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Diabetes
mellitus (IPA: /?da??'bi?ti?z/ or /?da??'bi?t?s/, /m?'la?t?s/
or /'m?l?t?s/), often referred to simply as diabetes (Greek: d?aß?t??),
is a syndrome characterized by disordered metabolism and abnormally
high blood sugar (hyperglycaemia) resulting from low levels of
the hormone insulin with or without abnormal resistance to insulin's
effects.[2] The characteristic symptoms are excessive urine production
(polyuria), excessive thirst and increased fluid intake (polydipsia),
blurred vision, unexplained weight loss and lethargy. These symptoms
are likely to be absent if the blood sugar is only mildly elevated.
The
World Health Organization recognizes three main forms of diabetes
mellitus: type 1, type 2, and gestational diabetes (occurring
during pregnancy),[3] which have different causes and population
distributions. While, ultimately, all forms are due to the beta
cells of the pancreas being unable to produce sufficient insulin
to prevent hyperglycemia, the causes are different.[4] Type 1
diabetes is usually due to autoimmune destruction of the pancreatic
beta cells. Type 2 diabetes is characterized by insulin resistance
in target tissues. This causes a need for abnormally high amounts
of insulin and diabetes develops when the beta cells cannot meet
this demand. Gestational diabetes is similar to type 2 diabetes
in that it involves insulin resistance; the hormones of pregnancy
can cause insulin resistance in women genetically predisposed
to developing this condition.
Gestational
diabetes typically resolves with delivery of the child, however
types 1 and 2 diabetes are chronic conditions.[2] All types have
been treatable since insulin became medically available in 1921.
Type 1 diabetes, in which insulin is not secreted by the pancreas,
is directly treatable only with injected insulin, although dietary
and other lifestyle adjustments are part of management. Type 2
may be managed with a combination of dietary treatment, tablets
and injections and, frequently, insulin supplementation. While
insulin was originally produced from natural sources such as porcine
pancreas, most insulin used today is produced through genetic
engineering, either as a direct copy of human insulin, or human
insulin with modified molecules that provide different onset and
duration of action. Insulin can also be delivered continuously
by a specialized pump which subcutaneously provides insulin through
a changeable catheter.
Diabetes
can cause many complications. Acute complications (hypoglycemia,
ketoacidosis or nonketotic hyperosmolar coma) may occur if the
disease is not adequately controlled. Serious long-term complications
include cardiovascular disease (doubled risk), chronic renal failure,
retinal damage (which can lead to blindness), nerve damage (of
several kinds), and microvascular damage, which may cause impotence
and poor healing. Poor healing of wounds, particularly of the
feet, can lead to gangrene, which may require amputation. Adequate
treatment of diabetes, as well as increased emphasis on blood
pressure control and lifestyle factors (such as not smoking and
keeping a healthy body weight), may improve the risk profile of
most aforementioned complications. In the developed world, diabetes
is the most significant cause of adult blindness in the non-elderly,
the leading cause of non-traumatic amputation in adults, and diabetic
nephropathy is the main illness requiring renal dialysis in the
United States.[5]
Diabetes
mellitus
--------------------------------------------------------------------------------
Types of Diabetes
Diabetes mellitus type 1
Diabetes mellitus type 2
Gestational diabetes
Pre-diabetes:
Impaired fasting glycaemia
Impaired glucose tolerance
Disease Management
Diabetes management:
•Diabetic diet
•Anti-diabetic drugs
•Conventional insulinotherapy
•Intensive insulinotherapy
Other Concerns
Cardiovascular disease
Diabetic comas:
•Diabetic hypoglycemia
•Diabetic ketoacidosis
•Nonketotic hyperosmolar
Diabetic
myonecrosis
Diabetic nephropathy
Diabetic neuropathy
Diabetic retinopathy
Diabetes
and pregnancy
Blood tests
Blood sugar
Fructosamine
Glucose tolerance test
Glycosylated hemoglobin
Classification
The term diabetes, without qualification, usually refers to diabetes
mellitus, which is associated with excessive sweet urine (known
as "glycosuria") but there are several rarer conditions
also named diabetes. The most common of these is diabetes insipidus
in which the urine is not sweet (insipidus meaning "without
taste" in Latin); it can be caused by either kidney (nephrogenic
DI) or pituitary gland (central DI) damage.
The
principal two idiopathic forms of diabetes mellitus are known
as types 1 and 2. The term "type 1 diabetes" has universally
replaced several former terms, including childhood-onset diabetes,
juvenile diabetes, and insulin-dependent diabetes (IDDM). Likewise,
the term "type 2 diabetes" has replaced several former
terms, including adult-onset diabetes, obesity-related diabetes,
and non-insulin-dependent diabetes (NIDDM). Beyond these two types,
there is no agreed-upon standard nomenclature. Various sources
have defined "type 3 diabetes" as, among others, gestational
diabetes,[6] insulin-resistant type 1 diabetes (or "double
diabetes"), type 2 diabetes which has progressed to require
injected insulin, and latent autoimmune diabetes of adults (or
LADA or "type 1.5" diabetes.[7]) There is also maturity
onset diabetes of the young (MODY) which is a group of several
single gene disorders with strong family histories that present
as type 2 diabetes before 30 years of age.
Type 1 diabetes mellitus
Main article: Diabetes mellitus type 1
Type 1 diabetes mellitus is characterized by loss of the insulin-producing
beta cells of the islets of Langerhans in the pancreas, leading
to a deficiency of insulin. The main cause of this beta cell loss
is a T-cell mediated autoimmune attack.[4] There is no known preventative
measure that can be taken against type 1 diabetes, which comprises
up to 10% of diabetes mellitus cases in North America and Europe
(though this varies by geographical location). Most affected people
are otherwise healthy and of a healthy weight when onset occurs.
Sensitivity and responsiveness to insulin are usually normal,
especially in the early stages. Type 1 diabetes can affect children
or adults but was traditionally termed "juvenile diabetes"
because it represents a majority of cases of diabetes affecting
children.
