Diabetes mellitus type 1
1. Diabetes
mellitus type 1, also known as type 1 diabetes, is a form
of diabetes mellitus in
which very little or no insulin is produced by
the pancreas. Before treatment this results
in high blood sugar levels
in the body. The classic symptoms are frequent urination, increased thirst, increased hunger, and weight
loss. Additional symptoms may include blurry vision, feeling tired, and poor healing. Symptoms
typically develop over a short period of time.
2. The cause of
type 1 diabetes is unknown. However, it is believed to involve a
combination of genetic and environmental factors. Risk factors include
having a family member with the condition. The underlying mechanism
involves an autoimmunedestruction of
the insulin-producing beta cells in
the pancreas. Diabetes is diagnosed by testing
the level of sugar or glycated hemoglobin (HbA1C)
in the blood. Type 1 diabetes can be distinguished from type 2 by
testing for the presence of autoantibodies.
3. There is no
known way to prevent type 1 diabetes. Treatment with insulin is required for survival. Insulin therapy is usually given by
injection just under the skin but can also be delivered by an insulin pump. A diabetic diet and exercise are important
parts of management. If left untreated, diabetes can cause many
complications. Complications of relatively rapid onset include diabetic ketoacidosis and nonketotic
hyperosmolar coma. Long-term complications include heart disease, stroke, kidney failure, foot ulcers and damage to the eyes. Furthermore,
complications may arise from low blood sugar caused by excessive dosing
of insulin.
4. Type 1
diabetes makes up an estimated 5–10% of all diabetes cases. The number of
people affected globally is unknown, although it is estimated that about 80,000
children develop the disease each year. Within the United States the
number of people affected is estimated at one to three million. Rates of
disease vary widely with approximately 1 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. It typically begins in children and
young adults.
Signs and symptoms
5. The
classical symptoms of type 1 diabetes include: polyuria (increased urination), polydipsia (increased thirst), dry mouth, polyphagia (increased hunger), fatigue, and
weight loss.
6. Many type 1
diabetics are diagnosed when they present with diabetic ketoacidosis.
The signs and symptoms of diabetic ketoacidosis include dry skin, rapid deep breathing, drowsiness,
increased thirst, frequent urination, abdominal pain, and vomiting.
7. About 12
percent of people with type 1 diabetes have clinical depression.
8. About 6
percent of people with type 1 diabetes have celiac disease, but in most cases there are no
digestive symptoms or are mistakenly attributed to poor control of diabetes,
gastroparesis or diabetic neuropathy. 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.
9. Some people
with type 1 diabetes experience dramatic and recurrent swings in glucose levels, often occurring for no
apparent reason; this is called "unstable diabetes","labile
diabetes" or "brittle diabetes". The results of such swings
can be irregular and unpredictable hyperglycemias, sometimes involving ketoacidosis, and sometimes serious hypoglycemias. Brittle diabetes occurs no more
frequently than in 1% to 2% of diabetics.
10.
Type 1 diabetes is associated with alopecia areata (AA). Type 1 diabetes
is also more common in the family members of people with AA.)
Cause
11. The cause of
type 1 diabetes is unknown. A number of explanatory theories have been put
forward, and the cause may be one or more of the following: genetic
susceptibility, a diabetogenic trigger, and exposure to an antigen.
Genetics
12.
Type 1 diabetes is a disease that involves many genes. The risk of a child developing type
1 diabetes is about 5% if the father has it, about 8% if a sibling has it, and
about 3% if the mother has it. If one identical twin is affected there is about a
40% chance the other will be too. Some studies of heritability have estimated it at 80 to
86%.
13.
More than 50 genes are associated with type 1
diabetes. 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.
Environmental
14.
There is on the order of a 10-fold difference in occurrence among
Caucasians living in different areas of Europe, and people tend to acquire the
disease at the rate of their particular country. Environmental triggers
and protective factors under research include dietary agents such as proteins
in gluten, time of weaning, gut
microbiota and viral infections.
Chemicals and drugs
15.
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. 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. 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 and for
treating metastatic cancer of
the pancreatic islet cells in patients whose cancer cannot be removed by
surgery. Other pancreatic problems, including trauma, pancreatitis, or tumors (either malignant or
benign) can also lead to loss of insulin production.
Pathophysiology
16.
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.
17.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.
18.
After starting treatment with insulin a person's own insulin
levels may temporarily improve. This is believed to be due to altered
immunity and is known as the "honeymoon phase".
Diagnosis
19.
Diabetes mellitus is characterized by recurrent or
persistent hyperglycemia, and is
diagnosed by demonstrating any one of the following:
A.
Fasting plasma glucose level at or above 7.0 mmol/l
(126 mg/dl).
B.
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.
C.
Symptoms of hyperglycemia and casual plasma glucose at or above
11.1 mmol/l (200 mg/dl).
D.
Glycated hemoglobin (hemoglobin
A1C) at or above 48 mmol/mol (≥ 6.5 DCCT %).
