Type 1 diabetes

From Wikipedia, the free encyclopedia

Type 1 diabetes
Other namesDiabetes mellitus type 1, insulin-dependent diabetes,[1] juvenile diabetes[2]
Blue circle for diabetes.svg
A blue circle, the symbol for diabetes.[3]
Pronunciation
  • /daɪəbiːtəs/
SpecialtyEndocrinology
SymptomsFrequent urination, increased thirst, increased hunger, weight loss[4]
ComplicationsDiabetic ketoacidosis, nonketotic hyperosmolar coma, poor healing, cardiovascular disease, damage to the eyes[2][4][5]
Usual onsetRelatively short period of time[1]
DurationLong term[4]
CausesBody does not produce enough insulin[4]
Risk factorsFamily history, celiac disease[5][6]
Diagnostic methodBlood sugar, A1C[5][7]
PreventionUnknown[4]
TreatmentInsulin, diabetic diet, exercise[1][2]
Frequency~7.5% of diabetes cases[8]

Type 1 diabetes (T1D), previously known as juvenile diabetes, is an autoimmune disease that is a form of diabetes in which very little or no insulin is produced by the islets of Langerhans (containing beta cells) in the pancreas.[4] Insulin is a hormone required for the cells to use blood sugar for energy and it helps regulate normal glucose levels in the bloodstream.[2] Before treatment this results in high blood sugar levels in the body.[1] The common symptoms are frequent urination, increased thirst, increased hunger, and weight loss.[4][9] Additional symptoms may include blurry vision, tiredness, and slow wound healing.[2] Symptoms typically develop over a short period of time, often a matter of weeks.[1]

The cause of type 1 diabetes is unknown,[4] but it is believed to involve a combination of genetic and environmental factors.[1] Risk factors include having a family member with the condition.[5] The underlying mechanism involves an autoimmune destruction of the insulin-producing beta cells in the pancreas.[2] Diabetes is diagnosed by testing the level of sugar or glycated hemoglobin (HbA1C) in the blood.[5][7] Type 1 diabetes can be distinguished from type 2 by testing for the presence of autoantibodies.[5]

There is no known way to prevent type 1 diabetes.[4] Treatment with insulin is required for survival.[1] Insulin therapy is usually given by injection just under the skin but can also be delivered by an insulin pump.[10] A diabetic diet and exercise are important parts of management.[2] If left untreated, diabetes can cause many complications.[4] Complications of relatively rapid onset include diabetic ketoacidosis and nonketotic hyperosmolar coma.[5] Long-term complications include heart disease, stroke, kidney failure, foot ulcers and damage to the eyes.[4] Furthermore, since insulin lowers blood sugar levels, complications may arise from low blood sugar if excessive amount of insulin is taken than necessary.[5]

Type 1 diabetes makes up an estimated 5–10% of all diabetes cases.[8] The number of people affected globally is unknown, although it is estimated that about 80,000 children develop the disease each year.[5] Within the United States the number of people affected is estimated at one to three million.[5][11] Rates of disease vary widely, with approximately one new case per 100,000 per year in East Asia and Latin America and around 30 new cases per 100,000 per year in Scandinavia and Kuwait.[12][13] It typically begins in children and young adults.[1]

Signs and symptoms[]

Overview of the most significant symptoms of diabetes

Type 1 diabetes begins suddenly, typically in childhood or adolescence.[14] The major sign of type 1 diabetes is very high blood sugar, which typically manifests in children as a few days to weeks of polyuria (increased urination), polydipsia (increased thirst), and weight loss.[15][16] Sometimes children can also experience increased appetite, blurred vision, bedwetting, recurrent skin infections, candidiasis of the perineum, irritability, and performance issues at school.[15][16] Adults with type 1 diabetes tend to have more varied symptoms that come on over months rather than days to weeks.[17][16]

Prolonged lack of insulin can also result in diabetic ketoacidosis, characterized by persistent fatigue, dry or flushed skin, abdominal pain, nausea or vomiting, confusion, trouble breathing, and a fruity breath odor.[17][18] Blood and urine tests reveal unusually high glucose and ketones in the blood and urine.[19] Untreated ketoacidosis can rapidly progress to loss of consciousness, coma, and death.[19] The percentage of children whose type 1 diabetes begins with an episode of diabetic ketoacidosis varies widely by geography, as low as 15% in parts of Europe and North America, and as high as 80% in the developing world.[19]

Cause[]

Type 1 diabetes is caused by the destruction of β-cells – the only cells in the body that produce insulin – and the consequent progressive insulin deficiency. Without insulin, the body is unable to respond effectively to increases in blood sugar and diabetics have persistent hyperglycemia.[20] In 70-90% of cases, β-cells are destroyed by someone's own immune system, for reasons that are not entirely clear.[20] The best-studied component of this autoimmune response are β-cell-targeted antibodies that begin to develop in the months or years before symptoms arise.[20] Typically someone will first develop antibodies against insulin or the protein GAD65, followed eventually by antibodies against the proteins IA-2, IA-2β, and/or ZNT8. People with more of these antibodies, and who develop them earlier in life, are at higher risk for developing symptomatic type 1 diabetes.[21] The trigger for the development of these antibodies remains unclear.[22] A number of explanatory theories have been put forward, and the cause may involve genetic susceptibility, a diabetogenic trigger, and/or exposure to an antigen.[23] The remaining 10-30% of type 1 diabetics have β-cell destruction but no sign of autoimmunity; this is called idiopathic type 1 diabetes and its cause remains unclear.[20]

Environmental[]

Various environmental risks have been studied in an attempt to understand what triggers β-cell autoimmunity. Many aspects of environment and life history are associated with slight increases in type 1 diabetes risk, however the connection between each risk and diabetes often remains unclear. Type 1 diabetes risk is slightly higher for children whose mothers are obese or older than 35, or for children born by caesarean section.[24] Similarly, a child's weight gain in the first year of life, total weight, and BMI are associated with slightly increased type 1 diabetes risk.[24] Some dietary habits have also been associated with type 1 diabetes risk, namely consumption of cow's milk and dietary sugar intake.[24] Animal studies and some large human studies have found small associations between type 1 diabetes risk and intake of gluten or dietary fiber; however, other large human studies have found no such association.[24] Many potential environmental triggers have been investigated in large human studies and found to be unassociated with type 1 diabetes risk including duration of breastfeeding, time of introduction of cow milk into the diet, vitamin D consumption, blood levels of active vitamin D, and maternal intake of omega-3 fatty acids.[24][25]

A longstanding hypothesis for an environmental trigger is that some viral infection early in life contributes to type 1 diabetes development. Much of this work has focused on enteroviruses, with some studies finding slight associations with type 1 diabetes, and others finding none.[26] Large human studies have searched for, but not yet found an association between type 1 diabetes and various other viral infections, including infections of the mother during pregnancy.[26] Conversely, some have postulated that reduced exposure to pathogens in the developed world increases the risk of autoimmune diseases, often called the hygiene hypothesis. Various studies of hygiene-related factors – including household crowding, daycare attendance, population density, childhood vaccinations, antihelminth medication, and antibiotic usage during early life or pregnancy – show no association with type 1 diabetes.[27]

Genetics[]

Type 1 diabetes is partially caused by genetics, and family members of type 1 diabetics have a higher risk of developing the disease themselves. In the general population, the risk of developing type 1 diabetes is around 1 in 250. For someone whose parent has type 1 diabetes, the risk rises to 1-9%. If a sibling has type 1 diabetes, the risk is 6-7%. If someone's identical twin has type 1 diabetes, they have a 30-70% of developing it themselves.[28]

About half of the disease's heritability is due to variations in three HLA class 2 genes involved in antigen presentation: HLA-DRB1, HLA-DQA1, and HLA-DQB1.[28] The variation patterns asssociated with increased risk of type 1 diabetes are called HLA-DR3 and HLA-DR4-HLA-DQ8, and are common in people of European descent. A pattern associated with reduced risk of type 1 diabetes is called HLA-DR15-HLA-DQ6.[28] Large genome-wide association studies have identified dozens of other genes associated with type 1 diabetes risk, mostly genes involved in the immune system.[28]

Chemicals and drugs[]

Some chemicals and drugs selectively destroy pancreatic cells. Pyrinuron (Vacor), a rodenticide introduced in the United States in 1976, selectively destroys pancreatic beta cells, resulting in type 1 diabetes after accidental poisoning.[29] Pyrinuron was withdrawn from the U.S. market in 1979 and it is not approved by the Environmental Protection Agency for use in the U.S.[30] Streptozotocin (Zanosar), an antineoplastic agent, is selectively toxic to the beta cells of the pancreatic islets. It is used in research for inducing type 1 diabetes on rodents[31] and for treating metastatic cancer of the pancreatic islet cells in patients whose cancer cannot be removed by surgery.[32] Other pancreatic problems, including trauma, pancreatitis, or tumors (either malignant or benign) can also lead to loss of insulin production.