The
principal treatment of type 1 diabetes, even from the earliest
stages, is replacement of insulin combined with careful monitoring
of blood glucose levels using blood testing monitors. Without
insulin, diabetic ketoacidosis can develop and may result in coma
or death. Emphasis is also placed on lifestyle adjustments (diet
and exercise) though these can do absolutely nothing to reverse
the loss. Apart from the common subcutaneous injections, it is
also possible to deliver insulin by a pump, which allows continuous
infusion of insulin 24 hours a day at preset levels, and the ability
to program doses (a bolus) of insulin as needed at meal times.
An inhaled form of insulin, Exubera, was approved by the FDA in
January 2006, although Pfizer discontinued Exubera in October
2007. [8]
Type
1 treatment must be continued indefinitely. Treatment does not
significantly impair normal activities, if sufficient patient
training, awareness, appropriate care, discipline in testing and
dosing of insulin is taken. However, treatment is burdensome for
patients, and insulin is replaced in a non-physiological manner,
and is therefore far from ideal. The average glucose level for
the type 1 patient should be as close to normal (80–120
mg/dl, 4–6 mmol/l) as is safely possible. Some physicians
suggest up to 140–150 mg/dl (7-7.5 mmol/l) for those having
trouble with lower values, such as frequent hypoglycemic events.
Values above 200 mg/dl (10 mmol/l) is sometimes accompanied by
discomfort and frequent urination leading to dehydration. Values
above 300 mg/dl (15 mmol/l) usually require treatment and may
lead to ketoacidosis, although is not immediately life-threatening.
However, low levels of blood glucose, called hypoglycemia, may
lead to seizures or episodes of unconsciousness and absolutely
must be treated immediately.
Type 2 diabetes mellitus
Main article: Diabetes mellitus type 2
Type 2 diabetes mellitus is due to insulin resistance or reduced
insulin sensitivity, combined with reduced insulin secretion.
The defective responsiveness of body tissues to insulin almost
certainly involves the insulin receptor in cell membranes. In
the early stage the predominant abnormality is reduced insulin
sensitivity, characterized by elevated levels of insulin in the
blood. At this stage hyperglycemia can be reversed by a variety
of measures and medications that improve insulin sensitivity or
reduce glucose production by the liver. As the disease progresses
the impairment of insulin secretion worsens, and therapeutic replacement
of insulin often becomes necessary.
There
are numerous theories as to the exact cause and mechanism in type
2 diabetes. Central obesity (fat concentrated around the waist
in relation to abdominal organs, but not subcutaneous fat) is
known to predispose individuals for insulin resistance. Abdominal
fat is especially active hormonally, secreting a group of hormones
called adipokines that may possibly impair glucose tolerance.
Obesity is found in approximately 55% of patients diagnosed with
type 2 diabetes.[9] Other factors include aging (about 20% of
elderly patients in North America have diabetes) and family history
(type 2 is much more common in those with close relatives who
have had it). In the last decade, type 2 diabetes has increasingly
begun to affect children and adolescents, likely in connection
with the increased prevalence of childhood obesity seen in recent
decades in some places.[10]
Type
2 diabetes may go unnoticed for years because visible symptoms
are typically mild, non-existent or sporadic, and usually there
are no ketoacidotic episodes. However, severe long-term complications
can result from unnoticed type 2 diabetes, including renal failure
due to diabetic nephropathy, vascular disease (including coronary
artery disease), vision damage due to diabetic retinopathy, loss
of sensation or pain due to diabetic neuropathy, and liver damage
from non-alcoholic steatohepatitis.
Type
2 diabetes is usually first treated by increasing physical activity,
decreasing carbohydrate intake, and losing weight. These can restore
insulin sensitivity even when the weight loss is modest, for example
around 5 kg (10 to 15 lb), most especially when it is in abdominal
fat deposits. It is sometimes possible to achieve long-term, satisfactory
glucose control with these measures alone. However, the underlying
tendency to insulin resistance is not lost, and so attention to
diet, exercise, and weight loss must continue. The usual next
step, if necessary, is treatment with oral antidiabetic drugs.
Insulin production is initially only moderately impaired in type
2 diabetes, so oral medication (often used in various combinations)
can be used to improve insulin production (e.g., sulfonylureas),
to regulate inappropriate release of glucose by the liver and
attenuate insulin resistance to some extent (e.g., metformin),
and to substantially attenuate insulin resistance (e.g., thiazolidinediones).
According to one study, overweight patients treated with metformin
compared with diet alone, had relative risk reductions of 32%
for any diabetes endpoint, 42% for diabetes related death and
36% for all cause mortality and stroke.[11] Oral medication may
eventually fail due to further impairment of beta cell insulin
secretion. At this point, insulin therapy is necessary to maintain
normal or near normal glucose levels.
Gestational diabetes
Main article: Gestational diabetes
Gestational diabetes mellitus (GDM) resembles type 2 diabetes
in several respects, involving a combination of relatively inadequate
insulin secretion and responsiveness. It occurs in about 2%–5%
of all pregnancies and may improve or disappear after delivery.
Gestational diabetes is fully treatable but requires careful medical
supervision throughout the pregnancy. About 20%–50% of affected
women develop type 2 diabetes later in life.
Even
though it may be transient, untreated gestational diabetes can
damage the health of the fetus or mother. Risks to the baby include
macrosomia (high birth weight), congenital cardiac and central
nervous system anomalies, and skeletal muscle malformations. Increased
fetal insulin may inhibit fetal surfactant production and cause
respiratory distress syndrome. Hyperbilirubinemia may result from
red blood cell destruction. In severe cases, perinatal death may
occur, most commonly as a result of poor placental profusion due
to vascular impairment. Induction may be indicated with decreased
placental function. A cesarean section may be performed if there
is marked fetal distress or an increased risk of injury associated
with macrosomia, such as shoulder dystocia.
