Diabetes mellitus type 1
||It has been suggested that Honeymoon period (diabetes) be merged into this article. (Discuss) Proposed since December 2013.|
|Diabetes type 1|
|Classification and external resources|
A blue circle symbol for diabetes.
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. 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.
While lack of care could be lethal, administration of insulin remains essential for the survival of these patients. 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.
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.
- 1 Signs and symptoms
- 2 Cause
- 3 Pathophysiology
- 4 Diagnosis
- 5 Prevention
- 6 Management
- 7 Psychological effects
- 8 Complications
- 9 Epidemiology
- 10 Research
- 11 Labile diabetes
- 12 See also
- 13 References
- 14 External links
Signs and symptoms
Many type 1 diabetics are diagnosed when they are present with diabetic ketoacidosis. The symptoms of diabetic ketoacidosis include xeroderma (dry skin), rapid deep breathing, drowsiness, abdominal pain, and vomiting.
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.
Boston Children’s Hospital research also identified ATP/P2X7R protein as a possible trigger.
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. Some variants also appear to be protective.
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.
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. 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.
One theory, discussed by DeLisa Fairweather and Noel R. Rose, among others, 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 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.
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.
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.
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.
|Condition||2 hour glucose||Fasting glucose||HbA1c|
|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|
- 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.
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). 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%. 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.
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, potentially due to an insufficient dosing schedule.
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.
Some research has suggested breastfeeding decreases 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 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.
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 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 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.
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). 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 .
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.
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 involving immunosuppressants, 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. 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
Stem Cell Educator Therapy induces immune balance by using cord blood-derived multipotent stem cells 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. 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 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).
After treatment, the increased expression of co-stimulating molecules (specifically, CD28 and ICOS), increases in the number of CD4+CD25+Foxp3+ Tregs, and restoration of Th1/Th2/Th3 cytokine balance indicate this therapy reverses autoimmunity, induces tolerance and promotes regeneration of islet beta cells 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.
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) Women with type 1 diabetes are more likely to be depressed than men with type 1 diabetes, and an increased incidence of depression has also been associated with youth with type 1 diabetes. According to the Canadian Diabetes Association, 15% of people living with diabetes have major depression. Psychological distress is also reported in the parents of youth with type 1 diabetes. 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.
Recent research has found that eating disorders are more common in females with type 1 diabetes (prevalence = 10.15%) than in females without it (prevalence = 4.5%), as were sub-threshold eating disorders (13.8% vs. 7.6%) 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
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. Type 1 diabetics may also neglect physical activity due to reduced perceived positive effects as well as increased perceived negative aspects of that activity.
Complications of poorly managed type 1 diabetes mellitus may include cardiovascular disease, diabetic neuropathy, and diabetic retinopathy, among others. However, cardiovascular disease as well as neuropathy may have an autoimmune basis, as well.
Studies conducted in the United States and Europe 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. This disruption in brain functioning, neuroglycopenia, can 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, 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. 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.
Type 1 diabetes causes an estimated 5–10% of all diabetes cases or 11–22 million worldwide. 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. The incidence of type 1 diabetes has been increasing by about 3% per year.
Rates vary widely by country. In Finland, the incidence is a high of 35 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.
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. Studies using antibody testing (glutamic acid decarboxylase antibodies, islet cell antibodies, and insulinoma-associated autoantibodies) to distinguish between type 1 and type 2 diabetes demonstrate that most new-onset type 1 diabetes is seen in adults. Adult-onset type 1 autoimmune diabetes is two to three times more common than classic childhood-onset autoimmune diabetes.
In the US in 2008, about one million people were diagnosed with type 1 diabetes. 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).
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. The Juvenile Diabetes Research Foundation, 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, Diabetes Australia, the Canadian Diabetes Association.
Types of research
A significant amount of research is being undertaken in type 1 diabetes, and these will be outlined in the links that fund the research mentioned above. Clinical trials in type 1 diabetes that are currently ongoing can also be found online.
Generally the research can be divided into the following categories:
Before people get type 1 diabetes
Research here relates to prevention of type 1 diabetes in those deemed at risk.
After people get type 1 diabetes
Research here relates to therapies aimed at cure (islet transplant, pancreas transplant and stem cells), the artificial pancreas, prevention of diabetic complications, new insulins and other drugs for treating type 1 diabetes.
