Diabetes mellitus (DM) also known as simply diabetes, is a group of metabolic diseases in which

there are high blood sugar levels over a prolonged period. This high blood sugar produces the symptoms
of frequent urination, increased thirst, and increased hunger. Untreated, diabetes can cause many
complications. Acute complications include diabetic ketoacidosis and nonketotic hyperosmolar coma.[4]
Serious long-term complications include heart disease, stroke, kidney failure, foot ulcers and damage to
the eyes.
Diabetes is due to either the pancreas not producing enough insulin, or the cells of the body not
responding properly to the insulin produced.[5] There are three main types of diabetes mellitus:

Type 1 DM results from the body's failure to produce enough insulin. This form was previously referred
to as "insulin-dependent diabetes mellitus" (IDDM) or "juvenile diabetes". The cause is unknown.[3]
Type 2 DM begins with insulin resistance, a condition in which cells fail to respond to insulin properly.[3]
As the disease progresses a lack of insulin may also develop.[6] This form was previously referred to as
non insulin-dependent diabetes mellitus (NIDDM) or "adult-onset diabetes". The primary cause is
excessive body weight and not enough exercise.[3]
Gestational diabetes, is the third main form and occurs when pregnant women without a previous
history of diabetes develop a high blood glucose level.[3]
Prevention and treatment involves a healthy diet, physical exercise, not using tobacco, and being a
normal body weight. Blood pressure control and proper foot care are also important for people with the
disease. Type 1 diabetes must be managed with insulin injections.[3] Type 2 diabetes may be treated
with medications with or without insulin.[7] Insulin and some oral medications can cause low blood
sugar.[8] Weight loss surgery in those with obesity is an effective measure in those with type 2 DM.[9]
Gestational diabetes usually resolves after the birth of the baby.[10]

Globally, as of 2013, an estimated 382 million people have diabetes worldwide, with type 2 diabetes
making up about 90% of the cases.[11][12] This is equal to 8.3% of the adults population,[12] with equal
rates in both women and men.[13] Worldwide in 2012 and 2013 diabetes resulted in 1.5 to 5.1 million
deaths per year, making it the 8th leading cause of death.[7][14] Diabetes overall at least doubles the
risk of death.[3] The number of people with diabetes is expected to rise to 592 million by 2035.[15] The
economic costs of diabetes globally was estimated in 2013 at $548 billion[14] and in the United States in
2012 $245 billion.



Signs and symptoms








The classic symptoms of untreated diabetes are weight loss, polyuria (frequent urination), polydipsia
(increased thirst), and polyphagia (increased hunger).[17] Symptoms may develop rapidly (weeks or
months) in type 1 diabetes, while they usually develop much more slowly and may be subtle or absent in
type 2 diabetes.
Several other signs and symptoms can mark the onset of diabetes, although they are not specific to the
disease. In addition to the when known ones above, they include blurry vision, headache, fatigue, slow
healing of cuts, and itchy skin. Prolonged high blood glucose can cause glucose absorption in the lens of
the eye, which leads to changes in its shape, resulting in vision changes. A number of skin rashes that
can occur in diabetes are collectively known as diabetic dermadromes.
Diabetic emergencies
People (usually with type 1 diabetes) may also experience episodes of diabetic ketoacidosis, a type of
metabolic problems characterized by nausea, vomiting and abdominal pain, the smell of acetone on the
breath, deep breathing known as Kussmaul breathing, and in severe cases a decreased level of
consciousness.[18]
A rare but equally severe possibility is hyperosmolar nonketotic state, which is more common in type 2
diabetes and is mainly the result of dehydration.
Complications
Main article: Complications of diabetes mellitus
All forms of diabetes increase the risk of long-term complications. These typically develop after many
years (1020), but may be the first symptom in those who have otherwise not received a diagnosis
before that time.
The major long-term complications relate to damage to blood vessels. Diabetes doubles the risk of
cardiovascular disease[19] and about 75% of deaths in diabetics are due to coronary artery disease.[20]
Other "macrovascular" diseases are stroke, and peripheral vascular disease.
The primary microvascular complications of diabetes include damage to the eyes, kidneys, and
nerves.[21] Damage to the eyes, known as diabetic retinopathy, is caused by damage to the blood
vessels in the retina of the eye, and can result in gradual vision loss and potentially blindness.[21]
Damage to the kidneys, known as diabetic nephropathy, can lead to tissue scarring, urine protein loss,
and eventually chronic kidney disease, sometimes requiring dialysis or kidney transplant.[21] Damage to
the nerves of the body, known as diabetic neuropathy, is the most common complication of
diabetes.[21] The symptoms can include numbness, tingling, pain, and altered pain sensation, which can
lead to damage to the skin. Diabetes-related foot problems (such as diabetic foot ulcers) may occur, and
can be difficult to treat, occasionally requiring amputation. Additionally, proximal diabetic neuropathy
causes painful muscle wasting and weakness. There is a link between cognitive deficit and diabetes.
Compared to those without diabetes, those with the disease have a 1.2 to 1.5-fold greater rate of
decline in cognitive function.
Causes
Diabetes mellitus is classified into four broad categories: type 1, type 2, gestational diabetes, and
"other specific types".
[5]
The "other specific types" are a collection of a few dozen individual
causes.
[5]
The term "diabetes", without qualification, usually refers to diabetes mellitus.
Type 1
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 insulin deficiency. This type can be further classified as
immune-mediated or idiopathic. The majority of type 1 diabetes is of the immune-mediated nature, in
which a T-cell-mediated autoimmune attack leads to the loss of beta cells and thus insulin.
[24]
It
causes approximately 10% of diabetes mellitus cases in North America and Europe. 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 a majority of these
diabetes cases were in children.
"Brittle" diabetes, also known as unstable diabetes or labile diabetes, is a term that was traditionally
used to describe the dramatic and recurrent swings in glucoselevels, often occurring for no apparent
reason in insulin-dependent diabetes. This term, however, has no biologic basis and should not be
used.
[25]
Still, type 1 diabetes can be accompanied by irregular and unpredictable hyperglycemia,
frequently with ketosis, and sometimes with serious hypoglycemia. Other complications include an
impaired counterregulatory response to hypoglycemia, infection, gastroparesis (which leads to
erratic absorption of dietary carbohydrates), and endocrinopathies (e.g., Addison's
disease).
[25]
These phenomena are believed to occur no more frequently than in 1% to 2% of
persons with type 1 diabetes.
[26]