Other types
There are several rare causes of diabetes mellitus that do not
fit into type 1, type 2, or gestational diabetes; attempts to
classify them remain controversial. Some cases of diabetes are
caused by the body's tissue receptors not responding to insulin
(even when insulin levels are normal, which is what separates
it from type 2 diabetes); this form is very uncommon. Genetic
mutations (autosomal or mitochondrial) can lead to defects in
beta cell function. Abnormal insulin action may also have been
genetically determined in some cases. Any disease that causes
extensive damage to the pancreas may lead to diabetes (for example,
chronic pancreatitis and cystic fibrosis). Diseases associated
with excessive secretion of insulin-antagonistic hormones can
cause diabetes (which is typically resolved once the hormone excess
is removed). Many drugs impair insulin secretion and some toxins
damage pancreatic beta cells. The ICD-10 (1992) diagnostic entity,
malnutrition-related diabetes mellitus (MRDM or MMDM, ICD-10 code
E12), was deprecated by the World Health Organization when the
current taxonomy was introduced in 1999.[3]
Signs and symptoms
The classical triad of diabetes symptoms is polyuria, polydipsia
and polyphagia, which are, respectively, frequent urination; increased
thirst and consequent increased fluid intake; and increased appetite.
Symptoms may develop quite rapidly (weeks or months) in type 1
diabetes, particularly in children. However, in type 2 diabetes
the symptoms develop much more slowly and may be subtle or completely
absent. Type 1 diabetes may also cause a rapid yet significant
weight loss (despite normal or even increased eating) and irreducible
fatigue. All of these symptoms except weight loss can also manifest
in type 2 diabetes in patients whose diabetes is poorly controlled.
When
the glucose concentration in the blood is raised beyond the renal
threshold, reabsorption of glucose in the proximal renal tubuli
is incomplete, and part of the glucose remains in the urine (glycosuria).
This increases the osmotic pressure of the urine and inhibits
the reabsorption of water by the kidney, resulting in increased
urine production (polyuria) and increased fluid loss. Lost blood
volume will be replaced osmotically from water held in body cells,
causing dehydration and increased thirst.
Prolonged
high blood glucose causes glucose absorption, which leads to changes
in the shape of the lenses of the eyes, resulting in vision changes.
Blurred vision is a common complaint leading to a diabetes diagnosis;
type 1 should always be suspected in cases of rapid vision change
whereas type 2 is generally more gradual, but should still be
suspected.
Patients
(usually with type 1 diabetes) may also present with diabetic
ketoacidosis (DKA), an extreme state of metabolic dysregulation
characterized by the smell of acetone on the patient's breath;
a rapid, deep breathing known as Kussmaul breathing; polyuria;
nausea; vomiting and abdominal pain; and any of many altered states
of consciousness or arousal (such as hostility and mania or, equally,
confusion and lethargy). In severe DKA, coma may follow, progressing
to death. Diabetic ketoacidosis is a medical emergency and requires
hospital admission.
A
rarer but equally severe possibility is hyperosmolar nonketotic
state, which is more common in type 2 diabetes and is mainly the
result of dehydration due to loss of body water. Often, the patient
has been drinking extreme amounts of sugar-containing drinks,
leading to a vicious circle in regard to the water loss.
Genetics
Both type 1 and type 2 diabetes are at least partly inherited.
Type 1 diabetes appears to be triggered by some (mainly viral)
infections, or in a less common group, by stress or environmental
exposure (such as exposure to certain chemicals or drugs). There
is a genetic element in individual susceptibility to some of these
triggers which has been traced to particular HLA genotypes (i.e.,
the genetic "self" identifiers relied upon by the immune
system). However, even in those who have inherited the susceptibility,
type 1 diabetes mellitus seems to require an environmental trigger.
A small proportion of people with type 1 diabetes carry a mutated
gene that causes maturity onset diabetes of the young (MODY).
There
is a stronger inheritance pattern for type 2 diabetes. Those with
first-degree relatives with type 2 have a much higher risk of
developing type 2, increasing with the number of those relatives.
Concordance among monozygotic twins is close to 100%, and about
25% of those with the disease have a family history of diabetes.
Candidate genes include KCNJ11 (potassium inwardly rectifying
channel, subfamily J, member 11), which encodes the islet ATP-sensitive
potassium channel Kir6.2, and TCF7L2 (transcription factor 7–like
2), which regulates proglucagon gene expression and thus the production
of glucagon-like peptide-1.[4] Moreover, obesity (which is an
independent risk factor for type 2 diabetes) is strongly inherited.[12]
Various
hereditary conditions may feature diabetes, for example myotonic
dystrophy and Friedreich's ataxia. Wolfram's syndrome is an autosomal
recessive neurodegenerative disorder that first becomes evident
in childhood. It consists of diabetes insipidus, diabetes mellitus,
optic atrophy, and deafness, hence the acronym DIDMOAD.[13]
Pathophysiology
Mechanism of insulin release in normal pancreatic beta cells.
Insulin production is more or less constant within the beta cells,
irrespective of blood glucose levels. It is stored within vacuoles
pending release, via exocytosis, which is triggered by increased
blood glucose levels.Insulin is the principal hormone that regulates
uptake of glucose from the blood into most cells (primarily muscle
and fat cells, but not central nervous system cells). Therefore
deficiency of insulin or the insensitivity of its receptors plays
a central role in all forms of diabetes mellitus.
Much
of the carbohydrate in food is converted within a few hours to
the monosaccharide glucose, the principal carbohydrate found in
blood and used by the body as fuel. Insulin is released into the
blood by beta cells (ß-cells), found in the Islets of Langerhans
in the pancreas, in response to rising levels of blood glucose
after eating. Insulin is used by about two-thirds of the body's
cells to absorb glucose from the blood for use as fuel, for conversion
to other needed molecules, or for storage. Insulin is also the
principal control signal for conversion of glucose to glycogen
for internal storage in liver and muscle cells. Lowered glucose
levels result both in the reduced release of insulin from the
beta cells and in the reverse conversion of glycogen to glucose
when glucose levels fall. This is mainly controlled by the hormone
glucagon which acts in an opposite manner to insulin. Glucose
thus recovered by the liver re-enters the bloodstream; muscle
cells lack the necessary export mechanism.
Higher
insulin levels increase some anabolic ("building up")
processes such as cell growth and duplication, protein synthesis,
and fat storage. Insulin (or its lack) is the principal signal
in converting many of the bidirectional processes of metabolism
from a catabolic to an anabolic direction, and vice versa. In
particular, a low insulin level is the trigger for entering or
leaving ketosis (the fat burning metabolic phase).
