Diabetes mellitus type 1 (also known as type 1 diabetes, or T1DM; 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]
Untreated, type 1 diabetes is ultimately fatal; however, the disease can be controlled with supplemental insulin. Insulin is most commonly administered by injection at periodic intervals several times per day, though other options, such as insulin pumps, exist.
Insulin therapy must be continued indefinitely and does not usually impair normal daily activities. Patients are usually trained to manage their disease independently; however, for some this can be challenging.
Incidence varies from 8 to 17 per 100,000 in Northern Europe and the U.S. with a high of about 35 per 100,000 in Scandinavia to a low of 1 per 100,000 in Japan and China.[4]
Type 1 diabetes can be distinguished from type 2 by autoantibody testing - glutamic acid decarboxylase autoantibodies (GADA), islet cell autoantibodies (ICA), insulinoma-associated (IA-2) autoantibodies, and zinc transporter autoantibodies (ZnT8) are present in individuals with type 1 diabetes, but not type 2. The C-peptide assay, which measures endogenous insulin production, can also be used.
Type 1 diabetes can lead to a number of complications, both in the short term and in the long term. Furthermore, complications may arise from both low blood sugar and high blood sugar, both 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. In the short term, untreated type 1 diabetes can lead to diabetic ketoacidosis, and in the long term it can lead to eye damage, organ damage, etc.
Signs and symptoms[edit]
The classical symptoms of type 1 diabetes include: polyuria (frequent urination), polydipsia (increased thirst), xerostomia (dry mouth),polyphagia (increased hunger), fatigue, and weight loss.[3]
Many type 1 diabetics are diagnosed when they are present with diabetic ketoacidosis. The symptoms of diabetic ketoacidosis includexeroderma (dry skin), rapid deep breathing, drowsiness, abdominal pain, and vomiting.[5]
Cause[edit]
Although the precise cause of type 1 diabetes is unknown, it is believed to be caused by one or more of the following: genetic susceptibility, a diabetogenic trigger and/or exposure to a driving antigen.[6]
Boston Children’s Hospital research also identified ATP/P2X7R protein as a possible trigger.
Genetics[edit]
Main article: Genetic causes of diabetes mellitus type 1
Type 1 diabetes is a polygenic disease, meaning numerous genes contribute to its onset. 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.[7] Some variants also appear to be protective.[7]
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.[8]
Environmental[edit]
Environmental factors can influence expression of type 1. For identical twins, when one twin had type 1 diabetes, the other twin only had it 30%–50% of the time. Despite having exactly the same genome, one twin had the disease, whereas the other did not; this suggests environmental factors, in addition to genetic factors, can influence the disease's prevalence.[9] Other indications of environmental influence include the presence of a 10-fold difference in occurrence 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.[6]
Virus[edit]
One theory, discussed by DeLisa Fairweather and Noel R. Rose, among others,[10] 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. 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. 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 virus develops type 1 diabetes. This has suggested presence of a genetic vulnerability[11]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 is still poorly understood.
Diet[edit]
Some researchers believe the autoimmune response is influenced by antibodies against cow's milk proteins.[12]
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.[13]
Having a short breastfeeding period as well as short attendance at day care are associated with an elevated risk of type 1 diabetes in Czech children.[14]
Chemicals and drugs[edit]
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[edit]
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 theinnate immune system.[7][15]
Diagnosis[edit]
See also: Glycated hemoglobin and Glucose tolerance test
| Condition | 2 hour glucose | Fasting glucose | HbA1c |
|---|---|---|---|
| mmol/l(mg/dl) | mmol/l(mg/dl) | % | |
| Normal | <7.8 (<140) | <6.1 (<110) | <6.0 |
| Impaired fasting glycaemia | <7.8 (<140) | ≥ 6.1(≥110) & <7.0(<126) | 6.0–6.4 |
| Impaired glucose tolerance | ≥7.8 (≥140) | <7.0 (<126) | 6.0–6.4 |
| Diabetes mellitus | ≥11.1 (≥200) | ≥7.0 (≥126) | ≥6.5 |
Diabetes mellitus is characterized by recurrent or persistent hyperglycemia, and is diagnosed by demonstrating any one of the following:[18]
- 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 theWHO.)[19]
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.[20] 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.[21]
Autoantibodies[edit]
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 beingislet 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).[6] 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%.[6] 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.[6] Islet cell autoantibodies are detected by conventional immunofluorescence, while the rest are measured with specific radiobinding assays.[6]
Prevention[edit]
Type 1 diabetes is not currently preventable.[22] Some researchers believe it might be prevented at the latent autoimmune stage, before it starts destroying beta cells.[7]
Immunosuppressive drugs[edit]
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.[7]
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.[7] 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.[7] The duration of the effect is still unknown, however.[7] In 2011, Phase III studies with otelixizumab and teplizumab both failed to show clinical efficacy, potentially due to an insufficient dosing schedule.[23][24]
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.[7]
Diet[edit]
Some research has suggested breastfeeding decreases the risk in later life;[25][26] various other nutritional risk factors are being studied, but no firm evidence has been found.[27]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.[28]
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.[29]
Type 1 diabetes is also referred to as "sugar diabetes" due to the fact that a diet consisting of large amounts of sugar can be fatal. Diets consisting of large quantities of fat (i.e. butter and oil) also put the patient at a higher risk of cardiovascular disease.[citation needed]
Management[edit]
Further information: Diabetes management
Insulin therapy[edit]
Main article: Insulin therapy
Injections of insulin—either via subcutaneous injection or insulin pump— is necessary for those living with type 1 diabetes. It can't be treated with 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 usingglucose 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.[30] 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.[31]
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).[32] 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). 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, although the nonphysiological method of delivery[clarification needed] also plays a role. 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].
