Labile diabetes

Insulin-dependent diabetes characterized by dramatic and recurrent swings in glucose levels, often occurring for no apparent reason, is sometimes known as brittle diabetes, unstable diabetes or labile diabetes, although some experts say the "brittle diabetes" concept "has no biologic basis and should not be used".^[87] The results of such swings can be irregular and unpredictable hyperglycemias, sometimes involving ketoacidosis, and sometimes serious hypoglycemias. Brittle diabetes occurs no more frequently than in 1% to 2% of diabetics.^[88] In a small study, 10 of 20 brittle diabetic patients aged 18–23 years who could be traced had died within 22 years, and the remainder, though suffering high rates of complications, were no longer brittle.^[89] These results were similar to those of an earlier study by the same authors which found a 19% mortality in 26 patients after 10.5 years.^[90]
Because labile diabetes is defined as "episodes of hypoglycemia or hyperglycemia that, whatever their cause, constantly disrupt a patient's life", it can have many causes, some of which include:^[91]

• errors in diabetes management, which can include too much insulin being given, in relation to carbohydrate being consumed
• interactions with other medical conditions
• psychological problems
• biological factors that interfere with how insulin is processed within the body
• hypoglycemia and hyperglycemia due to strenuous exercise; however, hypoglycemia is more frequent
• insulin exposed to higher temperatures that reduces effectiveness of the insulin hormone in the body
• spontaneous production of insulin in the body due to activity in the beta cells during the period shortly after diagnosis of type 1 diabetes

Exercise related hyperglycemia is caused when hormones (such as adrenaline and cortisol) are released during moderate to strenuous exercise. This happens when the muscles signal the liver to release glucose into the bloodstream by converting stored glycogen into glucose. The cause of exercise related hypoglycemia, on the other hand, occurs when the muscle group being exercised uses up glucose faster than it can be replenished by the body.
One of these biological factors is the production of insulin autoantibodies. High antibody titers can cause episodes of hyperglycemia by neutralizing the insulin, thereby causing clinical insulin resistance requiring doses of over 200 IU/day. However, antibodies may also fail to buffer the release of the injected insulin into the bloodstream after subcutaneous injection, resulting in episodes of hypoglycemia. In some cases, changing the type of insulin administered can resolve this problem.^[91] There have been a number of reports that insulin autoantibodies can act as a "sink" for insulin and affect the time to peak, half-life, distribution space, and metabolic clearance, though in most patients these effects are small.^[92]

Society and culture

See also: List of people with diabetes mellitus type 1

The disease was estimated to cause $10.5 billion in annual medical costs ($875 per month per diabetic) and an additional $4.4 billion in indirect costs ($366 per month per person with diabetes) in the U.S.^[80] In the United States $245 billion every year is attributed to diabetes. Individuals diagnosed with diabetes have 2.3 times the health care costs as individuals who do not have diabetes. One in 10 health care dollars are spent on individuals with diabetes.^[75]

Research

Funding for research into type 1 diabetes originates from government, industry (e.g., pharmaceutical companies), and charitable organizations. Government funding in the United States is distributed via the National Institute of Health, and in the UK via the National Institute for Health Research or the Medical Research Council. JDRF, founded by parents of children with type 1 diabetes, is the world's largest provider of charity based funding for type 1 diabetes research. Other charities include the American Diabetes Association, Diabetes UK, Diabetes Research and Wellness Foundation,^[81] Diabetes Australia, the Canadian Diabetes Association.

Treatments

A number of approaches have been explored to provide treatments for type 1.

Stem cells

Pluripotent stem cells can be used to generate beta cells but previously these cells did not function as well as normal beta cells.^[82] In 2014 more mature beta cells were produced which released insulin in response to blood sugar when transplanted into mice.^[83][84] Before these techniques can be used in humans more evidence of safety and effectiveness is needed.^[82]

Vaccine

Vaccines to treat or prevent Type 1 diabetes are designed to induce immune tolerance to insulin or pancreatic beta cells.^[85] While Phase II clinical trials of a vaccine containing alum and recombinant GAD65, an autoantigen involved in type 1 diabetes, were promising, as of 2014 Phase III had failed.^[85] As of 2014, other approaches, such as a DNA vaccine encoding proinsulin and a peptide fragment of insulin, were in early clinical development.^[85]