If
the amount of insulin available is insufficient, if cells respond
poorly to the effects of insulin (insulin insensitivity or resistance),
or if the insulin itself is defective, then glucose will not be
absorbed properly by those body cells that require it nor will
it be stored appropriately in the liver and muscles. The net effect
is persistent high levels of blood glucose, poor protein synthesis,
and other metabolic derangements, such as acidosis.
Diagnosis
The diagnosis of type 1 diabetes, and many cases of type 2, is
usually prompted by recent-onset symptoms of excessive urination
(polyuria) and excessive thirst (polydipsia), often accompanied
by weight loss. These symptoms typically worsen over days to weeks;
about a quarter of people with new type 1 diabetes have developed
some degree of diabetic ketoacidosis 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 is frequently
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.
Diabetes
mellitus is characterized by recurrent or persistent hyperglycemia,
and is diagnosed by demonstrating any one of the following:[3]
fasting
plasma glucose level at or above 126 mg/dL (7.0 mmol/l).
plasma glucose at or above 200 mg/dL (11.1 mmol/l) two hours after
a 75 g oral glucose load as in a glucose tolerance test.
random plasma glucose at or above 200 mg/dL (11.1 mmol/l).
A positive result, in the absence of clinical symptoms of diabetes,
should be confirmed by another 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. 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 between 100 and 125 mg/dL (6.1 and
7.0 mmol/l) are considered to have impaired fasting glycemia.
Patients with plasma glucose at or above 140 mg/dL or 7.8 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 as well as cardiovascular disease.
While
not used for diagnosis, an elevated level of glucose irreversibly
bound to hemoglobin (termed glycosylated hemoglobin or HbA1c)
of 6.0% or higher (the 2003 revised U.S. standard) is considered
abnormal by most labs; HbA1c is primarily used as a treatment-tracking
test reflecting average blood glucose levels over the preceding
90 days (approximately). However, some physicians may order this
test at the time of diagnosis to track changes over time. The
current recommended goal for HbA1c in patients with diabetes is
<7.0%, which is considered good glycemic control, although
some guidelines are stricter (<6.5%). People with diabetes
who have HbA1c levels within this range have a significantly lower
incidence of complications from diabetes, including retinopathy
and diabetic nephropathy.[14][15]
Screening
Diabetes screening is recommended for many people at various stages
of life, and for those with any of several risk factors. The screening
test varies according to circumstances and local policy, and may
be a random blood glucose test, a fasting blood glucose test,
a blood glucose test two hours after 75 g of glucose, or an even
more formal glucose tolerance test. Many healthcare providers
recommend universal screening for adults at age 40 or 50, and
often periodically thereafter. Earlier screening is typically
recommended for those with risk factors such as obesity, family
history of diabetes, high-risk ethnicity (Mestizo/Hispanic, Native
American, Afro-Caribbean, Pacific Island, and South Asian ancestry).[16][17]
Many
medical conditions are associated with diabetes and warrant screening.
A partial list includes: high blood pressure, elevated cholesterol
levels, coronary artery disease, past gestational diabetes, polycystic
ovary syndrome, chronic pancreatitis, fatty liver, hemochromatosis,
cystic fibrosis, several mitochondrial neuropathies and myopathies,
myotonic dystrophy, Friedreich's ataxia, some of the inherited
forms of neonatal hyperinsulinism. The risk of diabetes is higher
with chronic use of several medications, including high-dose glucocorticoids,
some chemotherapy agents (especially L-asparaginase), as well
as some of the antipsychotics and mood stabilizers (especially
phenothiazines and some atypical antipsychotics).
People
with a confirmed diagnosis of diabetes are screened routinely
for complications. This includes yearly urine testing for microalbuminuria
and examination of the retina (retinal photography) for retinopathy.
In the UK, screening for diabetic retinopathy has helped reduce
the incidence of legal blindness since its implementation in the
UK.[citation needed]
Prevention
Type 1 diabetes risk is known to depend upon a genetic predisposition
based on HLA types (particularly types DR3 and DR4), an unknown
environmental trigger (suspected to be an infection, although
none has proven definitive in all cases), and an uncontrolled
autoimmune response that attacks the insulin producing beta cells.[18]
Some research has suggested that breastfeeding decreased the risk;
[19][20] various other nutritional risk factors are being studied,
but no firm evidence has been found. [21] Giving children 2000
IU of Vitamin D during their first year of life is associated
with reduced risk of type 1 diabetes. [22]
Type
2 diabetes risk can be reduced in many cases by making changes
in diet and increasing physical activity.[23][24] The American
Diabetes Association (ADA) recommends maintaining a healthy weight,
getting at least 2½ hours of exercise per week (a brisk
sustained walk appears sufficient), having a modest fat intake,
and eating a good amount of fiber and whole grains. The ADA does
not recommend alcohol consumption as a preventative, but it is
interesting to note that moderate alcohol intake may reduce the
risk (though heavy consumption clearly increases damage to body
systems significantly). There is inadequate evidence that eating
foods of low glycemic index is clinically helpful.[25]
Some
studies have shown delayed progression to diabetes in predisposed
patients through prophylactic use of metformin,[24] rosiglitazone,[26]
or valsartan.[27] In patients on hydroxychloroquine for rheumatoid
arthritis, incidence of diabetes was reduced by 77%.[28] Breastfeeding
might also be associated with the prevention of type 2 of the
disease in mothers.[29]
It
is possible that adequate copper could help prevent insulin dependent
diabetes since it does so for ATZ poisoned mice [30] and copper
in drinking water has somewhat of a protective effect [31]. It
could be that copper produces its effects through super oxidase
dismutase (SOD) because metaloporpherin based superoxide dismutase
can prevent or delay the onset of the autoimmune cascade in diabetes,
using mice [32]. However, there are sufficient differences in
human and animal models to indicate this is only a theory at the
present time.