At the time people are diagnosed type 1 diabetes
People generally have some residual insulin producing beta cells present at the time they are diagnosed with type 1 diabetes. The exact number of cells is difficult to know but current estimates suggest that this can be anywhere between 10–25%. These cells are not sufficient to cope with the body's insulin requirements (which is why the blood sugar levels are high), and the person will need immediate insulin treatment. However preserving these cells has been shown to have long lasting health benefits including reducing the rates of hypoglycaemia and risks of complications. There is therefore a significant amount of research now being undertaken in patients newly diagnosed with type 1 diabetes to see if residual beta cells can be preserved. This research includes:
- using drugs to suppress the autoimmune response against the remaining beta cells. Many of these trials are coordinated via TRIALNET – an international group of researchers with an interest in preventing type 1 diabetes. These drugs can work either through suppressing the whole immune response (e.g. anti CD3, anti CD20, CTLA4-Ig, anti-IL1 beta), or whether more specific 'antigen specific' drugs can be found that just suppress the immune response against the islet. The latter will clearly be better because it has less risk of side effects, but is harder to achieve.
- adopting a healthier lifestyle to preserve beta cells. Research has already shown that exercise is very effective at preserving beta cells in people with type 2 diabetes. Therefore research is now being conducted to see if exercise can have the same benefit in type 1 diabetes.
Specific Areas of Research
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 to prevent 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 proinflammatory cytokines, the T-cells begin to release cytokines that inhibit inflammation. This phenomenon is commonly known as acquired immune tolerance.
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". The results of such swings can be irregular and unpredictable hyperglycemias, frequently involving ketosis, and sometimes serious hypoglycemias. Brittle diabetes occurs no more frequently than in 1% to 2% of diabetics. 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. 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. 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.
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:
- errors in diabetes management, which can include too much insulin being given.
- interactions with other medical conditions.
- psychological problems.
- biological factors that interfere with how insulin is processed within the body.
- hyperglycemia or hypoglycemia due to strenuous exercise.
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. 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.
- "Diabetes Blue Circle Symbol". International Diabetes Federation. 17 March 2006.
- "Type 1 Diabetes Mellitus". Retrieved 4 August 2008.
- Cooke DW, Plotnick L (November 2008). "Type 1 diabetes mellitus in pediatrics". Pediatr Rev 29 (11): 374–84; quiz 385. doi:10.1542/pir.29-11-374. PMID 18977856.
- Kasper, Dennis L; Braunwald, Eugene; Fauci, Anthony; et al. (2005). Harrison's Principles of Internal Medicine (16th ed.). New York: McGraw-Hill. ISBN 0-07-139140-1.
- "webmd Symptoms Type I Diabetes".
- Knip, M.; Veijola, R.; Virtanen, S. M.; Hyoty, H.; Vaarala, O.; Akerblom, H. K. (2005). "Environmental Triggers and Determinants of Type 1 Diabetes". Diabetes 54: S125–S136. doi:10.2337/diabetes.54.suppl_2.S125. PMID 16306330.
- Bluestone, J. A.; Herold, K.; Eisenbarth, G. (2010). "Genetics, pathogenesis and clinical interventions in type 1 diabetes". Nature 464 (7293): 1293–1300. Bibcode:2010Natur.464.1293B. doi:10.1038/nature08933. PMID 20432533.
- Genetics & Diabetes, Diabetes Information. Dr. Warram. Joslin Diabetes Center and Joslin Clinic
- "OMIM Entry – %222100 – DIABETES MELLITUS, INSULIN-DEPENDENT; IDDM". Ncbi.nlm.nih.gov. Retrieved 29 November 2011.
- "Nature Immunology 3", 338 – 340 (2002), doi:10.1038/ni0402-338
- "Donner", "Horst"; "Harald Rau, Paul G. Walfish, Jens Braun, Thorsten Siegmund, Reinhard Finke, Jürgen Herwig, Klaus H. Usadel and Klaus Badenhoop" ("2007"). "CTLA4 Alanine-17 Confers Genetic Susceptibility to Graves’ Disease and to type 1 Diabetes Mellitus". "The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 1 143–146". "The Journal of Clinical Endocrinology & Metabolism". Retrieved 6 February 2008.
- "content.nejm.org". content.nejm.org. Retrieved 29 November 2011.
