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Type 1 diabetes

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Type 1 diabetes
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Diabetes mellitus type 1 (type I diabetes, T1D, T1DM, IDDM, juvenile diabetes) is a form of diabetes mellitus. Type 1 diabetes is an autoimmune disease [1] that results in destruction of insulin-producing beta cells of the pancreas. Lack of insulin causes an increase of fasting blood glucose (around 70-120 mg/dL in nondiabetic people) that begins to appear in the urine above the renal threshold (about 190-200 mg/dl in most people), thus connecting to the symptom by which the disease was identified in antiquity, sweet urine. Glycosuria or glucose in the urine causes the patients to urinate more frequently, and drink more than normal (polydipsia). Classically, these were the characteristic symptoms which prompted discovery of the disease.

Type 1 is lethal unless treated with exogenous insulin. Injection is the traditional and still most common method for administering insulin; jet injection, indwelling catheters, and inhaled insulin has also been available at various times, and there are several experimental methods as well. All replace the missing hormone formerly produced by the now non-functional beta cells in the pancreas. In recent years, pancreas transplants have also been used to treat type 1 diabetes. Islet cell transplant is also being investigated and has been achieved in mice and rats, and in experimental trials in humans as well[2]. Use of stem cells to produce a new population of functioning beta cells seems to be a future possibility, but has yet to be demonstrated even in laboratories as of 2008.

Type 1 diabetes (formerly known as "childhood", "juvenile" or "insulin-dependent" diabetes) is not exclusively a childhood problem; the adult incidence of type 1 is noteworthy — many adults who contract type 1 diabetes are misdiagnosed with type 2 due to confusion on this point.

There is currently no clinically useful preventive measure against developing type 1 diabetes, though a vaccine has been proposed and anti-antibody approaches are also being investigated. Most people who develop type 1 were otherwise healthy and of a healthy weight on onset, but they can lose weight quickly and dangerously, if not promptly diagnosed. Although the cause of type 1 diabetes is still not fully understood, and diet and exercise may help, the immune system damage is characteristic of type 1.

The most definite laboratory test to distinguish type 1 from type 2 diabetes is the C-peptide assay, which is a measure of endogenous insulin production since external insulin has not (to date) included C-peptide. The presence of anti-islet antibodies (to Glutamic Acid Decarboxylase, Insulinoma Associated Peptide-2 or insulin), or lack of insulin resistance, determined by a glucose tolerance test, would also be suggestive of type 1. Many type 2 diabetics continue to produce insulin internally, and all have some degree of insulin resistance.

Testing for GAD 65 antibodies has been proposed as an improved test for differentiating between type 1 and type 2 diabetes as it appears that the immune system malfunction is connected with their presence.

Pathophysiology

The cause of type 1 diabetes is still not fully understood. Some theorize that type 1 diabetes is generally a virally triggered autoimmune response in which the immune system's attack on virus infected cells is also directed against the beta cells in the pancreas. The autoimmune attack may be triggered by reaction to an infection, for example by one of the viruses of the Coxsackie virus family or German measles, although the evidence is inconclusive. In type 1, pancreatic beta cells in the Islets of Langerhans are destroyed or damaged sufficiently to effectively abolish endogenous insulin production. This etiology distinguishes type 1's origin from type 2. It should also be noted that the use of insulin in treating a patient does not mean that patient has type 1 diabetes; the type of diabetes a patient has is determined only by the cause -- fundamentally by whether the patient is insulin resistant (type 2) or insulin deficient without insulin resistance (type 1).

This vulnerability is not shared by everyone, for not everyone infected by the suspected organisms develops type 1 diabetes. This has suggested presence of a genetic vulnerability[3] and there is indeed an observed inherited tendency to develop type 1. It has been traced to particular HLA genotypes, though the connection between them and the triggering of an auto-immune reaction is still poorly understood.