Children
with antibodies treated with vitamin B-3 (niacin) had less than
half the onset of diabetes incidence in a 7-year time span as
the general population and even lower incidence relative to those
with antibodies as above, but no vitamin B-3 [33]
Treatment and management
Main article: Diabetes management
Diabetes mellitus is currently a chronic disease, without a cure,
and medical emphasis must necessarily be on managing/avoiding
possible short-term as well as long-term diabetes-related problems.
There is an exceptionally important role for patient education,
dietetic support, sensible exercise, self glucose monitoring,
with the goal of keeping both short-term blood glucose levels,
and long term levels as well, within acceptable bounds. Careful
control is needed to reduce the risk of long term complications.
This is theoretically achievable with combinations of diet, exercise
and weight loss (type 2), various oral diabetic drugs (type 2
only), and insulin use (type 1 and increasingly for type 2 not
responding to oral medications). In addition, given the associated
higher risks of cardiovascular disease, lifestyle modifications
should be undertaken to control blood pressure[34] and cholesterol
by exercising more, smoking cessation, consuming an appropriate
diet, wearing diabetic socks, and if necessary, taking any of
several drugs to reduce pressure. Many Type 1 treatments include
the combination use of regular or NPH insulin, and/or synthetic
insulin analogs such as Humalog, Novolog or Apidra; the combination
of Lantus/Levemir and Humalog, Novolog or Apidra. Another Type
1 treatment option is the use of the insulin pump with some of
the most popular pump brands being: Cozmo, Animas, Medtronic Minimed,
and Omnipod.
In
countries using a general practitioner system, such as the United
Kingdom, care may take place mainly outside hospitals, with hospital-based
specialist care used only in case of complications, difficult
blood sugar control, or research projects. In other circumstances,
general practitioners and specialists share care of a patient
in a team approach. Optometrists, podiatrists/chiropodists, dietitians,
physiotherapists, clinical nurse specialists (eg, Certified Diabetes
Educators and DSNs (Diabetic Specialist Nurse)), or nurse practitioners
may jointly provide multidisciplinary expertise. In countries
where patients must provide their own health care (i.e., the United
States in the developed world), the impact of out-of-pocket costs
of diabetic care can be high. In addition to the medications and
supplies needed, patients are often advised to receive regular
consultation from a physician (e.g., at least every three to six
months).
Cure
Cures for type 1 diabetes
Main article: Cure for diabetes mellitus type 1
There is no practical cure now for type 1 diabetes. The fact that
type 1 diabetes is due to the failure of one of the cell types
of a single organ with a relatively simple function (i.e. the
failure of the islets of Langerhans) has led to the study of several
possible schemes to cure this form diabetes mostly by replacing
the pancreas or just the beta cells.[35] Only those type 1 diabetics
who have received either a pancreas or a kidney-pancreas transplant
(when they have developed diabetic nephropathy) and become insulin-independent
may now be considered "cured" from their diabetes. A
simultaneous pancreas-kidney transplant is a promising solution,
showing similar or improved survival rates over a kidney transplant
alone.[36] Still, they generally remain on long-term immunosuppressive
drugs and there is a possibility that the immune system will mount
a host versus graft response against the transplanted organ.[35]
Transplants
of exogenous beta cells have been performed experimentally in
both mice and humans, but this measure is not yet practical in
regular clinical practice partly due to the limited number of
beta cell donors. Thus far, like any such transplant, it has provoked
an immune reaction and long-term immunosuppressive drugs will
be needed to protect the transplanted tissue.[37] An alternative
technique has been proposed to place transplanted beta cells in
a semi-permeable container, isolating and protecting them from
the immune system. Stem cell research has also been suggested
as a potential avenue for a cure since it may permit regrowth
of Islet cells which are genetically part of the treated individual,
thus perhaps eliminating the need for immuno-suppressants.[35]
A 2007 trial of 15 newly diagnosed patients with type 1 diabetes
treated with stem cells raised from their own bone marrow after
immune suppression showed that the majority did not require any
insulin treatment for prolonged periods of time.[38].
Microscopic
or nanotechnological approaches are under investigation as well,
in one proposed case with implanted stores of insulin metered
out by a rapid response valve sensitive to blood glucose levels.
At least two approaches have been demonstrated in vitro. These
are, in some sense, closed-loop insulin pumps.
Cures for type 2 diabetes
Type 2 diabetes can be cured by one type of gastric bypass surgery
in 80-100% of severely obese patients. The effect is not due to
weight loss because it usually occurs within days of surgery,
which is before significant weight loss occurs. The pattern of
secretion of gastrointestinal hormones is changed by the bypass
and removal of the duodenum and proximal jejunum, which together
form the upper (proximal) part of the small intestine.[39] One
hypothesis is that the proximal small intestine is dysfunctional
in type 2 diabetes; its removal eliminates the source of an unknown
hormone that contributes to insulin resistance.[40] This surgery
has been widely performed on morbidly obese patients and has the
benefit of reducing the death rate from all causes by up to 40%.[41]
A small number of normal to moderately obese patients with type
2 diabetes have successfully undergone similar operations.[42][43]
Prognosis
Patient education, understanding, and participation is vital since
the complications of diabetes are far less common and less severe
in people who have well-controlled blood sugar levels.[44][45]
Wider health issues accelerate the deleterious effects of diabetes.
These include smoking, elevated cholesterol levels, obesity, high
blood pressure, and lack of regular exercise. According to a study,
women with high blood pressure have a threefold risk of developing
diabetes.
Anecdotal
evidence suggests that some of those with type 2 diabetes who
exercise regularly, lose weight, and eat healthy diets may be
able to keep some of the disease or some of the effects of the
disease in 'remission.' Certainly these tips can help prevent
people predisposed to type 2 diabetes and those at pre-diabetic
stages from actually developing the disorder as it helps restore
insulin sensitivity. However patients should talk to their doctors
about this for real expectations before undertaking it (esp. to
avoid hypoglycemia or other complications); few people actually
seem to go into total 'remission,' but some may find they need
less of their insulin medications since the body tends to have
lower insulin requirements during and shortly following exercise.
Regardless of whether it works that way or not for an individual,
there are certainly other benefits to this healthy lifestyle for
both diabetics and nondiabetics.