Monoclonal antibodies used for the treatment of cancer (checkpoint inhibitors inhibiting PD-1 and PD-L1), especially nivolumab and pembrolizumab have been reported to occasionally induce autoimmune diabetes.[33]

Diagnosis[]

Diabetes is typically diagnosed by a blood test showing unusually high blood sugar. The World Health Organization defines diabetes as blood sugar levels at or above 7.0 mmol/L (126 mg/dL) after fasting for at least eight hours, or a glucose level at or above 11.1 mmol/L (200 mg/dL) two hours after an oral glucose tolerance test.[34] The American Diabetes Association additionally recommends a diagnosis of diabetes for anyone with symptoms of hyperglycemia and blood sugar at any time at or above 11.1 nmol/L, or glycated hemoglobin (hemoglobin A1C) levels at or above 48 mmol/mol.[35]

Once a diagnosis of diabetes is established, type 1 diabetes is distinguished from other types by a blood test for the presence of autoantibodies that target various components of the beta cell.[36] The most commonly available tests detect antibodies against glutamic acid decarboxylase, the beta cell cytoplasm, or insulin, each of which are targeted by antibodies in around 80% of type 1 diabetics.[36] Some healthcare providers also have access to tests for antibodies targeting the beta cell proteins IA-2 and ZnT8; these antibodies are present in around 58% and 80% of type 1 diabetics respectively.[36] Some also test for , a byproduct of insulin synthesis. Very low C-peptide levels are suggestive of type 1 diabetes.[36]

Management[]

Further information: Diabetes management

The mainstay of type 1 diabetes treatment is the regular injection of insulin to manage hyperglycemia.[37] Injections of insulin – via subcutaneous injection using either a syringe or an insulin pump – are necessary multiple times per day, adjusting dosages to account for food intake, blood glucose levels and physical activity.[37] The goal of treatment is to maintain blood sugar in a normal range – 80–130 mg/dL before a meal; <180 mg/dL after – as often as possible.[38] To achieve this, people with diabetes often monitor their blood glucose levels at home. Healthcare providers can also monitor someone's hemoglobin A1C levels which reflect the average blood sugar over the last three months.[39] For most adults, the American Diabetes Association recommends a goal of keeping hemoglobin A1C levels under 7%.[39]

The ultimate goal 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).[5]

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 one to two hours with peak action of four to 10 hours. Long-acting insulin is usually given at the same time once per day.[40] The action onset is roughly 1 to 2 hours with a sustained action of up to 24 hours. Some insulins are biosynthetic products produced using genetic recombination techniques; formerly, cattle or pig insulins were used, and even sometimes insulin from fish.[41]

People with type 1 diabetes always need to use insulin, but treatment can lead to hypoglycemia, i.e. blood glucose 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. Symptoms include excess sweating, excessive hunger, fainting, fatigue, lightheadedness and shakiness.[42] 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 continuous glucose monitors still have a margin of error.[43]

The only non-insulin medication approved by the U.S. Food and Drug Administration is the amylin analog pramlintide, which replaces the beta-cell hormone amylin. Occasionally, metformin, GLP-1 receptor agonists, Dipeptidyl peptidase-4 inhibitors, or SGLT2 inhibitor are prescribed off-label to people with type 1 diabetes, although fewer than 5% of type 1 diabetics use these drugs.[37]

Lifestyle[]

There is limited evidence for the usefulness of routine use of low-carbohydrate dieting for people with type 1 diabetes.[44] Although for certain individuals it may be feasible to follow a low-carbohydrate regime combined with carefully managed insulin dosing, this is hard to maintain and there are concerns about possible adverse health effects caused by the diet.[44] In general, people with type 1 diabetes are advised to follow an individualized eating plan rather than a pre-decided one.[44]

There are camps for children to teach them how and when to use or monitor their insulin without parental help.[45] 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.[46]

Pancreas transplantation[]

Main article: Pancreas transplantation

In some cases, a pancreas transplant can restore proper glucose regulation. However, the surgery and accompanying immunosuppression required may be more dangerous than continued insulin replacement therapy, so is generally only used with or some time after a kidney transplant. One reason for this is that introducing a new kidney requires taking immunosuppressive drugs such as cyclosporine, which 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.[47]

Islet cell transplantation[]

Main article: Islet cell transplantation

Islet cell transplantation may be an option for some people with type 1 diabetes that is not well controlled with insulin.[48] Difficulties include finding donors that are compatible, getting the new islets to survive, and the side effects from the medications used to prevent rejection.[48][49] Success rates, defined as not needing insulin at 3 years following the procedure, occurred in 44% of people on registry from 2010.[48] In the United States, as of 2016, it is considered an experimental treatment.[49]

Pathophysiology[]

The pathophysiology in diabetes type 1 is a destruction of beta cells in the pancreas. Individual risk factors can have separate pathophysiological processes to cause this beta cell destruction. Still, a process that appears to be common to most risk factors is a type IV hypersensitivity 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.[50][51]

After starting treatment with insulin a person's own insulin levels may temporarily improve.[52] This is believed to be due to altered immunity and is known as the "honeymoon phase".[52]

Alpha cell dysfunction[]

Onset of autoimmune diabetes is accompanied by impaired ability to regulate the hormone glucagon,[53] which acts in antagonism with insulin to regulate blood sugar and metabolism. Progressive beta cell destruction leads to dysfunction in the neighboring alpha cells which secrete glucagon, exacerbating excursions away from euglycemia in both directions; overproduction of glucagon after meals causes sharper hyperglycemia, and failure to stimulate glucagon upon hypoglycemia prevents a glucagon-mediated rescue of glucose levels.[54]

Hyperglucagonemia[]

Onset of type 1 diabetes is followed by an increase in glucagon secretion after meals. Increases have been measured up to 37% during the first year of diagnosis, while c-peptide levels (indicative of islet-derived insulin), decline by up to 45%.[55] Insulin production will continue to fall as the immune system destroys beta cells, and islet-derived insulin will continue to be replaced by therapeutic exogenous insulin. Simultaneously, there is measurable alpha cell hypertrophy and hyperplasia in the early stage of the disease, leading to expanded alpha cell mass. This, together with failing beta cell insulin secretion, begins to account for rising glucagon levels that contribute to hyperglycemia.[54] Some researchers believe glucagon dysregulation to be the primary cause of early stage hyperglycemia.[56] Leading hypotheses for the cause of postprandial hyperglucagonemia suggest that exogenous insulin therapy is inadequate to replace the lost intraislet signalling to alpha cells previously mediated by beta cell-derived pulsatile insulin secretion.[57][58] Under this working hypothesis intensive insulin therapy has attempted to mimic natural insulin secretion profiles in exogenous insulin infusion therapies.[59]

Hypoglycemic glucagon impairment[]

Glucagon secretion is normally increased upon falling glucose levels, but normal glucagon response to hypoglycemia is blunted in type 1 diabetics.[60][61] Beta cell glucose sensing and subsequent suppression of administered insulin secretion is absent, leading to islet hyperinsulinemia which inhibits glucagon release.[60][62]

