD mice with imatinib, an anti-cancer drug used to treat patients with CML and other tumors, prevented and reversed the development of autoimmune diabetes in the mice. Also, limiting treatment to eight to ten weeks after disease onset was enough to reverse diabetes and induce long-term remission consistent with reestablishment of tolerance in these NOD mice, providing evidence that this kinase inhibitor or other similar drugs can provide what appears to be a promising treatment of type 1 diabetes as well as other auto-immune diseases (14).

NOD mice were given Gleevec, a tyrosine kinase inhibitor, starting at twelve weeks of age on a daily basis. As expected, none of the treated mice developed diabetes, compared to about forty percent that did in the control group. Next, experiments were performed in order to see if imatinib could reverse type 1 diabetes in NOD mice; after only one week of treatment after onset of diabetes, about forty percent of the treated mice showed no signs of diabetes, and after two weeks of treatment, remission was observed in approximately eighty percent of the mice. Next it was tested to see whether remission continues after cessation of treatment. After receiving treatment for ten weeks, NOD mice showed long-lasting diabetes remission (14). Unfortunately, it was noted that leukocyte infiltration still occurs in the pancreas, indicating that while imatinib prevents disease, it does not completely eliminate leukocyte infiltration of the pancreas.

In summary, it was noted that tyrosine kinase inhibitors such as imatinib may prove to be an efficient way to treat type 1 diabetes, while having the unexpected result of long-term remission even after cessation of short treatment (about ten weeks) without the need of continuous follow-ups.

Discussion

From the reviewed research experiments, the most promising appear to be the treatments that focus on blocking specific ligands on pancreating β cells, more specifically, tyrosine kinase receptors and NKp46. This is due to the treatments’ efficacy at inhibiting and even reversing type 1 diabetes, as well as the additional benefit of long-term remission after ceasing treatment. Moreover, they treat the cause of the deficiency itself, not just alleviate its symptoms, and also do not require the use of stem cells of any sort, which will always be accompanied by ethical issues.

As with intensive insulin therapy, it has been a dead end from the beginning; these treatments merely alleviate diabetes symptoms, which means patients will always be dependent on them despite how well they control their individual glucose levels. Even so, with CSII’s improving technology as well as increasing affordability, this treatment will at the very least give patients with diabetes a better control over their glucose levels, as well as reduce pain and burden of treatment while increasing quality of life.

Current research data indicates the possibility of new treatments for type 1 diabetes. The discussed procedures, however, have not surpassed mice or in vitro tests. For these reasons, all the reviewed experiments appear promising because they have only been successful in small-scale tests. It remains unknown how these treatments would affect humans, as well as the possible long-term risks associated with them. Moreover, it is not entirely understood how certain treatments work, which metabolic pathways they take, nor whether the efficacy of such treatment results directly from the observed reaction or through some other unknown means. Further experimentation is needed both at the small-scale and large-scale in order to evaluate these treatments as true potential treatments.

References

1. Calne, R (2005) Cell transplantation for diabetes. Philosophical Transactions: Biological Sciences 360: 1769–1774.

2. Shapiro A-M, et al. (2000) Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N. Engl. J. Med 243: 230–238.

3. Dekel B, et al. (2003) Human and porcine early kidney precursors as a new source for transplantation. Nat. Med 9: 55–60.

4. Ber I, et al. (2003) Functional, persistent and extended liver to pancreas transdifferentiation. J. Biol. Chem. 278: 31950–31957.

5. Castaing M, et al. (2001) Blood glucose normalization upon transplantation of human embryonic pancreas into beta-cell-deficient SCID mice. Diabetologia 44: 2066–2076.

6. Colman A (2004) Making new beta cells from stem cells. Semin. Cell Dev. Bio: 337–345.

7. Dor Y, Brown J, Martinez O-I, Melton D-A (2004) Adult pancreatic β-cells are formed by self-duplication rather than stem cell differentiation. Nature 429: 41–46.

8. Marshall E (1999) Gene therapy death prompts review of adenovirus vector. Science 286: 2244–2245.

9. Retnakaran R, et al. (2004)Continuous subcutaneous insulin infusion versus multiple daily injections: The impact of baseline A1c. Diabetes Care 27: 2590–2596.

10. Fatourechi M-M, et al. (2009) Hypoglycemia with intensive insulin therapy: A systematic review and meta-analyses of randomized trials of continuous subcutaneous insulin infusion versus multiple daily injections. Journal of Clinical Endocrinology & Metabolism 94: 729–740.

11. Chamuta G, et al. (2010) The activating receptor NKp46 is essential for the development of type 1 diabetes. Nature Immunology 11: 121–129.

12. Alba A, et al. (2008) Natural killer cells are required for accelerated type 1 diabetes driven by interferon-β. Immunology 151: 467–475.

13. Koulmanda M, et al. (2007) Modification of adverse inflammation is required to cure new-onset type 1 diabetic hosts. Proceedings of The National Academy of Sciences of the United States of America 104: 13074–13079.

14. Louvet C, et al. (2008) Tyrosine kinase inhibitors reverse type 1 diabetes in nonobese diabetic mice. Proceedings of the National Academy of Sciences of the United States of America 105: 18895–18900.

Added March 31, 2011

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Nominated by Dr. Ursula Shepherd,
UHON 222, Road to Discovery:

“Cesar completed this work as a freshman. It is outstanding as an example of a well-formulated study/review of the field and currently available literature. It was completed using the professional model for a scientific review paper and epitomizes this form. Excellent work. The first part details the requirements of the journal followed.”


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