The
way diabetes is managed changes with age. Insulin production decreases
due to age-related impairment of pancreatic beta cells. Additionally,
insulin resistance increases due to the loss of lean tissue and
the accumulation of fat, particularly intra-abdominal fat, and
the decreased tissue sensitivity to insulin. Glucose tolerance
progressively declines with age, leading to a high prevalence
of type 2 diabetes and postchallenge hyperglycemia in the older
population.[46] Age-related glucose intolerance in humans is often
accompanied by insulin resistance, but circulating insulin levels
are similar to those of younger people. [47] Treatment goals for
older patients with diabetes vary with the individual, and take
into account health status, as well as life expectancy, level
of dependence, and willingness to adhere to a treatment regimen.[48]
Acute complications
Main articles: Diabetic ketoacidosis , Nonketotic hyperosmolar
coma , Hypoglycemia , and Diabetic coma
Diabetic ketoacidosis
Diabetic ketoacidosis (DKA) is an acute and dangerous complication
that is always a medical emergency. Lack of insulin causes the
liver to turn fat into ketone bodies, a fuel mainly used by the
brain. Elevated levels of ketone bodies in the blood decrease
the blood's pH, leading to most of the symptoms of DKA. On presentation
at hospital, the patient in DKA is typically dehydrated and is
breathing rapidly and deeply. Abdominal pain is common and may
be severe. The level of consciousness is typically normal until
late in the process, when lethargy may progress to coma. Ketoacidosis
can become severe enough to cause hypotension, shock, and death.
Analysis of the urine reveals significant levels of ketone bodies
present (which spill over from the blood when the kidneys filter
blood). Prompt proper treatment usually results in full recovery,
though death can result from inadequate or delayed treatment,
or from complications. Ketoacidosis is much more common in type
1 diabetes than type 2.
Nonketotic
hyperosmolar coma
The hyperosmolar nonketotic state (HNS) is an acute complication
with many symptoms in common with DKA, but an entirely different
cause and different treatment. In a person with very high blood
glucose levels (usually considered to be above 300 mg/dl (16 mmol/l)),
water is drawn out of cells into the blood by osmosis and the
kidneys dump glucose into the urine. This results in loss of water
and an increase in blood osmolality. If fluid is not replaced
(by mouth or intravenously), the osmotic effect of high glucose
levels combined with the loss of water will eventually lead to
dehydration. The body's cells become progressively dehydrated
as water is taken from them and excreted. Electrolyte imbalances
are also common and dangerous. As with DKA, urgent medical treatment
is necessary, especially volume replacement. Lethargy may ultimately
progress to a coma, which is more common in type 2 diabetes than
type 1.
Hypoglycemia
Hypoglycemia, or abnormally low blood glucose, is a complication
of several diabetes treatments. It may develop if the glucose
intake does not cover the treatment. The patient may become agitated,
sweaty, and have many symptoms of sympathetic activation of the
autonomic nervous system resulting in feelings similar to dread
and immobilized panic. Consciousness can be altered or even lost
in extreme cases, leading to coma, seizures, or even brain damage
and death. In patients with diabetes, this may be caused by several
factors, such as too much or incorrectly timed insulin, too much
or incorrectly timed exercise (exercise decreases insulin requirements)
or not enough food (specifically glucose-producing carbohydrates),
but this is an over-simplification.
It
is more accurate to note that iatrogenic hypoglycemia is typically
the result of the interplay of absolute (or relative) insulin
excess and compromised glucose counterregulation in type 1 and
advanced type 2 diabetes. Decrements in insulin, increments in
glucagon, and, absent the latter, increments in epinephrine stand
high in the hierarchy of redundant glucose counterregulatory factors
that normally prevent or rapidly correct hypoglycemia. In insulin-deficient
diabetes (exogenous) insulin levels do not decrease as glucose
levels fall, and the combination of deficient glucagon and epinephrine
responses causes defective glucose counterregulation.
Furthermore,
reduced sympathoadrenal responses can cause hypoglycemia unawareness.
The concept of hypoglycemia-associated autonomic failure (HAAF)
in diabetes posits that recent incidents of hypoglycemia causes
both defective glucose counterregulation and hypoglycemia unawareness.
By shifting glycemic thresholds for the sympathoadrenal (including
epinephrine) and the resulting neurogenic responses to lower plasma
glucose concentrations, antecedent hypoglycemia leads to a vicious
cycle of recurrent hypoglycemia and further impairment of glucose
counterregulation. In many cases (but not all), short-term avoidance
of hypoglycemia reverses hypoglycemia unawareness in most affected
patients, although this is easier in theory than it is in practice.
In
most cases, hypoglycemia is treated with sugary drinks or food.
In severe cases, an injection of glucagon (a hormone with the
opposite effects of insulin) or an intravenous infusion of dextrose
is used for treatment, but usually only if the person is unconscious.
In hospitals, intravenous dextrose is often used.
Chronic complications
Vascular disease
Chronic elevation of blood glucose level leads to damage of blood
vessels (angiopathy). The endothelial cells lining the blood vessels
take in more glucose than normal, since they don't depend on insulin.
They then form more surface glycoproteins than normal, and cause
the basement membrane to grow thicker and weaker. In diabetes,
the resulting problems are grouped under "microvascular disease"
(due to damage to small blood vessels) and "macrovascular
disease" (due to damage to the arteries).
Image of fundus showing scatter laser surgery for diabetic retinopathyThe
damage to small blood vessels leads to a microangiopathy, which
can cause one or more of the following:
Diabetic
retinopathy, growth of friable and poor-quality new blood vessels
in the retina as well as macular edema (swelling of the macula),
which can lead to severe vision loss or blindness. Retinal damage
(from microangiopathy) makes it the most common cause of blindness
among non-elderly adults in the US.
Diabetic neuropathy, abnormal and decreased sensation, usually
in a 'glove and stocking' distribution starting with the feet
but potentially in other nerves, later often fingers and hands.
When combined with damaged blood vessels this can lead to diabetic
foot (see below). Other forms of diabetic neuropathy may present
as mononeuritis or autonomic neuropathy. Diabetic amyotrophy is
muscle weakness due to neuropathy.
