Diabetes mellitus type 1

Diabetes mellitus type 1 (Type 1 diabetes, T1DM, IDDM, or, formerly, juvenile diabetes) is a form of diabetes mellitus that results from autoimmune destruction of insulin-producing beta cells of the pancreas. The subsequent lack of insulin leads to increased blood and urine glucose. The classical symptoms are polyuria (frequent urination), polydipsia (increased thirst), polyphagia (increased hunger), and weight loss.

In the long run, type 1 diabetes is generally fatal unless treated with insulin. Injection is the most common method of administering insulin; insulin pumps and inhaled insulin have been available at various times. Pancreatic transplants and pancreatic islet cell transplantation have been used to treat type 1 diabetes; however, pancreatic islet cell transplantation is still viewed as experimental, although utilization of the procedure is growing.

Most people who develop type 1 are otherwise healthy. Although the cause of type 1 diabetes is still not fully understood it is believed to be of immunological origin.

Type 1 can be distinguished from type 2 diabetes via a C-peptide assay, which measures endogenous insulin production.

Type 1 treatment must be continued indefinitely in all cases. Treatment is not intended to significantly impair normal activities, and can be done adequately if sufficient patient training, awareness, appropriate care, discipline in testing and dosing of insulin is taken. However, treatment remains quite burdensome for many people. Complications may be associated with both low blood sugar and high blood sugar, both largely due to the non-physiological manner in which insulin is replaced. Low blood sugar may lead to seizures or episodes of unconsciousness and requires emergency treatment. High blood sugar may lead to increased fatigue and can also result in long term damage to organs.

Classification
Brittle diabetes, also known as unstable diabetes or labile diabetes, refers to a type of insulin-dependent diabetes characterized by dramatic and recurrent swings in glucose levels, often occurring for no apparent reason. The result can be irregular and unpredictable hyperglycemias, frequently with ketosis, and sometimes serious hypoglycemias. Brittle diabetes occurs no more frequently than in 1% to 2% of diabetics.

Signs and symptoms
The classical symptoms of type 1 diabetes include: polyuria (frequent urination), polydipsia (increased thirst), polyphagia (increased hunger), fatigue, and weight loss.

Cause
Evidence so far indicates that the development of diabetes type I is induced by more or less a combination of genetic susceptibility, a diabetogenic trigger and exposure to a driving antigen. Many risk factors have been suggested, and there is ongoing research into the influence of environmental factors. There is also research being conducted on individual factors, and whether some may be regarded as sufficient to cause the disease by themselves or only in addition to other risk factors.

Genetics
Type 1 diabetes is a polygenic disease, meaning many different genes contribute to its onset. 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. Certain variants of this gene increases the risk for decreased histocompatibility characteristic of type 1. Such variants include DRB1 0401, DRB1 0402, DRB1 0405, DQA 0301, DQB1 0302 and DQB1 0201, which are common in North Americans of European ancestry and in Europeans. There are also variants that appear to be protective.

The risk of a child developing type 1 diabetes is approximately 10% if the father has it, approximately 10% if a sibling has it, approximately 4% if the mother has type 1 diabetes and is/was aged 25 or younger when the child is/was born, and approximately 1% if the mother is/was over 25 years old when the child is/was born.

Environmental
Environmental factors can 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 exactly the same genome, one twin had the disease, where the other did not; this suggests that environmental factors, in addition to genetic factors, can influence disease prevalence. Other indications of environmental influence include the presence of a 10-fold difference in difference among Caucasians living in different areas of Europe, and a tendency to acquire the incidence of the disease of the destination country for people who migrate.

Virus
One theory, discussed by DeLisa Fairweather & Noel R. Rose, among others, proposes that type 1 diabetes is a virally triggered autoimmune response in which the immune system attacks virus infected cells along with the beta cells in the pancreas. The Coxsackie virus family or Rubella is implicated, although the evidence is inconclusive. In type 1, pancreatic beta cells in the Islets of Langerhans are destroyed decreasing endogenous insulin production. This distinguishes type 1's origin from type 2 DM. 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 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.

Diet
There is a growing body of evidence that diet may play a role in the development of type 1 diabetes, through influencing gut flora, intestinal permeability, and immune function in the gut; wheat in particular has been shown to have a connection to the development of type 1 diabetes, although the relationship is poorly understood.

Some researchers believe that the autoimmune response is influenced by antibodies against cow's milk proteins. 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 2 cases manifest a genetic form of the disease called maturity onset diabetes of the young (MODY).