Diet

There is evidence from experiments conducted in animal models that removal of gluten from the diet may prevent the onset type 1 diabetes^[32][86] but there has been conflicting research in humans.^[86]

Epidemiology

Type 1 diabetes makes up an estimated 5–10% of all diabetes cases^[8] or 11–22 million worldwide.^[41] In 2006 it affected 440,000 children under 14 years of age and was the primary cause of diabetes in those less than 10 years of age.^[72] The incidence of type 1 diabetes has been increasing by about 3% per year.^[72]
Rates vary widely by country. In Finland, the incidence is a high of 57 per 100,000 per year, in Japan and China a low of 1 to 3 per 100,000 per year, and in Northern Europe and the U.S., an intermediate of 8 to 17 per 100,000 per year.^[73][74]
In the United States, type 1 diabetes affected about 208,000 youths under the age of 20 in 2015. Over 18,000 youths are diagnosed with Type 1 diabetes every year. Every year about 234,051 Americans die due to diabetes (type I or II) or diabetes-related complications, with 69,071 having it as the primary cause of death.^[75]

History

Type 1 diabetes was described as an autoimmune disease in the 1970s, based on observations that autoantibodies against islets were discovered in diabetics with other autoimmune deficiencies.^[76] It was also shown in the 1980s that immunosuppressive therapies could slow disease progression, further supporting the idea that type 1 diabetes is an autoimmune disorder.^[77] The name juvenile diabetes was used earlier as it often first is diagnosed in childhood.
In Australia, approximately one million Australians have been diagnosed with type 1 diabetes and Australia ranks 7th-highest in the world with children under 14 years of age. Between 2000 and 2013, 31,895 new cases were established, with 2,323 in 2013, a rate of 10–13 cases per 100,00 people each year. Aboriginals and Torres Strait Islander people are less affected.^[78][79]

Complications

Complications

Further information: Complications of diabetes mellitus

Complications of poorly managed type 1 diabetes mellitus may include cardiovascular disease, diabetic neuropathy, and diabetic retinopathy, among others. However, cardiovascular disease^[61] as well as neuropathy^[62] may have an autoimmune basis, as well. Women with type 1 DM have a 40% higher risk of death as compared to men with type 1 DM.^[63] The life expectancy of an individual with type 1 diabetes is 11 years less for men and 13 years less for women.^[64]

Urinary tract infection

People with diabetes show an increased rate of urinary tract infection.^[65] The reason is bladder dysfunction that is more common in diabetics than in non-diabetics due to diabetic nephropathy. When present, nephropathy can cause a decrease in bladder sensation, which in turn, can cause increased residual urine, a risk factor for urinary tract infections.^[66]

Sexual dysfunction

Sexual dysfunction in diabetics is often a result of physical factors such as nerve damage and/or poor circulation, and psychological factors such as stress and/or depression caused by the demands of the disease.^[67][68]

Males

The most common sexual issues in diabetic males are problems with erections and ejaculation: "With diabetes, blood vessels supplying the penis’s erectile tissue can get hard and narrow, preventing the adequate blood supply needed for a firm erection. The nerve damage caused by poor blood glucose control can also cause ejaculate to go into the bladder instead of through the penis during ejaculation, called retrograde ejaculation. When this happens, semen leaves the body in the urine."^[67] Another cause for erectile dysfunction are the reactive oxygen species created as a result of the disease. Antioxidants can be used to help combat this.^[69]

Females

While there is less material on the correlation between diabetes and female sexual dysfunction than male sexual dysfunction, studies have shown there to be a significant prevalence of sexual problems in diabetic women.^[68] Common problems include reduced sensation in the genitals, dryness, difficulty/inability to orgasm, pain during sex, and decreased libido.^[67] In some cases diabetes has been shown to decrease oestrogen levels in females, which can affect vaginal lubrication.^[68]
Oral contraceptives can be taken by diabetics. Sometimes, contraceptive pills can cause a blood sugar imbalance, but this usually can be corrected by a dosage change.^[68] As with any medication, side effects should be taken into account and monitored to prevent serious complications with diabetes.^[68]
Women with type 1 diabetes show a higher than normal rate of polycystic ovarian syndrome (PCOS).^[70] The reason may be that the ovaries are exposed to high insulin concentrations since women with type 1 diabetes can have frequent hyperglycemia.^[71]