Diabetic nephropathy, damage to the kidney which can lead to chronic
renal failure, eventually requiring dialysis. Diabetes mellitus
is the most common cause of adult kidney failure worldwide in
the developed world.
Macrovascular disease leads to cardiovascular disease, to which
accelerated atherosclerosis is a contributor:
Coronary
artery disease, leading to angina or myocardial infarction ("heart
attack")
Stroke (mainly the ischemic type)
Peripheral vascular disease, which contributes to intermittent
claudication (exertion-related leg and foot pain) as well as diabetic
foot.
Diabetic myonecrosis ('muscle wasting')
Diabetic foot, often due to a combination of neuropathy and arterial
disease, may cause skin ulcer and infection and, in serious cases,
necrosis and gangrene. It is why diabetics are prone to leg and
foot infections and why it takes longer for them to heal from
leg and foot wounds. It is the most common cause of adult amputation,
usually of toes and or feet, in the developed world.
Carotid
artery stenosis does not occur more often in diabetes, and there
appears to be a lower prevalence of abdominal aortic aneurysm.
However, diabetes does cause higher morbidity, mortality and operative
risks with these conditions.[49]
Epidemiology
In 2000, according to the World Health Organization, at least
171 million people worldwide suffer from diabetes. Its incidence
is increasing rapidly, and it is estimated that by the year 2030,
this number will double. Diabetes mellitus occurs throughout the
world, but is more common (especially type 2) in the more developed
countries. The greatest increase in prevalence is, however, expected
to occur in Asia and Africa, where most patients will likely be
found by 2030. The increase in incidence of diabetes in developing
countries follows the trend of urbanization and lifestyle changes,
perhaps most importantly a "Western-style" diet. This
has suggested an environmental (i.e., dietary) effect, but there
is little understanding of the mechanism(s) at present, though
there is much speculation, some of it most compellingly presented.
Diabetes
is in the top 10, and perhaps the top 5, of the most significant
diseases in the developed world, and is gaining in significance
there and elsewhere (see big killers).
For
at least 20 years, diabetes rates in North America have been increasing
substantially. In 2005 there were about 20.8 million people with
diabetes in the United States alone. According to the American
Diabetes Association, there are about 6.2 million people undiagnosed
and about 41 million people that would be considered prediabetic.[50]
However, the criteria for diagnosing diabetes in the USA means
that it is more readily diagnosed than in some other countries.
The Centers for Disease Control has termed the change an epidemic.
The National Diabetes Information Clearinghouse estimates that
diabetes costs $132 billion in the United States alone every year.
About 5%–10% of diabetes cases in North America are type
1, with the rest being type 2. The fraction of type 1 in other
parts of the world differs; this is likely due to both differences
in the rate of type 1 and differences in the rate of other types,
most prominently type 2. Most of this difference is not currently
understood. The American Diabetes Association point out the 2003
assessment of the National Center for Chronic Disease Prevention
and Health Promotion (Centers for Disease Control and Prevention)
that 1 in 3 Americans born after 2000 will develop diabetes in
their lifetime.[51][50]
According
to the American Diabetes Association, approximately 18.3% (8.6
million) of Americans age 60 and older have diabetes. [52] Diabetes
mellitus prevalence increases with age, and the numbers of older
persons with diabetes are expected to grow as the elderly population
increases in number. The National Health and Nutrition Examination
Survey (NHANES III) demonstrated that, in the population over
65 years old, 18% to 20% have diabetes, with 40% having either
diabetes or its precursor form of impaired glucose tolerance.[46]
History
The term diabetes (Greek: d?aß?t??, diabetes) was coined
by Aretaeus of Cappadocia. It was derived from the Greek verb
d?aßa??e??, diabaínein, itself formed from the prefix
dia-, "across, apart," and the verb bainein, "to
walk, stand." The verb diabeinein meant "to stride,
walk, or stand with legs asunder"; hence, its derivative
diabetes meant "one that straddles," or specifically
"a compass, siphon." The sense "siphon" gave
rise to the use of diabetes as the name for a disease involving
the discharge of excessive amounts of urine. Diabetes is first
recorded in English, in the form diabete, in a medical text written
around 1425. In 1675, Thomas Willis added the word mellitus, from
the Latin meaning "honey", a reference to the sweet
taste of the urine. This sweet taste had been noticed in urine
by the ancient Greeks, Chinese, Egyptians, and Indians. In 1776,
Matthew Dobson confirmed that the sweet taste was because of an
excess of a kind of sugar in the urine and blood of people with
diabetes.[53]
The
ancient Indians tested for diabetes by observing whether ants
were attracted to a person's urine, and called the ailment "sweet
urine disease" (Madhumeha). The Korean, Chinese, and Japanese
words for diabetes are based on the same ideographs (???) which
mean "sugar urine disease".
Although
diabetes has been recognized since antiquity, and treatments of
various efficacy have been known in various regions since the
Middle Ages, and in legend for much longer, pathogenesis of diabetes
has only been understood experimentally since about 1900.[54]
The discovery of a role for the pancreas in diabetes is generally
ascribed to Joseph von Mering and Oskar Minkowski, who in 1889
found that dogs whose pancreas was removed developed all the signs
and symptoms of diabetes and died shortly afterwards.[55] In 1910,
Sir Edward Albert Sharpey-Schafer suggested that people with diabetes
were deficient in a single chemical that was normally produced
by the pancreas—he proposed calling this substance insulin,
from the Latin insula, meaning island, in reference to the insulin-producing
islets of Langerhans in the pancreas.[54]
The
endocrine role of the pancreas in metabolism, and indeed the existence
of insulin, was not further clarified until 1921, when Sir Frederick
Grant Banting and Charles Herbert Best repeated the work of Von
Mering and Minkowski, and went further to demonstrate they could
reverse induced diabetes in dogs by giving them an extract from
the pancreatic islets of Langerhans of healthy dogs.[56] Banting,
Best, and colleagues (especially the chemist Collip) went on to
purify the hormone insulin from bovine pancreases at the University
of Toronto. This led to the availability of an effective treatment—insulin
injections—and the first patient was treated in 1922. For
this, Banting and laboratory director MacLeod received the Nobel
Prize in Physiology or Medicine in 1923; both shared their Prize
money with others in the team who were not recognized, in particular
Best and Collip. Banting and Best made the patent available without
charge and did not attempt to control commercial production. Insulin
production and therapy rapidly spread around the world, largely
as a result of this decision.