Autonomic inputs to alpha cells are much more important for glucagon stimulation in the moderate to severe ranges of hypoglycemia, yet the autonomic response is blunted in a number of ways. Recurrent hypoglycemia leads to metabolic adjustments in the glucose sensing areas of the brain, shifting the threshold for counter regulatory activation of the sympathetic nervous system to lower glucose concentration.[62] This is known as hypoglycemic unawareness. Subsequent hypoglycemia is met with impairment in sending of counter regulatory signals to the islets and adrenal cortex. This accounts for the lack of glucagon stimulation and epinephrine release that would normally stimulate and enhance glucose release and production from the liver, rescuing the diabetic from severe hypoglycemia, coma, and death. Numerous hypotheses have been produced in the search for a cellular mechanism of hypoglycemic unawareness, and a consensus has yet to be reached.[63] The major hypotheses are summarized in the following table:[64][62][63]

Mechanisms of hypoglycemic unawareness
Glycogen supercompensation Increased glycogen stores in astrocytes might contribute supplementary glycosyl units for metabolism, counteracting the central nervous system perception of hypoglycemia.
Enhanced glucose metabolism Altered glucose transport and enhanced metabolic efficiency upon recurring hypoglycemia relieves oxidative stress that would activate sympathetic response.
Alternative fuel hypothesis Decreased reliance on glucose, supplementation of lactate from astrocytes, or ketones meet metabolic demands and reduce stress to brain.
Brain neuronal communication Hypothalamic inhibitory GABA normally decreases during hypoglycemia, disinhibiting signals for sympathetic tone. Recurrent episodes of hypoglycemia result in increased basal GABA which fails to decrease normally during subsequent hypoglycemia. Inhibitory tone remains and sympathetic tone is not increased.

In addition, autoimmune diabetes is characterized by a loss of islet specific sympathetic innervation.[65] This loss constitutes an 80-90% reduction of islet sympathetic nerve endings, happens early in the progression of the disease, and is persistent though the life of the patient.[66] It is linked to the autoimmune aspect of type 1 diabetics and fails to occur in type 2 diabetics. Early in the autoimmune event, the axon pruning is activated in islet sympathetic nerves. Increased BDNF and ROS that result from insulitis and beta cell death stimulate the p75 neurotrophin receptor (p75NTR), which acts to prune off axons. Axons are normally protected from pruning by activation of tropomyosin receptor kinase A (Trk A) receptors by NGF, which in islets is primarily produced by beta cells. Progressive autoimmune beta cell destruction, therefore, causes both the activation of pruning factors and the loss of protective factors to the islet sympathetic nerves. This unique form of neuropathy is a hallmark of type 1 diabetes, and plays a part in the loss of glucagon rescue of severe hypoglycemia.[65]

Complications[]

Further information: Complications of diabetes

The most pressing complication of type 1 diabetes are the always present risks of poor blood sugar control: severe hypoglycemia and diabetic ketoacidosis. Acute hypoglycemia can develop rapidly, causing confusion, loss of consciousness, and seizure.[67] On average, people with type 1 diabetes experience a hypoglycemia event that requires assistance of another 16-20 times in 100 person-years, and an event leading to unconsciousness or seizure 2-8 times per 100 person-years.[67] Acute hypoglycemic events cause 4-10% of type 1 diabetes-related deaths.[67] The other persistent risk is diabetic ketoacidosis – a state where lack of insulin results in cells burning fat rather than sugar, producing toxic ketones as a byproduct.[18] 13-19% of type 1 diabetes-related deaths are caused by ketoacidosis.[67] Diabetic ketoacidosis can cause cerebral edema (accumulation of liquid in the brain). This is a life-threatening issue and children are at a higher risk for cerebral edema than adults, causing ketoacidosis to be the most common cause of death in pediatric diabetes.[68]

In addition to the acute complications of diabetes, long-term hyperglycemia results in vascular damage that can affect various parts of the body. This vascular damage can manifest most prominently as cardiovascular disease, which is estimated to shorten the life of the average type 1 diabetic by 8-13 years.[69] Other complications of poorly managed type 1 diabetes may include diabetic neuropathy and diabetic retinopathy, among others. However, cardiovascular disease[70] as well as neuropathy[71] 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.[72]

About 12 percent of people with type 1 diabetes have clinical depression.[73] About 6 percent of people with type 1 diabetes also have celiac disease, but in most cases there are no digestive symptoms[6][74] or are mistakenly attributed to poor control of diabetes, gastroparesis or diabetic neuropathy.[74] In most cases, celiac disease is diagnosed after onset of type 1 diabetes. The association of celiac disease with type 1 diabetes increases the risk of complications, such as retinopathy and mortality. This association can be explained by shared genetic factors, and inflammation or nutritional deficiencies caused by untreated celiac disease, even if type 1 diabetes is diagnosed first.[6]

Urinary tract infection[]

People with diabetes show an increased rate of urinary tract infection.[75] The reason is bladder dysfunction is more common in people with diabetes than people without diabetes due to diabetes 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.[76]

Sexual dysfunction[]

Sexual dysfunction in people with diabetes is often a result of physical factors such as nerve damage and poor circulation, and psychological factors such as stress and/or depression caused by the demands of the disease.[77]

Males[]

The most common sexual issues in males with diabetes 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." Another cause of erectile dysfunction is reactive oxygen species created as a result of the disease. Antioxidants can be used to help combat this.[78]

Females[]

Sexual problems are common in women who have diabetes,[77] including reduced sensation in the genitals, dryness, difficulty/inability to orgasm, pain during sex, and decreased libido. Diabetes sometimes decreases estrogen levels in females, which can affect vaginal lubrication. Less is known about the correlation between diabetes and sexual dysfunction in females than in males.[77]

Oral contraceptive pills can cause blood sugar imbalances in women who have diabetes. Dosage changes can help address that, at the risk of side effects and complications.[77]

Women with type 1 diabetes show a higher than normal rate of polycystic ovarian syndrome (PCOS).[79] The reason may be that the ovaries are exposed to high insulin concentrations since women with type 1 diabetes can have frequent hyperglycemia.[80]

Autoimmune disorders[]

People with type 1 diabetes are at an increased risk for developing several autoimmune disorders, particularly the thyroid problems Hashimoto thyroiditis and Graves' disease, and coeliac disease.[67] Type 1 diabetics are also at increased risk of rheumatoid arthritis, lupus, autoimmune gastritis, pernicious anemia, vitiligo, and Addison's disease.[67] Conversely, complex autoimmune syndromes caused by mutations in the immunity-related genes AIRE (causing autoimmune polyglandular syndrome), FoxP3 (causing IPEX syndrome), or STAT3 include type 1 diabetes in their effects.[81]

Epidemiology[]

Type 1 diabetes makes up an estimated 10–15% of all diabetes cases[21] or 11–22 million worldwide.[82] In 2006 it affected 440,000 children under 14 years of age and was the primary cause of diabetes in those less than 15 years of age.[83][21] It is slightly more common in males than in females.[28]

Rates vary widely by country and region. Incidence is highest in Scandinavia, at 30–60 new cases per 100,000 children per year, intermediate in the U.S. and Southern Europe at 10–20 cases per 100,000 per year, and lowest in China, much of Asia, and South America at 1–3 cases per 100,000 per year.[25]

In the United States, type 1 and 2 diabetes affected about 208,000 youths under the age of 20 in 2015. Over 18,000 youths are diagnosed with Type 1 diabetes every year. Every year about 234,051 Americans die due to diabetes (type I or II) or diabetes-related complications, with 69,071 having it as the primary cause of death.[84]

In Australia, about one million people have been diagnosed with diabetes and of this figure 130,000 people have been diagnosed with type 1 diabetes. Australia ranks 6th-highest in the world with children under 14 years of age. Between 2000 and 2013, 31,895 new cases were established, with 2,323 in 2013, a rate of 10–13 cases per 100,00 people each year. Aboriginals and Torres Strait Islander people are less affected.[85][86]

Since the 1950s, the incidence of type 1 diabetes has been gradually increasing across the world by an average 3–4% per year.[25] The increase is more pronounced in countries that began with a lower incidence of type 1 diabetes.[25]

History[]

Further information: History of diabetes

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.[87] 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.[88] The name juvenile diabetes was used earlier as it often first is diagnosed in childhood.