- Hana Malcova, Zdenek Sumnik, Pavel Drevinek, Jitrenka Venhacova, Jan Lebl, Ondrej Cinek (7 October 2005). "Absence of breast-feeding is associated with the risk of type 1 diabetes: a case–control study in a population with rapidly increasing incidence". European Journal of Pediatrics 165 (Volume 165, Number 2 / February 2006): 114–119. doi:10.1007/s00431-005-0008-9. ISSN 0340-6199. PMID 16211397. (print) (online).
- Chatzigeorgiou A, Harokopos V, Mylona-Karagianni C, Tsouvalas E, Aidinis V, Kamper EF (September 2010). "The pattern of inflammatory/anti-inflammatory cytokines and chemokines in type 1 diabetic patients over time". Ann. Med. 42 (6): 426–38. doi:10.3109/07853890.2010.495951. PMID 20568978.
- Definition and diagnosis of diabetes mellitus and intermediate hyperglycemia: report of a WHO/IDF consultation. Geneva: World Health Organization. 2006. p. 21. ISBN 978-92-4-159493-6.
- Vijan, S (March 2010). "Type 2 diabetes". Annals of Internal Medicine 152 (5): ITC31-15. doi:10.1059/0003-4819-152-5-201003020-01003. PMID 20194231.
- World Health Organisation Department of Noncommunicable Disease Surveillance (1999). "Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications" (PDF).
- ""Diabetes Care" January 2010". American Diabetes Association. Retrieved 29 January 2010.
- Saydah SH, Miret M, Sung J, Varas C, Gause D, Brancati FL (August 2001). "Postchallenge hyperglycemia and mortality in a national sample of U.S. adults". Diabetes Care 24 (8): 1397–402. doi:10.2337/diacare.24.8.1397. PMID 11473076.
- Santaguida PL, Balion C, Hunt D, Morrison K, Gerstein H, Raina P, Booker L, Yazdi H. "Diagnosis, Prognosis, and Treatment of Impaired Glucose Tolerance and Impaired Fasting Glucose". Summary of Evidence Report/Technology Assessment, No. 128. Agency for Healthcare Research and Quality. Retrieved 20 July 2008.
- "Diabetes". World Health Organization. Retrieved 24 January 2011.
- "''Tolerx, Inc. and GlaxoSmithKline (GSK) Announce Phase 3 Defend-1 Study of Otelixizumab in Type 1 Diabetes Did Not Meet Its Primary Endpoint''". Biospace. Retrieved 29 November 2011.
- "Macrogenics press release: ''MacroGenics and Lilly Announce Pivotal Clinical Trial of Teplizumab Did Not Meet Primary Efficacy Endpoint''". Macrogenics.com. 20 October 2010. Retrieved 29 November 2011.
- Borch-Johnsen K, Joner G, Mandrup-Poulsen T, et al. (November 1984). "Relation between breast-feeding and incidence rates of insulin-dependent diabetes mellitus. A hypothesis". Lancet 2 (8411): 1083–6. doi:10.1016/S0140-6736(84)91517-4. PMID 6150150.
- Naim Shehadeh, Raanan Shamir, Moshe Berant, Amos Etzioni (2001). "Insulin in human milk and the prevention of type 1 diabetes". Pediatric Diabetes 2 (4): 175–7. doi:10.1034/j.1399-5448.2001.20406.x. PMID 15016183.
- Virtanen SM, Knip M (December 2003). "Nutritional risk predictors of beta cell autoimmunity and type 1 diabetes at a young age". The American Journal of Clinical Nutrition 78 (6): 1053–67. PMID 14668264.
- Hyppönen E, Läärä E, Reunanen A, Järvelin MR, Virtanen SM (November 2001). "Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study". Lancet 358 (9292): 1500–3. doi:10.1016/S0140-6736(01)06580-1. PMID 11705562.
- Elliott RB, Pilcher CC, Fergusson DM, Stewart AW (1996). "A population based strategy to prevent insulin-dependent diabetes using nicotinamide". Journal of Pediatric Endocrinology & Metabolism 9 (5): 501–9. doi:10.1515/JPEM.1918.104.22.1681. PMID 8961125.
- Dr James R Wright, Jr MD, in The Lancet, Volume 359, Issue 9313
- American Diabetes Association Clinical Guidelines, 2010.
- Jennifer L. Larsen. "Pancreas Transplantation: Indications and Consequences". Edrv.endojournals.org. Retrieved 29 November 2011.
- "Islet cell transplant: Experimental treatment for type 1 diabetes". Archived from the original on 10 April 2007. Retrieved 4 June 2007.