The
distinction between what is now known as type 1 diabetes and type
2 diabetes was first clearly made by Sir Harold Percival (Harry)
Himsworth, and published in January 1936.[57]
Despite
the availability of treatment, diabetes has remained a major cause
of death. For instance, statistics reveal that the cause-specific
mortality rate during 1927 amounted to about 47.7 per 100,000
population in Malta.[58]
Other
landmark discoveries include:[54]
identification
of the first of the sulfonylureas in 1942
reintroduction of the use of biguanides for Type 2 diabetes in
the late 1950s. The initial phenformin was withdrawn worldwide
(in the U.S. in 1977) due to its potential for sometimes fatal
lactic acidosis and metformin was first marketed in France in
1979, but not until 1994 in the US.
the determination of the amino acid sequence of insulin (by Sir
Frederick Sanger, for which he received a Nobel Prize)
the radioimmunoassay for insulin, as discovered by Rosalyn Yalow
and Solomon Berson (gaining Yalow the 1977 Nobel Prize in Physiology
or Medicine)[59]
the three-dimensional structure of insulin (PDB 2INS)
Dr Gerald Reaven's identification of the constellation of symptoms
now called metabolic syndrome in 1988
demonstration that intensive glycemic control in type 1 diabetes
reduces chronic side effects more as glucose levels approach 'normal'
in a large longitudinal study,[60] and also in type 2 diabetics
in other large studies
identification of the first thiazolidinedione as an effective
insulin sensitizer during the 1990s
-In 1980, U.S. biotech company Genentech developed human insulin.
The insulin is isolated from genetically-altered bacteria (the
bacteria contain the human gene for synthesizing human insulin),
which produce large quantities of insulin. Scientists then purify
the insulin and distribute it to pharmacies for use by diabetes
patients. (2004. Thieman,W.J. and Palladino,M.A. Introduction
To Biotechnology. page 6. Pearson, Benjamin Cummings)
Social issues
The 1989 Declaration of St Vincent was the result of international
efforts to improve the care accorded to those with diabetes. Doing
so is important both in terms of quality of life and life expectancy
but also economically - expenses to diabetes have been shown to
be a major drain on health- and productivity-related resources
for healthcare systems and governments.
Several
countries established more and less successful national diabetes
programmes to improve treatment of the disease.[61]
A
study shows that diabetic patients with neuropathic symptoms such
as numbness or tingling in feet or hands are twice more likely
to be unemployed than those without the symptoms.[62]
See also
List of terms associated with diabetes
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into insulin-sensitive and insulin-insensitive types". Lancet
i: 127–130.
^ Department of Health (Malta), 1897–1972:Annual Reports.
^ Yalow RS, Berson SA (1960). "Immunoassay of endogenous
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^ "The effect of intensive treatment of diabetes on the development
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diabetes mellitus. The Diabetes Control and Complications Trial
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External links
American Diabetes Association
Diabetes Australia-NSW
Canadian Diabetes Association
Diet, Nutrition and the prevention of chronic diseases (including
diabetes) by a Joint WHO/FAO Expert consultation (2003)
Centers for Disease Control Diabetes Section
Diabetes UK
Diabetes Health Institute
Diabetes Institute for Immunology and Transplantion
The Iacocca Foundation
The Immunology of Diabetes Society
International Diabetes Federation
Juvenile Diabetes Research Foundation
MedlinePlus Diabetes from the U.S. National Library of Medicine
National Diabetes Education Program
National Diabetes Information Clearinghouse
Primary Care Diabetes Europe
World Health Organization fact sheet on diabetes
World Health Organization—The Diabetes Programme
[hide]v • d • eEndocrine pathology: endocrine diseases
(E00-35, 240-259)
Thyroid Hypothyroidism (Iodine deficiency, Cretinism, Congenital
hypothyroidism, Goitre, Myxedema) - Hyperthyroidism (Graves disease,
Toxic multinodular goitre, Teratoma with thyroid tissue or Struma
ovarii) - Thyroiditis (De Quervain's thyroiditis, Hashimoto's
thyroiditis, Riedel's thyroiditis) - Euthyroid sick syndrome
Pancreas Diabetes mellitus (type 1, type 2, coma, angiopathy,
ketoacidosis, nephropathy, neuropathy, retinopathy) - Hypoglycemia
- Hyperinsulinism - Zollinger-Ellison syndrome - insulin receptor
(Rabson-Mendenhall syndrome)
Parathyroid Hypoparathyroidism (Pseudohypoparathyroidism) - Hyperparathyroidism
(Primary, Secondary, Tertiary)
Pituitary Hyperpituitarism (Acromegaly, Hyperprolactinaemia, SIADH)
- Hypopituitarism (Simmonds' disease/Sheehan's syndrome, Kallmann
syndrome, Growth hormone deficiency, Diabetes insipidus) - Adiposogenital
dystrophy - Empty sella syndrome
Adrenal Cushing's syndrome (Nelson's syndrome, Pseudo-Cushing's
syndrome) - CAH (due to 21-hydroxylase deficiency) - Hyperaldosteronism
(Conn syndrome, Bartter syndrome) - Adrenal insufficiency (Addison's
disease) - Hypoaldosteronism
Gonads ovarian dysfunction (Polycystic ovary syndrome, Premature
ovarian failure) - testicular dysfunction (5-alpha-reductase deficiency)
- testosterone biosynthesis (17-beta-hydroxysteroid dehydrogenase
deficiency) - general (Hypogonadism, Delayed puberty, Precocious
puberty)
Other Androgen insensitivity syndrome - Autoimmune polyendocrine
syndrome - Carcinoid syndrome - Gigantism - Short stature (Laron
syndrome, Psychogenic dwarfism) - Multiple endocrine neoplasia
(1, 2) - Progeria - Woodhouse-Sakati syndrome
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