Society and culture[]

See also: List of people with type 1 diabetes

Type 1 and 2 diabetes 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.[89] In the United States $245 billion every year is attributed to diabetes. Individuals diagnosed with diabetes have 2.3 times the health care costs as individuals who do not have diabetes. One in ten health care dollars are spent on individuals with type 1 and 2 diabetes.[84]

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 Institutes of Health, and in the UK via the National Institute for Health Research or the Medical Research Council. The Juvenile Diabetes Research Foundation (JDRF), founded by parents of children with type 1 diabetes, is the world's largest provider of charity-based funding for type 1 diabetes research.[citation needed] Other charities include the American Diabetes Association, Diabetes UK, Diabetes Research and Wellness Foundation,[90] Diabetes Australia, the Canadian Diabetes Association.

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

Prevention[]

Type 1 diabetes is not currently preventable.[82] Several trials have attempted dietary interventions with the hope of reducing the autoimmunity that leads to type 1 diabetes. Trials that witheld cow's milk or gave infants formula free of bovine insulin decreased the development of β-cell-targeted antibodies, but did not prevent the development of type 1 diabetes.[91] Similarly, trials that gave high-risk individuals injected insulin, oral insulin, or nicotinamide did not prevent diabetes development.[91]

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.[50] 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.[50] In 2011, Phase III studies with otelixizumab and teplizumab both failed to show clinical efficacy, potentially due to an insufficient dosing schedule.[92][93] 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.[50]

Diet[]

Data suggest that gliadin (a protein present in gluten) might play a role in the development of type 1 diabetes, but the mechanism is not fully understood.[94][95] Increased intestinal permeability caused by gluten and the subsequent loss of intestinal barrier function, which allows the passage of pro-inflammatory substances into the blood, may induce the autoimmune response in genetically predisposed individuals to type 1 diabetes.[6][95] There is evidence from experiments conducted in animal models that removal of gluten from the diet may prevent the onset of type 1 diabetes[94][96] but there has been conflicting research in humans.[96]

Gene therapy[]

Gene therapy has also been proposed as a possible cure for type 1 diabetes.[97]

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.[98] In 2014 more mature beta cells were produced which released insulin in response to blood sugar when transplanted into mice.[99][100] Before these techniques can be used in humans more evidence of safety and effectiveness is needed.[98]

Vaccine[]

Vaccines are being looked at to treat or prevent type 1 diabetes by inducing immune tolerance to insulin or pancreatic beta cells.[101] 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.[101] As of 2014, other approaches, such as a DNA vaccine encoding proinsulin and a peptide fragment of insulin, were in early clinical development.[101] The rotavirus vaccine and BCG vaccine are associated with a lower risk of type 1 diabetes.[102][103][104] Research continues to look at the BCG vaccine in type 1 diabetes as of 2019.[104]

Organ replacement[]

As of 2016 an artificial pancreas continues to look promising with safety issues still being studied.[105] In 2018 they were deemed to be relatively safe.[106]

Animal models in DM type 1 research[]

Animal models are used in autoimmune diabetes research to understand the pathogenesis and etiology of this disease, and to find and test predictive biomarkers and therapeutic interventions. Currently available models of T1D can be divided into spontaneously autoimmune, chemically induced, virus induced and genetically induced.[107]

Spontaneous autoimmune[]

  • Non-obese diabetic (NOD) mouse

The NOD mouse is the best known and most widely used animal model for type 1 DM research.[107] It is an inbred, genetically well characterized mouse strain that spontaneously develops T1D. The onset of insulitis occurs at 3–4 weeks of age. The islets of Langerhans are infiltrated by CD4+, CD8+ T lymphocytes, NK cells, B lymphocytes, dendritic cells, macrophages and neutrophils, similar to the disease process in humans.[108] Insulitis leads to destruction of β-cells, resulting in the apparent occurrence of T1D, which varies by sex. The incidence is about 60-80% in females and 10-30% in males.[109] In addition to sex, breeding conditions, gut microbiome composition or diet also influence the onset of T1D.[110] NOD Mice are used to understand the pathogenesis and etiology of the disease, to identify novel autoantigens and biomarkers or to test new intervention strategies.[107][108][111]

  • BioBreeding Diabetes-Prone (BB) rat

The BB rat is another widely used spontaneous experimental model for T1D. The onset of diabetes occurs, in up to 90% of individuals (regardless of sex) at 8–16 weeks of age.[108] During insulitis, the pancreatic islets are infiltrated by T lymphocytes, B lymphocytes, macrophages, and NK cells, with the difference from the human course of insulitis being that CD4 + T lymphocytes are markedly reduced and CD8 + T lymphocytes are almost absent. The aforementioned lymphopenia is the major drawback of this model. The disease is characterized by hyperglycemia, hypoinsulinemia, weight loss, ketonuria, and the need for insulin therapy for survival.[108] BB Rats are used to study the genetic aspects of T1D and are also used for interventional studies and diabetic nephropathy studies.[112]

  • LEW -1AR1 / -iddm (IDDM) rat

LEW-1AR1 / -iddm rats are derived from congenital Lewis rats and represent a rarer spontaneous model for T1D. These rats develop diabetes at about 8–9 weeks of age with no sex differences unlike NOD mice.[113] In LEW mice, diabetes presents with hyperglycemia, glycosuria, ketonuria, and polyuria.[114][108] The advantage of the model is the progression of the prediabetic phase, which is very similar to human disease, with infiltration of islet by immune cells about a week before hyperglycemia is observed. This model is suitable for intervention studies or for the search for predictive biomarkers. It is also possible to observe individual phases of pancreatic infiltration by immune cells. The advantage of congenic LEW mice is also the good viability after the manifestation of T1D (compared to NOD mice and BB rats).[111]

Chemically induced[]

The chemical compounds aloxan and streptozotocin (STZ) are commonly used to induce diabetes and destroy β-cells in mouse/rat animal models.[108] In both cases, it is a cytotoxic analog of glucose that passes GLUT2 transport and accumulates in β-cells, causing their destruction. The chemically induced destruction of β-cells leads to decreased insulin production, hyperglycemia and weight loss in the experimental animal.[115] The animal models prepared in this way are suitable for research into blood sugar-lowering drugs and therapies (e.g. for testing new insulin preparations). They are also suitable for testing transplantation therapies. Their advantage is mainly the low cost, the disadvantage is the cytotoxicity of the chemical compounds.[116]

Genetically induced[]

The most commonly used genetically induced T1D model is the so-called AKITA mouse (originally C57BL/6NSIc mouse). The development of diabetes in AKITA mice is caused by a spontaneous point mutation in the Ins2 gene, which is responsible for the correct composition of insulin in the endoplasmic reticulum. Decreased insulin production is then associated with hyperglycemia, polydipsia and polyuria. If severe diabetes develops within 3–4 weeks, AKITA mice survive no longer than 12 weeks without treatment intervention. The description of the etiology of the disease shows that, unlike spontaneous models, the early stages of the disease are not accompanied by insulitis.[117] AKITA mice are used to test drugs targeting endoplasmic reticulum stress reduction, to test islet transplants, and to study diabetes-related complications such as nephropathy, sympathetic autonomic neuropathy, and vascular disease.[108][118]

Virally induced[]

Viral infections play a role in the development of a number of autoimmune diseases, including human type 1 diabetes. However, the mechanisms by which viruses are involved in the induction of type 1 DM are not fully understood. Virus-induced models are used to study the etiology and pathogenesis of the disease, in particular they help us to uncover the mechanisms by which environmental factors contribute to or protect against the occurrence of type 1 DM.[119] Among the most commonly used are Coxsackie virus, lymphocytic choriomeningitis virus, encephalomyocarditis virus, and Kilham rat virus. Examples of virus-induced animals include NOD mice infected with coxsackie B4 that developed type 1 DM within two weeks.[120]

