Diabetes mellitus type 1

Diabetes type 1

A blue circle, the symbol for diabetes.[1]
Classification and external resources
Specialty Endocrinology
ICD-10 E10
ICD-9-CM 250.01
OMIM 222100
DiseasesDB 3649
MedlinePlus 000305
eMedicine med/546
MeSH D003922

Diabetes mellitus type 1 (also known as type 1 diabetes, or T1D; formerly insulin-dependent diabetes or juvenile diabetes) is a form of diabetes mellitus that results from the autoimmune destruction of the insulin-producing beta cells in the pancreas.[2] 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.[3]

The cause of diabetes mellitus type 1 is unknown.[4] Type 1 diabetes can be distinguished from type 2 by autoantibody testing. The C-peptide assay, which measures endogenous insulin production, can also be used.

Administration of insulin is essential for survival. Insulin therapy must be continued indefinitely and typically does not impair normal daily activities. People are usually trained to independently manage their diabetes; however, for some this can be challenging. Untreated, diabetes can cause many complications.[4] Acute complications include diabetic ketoacidosis and nonketotic hyperosmolar coma. Serious long-term complications related to high blood sugar include heart disease, stroke, kidney failure, foot ulcers and damage to the eyes.[4] Furthermore, complications may arise from low blood sugar caused by excessive insulin treatment.

Diabetes mellitus type 1 accounts for between 5% and 10% of all diabetes cases.[5][6] Globally, the number of people with DM type 1 is unknown,[7] although it is estimated that about 80,000 children develop the disease each year.[7] Within the United States the number of affected persons is estimated at one to three million.[7][8] The development of new cases vary by country and region; the lowest rates appear to be in Japan and China with approximately 1 person per 100,000 per year; the highest rates are found in Scandinavia where it is closer to 35 new cases per 100,000 per year.[9] The United States and other countries in northern Europe fall somewhere in between with 8-17 new cases per 100,000 per year.[9]

Signs and symptoms

Overview of the most significant symptoms of diabetes

The classical symptoms of type 1 diabetes include: polyuria (excessive urination), polydipsia (increased thirst), xerostomia (dry mouth), polyphagia (increased hunger), fatigue, and weight loss.[3]

Many type 1 diabetics are diagnosed when they present with diabetic ketoacidosis. The signs and symptoms of diabetic ketoacidosis include xeroderma (dry skin), rapid deep breathing, drowsiness, abdominal pain, and vomiting.[10]

About 12 percent of people with type 1 diabetes have clinical depression.[11]

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/or exposure to an antigen.[12]

Genetics

Type 1 diabetes is a disease that involves many genes. More than 50 genes are associated to type 1 diabetes.[13] 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.[14] Some variants also appear to be protective.[14]

The risk of a child developing type 1 diabetes is about 10% if the father has it, about 10% if a sibling has it, about 4% if the mother has type 1 diabetes and was aged 25 or younger when the child was born, and about 1% if the mother was over 25 years old when the child was born.[15]

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 environmental factors, in addition to genetic factors, can influence the disease's prevalence.[16] 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.[12]

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.[17] The Coxsackie virus family or rubella is implicated, although the evidence is inconclusive. This vulnerability is not shared by everyone, for not everyone infected by the suspected virus develops type 1 diabetes. This has suggested presence of a genetic vulnerability[18] 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 autoimmune reaction remains poorly understood.

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 after ingestion. Pyrinuron was withdrawn from the U.S. market in 1979 but is still used in some countries. Streptozotocin (Zanosar), an antibiotic and antineoplastic agent used in chemotherapy for pancreatic cancer, 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 1 is 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+ T helper cells and CD8+ T cells, autoantibody-producing B cells and activation of the innate immune system.[14][19]

After starting treatment with insulin a person's own insulin levels may temporarily improve.[20] This is believed to be due to altered immunity and is known as the "honeymoon phase".[20]

Diagnosis

WHO diabetes diagnostic criteria[21][22]  
Condition 2 hour glucose Fasting glucose HbA1c
Unitmmol/l(mg/dl)mmol/l(mg/dl) mmol/mol DCCT %
Normal <7.8 (<140)<6.1 (<110) <42 <6.0
Impaired fasting glycaemia <7.8 (<140) ≥6.1(≥110) & <7.0(<126) 42-46 6.0–6.4
Impaired glucose tolerance≥7.8 (≥140) <7.0 (<126) 42-46 6.0–6.4
Diabetes mellitus ≥11.1 (≥200) ≥7.0 (≥126) ≥48 ≥6.5

Diabetes mellitus is characterized by recurrent or persistent hyperglycemia, and is diagnosed by demonstrating any one of the following:[23]

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 unexplained 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 (low blood sugar).

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.[25] According to the current definition, two fasting glucose measurements above 126 mg/dL (7.0 mmol/L) is considered diagnostic for diabetes mellitus.