Pancreas transplantation[edit]
Main article: 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, 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, 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.[33]
Islet cell transplantation[edit]
Main article: 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 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 an identical twin is 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 involvingimmunosuppressants, which reduce immune system activity.
Recent studies have shown islet cell transplants have progressed to the point where 58% of the patients in one study were insulin-independent one year after transplantation.[34]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.
Stem Cell Educator Therapy[edit]
Stem Cell Educator Therapy induces immune balance by using cord blood-derived multipotent stem cells[35] with embryonic and hematopoietic characteristics. A closed-loop system that circulates a patient's blood through a blood cell separator, briefly co-cultures the patient's lymphocytes with adherent cord blood stem cells in vitro, and returns the educated lymphocytes (but not the cord blood stem cells) to the patient's circulation.[36] Through the Stem Cell Education process the patient's lymphocytes are modified by the Autoimmune Regulator AIRE that activates certain genes due to contact with the cord blood stem cells.
The clinical trial (NCT01350219) reveals that a single treatment with the Stem Cell Educator provides lasting reversal of autoimmunity that allows improvement of metabolic control[37] in subjects with long-standing type 1 diabetes. The on-going phase II clinical study about Stem Cell Educator Therapy has proved 100% effectiveness in type 1 diabetics, even in patients who lost the ability to produce their own insulin (C-peptide < 0,01 µg/l before treatment)[citation needed].
After treatment, the increased expression of co-stimulating molecules (specifically, CD28 and ICOS), increases in the number of CD4+CD25+Foxp3+ Tregs, and restoration ofTh1/Th2/Th3 cytokine balance indicate this therapy reverses autoimmunity, induces tolerance and promotes regeneration of islet beta cells[38] without showing any adverse effects so far.
Successful immune modulation by cord blood stem cells and the resulting clinical improvement in patient status may have important implications for other autoimmune diseases but does not raise any safety or ethical issues.
Psychological effects[edit]
Depression[edit]
Depression and depressive symptoms are generally more common in people living with type 1 diabetes. One review article suggested that the prevalence rate of depression is more than three times higher in diabetics than non-diabetics; an average prevalence of 12% was found (range of 5.8–43.4% in studies reviewed)[39] Women with type 1 diabetes are more likely to be depressed than men with type 1 diabetes,[39] and an increased incidence of depression has also been associated with youth with type 1 diabetes.[40] According to the Canadian Diabetes Association, 15% of people living with diabetes have major depression.[41] Psychological distress is also reported in the parents of youth with type 1 diabetes.[42] Recent evidence has suggested that reduced pre-frontal cortical thickness is associated with depression in people with type 1 diabetes. These neurological changes may be caused by long-term reduced glycemic control and may increase risk of depression.[43]
Eating disorders[edit]
Recent research has found that eating disorders are more common in females with type 1 diabetes[44] (prevalence = 10.15%) than in females without it (prevalence = 4.5%), as were sub-threshold eating disorders (13.8% vs. 7.6%)[45] Some participants (11.0%) in the same study reported manipulating insulin dosages to promote weight loss. Higher blood-sugar levels are associated with polyuria and reduced appetite, which can result in weight loss. Similarly, mean hemoglobin A1c levels were higher in participant with a DSM-IV disorder (9.4%) than those without (8.6%). This behavior was reported by 42% of participant who had a DSM-IV disorder.
The disorder of omission of insulin for weight control has been named diabulimia, a portmanteau of diabetes and bulimia, although it is not currently recognized as a formal diagnosis in the medical community.
Social cognition and self-care[edit]
Results from recent research suggest that people with type 1 diabetes may neglect precise self-care due to social fear related to fear of hypoglycemia.[46] Type 1 diabetics may also neglect physical activity due to reduced perceived position effects as well as increased perceived negative aspects of that activity.[47]
Complications[edit]
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[48] as well as neuropathy[49] may have an autoimmune basis, as well.
Driving[edit]
Studies conducted in the United States[50] and Europe[51] showed that drivers with type 1 diabetes had twice as many collisions as their nondiabetic 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 processes, coordination, and state of consciousness.[52][53] This disruption in brain functioning, neuroglycopenia, can impair driving ability.[52][54] 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.[55] 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[56] and are relatively slower at processing information.[57] 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, drivers with type 1 diabetes and a history of driving mishaps are recommended to never drive when their BG is less than 80 mg/dl. Instead, these drivers are advised to treat hypoglycemia and delay driving until their BG is above 90 mg/dl.[55] 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.[58][59][60] An internet-version of this training has also been shown to have significant beneficial results.[61] Additional NIH funded research to develop internet interventions specifically to help improve driving safety in drivers with type 1 diabetes is currently underway.[62]
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