References[]

  1. ^ Jump up to: a b c d e f g h "Causes of Diabetes". NIDDK. August 2014. Archived from the original on 10 August 2016. Retrieved 31 July 2016.
  2. ^ Jump up to: a b c d e f g "Types of Diabetes". NIDDK. February 2014. Archived from the original on 16 August 2016. Retrieved 31 July 2016.
  3. ^ "Diabetes Blue Circle Symbol". International Diabetes Federation. 17 March 2006. Archived from the original on 5 August 2007.
  4. ^ Jump up to: a b c d e f g h i j k "Diabetes Fact sheet N°312". WHO. November 2016. Archived from the original on 26 August 2013. Retrieved 29 May 2017.
  5. ^ Jump up to: a b c d e f g h i j k Chiang JL, Kirkman MS, Laffel LM, Peters AL (July 2014). "Type 1 diabetes through the life span: a position statement of the American Diabetes Association". Diabetes Care. 37 (7): 2034–54. doi:10.2337/dc14-1140. PMC 5865481. PMID 24935775.
  6. ^ Jump up to: a b c d Elfström P, Sundström J, Ludvigsson JF (November 2014). "Systematic review with meta-analysis: associations between coeliac disease and type 1 diabetes". Alimentary Pharmacology & Therapeutics. 40 (10): 1123–32. doi:10.1111/apt.12973. PMID 25270960. S2CID 25468009.
  7. ^ Jump up to: a b "Diagnosis of Diabetes and Prediabetes". NIDDK. May 2015. Archived from the original on 16 August 2016. Retrieved 31 July 2016.
  8. ^ Jump up to: a b Daneman D (March 2006). "Type 1 diabetes". The Lancet. 367 (9513): 847–58. doi:10.1016/S0140-6736(06)68341-4. PMID 16530579. S2CID 21485081.
  9. ^ Torpy, JM (September 2007). "Type 1 Diabetes". JAMA. 298 (12): 1472. doi:10.1001/jama.298.12.1472. PMID 17895465.
  10. ^ "Alternative Devices for Taking Insulin". NIDDK. July 2016. Archived from the original on 16 August 2016. Retrieved 31 July 2016.
  11. ^ {{cite web |title=Fast Facts Data and Statistics about Diabetes |url=http://professional.diabetes.org/ResourcesForProfessionals.aspx?cid=91777 |publisher=American Diabetes Association |access-date=25 July 2014 |url-status=live |archive-url=https://web.archive.org/web/20151216001425/http://professional.diabetes.org/ResourcesForProfessionals.aspx?cid=91777 |archive-date=16 December 2015}
  12. ^ Global report on diabetes (PDF). World Health Organization. 2016. pp. 26–27. ISBN 978-92-4-156525-7. Archived (PDF) from the original on 7 October 2016. Retrieved 31 July 2016.
  13. ^ Skyler, Jay (2012). Atlas of diabetes (4th ed.). New York: Springer. pp. 67–68. ISBN 978-1-4614-1028-7. Archived from the original on 8 September 2017.
  14. ^ Atkinson et al. 2020, Table 36.1.
  15. ^ Jump up to: a b Wolsdorf & Garvey 2016, "Type 1 Diabetes".
  16. ^ Jump up to: a b c Atkinson et al. 2020, "Clinical presentation".
  17. ^ Jump up to: a b DiMeglio, Evans-Molina & Oram 2018, p. 2449.
  18. ^ Jump up to: a b "DKA (Ketoacidosis) & Ketones". American Diabetes Association. Retrieved 28 July 2021.
  19. ^ Jump up to: a b c Delli & Lernmark 2016, "Signs and symptoms".
  20. ^ Jump up to: a b c d Katsarou et al. 2017, p. 1.
  21. ^ Jump up to: a b c Katsarou et al. 2017, "Epidemiology".
  22. ^ Katsarou et al. 2017, "Introduction".
  23. ^ Knip M, Veijola R, Virtanen SM, Hyöty H, Vaarala O, Akerblom HK (December 2005). "Environmental triggers and determinants of type 1 diabetes". Diabetes. 54 Suppl 2: S125–36. doi:10.2337/diabetes.54.suppl_2.S125. PMID 16306330.
  24. ^ Jump up to: a b c d e Norris, Johnson & Stene 2020, "Environmental factors".
  25. ^ Jump up to: a b c d Norris, Johnson & Stene 2020, "Trends in epidemiology".
  26. ^ Jump up to: a b Norris, Johnson & Stene 2020, "Infections".
  27. ^ Norris, Johnson & Stene 2020, "The hygiene hypothesis and proxies of microbial exposures".
  28. ^ Jump up to: a b c d e DiMeglio, Evans-Molina & Oram 2018, p. 2450.
  29. ^ Thayer KA, Heindel JJ, Bucher JR, Gallo MA (June 2012). "Role of environmental chemicals in diabetes and obesity: a National Toxicology Program workshop review". Environmental Health Perspectives (Review). 120 (6): 779–89. doi:10.1289/ehp.1104597. PMC 3385443. PMID 22296744.
  30. ^ "Pyriminil". U.S. National Library of Medicine. Archived from the original on 4 July 2013.
  31. ^ Wu J, Yan LJ (April 2015). "Streptozotocin-induced type 1 diabetes in rodents as a model for studying mitochondrial mechanisms of diabetic β cell glucotoxicity". Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy (Review). 8: 181–8. doi:10.2147/DMSO.S82272. PMC 4396517. PMID 25897251.
  32. ^ Brentjens R, Saltz L (June 2001). "Islet cell tumors of the pancreas: the medical oncologist's perspective". The Surgical Clinics of North America (Review). 81 (3): 527–42. doi:10.1016/S0039-6109(05)70141-9. PMID 11459269.
  33. ^ de Filette, Jeroen; Andreescu, Corina; Cools, Filip; Bravenboer, Bert; Velkeniers, Brigitte (12 March 2019). "A systematic review and meta-analysis of endocrine-related adverse events associated with immune checkpoint inhibitors". Hormone and Metabolic Research. 51 (3): 145–156. doi:10.1055/a-0843-3366. PMID 30861560.
  34. ^ Definition and Diagnosis of Diabetes Mellitus and Intermediate Hyperglycemia (PDF). Geneva: World Health Organization. 2006. p. 1. ISBN 978-92-4-159493-6. Retrieved 28 July 2021.
  35. ^ American Diabetes Association (January 2021). "2. Classification and diagnosis of Diabetes: Standards of Medical Care in Diabetes - 2021". Diabetes Care. American Diabetes Association. 44 (Supplement 1): S15–S33. doi:10.2337/dc21-S002. PMID 33298413.
  36. ^ Jump up to: a b c d Butler & Misselbrook 2020, "What is the next investigation?".
  37. ^ Jump up to: a b c DiMeglio, Evans-Molina & Oram 2018, p. 2453.
  38. ^ Katsarou et al. 2017, p. 11.
  39. ^ Jump up to: a b American Diabetes Association (January 2021). "6. Glycemic Targets: Standards of Medical Care in Diabetes-2021". Diabetes Care. 44 (Supplement 1): S73–S84. doi:10.2337/dc21-S006. PMID 33298417. "Glycemic assessment"CS1 maint: postscript (link)
  40. ^ "Long-Acting Insulin: How It Works". Healthline. 23 October 2015. Retrieved 10 February 2019.
  41. ^ Wright JR (April 2002). "From ugly fish to conquer death: J J R Macleod's fish insulin research, 1922-24". The Lancet. 359 (9313): 1238–42. doi:10.1016/S0140-6736(02)08222-3. PMID 11955558. S2CID 26381227.
  42. ^ "Low Blood Glucose (Hypoglycemia) - NIDDK". nih.gov.
  43. ^ Pandit K (December 2012). "Continuous glucose monitoring". Indian Journal of Endocrinology and Metabolism. 16 (Suppl 2): S263–6. doi:10.4103/2230-8210.104056 (inactive 31 May 2021). PMC 3603043. PMID 23565395.CS1 maint: DOI inactive as of May 2021 (link)