Some researchers believe that the autoimmune response is influenced by antibodies against cow's milk proteins.[4] A large retrospective controlled study published in 2006 strongly suggests that infants who were never breastfed had a risk for developing type 1 diabetes twice that of infants who were breastfed for at least three months.[citation needed] The mechanism is not fully understood. No connection has been established between autoantibodies, antibodies to cow's milk proteins, and type 1 diabetes. A subtype of type 1 (identifiable by the presence of antibodies against beta cells) typically develops slowly and so is often confused with type 2. In addition, a small proportion of type 1 cases have the hereditary condition maturity onset diabetes of the young (MODY) which can also be confused with type 2.

Vitamin D in doses of 2000 IU per day given during the first year of a child's life has been connected in one study in Northern Finland (where intrinsic production of Vitamin D is low due to low natural light levels) with an 80% reduction in the risk of getting type 1 diabetes later in life. The causal connection, if any, is obscure.

Some suggest that deficiency of Vitamin D3 (one of several related chemicals with Vitamin D activity) may be an important pathogenic factor in type 1 diabetes independent of geographical latitude, and so of available sun intensity.[citation needed]

Some chemicals and drugs preferentially destroy pancreatic cells. Vacor (N-3-pyridylmethyl-N'-p-nitrophenyl urea), a rodenticide introduced in the United States in 1976, selectively destroys pancreatic beta cells, resulting in type 1 diabetes after accidental or intentional ingestion. Vacor was withdrawn from the U.S. market in 1979, but is still used in some countries. Zanosar is the trade name for streptozotocin, an antibiotic and antineoplastic agent used in chemotherapy for pancreatic cancer; it also kills beta cells, resulting in loss of insulin production. Other pancreatic problems, including trauma, pancreatitis or tumors (either malignant or benign), can also lead to loss of insulin production.

The exact cause(s) of type 1 diabetes are not yet fully understood, and research on those mentioned, and others, continues.

In December 2006, researchers from Toronto Hospital for Sick Children published research that shows a link between type 1 diabetes and the immune and nervous system. Using mice, the researchers discovered that a control circuit exists between insulin-producing cells and their associated sensory (pain-related) nerves.[5] It's being suggested that faulty nerves in the pancreas could be a cause of type 1 diabetes.[citation needed]

Inheritance

Type 1 Diabetes is a polygenic disease, meaning many different genes contribute to its expression. Depending on locus or combination of loci, it can be dominant, recessive, or somewhere in between. The strongest gene, IDDM1, is located in the MHC Class II region on chromosome 6, at staining region 6p21. This is believed to be responsible for the histocompatibility disorder characteristic of type 1: Insulin-producing pancreas cells (beta cells) display improper antigens to T Cells. This eventually leads to the production of antibodies that attack these beta cells. Weaker genes are also located on chromosomes 11 and 18.

Environmental factors can strongly influence expression of type 1. A study showed that for identical twins, when one twin had type 1 diabetes, the other twin only had type 1 30-50% of the time. Despite having the exact same genome, one twin had the disease, where the other did not; this shows that environmental factors, in addition to genetic factors, can influence disease prevalence. [6]

Treatment

Main article: Diabetes management

Type 1 is treated with insulin replacement therapy — usually by insulin injection or insulin pump, along with attention to dietary management, typically including carbohydrate tracking, and careful monitoring of blood glucose levels using Glucose meters. Today the most common insulins are produced using genetic recombination techniques; formerly, cattle or pig insulins were used, and even sometimes insulin from fish. Major suppliers include Eli Lilly and Company, Novo-Nordisk, and Sanofi-Aventis. A more recent trend, from several suppliers, is insulin analogs which are slightly modified insulins which have different onset of action times or duration of action times.

Untreated type 1 diabetes commonly leads to coma, often from diabetic ketoacidosis, which is fatal if untreated. At present, insulin treatment must be continued for life; this may perhaps change if better treatment, or a cure, becomes clinically available. Continuous glucose monitors have been developed and marketed which can alert patients to the presence of dangerously high or low blood sugar levels, but the general lack of widespread insurance coverage (certainly in the US) and technical limitations has limited the impact these devices have had on clinical practice so far.