Management

Further information: Diabetes management

Lifestyle

A low-carbohydrate diet, in addition to medications, is useful in type 1 DM.^[50] There are camps for children to teach them how and when to use or monitor their insulin without parental help.^[51] As psychological stress may have a negative effect on diabetes, a number of measures have been recommended including: exercising, taking up a new hobby, or joining a charity among others.^[52]

Insulin

Main article: Insulin therapy

There are four main types of insulin: rapid acting insulin, short acting insulin, intermediate acting insulin, and long acting insulin. The rapid acting insulin is used as a bolus dosage. The action onsets in 15 minutes with peak actions in 30 to 90 minutes. Short acting insulin action onsets within 30 minutes with the peak action around 2 to 4 hours. Intermediate acting insulin action onsets within 1 to 2 hours with peak action of 4 to 10 hours. Long acting insulin is usually given once per day. The action onset is roughly 1 to 2 hours with a sustained action of up to 24 hours.
Injections of insulin—either via subcutaneous injection or insulin pump— are necessary for those living with type 1 diabetes because it cannot be treated by diet and exercise alone.^[53] In addition to insulin therapy dietary management is important. This includes keeping track of the carbohydrate content of food 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.^[54]
Untreated type 1 diabetes can commonly lead to diabetic ketoacidosis which is a diabetic coma which can be fatal if untreated.^[55] Diabetic ketoacidosis can cause cerebral edema (accumulation of liquid in the brain). This is a life-threatening issue and children are at a higher risk for cerebral edema than adults, causing ketoacidosis to be the most common cause of death in pediatric diabetes.^[56]
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).^[57] 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). This level of control over a prolonged period of time can be varied by a target HbA_1c level of less than 7.5%.^[5]
People with type 1 diabetes always need to use insulin, but treatment can lead to low BG (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. Mild cases are self-treated by eating or drinking something high in sugar. Severe cases can lead to unconsciousness and are treated with intravenous glucose or injections with glucagon. Continuous glucose monitors can alert patients to the presence of dangerously high or low blood sugar levels, but technical issues have limited the effect these devices have had on clinical practice.^{[citation needed]}
As of 2016 an artificial pancreas looks promising with safety issues still being studied.^[58]

Pancreas transplantation

Main article: Pancreas transplantation

In some cases, a pancreas transplant can restore proper glucose regulation. However, the surgery and accompanying immunosuppression required may be more dangerous than continued insulin replacement therapy, so is generally only used 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 pancreas to a person with diabetes without any additional immunosuppressive therapy. However, pancreas transplants alone may be beneficial in people with extremely labile type 1 diabetes mellitus.^[59]

Islet cell transplantation

Main article: Islet cell transplantation

Islet cell transplantation may be an option for some people with type 1 diabetes that are not well controlled with insulin.^[60] Difficulties include finding donors that are a compatible, getting the new islets to survive, and the side effects from the medications used to prevent rejection.^[60] Success rates, defined as not needing insulin at 3 years follow the procedure occurred in 44% in on registry from 2010.^[60]

Cause

The cause of type 1 diabetes is unknown.^[4] A number of explanatory theories have been put forward, and the cause may be one or more of the following: genetic susceptibility, a diabetogenic trigger, and exposure to an antigen.^[16]

Genetics

Main article: Genetic causes of diabetes mellitus type 1

Type 1 diabetes is a disease that involves many genes. The risk of a child developing type 1 diabetes is about 5% if the father has it, about 8% if a sibling has it, and about 3% if the mother has it.^[17] If one identical twin is affected there is about a 50% chance the other will also be affected.^[18] Some studies of heritability has estimated it at 80 to 86%.^[19][20]
More than 50 genes are associated with type 1 diabetes.^[21] Depending on locus or combination of loci, they 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 increase 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.^[22] Some variants also appear to be protective.^[22]