- Zhao Y, Lin B, Dingeldein M, Guo C, Hwang D, Holterman MJ. (May 2010). "New type of human blood stem cell: a double-edged sword for the treatment of type 1 diabetes". Transl Res. (Previous name: the Journal of Laboratory and Clinical Medicine) Epub 2010 Feb 12. 155 (5): 211–216. doi:10.1016/j.trsl.2010.01.003. PMID 20403575.
- Yong Zhao, Zhaoshun Jiang, Tingbao Zhao, Mingliang Ye, Chengjin Hu, Zhaohui Yin, Heng Li, Ye Zhang, Yalin Diao, Yunxiang Li, Yingjian Chen, Xiaoming Sun, Mary Beth Fisk, Randal Skidgel, Mark Holterman, Bellur Prabhakar, Theodore Mazzone (Jan 10, 2012). "Reversal of type 1 diabetes via islet β cell regeneration following immune modulation by cord blood-derived multipotent stem cells". BMC Medicine 2012, 10:3 doi:10.1186/1741-7015-10-3 10: 1–11. doi:10.1186/1741-7015-10-3. PMC 3322343. PMID 22233865.
- Yong Zhao (Oct 2012). "Stem cell educator therapy and induction of immune balance". Curr Diab Rep. 12 (5): 517–523. doi:10.1007/s11892-012-0308-1. PMID 22833322.
- Yong Zhao, Theodore Mazzone (Dec 2010). "Human cord blood stem cells and the journey to a cure for type 1 diabetes". Autoimmun Rev. Epub 2010 Aug 20. 10 (2): 103–107. doi:10.1016/j.autrev.2010.08.011. PMID 20728583.
- Roy, T., & Lloyd, C. E. (2012). Epidemiology of depression and Diabetes: A systematic review" Journal of Affective Disorders 142, 8–21. doi:10.1016/S0165-0327(12)70004-6
- Type 1 Diabetes: Poor blood sugar control linked to depression in youth with Diabetes. Mental Health Business Week (6 May 2006) 97.
- Jaser. S, S., Linsky, R., & Grey M. (2013). Coping and psychological distress in mothers of adolescents with Type 1 Diabetes. Maternal Child Health Journal, 19 Feb. [Epub ahead of print]
- Lyoo, I. K., Yoon, S., Jacobson, A. M., Hwang, J., Musen, G., Kim, J. E., Simonson, D. C., Bae, S., Bolo, N., Kim, D. J., Weinger, K., Lee, J. H., Ryan, C. M., & Renshaw, P. F. (2012). Prefrontal cortical deficits in type 1 diabetes mellitus: brain correlates of comorbid depression. Archives of General Pscyhiatry, 69, 1267–1276. doi:10.1001/archgenpsychiatry.2012.543
- Colton, P. A., Olmsted, M. P., Daneman D., & Rodin, G. M. (2013). Depression, disturbed eating behavior, and metabolic control in teenage girls with Type 1 Diabetes. Pediatric Diabetes, 19 Feb. doi:10.1111/pedi.12016
- Jones, Jennifer Michelle. (2000). Eating disorders in adolescent females with Type 1 Diabetes Mellitus: A controlled three-site study. ProQuest, UMI Dissertations Publishing. NQ49954.
- Di Battista, Ashley M., Hart, Trevor A., Greco, & Laurie, Gloizer. (2009). Type 1 Diabetes among adolescents: Reduced Diabetes self-care caused by social fear of hypoglycemia. The Diabetes Educator, 35, 465–475.
- Plotnikoff, Ronald C., Karunamuni, Nandini, & Brunet, Stephanie. (2009). A comparison of physical activity-related social-cognitive factors between those with Type 1 Diabetes and Diabetes free adults. Psychology, Health & Medicine, 14, 536–544.
- "Sridevi Devaraj, Nicole Glaser, Steve Griffen, Janice Wang-Polagruto, Eric Miguelino and Ishwarlal Jialal; "Increased Monocytic Activity and Biomarkers of Inflammation in Patients With Type 1 Diabetes"; ''Diabetes'' 2006 March 55: 774–779". Nature.com. Retrieved 29 November 2011.
- "Viktoria Granberg, MD, Niels Ejskjaer, MD, PHD, Mark Peakman, MD, PHD and Göran Sundkvist, MD, PHD; "Autoantibodies to Autonomic Nerves Associated With Cardiac and Peripheral Autonomic Neuropathy"; ''Diabetes Care'' 2005 28: 1959–1964". Care.diabetesjournals.org. Retrieved 29 November 2011.