In more extreme cases, a pancreas transplant can restore proper glucose regulation. However, the surgery and accompanying immunosuppression required is considered by many physicians to be more dangerous than continued insulin replacement therapy, and is therefore often used only as a last resort (such as when a kidney must also be transplanted, or in cases where the patient's blood glucose levels are extremely volatile). Experimental replacement of beta cells (by transplant or from stem cells) is being investigated in several research programs and may become clinically available in the future. Thus far, beta cell replacement has only been performed on patients over age 18, and with tantalizing successes amidst nearly universal failure.

Pancreas transplantation

Main article: Pancreas transplantation

Pancreas transplants are generally performed together with or some time after a kidney transplant. One reason for this is that introducing a new kidney requires taking immunosuppressive drugs anyway, and this allows the introduction of a new, functioning pancreas to a patient with diabetes without any additional immunosuppressive therapy. However, pancreas transplants alone can be wise in patients with extremely labile type 1 diabetes mellitus.[7]

Islet cell transplantation

Main article: Islet cell transplantation

Islet cell transplantation is expected to be less invasive than a pancreas transplant which is currently the most commonly used approach in humans.

In one variant of this procedure, islet cells are injected into the patient's liver, where they take up residence and begin to produce insulin. The liver is expected to be the most reasonable choice because it is more accessible than the pancreas, and islet cells seem to produce insulin well in that environment. The patient's body, however, will treat the new cells just as it would any other introduction of foreign tissue, unless a method is developed to produce them from the patient's own stem cells or there is an identical twin available who can donate stem cells. The immune system will attack the cells as it would a bacterial infection or a skin graft. Thus, patients now also need to undergo treatment involving immunosuppressants, which reduce immune system activity.

Recent studies have shown that islet cell transplants have progressed to the point that 58% of the patients in one study were insulin independent one year after islet cell transplant.[8] Ideally, it would be best to use islet cells which will not provoke this immune reaction, but scientists in New Zealand are also looking into placing them within a protective housing derived of sea-weed which enables insulin to flow out and nutrients to flow in while protecting the islets from immune system attack via white blood cells.

Prevalence

It is estimated that about 5%–10% of North American diabetes patients have type 1. The fraction of type 1 in other parts of the world differs; this is likely due to both differences in the rate of type 1 and differences in the rate of other types, most prominently type 2. Most of this difference is not currently understood. Variable criteria for categorizing diabetes types may play a part. Some notable people with type 1 are American football quarterback Jay Cutler, swimmer Gary Hall, Jr. and American singer Nick Jonas.

Research foundations

The Juvenile Diabetes Research Foundation (JDRF) is the major charitable organization in the USA, Canada and Australia devoted to type 1 diabetes research. JDRF's mission is to cure type 1 diabetes and its complications through the support of research. Since its founding in 1970, JDRF has contributed more than $1.3 billion to diabetes research, including more than $156 million in FY 2008. In FY 2008, the Foundation funded 1,000 centers, grants and fellowships in 22 countries. In November 2008 JDRF launched a new online social network for people with type 1 diabetes--*Juvenation.

The International Diabetes Federation is a worldwide alliance of over 160 countries to address diabetes research and treatment. The American Diabetes Association funds some work on type 1 but devotes much of its resources to type 2 diabetes due to the increasing prevalence of the latter type. Diabetes Australia is involved in promoting research and education in Australia on both type 1 and type 2 diabetes. The Canadian Diabetes Association is also involved in educating, researching, and sustaining sufferers of type 1 Diabetics in Canada. Pacific Northwest Diabetes Research Institute conducts clinical and basic research on type 1 and type 2 diabetes.