(This criterion was recommended by the American
Diabetes Association in 2010, although it has yet to be adopted
by the WHO.)
20.
About a quarter of people with new type 1 diabetes have
developed some degree of diabetic ketoacidosis (a type of metabolic acidosis
which is caused by high concentrations of ketone bodies, formed by the
breakdown of fatty acids and the deamination of amino acids) by the time the
diabetes is recognized. The diagnosis of other types of diabetes is usually
made in other ways. These include ordinary health screening, detection of
hyperglycemia during other medical investigations, and secondary symptoms such
as vision changes or unexplained fatigue. Diabetes is often detected when a
person suffers a problem that may be caused by diabetes, such as a heart
attack, stroke, neuropathy, poor wound
healing or a foot ulcer, certain eye problems, certain fungal infections,
or delivering a baby with macrosomia or hypoglycemia (low blood sugar).
21.
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.
22.
In type 1, pancreatic beta cells in the islets of Langerhans are
destroyed, decreasing endogenous insulin production. This distinguishes
type 1's origin from type 2. Type 2 diabetes is characterized by
insulin resistance, while type 1 diabetes is characterized by insulin
deficiency, generally without insulin resistance. Another hallmark of type 1
diabetes is islet autoreactivity, which is generally measured by the presence
of autoantibodies directed towards the beta cells.
Autoantibodies
23.
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 clinically
diagnosable diabetes can be a few months in infants and young children, but in
some people it may take years – in some cases more than 10 years. Islet
cell autoantibodies are detected by conventional immunofluorescence,
while the rest are measured with specific radiobinding assays.
Prevention
24.
Type 1 diabetes is not currently preventable. Some
researchers believe it might be prevented at the latent autoimmune stage,
before it starts destroying beta cells.
Immunosuppressive drugs
25.
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.
26.
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.
27.
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.
Diet
28.
Some research has suggested breastfeeding decreases the risk in later
life and early introduction of gluten-containing cereals in the diet increases
the risk of developing islet cell
autoantibodies; various other nutritional risk factors are being
studied, but no firm evidence has been found. Giving children 2000 IU
of vitamin D daily during their first year of
life is associated with reduced risk of type 1 diabetes, though the causal
relationship is obscure.
29.
Children with antibodies to beta cell proteins (i.e. at early
stages of an immune reaction to them) but no overt diabetes, and treated
with niacinamide (vitamin
B3), had less than half the diabetes onset incidence in a seven-year time span
than did the general population, and an even lower incidence relative to those
with antibodies as above, but who received no niacinamide.
30.
People with type 1 diabetes and undiagnosed celiac disease have
worse glycaemic control and a higher prevalence of nephropathy and retinopathy. Gluten-free diet, when performed strictly,
improves diabetes symptoms and appears to have a protective effect against
developing long-term complications. Nevertheless, dietary management of both
these diseases is challenging and these patients have poor compliance of the
diet.
Management
31.
Diabetes is often managed by a number of health care providers
including a dietitian, nurse educator, eye doctor, endocrinologist, and
podiatrist.
Lifestyle
32.
A low-carbohydrate diet,
exercise, and medications is useful in type 1 DM. There are camps for
children to teach them how and when to use or monitor their insulin without
parental help. 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.
Insulin
33.
Injections of insulin –
either via subcutaneous injection or insulin pump – are necessary for those
living with type 1 diabetes because it cannot be treated by diet and exercise
alone. Insulin dosage is adjusted taking into account food intake, blood
glucose levels and physical activity.
34.
Untreated type 1 diabetes can commonly lead to diabetic ketoacidosis which
is a diabetic coma which can be fatal if untreated. 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.
35.
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). This level of control
over a prolonged period of time can be varied by a target HbA1c level of
less than 7.5%.
36.
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 once per day. 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.
37.
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. Symptoms include excess
sweating, excessive hunger, fainting, fatigue, lightheadedness and
shakiness. Mild cases are self-treated by eating or drinking something
high in sugar. Severe cases can lead to unconsciousness and are treated with
intravenous glucose or injections with glucagon. Continuous glucose
monitors can alert patients to the presence of dangerously high
or low blood sugar levels, but technical issues have limited the effect these
devices have had on clinical practice.
38.
As of 2016 an artificial pancreas looks
promising with safety issues still being studied. In 2018 they were deemed
to be relatively safe.
Pancreas transplantation
39.
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 mellitus.
Islet cell transplantation
40.
Islet cell transplantation may be an option for some people with
type 1 diabetes that are not well controlled with insulin. Difficulties
include finding donors that are compatible, getting the new islets to survive,
and the side effects from the medications used to prevent rejection. Success
rates, defined as not needing insulin at 3 years follow the procedure occurred
in 44% in on registry from 2010. In the United States, as of 2016, it is
considered an experimental treatment.
Complications
41.
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. Women with type 1 DM
have a 40% higher risk of death as compared to men with type 1 DM. The
life expectancy of an individual with type 1 diabetes is 11 years less for men
and 13 years less for women.
