type 2 diabetes mellitus

Diabetes mellitus type 1

Diabetes mellitus type 1 (Type 1 diabetes, Type I diabetes, T1D, T1DM, IDDM, juvenile diabetes) is a form of diabetes mellitus. Type 1 diabetes is an autoimmune disease that results in the permanent destruction of insulin-producing beta cells of the pancreas (Many scientists now believe it is NOT permanent and that regeneration occurs if the immune system is brought under control). The lack of insulin causes an increase of fasting blood glucose (around 70-120 mg/dL in the healthy people)that, when it gets to 180 mg/dL it starts to appear in the urine making it sweet "mellitus" (honey in latin). Glycosuria or glucose in the urine causes the patients to urinate more frequently. Of course, patients also drink more and are always thirsty (polidipsia). These are the first clear symptoms of diabetes, that if not recognized, may take to ketoacidic coma, an extremely dangerous situation. Type 1 is lethal unless treatment with exogenous insulin via injections replaces the missing hormone, or a functional replacement for the destroyed pancreatic beta cells is provided (such as via a pancreas transplant, islet transplant, cell therapy or by treatment and regeneration).

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 the misconception of Type 1 as a disease of children — and since there is no cure as of yet, all children with Type 1 diabetes will grow up to be adults with Type 1 diabetes.

There is currently no preventive measure that can be taken against type 1 diabetes. Most people affected by type 1 diabetes are otherwise healthy and of a healthy weight when onset occurs, but they can lose weight quickly and dangerously, if not diagnosed in a relatively short amount of time. Although the cause of Type 1 diabetes is still not fully understood, diet and exercise may help insulin to act more effectively.

The most useful 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 (to date) has included no C-peptide. However, C-peptide is not absent in Type 1 diabetes until insulin production has fully ceased, which may take months. 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. As opposed to that, many Type 2 diabetics still 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.

Pathophysiology

The cause of Type 1 diabetes is still not fully understood. Some theorize that Type 1 diabetes could be a virally induced autoimmune response. Autoimmunity is a condition where one's own immune system "attacks" structures in one's own body either destroying the tissue or decreasing its functionality. In the proposed scenario, pancreatic beta cells in the Islets of Langerhans are destroyed or damaged sufficiently to abolish endogenous insulin production. This etiology makes type 1 distinct from type 2 diabetes mellitus. It should also be noted that the use of insulin in a patient's diabetes treatment protocol does not render them as having type 1 diabetes, the type of diabetes a patient has is determined only by disease etiology. 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.

This vulnerability is not shared by everyone, for not everyone infected by these organisms develops Type 1 diabetes. This has suggested a genetic vulnerability 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 poorly understood. Wide-scale genetic studies have shown links between genetic vulnerabilities for type 1 diabetes and Multiple Sclerosis and Crohn's Disease.

Some researchers believe that the autoimmune response is influenced by antibodies against cow's milk proteins. 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. The mechanism, if any, is not 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.

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.

Some chemicals and drugs specifically 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. Zanosar is the trade name for streptozotocin, an antibiotic and antineoplastic agent used in chemotherapy for pancreatic cancer, that 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 revealed 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. It's being suggested that faulty nerves in the pancreas could be a cause of type 1 diabetes.

Treatment

Type 1 is treated with insulin replacement therapy — usually by injection or insulin pump, along with attention to dietary management, typically including carbohydrate tracking, and careful monitoring of blood glucose levels using Glucose meters.

Untreated Type 1 diabetes can lead to one form of diabetic coma, diabetic ketoacidosis, which can be fatal. At present, insulin treatment must be continued for a lifetime; this will change when better treatment, or a cure, is discovered. Continuous glucose monitors have been developed which can alert patients to the presence of dangerously high or low blood sugar levels, but the lack of widespread insurance coverage has limited the impact these devices have had on clinical practice so far.

In more extreme cases, a pancreas transplant can help 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

Pancreas transplants are generally recommended if a kidney transplant is also necessary. The 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.

Islet cell transplantation

Less invasive than a pancreas transplant, islet cell transplantation is currently the most highly used approach in humans to temporarily cure type 1 diabetes.

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 the 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. The immune system will attack the cells as it would a bacterial infection or a skin graft. Thus, the patient also needs 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 the operation. Ideally, it would be best to use islet cells which will not provoke this immune reaction, but investigators are also looking into placing islets into a protective coating which enables insulin to flow out while protecting the islets from 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.

Research foundations

The Juvenile Diabetes Research Foundation (JDRF) is the major charitable organization in the USA and Canada 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 $1.16 billion to diabetes research, including more than $137 million in FY 2007. In FY2007, the Foundation funded 700 centers, grants and fellowships in 20 countries.

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 2008, there is no known cure for diabetes mellitus type 1 used by modern medical institutes or hospitals. There is ongoing research on various approaches to curing diabetes type 1.

Diabetes type 1 is caused by the destruction of sufficient beta cells in the body; 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, and also the hormone amylin, another hormone required for glucose homeostasis, as well as the counterregulatory hormone glucagon which is secreted by the alpha cells. 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 full restoration of the counterregulatory function. This section does not deal with approaches other than that (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". Instead, it only deals with such approaches for thoroughly 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.

Reversion

Encapsulation approach

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 immunosuppression. 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.

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.

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.

Islet cell regeneration approach

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

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 in Montreal, Canada) discovered in a protein they refer to as INGAP, which stands for Islet Neogenesis Associated Protein back in 1997. INGAP is a gene that is responsible for regenerating the islets that make insulin and other important hormones in the pancreas.

INGAP has something of a checkered history as far as commercialization is concerned. Although it appears promising, the rights to commercialize it have traded hands a repeatedly over, having once been owned by Procter & Gamble Pharmaceuticals, but P&G later dropped it. The rights were then acquired by GMP Companies. More recently, Kinexum Metabolics, Inc. has since sublicensed INGAP Peptide from GMP Companies for further clinical trials. Kinexum has continued development under the guidance of Dr. G. Alexander Fleming, a well-known authority on metabolic drug development, 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 the developers were investigating 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. 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.
Study in 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.
Study in 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.

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.

University of North Carolina study
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.

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

However, other scientists cast 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

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

  • 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.
  • 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.
  • 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.

Yonsei University study
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.

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. The way several groups are trying to achieve this is 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. 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. 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.
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.
Denise Faustman research
Tumor necrosis factor-alpha, or TNF-a, is part of the immune system. It helps the immune system discern between self and non-self. People with type 1 diabetes are deficient in this substance. Dr. Faustman theorizes that giving Bacillus Calmette-Guérin (BCG), an inexpensive drug, would have the same impact as injecting diabetic mice with Freund's Adjuvant, which stimulates TNF-a production. TNF-a kills the white blood cells responsible for destroying beta cells, and thus prevents, or reverses diabetes. She has reversed diabetes in laboratory mice with this techniqe, 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. Phase III trials are under way in the USA and in Europe.

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 – Present status: Unknown
  • Denise Faustman – Present status: Working on immune modification
  • DeveloGen – Present status: Developing DiaPep 277
  • Diamyd Medical – Present status: Developing GAD65-based vaccine (phase III trial started)
  • Encelle – Present status: On hold, awaiting decision on moving forward into encapsulated beta cell transplantation.

See also

Further reading

References

External links

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