  44. ^ Jump up to: a b c Seckold R, Fisher E, de Bock M, King BR, Smart CE (October 2018). "The ups and downs of low-carbohydrate diets in the management of Type 1 diabetes: a review of clinical outcomes". Diabet. Med. (Review). 36 (3): 326–334. doi:10.1111/dme.13845. PMID 30362180. S2CID 53102654. Low‐carbohydrate diets are of interest for improving glycaemic outcomes in the management of Type 1 diabetes. There is limited evidence to support their routine use in the management of Type 1 diabetes.
  45. ^ Ly TT (2015). "Technology and type 1 diabetes: Closed-loop therapies". Current Pediatrics Reports. 3 (2): 170–176. doi:10.1007/s40124-015-0083-y. S2CID 68302123.
  46. ^ "Stress". www.diabetes.org. American Diabetes Association. Archived from the original on 12 November 2014. Retrieved 11 November 2014.
  47. ^ Larsen JL (2004). "Pancreas Transplantation: Indications and Consequences". Endocrine Reviews. Edrv.endojournals.org. 25 (6): 919–46. doi:10.1210/er.2002-0036. PMID 15583023. Archived from the original on 15 July 2012. Retrieved 29 November 2011.
  48. ^ Jump up to: a b c Bruni A, Gala-Lopez B, Pepper AR, Abualhassan NS, Shapiro AJ (2014). "Islet cell transplantation for the treatment of type 1 diabetes: recent advances and future challenges". Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy. 7: 211–23. doi:10.2147/DMSO.S50789. PMC 4075233. PMID 25018643.
  49. ^ Jump up to: a b Hatipoglu B (December 2016). "Islet Cell Transplantation and Alternative Therapies". Endocrinology and Metabolism Clinics of North America. 45 (4): 923–931. doi:10.1016/j.ecl.2016.06.004. PMID 27823612.
  50. ^ Jump up to: a b c d Bluestone JA, Herold K, Eisenbarth G (April 2010). "Genetics, pathogenesis and clinical interventions in type 1 diabetes". Nature. 464 (7293): 1293–300. Bibcode:2010Natur.464.1293B. doi:10.1038/nature08933. PMC 4959889. PMID 20432533.
  51. ^ 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". Annals of Medicine. 42 (6): 426–38. doi:10.3109/07853890.2010.495951. PMID 20568978. S2CID 10243765.
  52. ^ Jump up to: a b Aly H, Gottlieb P (August 2009). "The honeymoon phase: intersection of metabolism and immunology". Current Opinion in Endocrinology, Diabetes and Obesity. 16 (4): 286–92. doi:10.1097/med.0b013e32832e0693. PMID 19506474. S2CID 5242656.
  53. ^ Farhy LS, McCall AL (July 2015). "Glucagon - the new 'insulin' in the pathophysiology of diabetes". Current Opinion in Clinical Nutrition and Metabolic Care. 18 (4): 407–14. doi:10.1097/mco.0000000000000192. PMID 26049639. S2CID 19872862.
  54. ^ Jump up to: a b Yosten GL (February 2018). "Alpha cell dysfunction in type 1 diabetes". Peptides. 100: 54–60. doi:10.1016/j.peptides.2017.12.001. PMID 29412832. S2CID 46878644.
  55. ^ Brown RJ, Sinaii N, Rother KI (July 2008). "Too much glucagon, too little insulin: time course of pancreatic islet dysfunction in new-onset type 1 diabetes". Diabetes Care. 31 (7): 1403–4. doi:10.2337/dc08-0575. PMC 2453684. PMID 18594062.
  56. ^ Unger RH, Cherrington AD (January 2012). "Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover". The Journal of Clinical Investigation. 122 (1): 4–12. doi:10.1172/JCI60016. PMC 3248306. PMID 22214853.
  57. ^ Meier JJ, Kjems LL, Veldhuis JD, Lefèbvre P, Butler PC (April 2006). "Postprandial suppression of glucagon secretion depends on intact pulsatile insulin secretion: further evidence for the intraislet insulin hypothesis". Diabetes. 55 (4): 1051–6. doi:10.2337/diabetes.55.04.06.db05-1449. PMID 16567528.
  58. ^ Cooperberg BA, Cryer PE (December 2009). "Beta-cell-mediated signaling predominates over direct alpha-cell signaling in the regulation of glucagon secretion in humans". Diabetes Care. 32 (12): 2275–80. doi:10.2337/dc09-0798. PMC 2782990. PMID 19729529.
  59. ^ Paolisso G, Sgambato S, Torella R, Varricchio M, Scheen A, D'Onofrio F, Lefèbvre PJ (June 1988). "Pulsatile insulin delivery is more efficient than continuous infusion in modulating islet cell function in normal subjects and patients with type 1 diabetes". The Journal of Clinical Endocrinology and Metabolism. 66 (6): 1220–6. doi:10.1210/jcem-66-6-1220. PMID 3286673.
  60. ^ Jump up to: a b Banarer S, McGregor VP, Cryer PE (April 2002). "Intraislet hyperinsulinemia prevents the glucagon response to hypoglycemia despite an intact autonomic response". Diabetes. 51 (4): 958–65. doi:10.2337/diabetes.51.4.958. PMID 11916913.
  61. ^ Raju B, Cryer PE (March 2005). "Loss of the decrement in intraislet insulin plausibly explains loss of the glucagon response to hypoglycemia in insulin-deficient diabetes: documentation of the intraislet insulin hypothesis in humans". Diabetes. 54 (3): 757–64. doi:10.2337/diabetes.54.3.757. PMID 15734853.
  62. ^ Jump up to: a b c Tesfaye N, Seaquist ER (November 2010). "Neuroendocrine responses to hypoglycemia". Annals of the New York Academy of Sciences. 1212 (1): 12–28. Bibcode:2010NYASA1212...12T. doi:10.1111/j.1749-6632.2010.05820.x. PMC 2991551. PMID 21039590.
  63. ^ Jump up to: a b Reno CM, Litvin M, Clark AL, Fisher SJ (March 2013). "Defective counterregulation and hypoglycemia unawareness in diabetes: mechanisms and emerging treatments". Endocrinology and Metabolism Clinics of North America. 42 (1): 15–38. doi:10.1016/j.ecl.2012.11.005. PMC 3568263. PMID 23391237.
  64. ^ Martín-Timón I, Del Cañizo-Gómez FJ (July 2015). "Mechanisms of hypoglycemia unawareness and implications in diabetic patients". World Journal of Diabetes. 6 (7): 912–26. doi:10.4239/wjd.v6.i7.912. PMC 4499525. PMID 26185599.
  65. ^ Jump up to: a b Mundinger TO, Taborsky GJ (October 2016). "Early sympathetic islet neuropathy in autoimmune diabetes: lessons learned and opportunities for investigation". Diabetologia. 59 (10): 2058–67. doi:10.1007/s00125-016-4026-0. PMC 6214182. PMID 27342407.
  66. ^ Mundinger TO, Mei Q, Foulis AK, Fligner CL, Hull RL, Taborsky GJ (August 2016). "Human Type 1 Diabetes Is Characterized by an Early, Marked, Sustained, and Islet-Selective Loss of Sympathetic Nerves". Diabetes. 65 (8): 2322–30. doi:10.2337/db16-0284. PMC 4955989. PMID 27207540.
  67. ^ Jump up to: a b c d e f DiMeglio, Evans-Molina & Oram 2018, p. 2455.