Cure

As of 2009, there is no known cure for diabetes mellitus type 1 in modern clinical use. Pancreas transplant is not practical (too few are available, and pancreas transplant is technically difficult. The requirement for immuno-suppressive drugs contributes to the unsatisfactory nature of pancreas transplant as a cure). Nor is a cure known from any other source including traditional or alternative medical practice. There is ongoing research on various approaches to curing diabetes type 1.

Diabetes type 1 is caused by the destruction of enough beta cells to produce symptoms; these cells, which are found in the Islets of Langerhans in the pancreas, produce and secrete insulin, the single hormone responsible for allowing glucose to enter from the blood into cells (in addition to the hormone amylin, another hormone required for glucose homeostasis). Hence, the phrase "curing diabetes type 1" means "causing a maintenance or restoration of the endogenous ability of the body to produce insulin in response to the level of blood glucose" and cooperative operation with counterregulatory hormones.

This section deals only with approaches for curing the underlying condition of diabetes type 1, by enabling the body to endogenously, in vivo, produce insulin in response to the level of blood glucose. It does not cover other approaches, such as, for instance, closed-loop integrated glucometer/insulin pump products, which could potentially increase the quality-of-life for some who have diabetes type 1, and may by some be termed "artificial pancreas".

Reversion

Encapsulation approach

The Bio-artificial pancreas: a cross section of bio-engineered tissue with encapsulated islet cells delivering endocrine hormones in response to glucose

A biological approach to the artificial pancreas is to implant bioengineered tissue containing islet cells, which would secrete the amounts of insulin, amylin and glucagon needed in response to sensed glucose.

When islet cells have been transplanted via the Edmonton protocol, insulin production (and glycemic control) was restored, but at the expense of continued immunosuppression drugs. Encapsulation of the islet cells in a protective coating has been developed to block the immune response to transplanted cells, which relieves the burden of immunosuppression and benefits the longevity of the transplant.[9]

One concept of the bio-artificial pancreas uses encapsulated islet cells to build an islet sheet which can be surgically implanted to function as an artificial pancreas.[10]

This islet sheet design consists of:

  • an inner mesh of fibers to provide strength for the islet sheet;
  • islet cells, encapsulated to avoid triggering a proliferating immune response, adhered to the mesh fibers;
  • a semi-permeable protective layer around the sheet, to allow the diffusion of nutrients and secreted hormones;
  • a protective coating, to prevent a foreign body response resulting in a fibrotic reaction which walls off the sheet and causes failure of the islet cells.

Islet sheet with encapsulation research is pressing forward with large animal studies at the present, with plans for human clinical trials within a few years.

Clinical studies underway in New Zealand by Living Cell Technologies have encapsulated pig islet cells in a sea-weed derived capsule. This approach has had very positive clinical studies and is currently underway in human trials as of 2008. So far, treatment using this method of cell encapsulation has been proven safe and effective and is the first to achieve insulin independence in human trials without immunosupressant drugs.[11]

Islet cell regeneration approach

Research undertaken at the Massachusetts General Hospital between 2001 and 2003 demonstrated a protocol to reverse type 1 diabetes in non-obese diabetic mice (a frequently used animal model for type 1 diabetes mellitus).[12] Three other institutions have had similar results, as published in the March 24, 2006 issue of Science. A fourth study by the National Institutes of Health achieved similar results, and also sheds light on the biological mechanisms involved.[13]

Other researchers, most notably Dr. Aaron I. Vinik of the Strelitz Diabetes Research Institute of Eastern Virginia Medical School and a former colleague, Dr. Lawrence Rosenberg (now at McGill University) discovered in a protein they refer to as INGAP, which stands for Islet Neogenesis Associated Protein back in 1997. INGAP seems to be the product of a gene responsible for regenerating the islets that make insulin and other important hormones in the pancreas.