Urinary tract infection
42.
People with diabetes show an increased rate of urinary tract
infection. The reason is bladder dysfunction that is more
common in diabetics than in non-diabetics due to diabetic nephropathy. When
present, nephropathy can cause a decrease in bladder sensation, which in turn,
can cause increased residual urine, a risk factor for urinary tract infections.
Sexual dysfunction
43.
Sexual dysfunction in
diabetics 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.
Males
44.
The most common sexual issues in diabetic males are problems with
erections and ejaculation: "With diabetes, blood vessels supplying the
penis’s erectile tissue can get hard and narrow, preventing the adequate blood
supply needed for a firm erection. The nerve damage caused by poor blood glucose
control can also cause ejaculate to go into the bladder instead of through the
penis during ejaculation, called retrograde ejaculation. When this happens,
semen leaves the body in the urine." Another cause for erectile
dysfunction are the reactive oxygen species created as a result of the disease.
Antioxidants can be used to help combat this.
Females
45.
Studies find a significant prevalence of sexual problems in
diabetic women, including reduced sensation in the genitals, dryness,
difficulty/inability to orgasm, pain during sex, and decreased
libido. Diabetes sometimes decreases oestrogen levels in females, which
can affect vaginal lubrication. Less is known about the correlation between
diabetes and sexual dysfunction in females than in males.
46.
Oral contraceptive
pills can cause blood sugar imbalances in diabetic women.
Dosage changes can help address that, at the risk of side effects and
complications.
47.
Women with type 1 diabetes show a higher than normal rate of polycystic
ovarian syndrome (PCOS). The reason may be that the
ovaries are exposed to high insulin concentrations since women with type 1
diabetes can have frequent hyperglycemia.
48.
Women with type 1 diabetes are higher risk for other autoimmune
diseases, such as autoimmune thyroid disease, rheumatoid arthritis and lupus.
Epidemiology
49.
Type 1 diabetes makes up 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.
50.
Rates vary widely by country. In Finland, the incidence is a high
of 57 per 100,000 per year, in Japan and China a low of 1 to 3 per 100,000 per
year, and in Northern Europe and the U.S., an intermediate of 8 to 17 per 100,000
per year.
51.
In the United States, type 1 diabetes affected about 208,000
youths under the age of 20 in 2015. Over 18,000 youths are diagnosed with Type
1 diabetes every year. Every year about 234,051 Americans die due to diabetes
(type I or II) or diabetes-related complications, with 69,071 having it as the
primary cause of death.
52.
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.
History
53.
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. 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. The
name juvenile diabetes was used earlier as it often first is
diagnosed in childhood.
Society and culture
54.
The disease was estimated to cause $10.5 billion in annual medical
costs ($875 per month per diabetic) and an additional $4.4 billion in indirect
costs ($366 per month per person with diabetes) in the U.S. In the United
States $245 billion every year is attributed to diabetes. Individuals diagnosed
with diabetes have 2.3 times the health care costs as individuals who do not
have diabetes. One in 10 health care dollars are spent on individuals with
diabetes.
Research
55.
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 (JDRF), founded by parents of
children with type 1 diabetes, is the world's largest provider of charity-based
funding for type 1 diabetes research. Other charities include the American
Diabetes Association, Diabetes UK, Diabetes Research and Wellness
Foundation, Diabetes Australia,
the Canadian
Diabetes Association.
56.
A number of approaches have been explored to understand causes and
provide treatments for type 1.
Diet
57.
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. 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. There is evidence from
experiments conducted in animal models that removal of gluten from the diet may prevent the onset
type 1 diabetes but there has been conflicting research in humans.
Virus
58.
One theory proposes that type 1 diabetes is a
virus-triggered autoimmune response
in which the immune system attacks virus-infected cells along with the beta
cells in the pancreas. Several viruses have been implicated,
including enteroviruses (especially coxsackievirus B), cytomegalovirus, Epstein–Barr virus, mumps virus, rubella virus and rotavirus, but to date there is no stringent
evidence to support this hypothesis in humans. A 2011 systematic review
and meta-analysis showed an association between enterovirus infections and type
1 diabetes, but other studies have shown that, rather than triggering an
autoimmune process, enterovirus infections, as coxsackievirus B, could protect
against onset and development of type 1 diabetes.
Stem cells
59.
Pluripotent stem cells can be used to generate beta cells but
previously these cells did not function as well as normal beta cells. In
2014 more mature beta cells were produced which released insulin in response to
blood sugar when transplanted into mice. Before these techniques can be
used in humans more evidence of safety and effectiveness is needed.
Vaccine
Vaccines to treat or prevent Type 1 diabetes are designed to
induce immune tolerance to
insulin or pancreatic beta cells. While Phase II clinical trials of a
vaccine containing alumand recombinant GAD65,
an autoantigen involved in type 1 diabetes, were promising, as of 2014
Phase III had failed. As of 2014, other approaches, such as a DNA vaccineencoding proinsulin and a peptide fragment of insulin, were in early
clinical development.
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