Environmental

Environmental factors can influence expression of type 1. For identical twins, when one twin has type 1 diabetes, the other twin only has it 30%-50% of the time. Thus for 50%-70% of identical twins where one has the disease, the other will not, despite having exactly the same genome; this suggests that environmental factors, in addition to genetic factors, can influence the disease's prevalence.^[23] Other indications of environmental influence include the presence of a 10-fold difference in occurrence among Caucasians living in different areas of Europe, and that people tend to acquire the rate of disease of their particular destination country.^[16]

Virus

One theory proposes that type 1 diabetes is a virus-triggered autoimmune response in which the immune system attacks virus-infected cells along with the beta cells in the pancreas.^[24][25] Several viruses have been implicated, including enteroviruses (especially coxsackievirus B), cytomegalovirus, Epstein–Barr virus, mumps virus, rubella virus and rotavirus, but to date there is no stringent evidence to support this hypothesis in humans.^[26] A 2011 systematic review and meta-analysis showed an association between enterovirus infections and type 1 diabetes, but other studies have shown that, rather than triggering an autoimmune process, enterovirus infections, as coxsackievirus B, could protect against onset and development of type 1 diabetes.^[27]

Chemicals and drugs

Some chemicals and drugs selectively destroy pancreatic cells. Pyrinuron (Vacor), a rodenticide introduced in the United States in 1976, selectively destroys pancreatic beta cells, resulting in type 1 diabetes after accidental poisoning.^[28] Pyrinuron was withdrawn from the U.S. market in 1979 and it is not approved by the Environmental Protection Agency for use in the U.S.^[29] Streptozotocin (Zanosar), an antineoplastic agent, is selectively toxic to the beta cells of the pancreatic islets. It is used in research for inducing type 1 diabetes on rodents^[30] and for treating metastatic cancer of the pancreatic islet cells in patients whose cancer cannot be removed by surgery.^[31] Other pancreatic problems, including trauma, pancreatitis, or tumors (either malignant or benign) can also lead to loss of insulin production.

Gluten

Data suggest that gliadin (a protein present in gluten) may play a role in the development of type 1 diabetes, but the mechanism is not fully understood.^[32][33] Increased intestinal permeability caused by gluten and the subsequent loss of intestinal barrier function, which allows the passage of pro-inflammatory substances into the blood, may induce the autoimmune response in genetically predisposed individuals to type 1 diabetes.^[15][33] Early introduction of gluten-containing cereals in the diet increases the risk of developing islet cell autoantibodies, which are responsible for the destruction of the insulin-producing beta cells in the pancreas.^[33]

Pathophysiology

Prevention

Type 1 diabetes is not currently preventable.^[41] Some researchers believe it might be prevented at the latent autoimmune stage, before it starts destroying beta cells.^[22]

Immunosuppressive drugs

Cyclosporine A, an immunosuppressive agent, has apparently halted destruction of beta cells (on the basis of reduced insulin usage), but its kidney toxicity and other side effects make it highly inappropriate for long-term use.^[22]
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.^[22] 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.^[22] The duration of the effect is still unknown, however.^[22] In 2011, Phase III studies with otelixizumab and teplizumab both failed to show clinical efficacy, potentially due to an insufficient dosing schedule.^[42][43]
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.^[22]

Diet

Some research has suggested breastfeeding decreases the risk in later life^[44][45] and early introduction of gluten-containing cereals in the diet increases the risk of developing islet cell autoantibodies;^[33] various other nutritional risk factors are being studied, but no firm evidence has been found.^[46] Giving children 2000 IU of vitamin D daily during their first year of life is associated with reduced risk of type 1 diabetes, though the causal relationship is obscure.^[47]
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 niacinamide (vitamin B₃), had less than half the diabetes onset incidence in a seven-year time span than did the general population, and an even lower incidence relative to those with antibodies as above, but who received no niacinamide.^[48]
People with type 1 diabetes and undiagnosed celiac disease have worse glycaemic control and a higher prevalence of nephropathy and retinopathy. Gluten-free diet, when performed strictly, improves diabetes symptoms and appears to have a protective effect against developing long-term complications. Nevertheless, dietary management of both these diseases is challenging and these patients have poor compliance of the diet.^[49]