INGAP has had commercialization difficulties. Although it has appeared promising, commercial rights have changed hands repeatedly, having once been owned by Procter & Gamble Pharmaceuticals, which eventually dropped it. Rights were then acquired by GMP Companies. More recently, Kinexum Metabolics, Inc. has since sublicensed INGAP from GMP for further clinical trials. Kinexum has continued development under Dr. G. Alexander Fleming, an experienced metabolic drug developer, who headed diabetes drug review at the FDA for over a decade. As of 2008, the protein had undergone Phase 2 Human Clinical Trials, and developers were analyzing the results. At the American Diabetes Association's 68th Annual Scientific Sessions in San Francisco, Kinexum announced a Phase 2 human clinical trial with a combination therapy, consisting of DiaKine's Lisofylline (LSF) and Kinexum's INGAP peptide, which is expected to begin in late 2008.[14] The trial will be unique in that patients who are beyond the 'newly diagnosed' period will be included in the study. Most current trials seeking to treat people with type 1 diabetes do not include those with established disease.

Stem cells approach

Research is being done at several locations in which islet cells are developed from stem cells.

South Korea

In January 2006, a team of South Korean scientists has grown pancreatic beta cells, which can help treat diabetes, from stem cells taken from the umbilical cord blood of newborn babies.

Brazil

In April 2007, it was reported by the Times Online that 15 young Brazilian patients diagnosed with type 1 diabetes were able to naturally produce insulin once again after undergoing mild chemotherapy to temporarily weaken their immune systems and then injection of their own stem cells. This allowed the pancreatic beta cells to produce insulin. Since white blood cells were blocking the pancreas from producing insulin, Dr. Voltarelli and colleagues killed the immune cells, allowing the pancreas to secrete insulin once more.[15]

However, there were no control subjects, which means that all of the processes could have been completely or partially natural. Secondly, no theory for the mechanism of cure has been promoted. It is too early to say whether the results will be positive or negative in the long run.[16]

University of North Carolina

In September 2008, scientists from the University of North Carolina at Chapel Hill School of Medicine have announced their success in transforming cells from human skin into cells that produce insulin.[17]

The skin cells were first transformed into stem cells and then had been differentiated into insulin-secreting cells.[18]

However, other scientists have doubts, as the research papers fail to detail the new cells' glucose responsiveness and the amount of insulin they are capable of producing.

Gene therapy approach

Gene therapy: Designing a viral vector to deliberately infect cells with DNA to carry on the viral production of insulin in response to the blood sugar level.

Technology for gene therapy is advancing rapidly such that there are multiple pathways possible to support endocrine function, with potential to practically cure diabetes.[19]

  • Gene therapy can be used to manufacture insulin directly: an oral medication, consisting of viral vectors containing the insulin sequence, is digested and delivers its genes to the upper intestines. Those intestinal cells will then behave like any viral infected cell, and will reproduce the insulin protein. The virus can be controlled to infect only the cells which respond to the presence of glucose, such that insulin is produced only in the presence of high glucose levels. Due to the limited numbers of vectors delivered, very few intestinal cells would actually be impacted and would die off naturally in a few days. Therefore by varying the amount of oral medication used, the amount of insulin created by gene therapy can be increased or decreased as needed. As the insulin producing intestinal cells die off, they are boosted by additional oral medications.[20]
  • Gene therapy might eventually be used to cure the cause of beta cell destruction, thereby curing the new diabetes patient before the beta cell destruction is complete and irreversible.[21]
  • Gene therapy can be used to turn duodenum cells and duodenum adult stem cells into beta cells which produce insulin and amylin naturally. By delivering beta cell DNA to the intestine cells in the duodenum, a few intestine cells will turn into beta cells, and subsequently adult stem cells will develop into beta cells. This makes the supply of beta cells in the duodenum self replenishing, and the beta cells will produce insulin in proportional response to carbohydrates consumed.[22]
Yonsei University

Scientists in the South Korean university of Yonsei have, in 2000, succeeded in reversing diabetes in mice and rats. Using a viral vector, a DNA encoding the production of an insulin analog was injected to the animals, which remained non-diabetic for at least the eight months duration of the study.[23]