- Songer, TJ. Low blood sugar and motor vehicle crashes in persons with type 1 diabetes, Annu Proc Assoc Adv Automotive Med, 46:424–427 (2002)
- Cox DJ, Penberthy JK, Zrebiec J, Weinger K, Aikens JE, Frier BM, Stetson B, DeGroot M, Trief P et al. (2003). "Diabetes and Driving Mishaps: Frequency and correlations from a multinational survey". Diabetes Care 26 (8): 2329–2334. doi:10.2337/diacare.26.8.2329. PMID 12882857.
- Cox DJ, Gonder-Frederick LA, Clarke WL (1993). "Driving decrements in type 1 diabetes during moderate hypoglycemia". [[Diabetes (journal)|]] 42 (2): 239–243. doi:10.2337/diabetes.42.2.239. PMID 8425660.
- Clarke WL, Cox DJ, Gonder-Frederick LA, Kovatchev B (1999). "Hypoglycemia and the Decision to Drive a Motor Vehicle by Persons With Diabetes". JAMA 282 (8): 750–754. doi:10.1001/jama.282.8.750. PMID 10463710.
- Cox D, Gonder-Frederick LA, Kovatchev BP, Julian DM, Clarke WL (2000). "Progressive hypoglycemia's impact on driving simulation performance". Diabetes Care 23 (2): 163–170. doi:10.2337/diacare.23.2.163. PMID 10868825.
- Cox DJ, Kovatchev BP, Anderson SM, Clarke WL, Gonder-Frederick LA (November 2010). "Type 1 diabetic drivers with and without a history of recurrent hypoglycemia-related driving mishaps: physiological and performance differences during euglycemia and the induction of hypoglycemia". Diabetes Care 33 (11): 2430–5. doi:10.2337/dc09-2130. PMC 2963507. PMID 20699432.
- Cox DJ, Gonder-Frederick LA, Kovatchev BP, Clarke WL (2002). "The metabolic demands of driving for drivers with type 1 diabetes mellitus". Diabetes/Metabolism Research and Review 18 (5): 381–385. doi:10.1002/dmrr.306.
- Campbell LK, Gonder-Frederick LA, Broshek DK, Kovatchev BP, Anderson S, Clarke WL & Cox DJ (2010). Neurocognitive differences between drivers with type 1 diabetes with and without a recent history of recurrent driving mishaps. International Journal of Diabetes in Developing Countries, 2(2), 73–77. NIHMS
- Cox DJ, Gonder-Frederick LA, Julian D, Clarke W (1994). "Long-term follow-up evaluation of blood glucose awareness training". Diabetes Care 17 (1): 1–5. doi:10.2337/diacare.17.1.1. PMID 8112183.
- Cox DJ, Gonder-Frederick LA, Polonsky W, Schlundt D, Julian D, Kovatchev B, Clarke WL (2001). "Blood Glucose Awareness Training (BGAT-II): Long term benefits". Diabetes Care 24 (4): 637–642. doi:10.2337/diacare.24.4.637. PMID 11315822.
- Broers S., le Cessie S., van Vliet KP, Spinhoven P., van der Ven NC, Radder JK (2002). "Blood glucose awareness training in Dutch type 1 diabetes patients". Diabet. Med. 19 (2): 157–161. doi:10.1046/j.1464-5491.2002.00682.x. PMID 11874433.
- Cox DJ, Ritterband L, Magee J, Clarke W, Gonder-Frederick L (2008). "Blood Glucose Awareness Training Delivered Over The Internet". Diabetes Care 31 (8): 1527–1528. doi:10.2337/dc07-1956. PMC 2494647. PMID 18477813.
- http://www.DiabetesDriving.com Diabetes Driving.
- Daneman, D (11 March 2006). "Type 1 diabetes". Lancet 367 (9513): 847–58. doi:10.1016/S0140-6736(06)68341-4. PMID 16530579.
- Aanstoot, HJ; Anderson, BJ, Daneman, D, Danne, T, Donaghue, K, Kaufman, F, Réa, RR, Uchigata, Y (October 2007). "The global burden of youth diabetes: perspectives and potential". Pediatric diabetes. 8. Suppl 8 (s8): 1–44. doi:10.1111/j.1399-5448.2007.00326.x. PMID 17767619.