  68. ^ Tasker RC, Acerini CL (June 2014). "Cerebral edema in children with diabetic ketoacidosis: vasogenic rather than cellular?". Pediatric Diabetes. 15 (4): 261–70. doi:10.1111/pedi.12153. PMID 24866062. S2CID 6639587.
  69. ^ DiMeglio, Evans-Molina & Oram 2018, p. 2456.
  70. ^ Devaraj S, Glaser N, Griffen S, Wang-Polagruto J, Miguelino E, Jialal I (March 2006). "Increased monocytic activity and biomarkers of inflammation in patients with type 1 diabetes". Diabetes. 55 (3): 774–9. doi:10.2337/diabetes.55.03.06.db05-1417. PMID 16505242.
  71. ^ Granberg V, Ejskjaer N, Peakman M, Sundkvist G (August 2005). "Autoantibodies to autonomic nerves associated with cardiac and peripheral autonomic neuropathy". Diabetes Care. 28 (8): 1959–64. doi:10.2337/diacare.28.8.1959. PMID 16043739.
  72. ^ Huxley RR, Peters SA, Mishra GD, Woodward M (March 2015). "Risk of all-cause mortality and vascular events in women versus men with type 1 diabetes: a systematic review and meta-analysis". The Lancet. Diabetes & Endocrinology. 3 (3): 198–206. doi:10.1016/S2213-8587(14)70248-7. PMID 25660575.
  73. ^ Roy T, Lloyd CE (October 2012). "Epidemiology of depression and diabetes: a systematic review". Journal of Affective Disorders. 142 Suppl: S8–21. doi:10.1016/S0165-0327(12)70004-6. PMID 23062861.
  74. ^ Jump up to: a b See JA, Kaukinen K, Makharia GK, Gibson PR, Murray JA (October 2015). "Practical insights into gluten-free diets". Nature Reviews. Gastroenterology & Hepatology (Review). 12 (10): 580–91. doi:10.1038/nrgastro.2015.156. PMID 26392070. S2CID 20270743. Coeliac disease in T1DM is asymptomatic ...Clinical manifestations of coeliac disease, such as abdominal pain, gas, bloating, diarrhoea and weight loss can be present in patients with T1DM, but are often attributed to poor control of diabetes, gastroparesis or diabetic neuropathy
  75. ^ Chen HS, Su LT, Lin SZ, Sung FC, Ko MC, Li CY (January 2012). "Increased risk of urinary tract calculi among patients with diabetes mellitus--a population-based cohort study". Urology. 79 (1): 86–92. doi:10.1016/j.urology.2011.07.1431. PMID 22119251.
  76. ^ James R, Hijaz A (October 2014). "Lower urinary tract symptoms in women with diabetes mellitus: a current review". Current Urology Reports. 15 (10): 440. doi:10.1007/s11934-014-0440-3. PMID 25118849. S2CID 30653959.
  77. ^ Jump up to: a b c d "Sexual Dysfunction in Women". Diabetes.co.uk. Diabetes Digital Media Ltd. Archived from the original on 9 November 2014. Retrieved 28 November 2014.
  78. ^ Goswami SK, Vishwanath M, Gangadarappa SK, Razdan R, Inamdar MN (August 2014). "Efficacy of ellagic acid and sildenafil in diabetes-induced sexual dysfunction". Pharmacognosy Magazine. 10 (Suppl 3): S581–7. doi:10.4103/0973-1296.139790. PMC 4189276. PMID 25298678. ProQuest 1610759650.
  79. ^ Escobar-Morreale HF, Roldán B, Barrio R, Alonso M, Sancho J, de la Calle H, García-Robles R (November 2000). "High prevalence of the polycystic ovary syndrome and hirsutism in women with type 1 diabetes mellitus". The Journal of Clinical Endocrinology and Metabolism. 85 (11): 4182–7. doi:10.1210/jcem.85.11.6931. PMID 11095451.
  80. ^ Codner E, Escobar-Morreale HF (April 2007). "Clinical review: Hyperandrogenism and polycystic ovary syndrome in women with type 1 diabetes mellitus". The Journal of Clinical Endocrinology and Metabolism. 92 (4): 1209–16. doi:10.1210/jc.2006-2641. PMID 17284617.
  81. ^ Redondo, Steck & Pugliese 2018, "Evidence for the contribution of genetics to type I diabetes".
  82. ^ Jump up to: a b "Diabetes". World Health Organization. Archived from the original on 26 January 2011. Retrieved 24 January 2011.
  83. ^ 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. 8 Suppl 8 (s8): 8–9. doi:10.1111/j.1399-5448.2007.00326.x. PMID 17767619.
  84. ^ Jump up to: a b "Fast Facts" (PDF). American Diabetes Association. Archived from the original (PDF) on 29 April 2015.
  85. ^ Australian Institute of Health and Welfare (2015). "Incidence of type 1 diabetes in Australia 2000–2013". Archived from the original on 7 October 2016. Retrieved 19 October 2016.
  86. ^ Shaw, Jonathan (2012). "diabetes: the silent pandemic and its impact on Australia" (PDF). Archived (PDF) from the original on 7 October 2016. Retrieved 19 October 2016.
  87. ^ Bottazzo GF, Florin-Christensen A, Doniach D (November 1974). "Islet-cell antibodies in diabetes mellitus with autoimmune polyendocrine deficiencies". The Lancet. 2 (7892): 1279–83. doi:10.1016/s0140-6736(74)90140-8. PMID 4139522.
  88. ^ Herold KC, Vignali DA, Cooke A, Bluestone JA (April 2013). "Type 1 diabetes: translating mechanistic observations into effective clinical outcomes". Nature Reviews. Immunology. 13 (4): 243–56. doi:10.1038/nri3422. PMC 4172461. PMID 23524461.
  89. ^ Johnson L (18 November 2008). "Study: Cost of diabetes $218B". USA Today. Associated Press. Archived from the original on 1 July 2012.
  90. ^ Diabetes Research and Wellness Foundation Archived 11 May 2013 at the Wayback Machine
  91. ^ Jump up to: a b Dayan et al. 2019, "Previous prevention trials".
  92. ^ "Tolerx, Inc. and GlaxoSmithKline (GSK) Announce Phase 3 Defend-1 Study of Otelixizumab in Type 1 Diabetes Did Not Meet Its Primary Endpoint". Biospace. Archived from the original on 29 September 2011. Retrieved 29 November 2011.
  93. ^ "Macrogenics press release: MacroGenics and Lilly Announce Pivotal Clinical Trial of Teplizumab Did Not Meet Primary Efficacy Endpoint". Macrogenics.com. 20 October 2010. Archived from the original on 22 January 2012. Retrieved 29 November 2011.
  94. ^ Jump up to: a b Serena G, Camhi S, Sturgeon C, Yan S, Fasano A (August 2015). "The Role of Gluten in Celiac Disease and Type 1 Diabetes". Nutrients. 7 (9): 7143–62. doi:10.3390/nu7095329. PMC 4586524. PMID 26343710. open access
  95. ^ Jump up to: a b Visser J, Rozing J, Sapone A, Lammers K, Fasano A (May 2009). "Tight junctions, intestinal permeability, and autoimmunity: celiac disease and type 1 diabetes paradigms". Annals of the New York Academy of Sciences. 1165 (1): 195–205. Bibcode:2009NYASA1165..195V. doi:10.1111/j.1749-6632.2009.04037.x. PMC 2886850. PMID 19538307.
  96. ^ Jump up to: a b Antvorskov JC, Josefsen K, Engkilde K, Funda DP, Buschard K (September 2014). "Dietary gluten and the development of type 1 diabetes". Diabetologia (Review). 57 (9): 1770–80. doi:10.1007/s00125-014-3265-1. PMC 4119241. PMID 24871322.