Prevention

"Immunization" approach

If a biochemical mechanism can be found that prevents the immune system from attacking beta cells, it may be administered to prevent commencement of diabetes type 1. Several groups are trying to achieve this by causing the activation state of the immune system to change from Th1 state (“attack” by killer T Cells) to Th2 state (development of new antibodies). This Th1-Th2 shift occurs via a change in the type of cytokine signaling molecules being released by regulatory T-cells. Instead of pro-inflammatory cytokines, the regulatory T-cells begin to release cytokines that inhibit inflammation.[24] This phenomenon is commonly known as "acquired immune tolerance".

DiaPep277

A substance designed to cause lymphocyte cells to cease attacking beta cells, DiaPep277 is a peptide fragment of a larger protein called HSP60. Given as a subcutaneous injection, its mechanism of action involves a Th1-Th2 shift. Clinical success has been demonstrated in prolonging the "honeymoon" period for people who already have type 1 diabetes.[25] The product is currently being tested in people with latent autoimmune diabetes of adults (LADA). Ownership of the drug has changed hands several times over the last decade. In 2007, Clal Biotechnology Industries (CBI) Ltd., an Israeli investment group in the field of life sciences, announced that Andromeda Biotech Ltd., a wholly owned subsidiary of CBI, signed a Term Sheet with Teva Pharmaceutical Industries Ltd. to develop and commercialize DiaPep277.[26]

Intra-nasal insulin

There is pre-clinical evidence that a Th1-Th2 shift can be induced by administration of insulin directly onto the immune tissue in the nasal cavity. This observation has led to a clinical trial, called INIT II, which began in late 2006, based in Australia and New Zealand.

BCG research

Tumor necrosis factor-alpha, or TNF-α, is part of the immune system. It helps the immune system distinguish self from non-self tissue. People with type 1 diabetes are deficient in this substance. Dr. Denise Faustman theorizes that giving Bacillus Calmette-Guérin (BCG), an inexpensive generic drug, would have the same impact as injecting diabetic mice with Freund's Adjuvant, which stimulates TNF-α production. TNF-α kills the white blood cells responsible for destroying beta cells, and thus prevents, or reverses diabetes.[27] She has reversed diabetes in laboratory mice with this technique, but was only able to receive funding for subsequent research from The Iaccoca Foundation, founded by Lee Iacocca in honor of his late wife, who died from diabetes complications. Human trials are set to begin in 2008.

Diamyd

Diamyd is the name of a vaccine being developed by Diamyd Medical. Injections with GAD65, an autoantigen involved in type 1 diabetes, has in clinical trials delayed the destruction of beta cells for at least 30 months, without serious adverse effects. Patients treated with the substance showed higher levels of regulatory cytokines, thought to protect the beta cells.[28] Phase III trials are under way in the USA [29] and in Europe[30].[31][32] Two prevention studies, where the vaccine is given to persons who have not yet developed diabetes, will start in 2009[33][34].

Entities involved in research

This section is an incomplete list of mainly commercial companies but also other entities, namely governmental institutions and individual persons, actively involved in research towards finding a cure to diabetes type 1.
It does not list research funds, hospitals in which research is undertaken, etc., but only the industrious, actual developers of such products.

Entities are listed alphabetically along with their status of research in that field, so that also entities which ceased research into finding a cure to diabetes type 1 may be listed.

  • Amylin Pharmaceuticals – is working toward finding a cure, and has a drug on the market called Symlin (pramlintide acetate) that helps in treating Type 1 diabetes
  • Cerco Medical [1] – Present status: Unknown
  • Denise Faustman [2] – Present status: Working on immune modification
  • DeveloGen [3] – Present status: Developing DiaPep 277
  • Diamyd Medical [4] – Present status: Developing GAD65-based vaccine (phase III trial started)
  • Tolerx, Inc. [www.defendagainstdiabetes.com] - Present status: Now (4/2009) in Phase 3 clinical study of otelixizumab, an Fc-disabled, anti-CD3 monoclonal antibody in patients with new onset (diagnosis within last 10 weeks) type 1 diabetes.