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.

Short breast-feeding period and short attendance to day care is associated with the risk of type 1 diabetes in Czech children.

Chemicals and drugs
Some chemicals and drugs preferentially destroy pancreatic cells. Pyrinuron (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.

Pathophysiology
The pathophysiology in diabetes type I is basically a destruction of beta cells in the pancreas, regardless of which risk factors or causative entities have been present.

Individual risk factors can have separate pathophysiological processes to, in turn, cause this beta cell destruction. Still, a process that appears to be common to most risk factors is an autoimmune response towards beta cells, involving an expansion of autoreactive CD4+ and CD8+ T helper cells, autoantibody-producing B cells and activation of the innate immune system.

Diagnosis
Diabetes mellitus is characterized by recurrent or persistent hyperglycemia, and is diagnosed by demonstrating any one of the following:


 * Fasting plasma glucose level at or above 7.0 mmol/L (126 mg/dL).
 * Plasma glucose at or above 11.1 mmol/L (200 mg/dL) two hours after a 75 g oral glucose load as in a glucose tolerance test.
 * Symptoms of hyperglycemia and casual plasma glucose at or above 11.1 mmol/L (200 mg/dL).
 * Glycated hemoglobin (hemoglobin A1C) at or above 6.5. (This criterion was recommended by the American Diabetes Association in 2010, although it has yet to be adopted by the WHO.)

About a quarter of people with new type 1 diabetes have developed some degree of diabetic ketoacidosis (a type of metabolic acidosis which is caused by high concentrations of ketone bodies, formed by the breakdown of fatty acids and the deamination of amino acids) by the time the diabetes is recognized. The diagnosis of other types of diabetes is usually made in other ways. These include ordinary health screening, detection of hyperglycemia during other medical investigations, and secondary symptoms such as vision changes or unexplainable fatigue. Diabetes is often detected when a person suffers a problem that may be caused by diabetes, such as a heart attack, stroke, neuropathy, poor wound healing or a foot ulcer, certain eye problems, certain fungal infections, or delivering a baby with macrosomia or hypoglycemia.

A positive result, in the absence of unequivocal hyperglycemia, should be confirmed by a repeat of any of the above-listed methods on a different day. Most physicians prefer to measure a fasting glucose level because of the ease of measurement and the considerable time commitment of formal glucose tolerance testing, which takes two hours to complete and offers no prognostic advantage over the fasting test. According to the current definition, two fasting glucose measurements above 126 mg/dL (7.0 mmol/L) is considered diagnostic for diabetes mellitus.

Patients with fasting glucose levels from 100 to 125 mg/dL (5.6 to 6.9 mmol/L) are considered to have impaired fasting glucose. Patients with plasma glucose at or above 140 mg/dL (7.8 mmol/L), but not over 200 mg/dL (11.1 mmol/L), two hours after a 75 g oral glucose load are considered to have impaired glucose tolerance. Of these two pre-diabetic states, the latter in particular is a major risk factor for progression to full-blown diabetes mellitus and cardiovascular disease.

Autoantibodies
The appearance of diabetes-related autoantibodies has been shown to be able to predict the appearance of diabetes type 1 before any hyperglycemia arises, the main ones being islet cell autoantibodies, insulin autoantibodies, autoantibodies targeting the 65 kDa isoform of glutamic acid decarboxylase (GAD) and autoantibodies targeting the phosphatase-related IA-2 molecule. Per definition, the diagnosis of diabetes type 1 can be made first at the appearance of clinical symptoms and/or signs, but the emergence of autoantibodies may itself be termed latent autoimmune diabetes. Not everyone with autoantibodies progress to diabetes type 1, but the risk increases with the number of antibody types, with three to four antibody types giving a risk of progressing to diabetes type 1 of 60%-100%. The time interval from emergence of autoantibodies to frank diabetes type 1 can be a few months in infants and young children, but in some people it may take years - in some cases more than 10 years. Islet cell autoantibodies are detected by conventional immunofluorescence while the rest are measured with specific radiobinding assays.

Prevention
Type 1 diabetes is not currently preventable. Still, promising therapies are emerging, and it has been suggested that, in the future, diabetes type 1 may be prevented at the latent autoimmune stage, probably by a combination therapy of several methods.