  97. ^ Bagley J, Paez-Cortez J, Tian C, Iacomini J (2008). "Gene therapy in type 1 diabetes". Critical Reviews in Immunology. 28 (4): 301–24. doi:10.1615/CritRevImmunol.v28.i4.30. PMID 19166382.
  98. ^ Jump up to: a b Minami K, Seino S (March 2013). "Current status of regeneration of pancreatic β-cells". Journal of Diabetes Investigation. 4 (2): 131–41. doi:10.1111/jdi.12062. PMC 4019265. PMID 24843642.
  99. ^ Pagliuca FW, Millman JR, Gürtler M, Segel M, Van Dervort A, Ryu JH, Peterson QP, Greiner D, Melton DA (October 2014). "Generation of functional human pancreatic β cells in vitro". Cell. 159 (2): 428–39. doi:10.1016/j.cell.2014.09.040. PMC 4617632. PMID 25303535.
  100. ^ Rezania A, Bruin JE, Arora P, Rubin A, Batushansky I, Asadi A, O'Dwyer S, Quiskamp N, Mojibian M, Albrecht T, Yang YH, Johnson JD, Kieffer TJ (November 2014). "Reversal of diabetes with insulin-producing cells derived in vitro from human pluripotent stem cells". Nature Biotechnology. 32 (11): 1121–33. doi:10.1038/nbt.3033. PMID 25211370. S2CID 205280579.
  101. ^ Jump up to: a b c Lernmark A, Larsson HE (February 2013). "Immune therapy in type 1 diabetes mellitus". Nature Reviews. Endocrinology. 9 (2): 92–103. doi:10.1038/nrendo.2012.237. PMID 23296174. S2CID 10371556.
  102. ^ "Rotavirus vaccination tied to lower rates of type 1 diabetes". Reuters. 22 January 2019. Retrieved 10 February 2019.
  103. ^ Bakalar, Nicholas (30 January 2019). "Rotavirus Vaccine May Protect Against Type 1 Diabetes". The New York Times. ISSN 0362-4331. Retrieved 10 February 2019.
  104. ^ Jump up to: a b Ristori G, Faustman D, Matarese G, Romano S, Salvetti M (December 2018). "Bridging the gap between vaccination with Bacille Calmette-Guérin (BCG) and immunological tolerance: the cases of type 1 diabetes and multiple sclerosis". Current Opinion in Immunology. 55: 89–96. doi:10.1016/j.coi.2018.09.016. PMID 30447407.
  105. ^ Blauw H, Keith-Hynes P, Koops R, DeVries JH (November 2016). "A Review of Safety and Design Requirements of the Artificial Pancreas". Annals of Biomedical Engineering. 44 (11): 3158–3172. doi:10.1007/s10439-016-1679-2. PMC 5093196. PMID 27352278.
  106. ^ Bekiari E, Kitsios K, Thabit H, Tauschmann M, Athanasiadou E, Karagiannis T, Haidich AB, Hovorka R, Tsapas A (April 2018). "Artificial pancreas treatment for outpatients with type 1 diabetes: systematic review and meta-analysis". BMJ. 361: k1310. doi:10.1136/bmj.k1310. PMC 5902803. PMID 29669716.
  107. ^ Jump up to: a b c Animal models of diabetes : methods and protocols. Aileen J. F. King. New York, NY. 2020. ISBN 978-1-0716-0385-7. OCLC 1149391907.CS1 maint: others (link)
  108. ^ Jump up to: a b c d e f g Pandey, Shashank; Dvorakova, Magdalena C. (7 January 2020). "Future Perspective of Diabetic Animal Models". Endocrine, Metabolic & Immune Disorders - Drug Targets. 20 (1): 25–38. doi:10.2174/1871530319666190626143832. PMC 7360914. PMID 31241444.
  109. ^ "The Jackson Laboratory". The Jackson Laboratory. Retrieved 30 June 2021.
  110. ^ Chen, Dawei; Thayer, Terri C.; Wen, Li; Wong, F. Susan (2020), King, Aileen J. F. (ed.), "Mouse Models of Autoimmune Diabetes: The Nonobese Diabetic (NOD) Mouse", Animal Models of Diabetes, New York, NY: Springer US, 2128, pp. 87–92, doi:10.1007/978-1-0716-0385-7_6, ISBN 978-1-0716-0384-0, PMC 8253669, PMID 32180187
  111. ^ Jump up to: a b Lenzen, Sigurd (October 2017). "Animal models of human type 1 diabetes for evaluating combination therapies and successful translation to the patient with type 1 diabetes". Diabetes/Metabolism Research and Reviews. 33 (7): e2915. doi:10.1002/dmrr.2915. PMID 28692149. S2CID 34331597.
  112. ^ Lenzen, Sigurd; Arndt, Tanja; Elsner, Matthias; Wedekind, Dirk; Jörns, Anne (2020). "Rat Models of Human Type 1 Diabetes". In King, Aileen J. F. (ed.). Animal Models of Diabetes. 2128. New York, NY: Springer US. pp. 69–85. doi:10.1007/978-1-0716-0385-7_5. ISBN 978-1-0716-0384-0. PMID 32180186.
  113. ^ Al-awar, Amin; Kupai, Krisztina; Veszelka, Médea; Szűcs, Gergő; Attieh, Zouhair; Murlasits, Zsolt; Török, Szilvia; Pósa, Anikó; Varga, Csaba (2016). "Experimental Diabetes Mellitus in Different Animal Models". Journal of Diabetes Research. 2016: 1–12. doi:10.1155/2016/9051426. ISSN 2314-6745. PMC 4993915. PMID 27595114.
  114. ^ Lenzen S, Tiedge M, Elsner M, Lortz S, Weiss H, Jörns A, Klöppel G, Wedekind D, Prokop C, Hedrich HJ (1 September 2001). "The LEW.1AR1/Ztm-iddm rat: a new model of spontaneous insulin-dependent diabetes mellitus". Diabetologia. 44 (9): 1189–1196. doi:10.1007/s001250100625. ISSN 0012-186X. PMID 11596676.
  115. ^ Radenković, Miroslav; Stojanović, Marko; Prostran, Milica (March 2016). "Experimental diabetes induced by alloxan and streptozotocin: The current state of the art". Journal of Pharmacological and Toxicological Methods. 78: 13–31. doi:10.1016/j.vascn.2015.11.004. PMID 26596652.
  116. ^ King, Aileen J. F.; Estil·les, Elisabet; Montanya, Eduard (2020). "Use of Streptozotocin in Rodent Models of Islet Transplantation". In King, Aileen J. F. (ed.). Animal Models of Diabetes. 2128. New York, NY: Springer US. pp. 135–147. doi:10.1007/978-1-0716-0385-7_10. ISBN 978-1-0716-0384-0. PMID 32180191.
  117. ^ Salpea, Paraskevi; Cosentino, Cristina; Igoillo-Esteve, Mariana (2020). "A Review of Mouse Models of Monogenic Diabetes and ER Stress Signaling". In King, Aileen J. F. (ed.). Animal Models of Diabetes (PDF). 2128. New York, NY: Springer US. pp. 55–67. doi:10.1007/978-1-0716-0385-7_4. ISBN 978-1-0716-0384-0. PMID 32180185.
  118. ^ Chang, Jae-Hyung; Gurley, Susan B. (2012). "Assessment of Diabetic Nephropathy in the Akita Mouse". In Joost, Hans-Georg; Al-Hasani, Hadi; Schürmann, Annette (eds.). Animal Models in Diabetes Research. 933. Totowa, NJ: Humana Press. pp. 17–29. doi:10.1007/978-1-62703-068-7_2. ISBN 978-1-62703-067-0. PMID 22893398.
  119. ^ Christoffersson, Gustaf; Flodström-Tullberg, Malin (2020). "Mouse Models of Virus-Induced Type 1 Diabetes". In King, Aileen J. F. (ed.). Animal Models of Diabetes. 2128. New York, NY: Springer US. pp. 93–105. doi:10.1007/978-1-0716-0385-7_7. ISBN 978-1-0716-0384-0. PMID 32180188.
  120. ^ King, Aileen JF (June 2012). "The use of animal models in diabetes research: Animal models of diabetes". British Journal of Pharmacology. 166 (3): 877–894. doi:10.1111/j.1476-5381.2012.01911.x. PMC 3417415. PMID 22352879.

Citations[]

External links[]

Classification
External resources
Retrieved from ""