See also

Further reading

References

  1. ^ ""Type 1 Diabetes Mellitus"". Retrieved 2008-08-04.
  2. ^ ""One Step Closer to a Cure - Interview; Patrick Perry, Saturday Evening Post"". Retrieved 2008-11-02.
  3. ^ "Donner", "Horst" ("2007"). ""CTLA4 Alanine-17 Confers Genetic Susceptibility to Graves' Disease and to Type 1 Diabetes Mellitus"". "The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 1 143-146". "The Journal of Clinical Endocrinology & Metabolism". Retrieved 2008-02-06. {{cite web}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  4. ^ content.nejm.org
  5. ^ "Canadian scientists reverse diabetes in mice". Retrieved 2007-06-04.
  6. ^ http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=222100
  7. ^ Pancreas Transplantation: Indications and Consequences
  8. ^ "Islet cell transplant: Experimental treatment for type 1 diabetes - MayoClinic.com". Retrieved 2007-06-04.
  9. ^ Cerco Medical: Science: Methods
  10. ^ Cerco Medical: Company: Islet Sheet Research
  11. ^ Living Cell Technologies web site: Diabecell
  12. ^ "November 13, 2003 Regeneration of insulin-producing islets may lead to diabetes cure". Retrieved 2007-06-04.
  13. ^ Faustman DL, Tran SD, Kodama S; et al. (2006). "Comment on papers by Chong et al., Nishio et al., and Suri et al. on diabetes reversal in NOD mice". Science. 314 (5803): 1243, author reply 1243. doi:10.1126/science.1129811. PMID 17124308. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  14. ^ DiaKine Therapeutics and Kinexum Metabolics to Develop Novel Combination Treatment to Type 1 Diabetes
  15. ^ http://www.timesonline.co.uk/tol/comment/leading_article/article1637235.ece
  16. ^ Voltarelli JC, Couri CE, Stracieri AB; et al. (2007). "Autologous nonmyeloablative hematopoietic stem cell transplantation in newly diagnosed type 1 diabetes mellitus". JAMA. 297 (14): 1568–76. doi:10.1001/jama.297.14.1568. PMID 17426276. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  17. ^ http://www.eurekalert.org/pub_releases/2008-09/uonc-ust091708.php
  18. ^ http://www.jbc.org/cgi/content/abstract/M806597200v1
  19. ^ Gene Therapy Approaches to Diabetes
  20. ^ Mary Ann Liebert, Inc. - Cookie absent
  21. ^ hopkinsbayview.org
  22. ^ Engene Inc
  23. ^ Gene Therapy for Diabetes: Scientific American
  24. ^ jci.org
  25. ^ interscience.wiley.com
  26. ^ medicalnewstoday.com
  27. ^ Shinichiro Ryu, Shohta Kodama, Kazuko Ryu, David A. Schoenfeld & Denise L. Faustman. 2001. Reversal of established autoimmune diabetes by restoration of endogenous β cell function. J. Clin. Invest. 108(1): 63-72.
  28. ^ New England Journal of Medicine: GAD Treatment and Insulin Secretion in Recent-Onset Type 1 Diabetes
  29. ^ Diamyd US Phase III Trial
  30. ^ Diamyd European Phase III Trial
  31. ^ Further Evidence for Lasting Immunological Efficacy of Diamyd Diabets Vaccine
  32. ^ Diamyd Announces Completion of Type 1 Diabetes Vaccine Trial with Long Term Efficcacy Demonstrated at 30 Months
  33. ^ MSNBC News: Pioneering Diamyd(r) Study to Prevent Childhood Diabetes Approved
  34. ^ Diamyd press release: Diamyd approved for groundbreking study in Norway

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