Immunosuppressive drugs
Cyclosporine A, an immunosuppressive agent, has apparently halted destruction of beta cells (on the basis of reduced insulin usage), but its nephrotoxicity and other side effects make it highly inappropriate for long-term use.

Anti-CD3 antibodies, including teplizumab and otelixizumab, had suggested evidence of preserving insulin production (as evidenced by sustained C-peptide production) in newly diagnosed type 1 diabetes patients. A probable mechanism of this effect was believed to be preservation of regulatory T cells that suppress activation of the immune system and thereby maintain immune system homeostasis and tolerance to self-antigens. The duration of the effect is still unknown, however. In 2011, Phase III studies with otelixizumab and teplizumab both failed to show clinical efficacy.

An anti-CD20 antibody, rituximab, inhibits B cells and has been shown to provoke C-peptide responses three months after diagnosis of type 1 diabetes, but long-term effects of this have not been reported.

Diet
Some research has suggested that breastfeeding decreased the risk in later life; various other nutritional risk factors are being studied, but no firm evidence has been found. Giving children 2000 IU of Vitamin D during their first year of life is associated with reduced risk of type 1 diabetes, though the causal relationship is obscure.

Children with antibodies to beta cell proteins (i.e. at early stages of an immune reaction to them) but no overt diabetes, and treated with vitamin B3 (niacin), had less than half the diabetes onset incidence in a 7-year time span as did the general population, and an even lower incidence relative to those with antibodies as above, but who received no vitamin B3.

Insulin therapy
Type 1 is treated with insulin replacement therapy—either via subcutaneous 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 biosynthetic products produced using genetic recombination techniques; formerly, cattle or pig insulins were used, and even sometimes insulin from fish. Major global 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. Continuous glucose monitors have been developed and marketed which can alert patients to the presence of dangerously high or low blood sugar levels, but technical limitations have limited the impact these devices have had on clinical practice so far.

Treatment of diabetes focuses on lowering blood sugar or glucose (BG) to the near normal range, approximately 80–140 mg/dl (4.4-7.8 mmol/L). The ultimate goal of normalizing BG is to avoid long term complications that affect the nervous system (e.g. peripheral neuropathy leading to pain and/or loss of feeling in the extremities), and the cardiovascular system (e.g. heart attacks, vision loss). There are two primary types of diabetes, type 1 and type 2. People with type 1 diabetes always need to take insulin. Treatment with insulin can lead to low BG, or hypoglycemia, i.e. BG less than 70 mg/dl (3.9 mmol/L). Hypoglycemia is a very common occurrence in people with diabetes, usually the result of a mismatch in the balance among insulin, food and physical activity, although the non-physiological method of delivery also plays a role.

Pancreas transplantation
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 generally only used together with or some time after a kidney transplant. One reason for this is that introducing a new kidney requires taking immunosuppressive drugs such as cyclosporine. Nevertheless 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
Experimental replacement of beta cells (by transplant or from stem cells) is being investigated in several research programs. 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. Ideally, it would be best to use islet cells which will not provoke this immune reaction. Scientists in New Zealand with Living Cell Technologies are currently in human trials with Diabecell, placing pig islets within a protective capsule derived of seaweed which enables insulin to flow out and nutrients to flow in while protecting the islets from immune system attack via white blood cells.

Complications
Complications of poorly-managed type 1 diabetes mellitus may include cardiovascular disease, diabetic neuropathy, diabetic retinopathy among others. However, there is some evidence that cardiovascular disease as well as neuropathy may, in fact, have an autoimmune basis as well.

Driving
Studies conducted in the United States and Europe showed that drivers with type 1 diabetes had twice as many collisions as their non-diabetic spouses, demonstrating the increased risk of driving collisions in the type 1 diabetes population. Diabetes can compromise driving safety in several ways. First, long-term complications of diabetes can interfere with the safe operation of a vehicle. For example, diabetic retinopathy (loss of peripheral vision or visual acuity), or peripheral neuropathy (loss of feeling in the feet) can impair a driver’s ability to read street signs, control the speed of the vehicle, apply appropriate pressure to the brakes, etc.