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. Type 2 diabetes is characterized by insulin resistance, while type 1 diabetes is characterized by insulin deficiency, generally without insulin resistance. Another hallmark of type 1 diabetes is islet autoreactivity, which is generally measured by the presence of autoantibodies directed towards the beta cells.

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), autoantibodies targeting the phosphatase-related IA-2 molecule, and zinc transporter autoantibodies (ZnT8).[12] By 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 progresses 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%.[12] The time interval from emergence of autoantibodies to clinically diagnosable diabetes 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.[12] Islet cell autoantibodies are detected by conventional immunofluorescence, while the rest are measured with specific radiobinding assays.[12]

Prevention

Type 1 diabetes is not currently preventable.[26] Some researchers believe it might be prevented at the latent autoimmune stage, before it starts destroying beta cells.[14]

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.[14]

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.[14] 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.[14] The duration of the effect is still unknown, however.[14] In 2011, Phase III studies with otelixizumab and teplizumab both failed to show clinical efficacy, potentially due to an insufficient dosing schedule.[27][28]

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.[14]

Diet

Some research has suggested breastfeeding decreases the risk in later life;[29][30] various other nutritional risk factors are being studied, but no firm evidence has been found.[31] 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.[32]

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 the niacinamide version, 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.[33]

Management

Further information: Diabetes management

Lifestyle

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.[34]

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.

Because of the insulin deficiency, injections of insulin—either via subcutaneous injection or insulin pump— is necessary for those living with type 1 diabetes. It cannot be treated by diet and exercise alone. 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.[35] 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 with different onset or duration of action times.

Untreated type 1 diabetes commonly leads to coma, often from diabetic ketoacidosis, which is fatal if untreated. Diabetic ketoacidosis can cause cerebral edema (accumulation of liquid in the brain). This complication is life-threatening. Children are at an increased risk for cerebral edema, making ketoacidosis the most common cause of death in pediatric diabetes.[36]

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).[37] 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 HbA1c level of less than 7.5%.[7]

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.

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.[38]

Islet cell transplantation

Islet cell transplantation may be an option for some people with type 1 diabetes that are not well controlled with insulin.[39] 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.[39] Success rates, defined as not needing insulin at 3 years follow the procedure occurred in 44% in on registry from 2010.[39]

Complications

Complications of poorly managed type 1 diabetes mellitus may include cardiovascular disease, diabetic neuropathy, and diabetic retinopathy, among others. However, cardiovascular disease[40] as well as neuropathy[41] 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.[42]

Urinary tract infection

People with diabetes show an increased rate of urinary tract infection.[43] 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.[44]

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.[45][46]

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."[45] 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.[47]

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.[46] Common problems include reduced sensation in the genitals, dryness, difficulty/inability to orgasm, pain during sex, and decreased libido.[45] In some cases diabetes has been shown to decrease oestrogen levels in females, which can affect vaginal lubrication.[46]

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.[46] As with any medication, side effects should be taken into account and monitored to prevent serious complications with diabetes.[46]

Epidemiology

Type 1 diabetes causes an estimated 5–10% of all diabetes cases[48] or 11–22 million worldwide.[26] 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.[49] The incidence of type 1 diabetes has been increasing by about 3% per year.[49]

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.[9][50]

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. Compared to non-Hispanic whites, Asian Americans, Hispanic Americans and Hispanic-Black Americans have greater odds of being diagnosed with diabetes. Every year about 234,051 Americans die due to diabetes or diabetes-related complications, with 69,071 having it as the primary cause of death.[51]

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.[52] 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.[53] The name juvenile diabetes was used earlier as it often first is diagnosed in childhood.

Society and culture

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.[54] In the United States $245 billion every year is attributed to diabetes. Individuals diagnosed with diabetes have 2.3 times the health care costs than individuals who do not have diabetes. 1 in 10 health care dollars are spent on individuals with diabetes.[51]

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, originally 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,[55] Diabetes Australia, the Canadian Diabetes Association.

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.[56] In 2014 more mature beta cells were produced which released insulin in response to blood sugar when transplanted into mice.[57][58] Before these techniques can be used in humans more evidence of safety and effectiveness is needed.[56]

Vaccine

Vaccines to treat or prevent Type 1 diabetes are designed to induce immune tolerance to insulin or pancreatic beta cells.[59] 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.[59] As of 2014, other approaches, such as a DNA vaccine encoding proinsulin and a peptide fragment of insulin, were in early clinical development.[59]

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".[60] 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.[61] An insulin pump may be recommended for brittle diabetes to reduce the number of hypoglycemic episodes and better control the morning rise of blood sugar due to the dawn phenomenon.[62] 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.[63] 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.[64]

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:[65]

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, cause 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.[65] 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.[66]

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