- Soltesz, G; Patterson, CC, Dahlquist, G, EURODIAB Study, Group (October 2007). "Worldwide childhood type 1 diabetes incidence—what can we learn from epidemiology?". Pediatric diabetes. 8. Suppl 6 (s6): 6–14. doi:10.1111/j.1399-5448.2007.00280.x. PMID 17727380.
- Type 1 Diabetes in Adults: Principles and Practice, Informa Healthcare, 2008, p. 27.
- Johnson, Linda (18 November 2008). "Study: Cost of diabetes $218B". USA Today. Associated Press.
- Diabetes Research and Wellness Foundation
- Steffes, M. W.; Sibley, S.; Jackson, M.; Thomas, W. (2003). "-Cell Function and the Development of Diabetes-Related Complications in the Diabetes Control and Complications Trial". Diabetes Care 26 (3): 832–6. doi:10.2337/diacare.26.3.832. PMID 12610045.
- "New England Journal of Medicine: GAD Treatment and Insulin Secretion in Recent-Onset type 1 Diabetes". Content.nejm.org. Retrieved 29 November 2011.
- "Diamyd US Phase III Trial". Clinicaltrials.gov. Retrieved 29 November 2011.
- "Diamyd European Phase III Trial". Clinicaltrials.gov. Retrieved 29 November 2011.
- "Further Evidence for Lasting Immunological Efficacy of Diamyd Diabets Vaccine". Diamyd.com. 19 September 2007. Retrieved 29 November 2011.
- "Diamyd Announces Completion of type 1 Diabetes Vaccine Trial with Long Term Efficcacy Demonstrated at 30 Months". Diamyd.com. 21 January 2008. Retrieved 29 November 2011.
- MSNBC News: Pioneering Diamyd(r) Study to Prevent Childhood Diabetes Approved[dead link]
- "Diamyd press release: Diamyd approved for groundbreking study in Norway". Diamyd.com. Retrieved 29 November 2011.
- "Diabetes Prevention – Immune Tolerance (DIAPREV-IT)". Clinicaltrials.gov. Retrieved 29 November 2011.
- "jci.org". jci.org. 15 April 2000. Retrieved 29 November 2011.
- "Diabetes Mellitus (DM): Diabetes Mellitus and Disorders of Carbohydrate Metabolism: Merck Manual Professional". Merck.com. Retrieved 30 July 2010.
- Dorner M, Pinget M, Brogard JM (May 1977). "[Essential labile diabetes (author's transl)]". MMW Munch Med Wochenschr 119 (19): 671–4. PMID 406527.
- Higuchi, Chigusa; Tone, Atsuhito; Iseda, Izumi; Tsukamoto, Keiko; Katayama, Akihiro (2010). "A Pregnant Patient with Brittle Type 1 Diabetes Successfully Managed by CSII Therapy with Insulin Aspart". Journal of Diabetes & Metabolism 01. doi:10.4172/2155-6156.1000104.
- Cartwright, A.; Wallymahmed, M.; MacFarlane, I. A.; Wallymahmed, A.; Williams, G.; Gill, G. V. (2011). "The outcome of brittle type 1 diabetes--a 20 year study". QJM 104 (7): 575–9. doi:10.1093/qjmed/hcr010. PMID 21285231.
- Kent, La; Williams, G.; Gill, G.V. (1994). "Mortality and outcome of patients with brittle diabetes and recurrent ketoacidosis". The Lancet 344 (8925): 778. doi:10.1016/S0140-6736(94)92340-X.
- Davidson, MB; Kumar, D; Smith, W (1991). "Successful treatment of unusual case of brittle diabetes with sulfated beef insulin". Diabetes Care 14 (11): 1109–10. PMID 1797500.
- Fineberg, S. E.; Kawabata, T. T.; Finco-Kent, D.; Fountaine, R. J.; Finch, G. L.; Krasner, A. S. (2007). "Immunological Responses to Exogenous Insulin". Endocrine Reviews 28 (6): 625–52. doi:10.1210/er.2007-0002. PMID 17785428.
- Diabetes mellitus type 1 at DMOZ
- Kids and Teens: Type 1 Diabetes at DMOZ
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) – Diabetes in America Textbook (PDFs)
- IDF Diabetes Atlas
- International Diabetes Federation
- type 1 Diabetes at the American Diabetes Association
- National Diabetes Information Clearinghouse