Second, hypoglycemia can affect a person’s thinking process, coordination, and state of consciousness. This disruption in brain functioning is called neuroglycopenia. Studies have demonstrated that the effects of neuroglycopenia impair driving ability. A study involving people with type 1 diabetes found that individuals reporting two or more hypoglycemia-related driving mishaps differ physiologically and behaviorally from their counterparts who report no such mishaps. For example, during hypoglycemia, drivers who had two or more mishaps reported fewer warning symptoms, their driving was more impaired, and their body released less epinephrine (a hormone that helps raise BG). Additionally, individuals with a history of hypoglycemia-related driving mishaps appear to use sugar at a faster rate and are relatively slower at processing information. These findings indicate that although anyone with type 1 diabetes may be at some risk of experiencing disruptive hypoglycemia while driving, there is a subgroup of type 1 drivers who are more vulnerable to such events.

Given the above research findings, it is recommended that drivers with type 1 diabetes with a history of driving mishaps should never drive when their BG is less than 70 mg/dl. Instead, these drivers are advised to treat hypoglycemia and delay driving until their BG is above 90 mg/dl. Such drivers should also learn as much as possible about what causes their hypoglycemia, and use this information to avoid future hypoglycemia while driving.

Studies funded by the National Institutes of Health (NIH) have demonstrated that face-to-face training programs designed to help individuals with type 1 diabetes better anticipate, detect, and prevent extreme BG can reduce the occurrence of future hypoglycemia-related driving mishaps. An internet-version of this training has also been shown to have significant beneficial results. Additional NIH funded research to develop internet interventions specifically to help improve driving safety in drivers with type 1 diabetes is currently underway.

Epidemiology
Type 1 diabetes causes an estimated 5%–10% of all diabetes cases or 11–22 million worldwide. In 2006 it affected 440 thousand children under 14 years of age and was the primary cause of diabetes in those less than 10 years of age. The incidence of type 1 diabetes has been increasing by about 3% per year. Rates vary widely in different countries with a low of 0.1 cases per 100,000 people per year in China and Venezuela to a high of 37 cases per 100,000 people per year in Finland and Sardinia.

Type 1 diabetes was previously known as juvenile diabetes to distinguish it from type 2 diabetes, which generally has a later onset; however, the majority of new-onset type 1 diabetes is seen in adults. Scientific studies that use antibody testing (glutamic acid decarboxylase antibodies (GADA), islet cell antibodies (ICA), and insulinoma-associated autoantibodies (IA-2)) to distinguish between type 1 and type 2 diabetes demonstrate that most new-onset type 1 diabetes is seen in adults. A 2008 book, Type 1 Diabetes in Adults: Principles and Practice, says that adult-onset type 1 autoimmune diabetes is two to three times more common than classic childhood-onset autoimmune diabetes.

Foundations
The Juvenile Diabetes Research Foundation (JDRF) is the leading charitable funder of research into type 1 diabetes in the world. It has offices in the UK, Denmark, USA, Canada, Australia, Israel, Mexico and India. 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 an online social network for people with type 1 diabetes: Juvenation.

The Diabetes Research Institute Foundation is the only organization solely dedicated to curing diabetes. Founded by a group of parents of children with diabetes who wanted to put an end to type 1 diabetes, the Diabetes Research Institute Foundation has grown into an international coalition of business leaders, celebrities, research scientists, clinicians, families and other concerned individuals who have been a strong voice for cure-focused research. Supported by private philanthropy, the DRI Foundation has been and continues to be the organization of choice for those who are serious, passionate and committed to finding a cure for diabetes. Its mission is to provide the Diabetes Research Institute with the funding necessary to cure diabetes now.

The International Diabetes Federation is a worldwide alliance of over 160 countries to address diabetes research and treatment. The American Diabetes Association funds some type 1 research along with other a variety of diabetes-related research (not necessarily cure-specific) including type 2 diabetes, gestational diabetes and others) that looks at treatments, prevention, as well as some cure-specific research. Diabetes Australia is involved in promoting research and education in Australia on both type 1 and type 2 diabetes. The Canadian Diabetes Association is involved in educating, researching, and sustaining type 1 diabetes patients in Canada. Pacific Northwest Diabetes Research Institute conducts clinical and basic research on type 1 and type 2 diabetes.

GAD65 vaccine
Injections with a vaccine containing GAD65, an autoantigen involved in type 1 diabetes, has in clinical trials delayed the destruction of beta cells when treated within six months of diagnosis. 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. Two prevention studies, where the vaccine is given to persons who have not yet developed diabetes are underway.

T helper cell shift
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 type 1 T helper cell (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 T-cells. Instead of pro-inflammatory cytokines, the T-cells begin to release cytokines that inhibit inflammation. This phenomenon is commonly known as "acquired immune tolerance".