Type 1 diabetes is partly inherited, with multiple genes, including certain HLA genotypes, known to
influence the risk of diabetes. In genetically susceptible people, the onset of diabetes can be
triggered by one or more environmental factors, such as a viral infection or diet. There is some
evidence that suggests an association between type 1 diabetes and Coxsackie B4 virus. Unlike type
2 diabetes, the onset of type 1 diabetes is unrelated to lifestyle.



Type 2
Main article: Diabetes mellitus type 2
Type 2 diabetes mellitus is characterized by insulin resistance, which may be combined with
relatively reduced insulin secretion.
[5]
The defective responsiveness of body tissues to insulin is
believed to involve the insulin receptor. However, the specific defects are not known. Diabetes
mellitus cases due to a known defect are classified separately. Type 2 diabetes is the most common
type.
In the early stage of type 2, the predominant abnormality is reduced insulin sensitivity. At this stage,
hyperglycemia can be reversed by a variety of measures andmedications that improve insulin
sensitivity or reduce glucose production by the liver.
Type 2 diabetes is due primarily to lifestyle factors and genetics.
[27]
A number of lifestyle factors are
known to be important to the development of type 2 diabetes, including obesity (defined by a body
mass index of greater than thirty), lack of physical activity, poor diet, stress,
and urbanization.
[11]
Excess body fat is associated with 30% of cases in those of Chinese and
Japanese descent, 60-80% of cases in those of European and African descent, and 100% of Pima
Indians and Pacific Islanders.
[5]
Those who are not obese often have a high waisthip ratio.
[5]

Dietary factors also influence the risk of developing type 2 diabetes. Consumption of sugar-
sweetened drinks in excess is associated with an increased risk.
[28][29]
The type of fats in the diet is
also important, with saturated fats and trans fatty acids increasing the risk
and polyunsaturated and monounsaturated fat decreasing the risk.
[27]
Eating lots of white
rice appears to also play a role in increasing risk.
[30]
A lack of exercise is believed to cause 7% of
cases.
[31]

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 2-10%
of all pregnancies and may improve or disappear after delivery.
[32]
However, after pregnancy
approximately 5-10% of women with gestational diabetes are found to have diabetes mellitus, most
commonly type 2.
[32]
Gestational diabetes is fully treatable, but requires careful medical supervision
throughout the pregnancy. Management may include dietary changes, blood glucose monitoring,
and in some cases insulin may be required.
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 causerespiratory 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 perfusion due to vascular impairment. Labor induction may be indicated with
decreased placental function. A Caesarean 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
Prediabetes indicates a condition that occurs when a person's blood glucose levels are higher than
normal but not high enough for a diagnosis of type 2 DM. Many people destined to develop type 2
DM spend many years in a state of prediabetes.
Latent autoimmune diabetes of adults (LADA) is a condition in which type 1 DM develops in adults.
Adults with LADA are frequently initially misdiagnosed as having type 2 DM, based on age rather
than etiology.
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.
[33]
Other forms of diabetes mellitus include congenital diabetes, which is due
to genetic defects of insulin secretion, cystic fibrosis-related diabetes, steroid diabetes induced by
high doses of glucocorticoids, and several forms of monogenic diabetes.
Genetic defects of -cell function
Maturity onset diabetes of the young
Mitochondrial DNA mutations
Genetic defects in insulin processing or
insulin action
Defects in proinsulin conversion
Insulin gene mutations
Insulin receptor mutations
Exocrine pancreatic defects
Chronic pancreatitis
Pancreatectomy
Pancreatic neoplasia
Cystic fibrosis
Hemochromatosis
Fibrocalculous pancreatopathy
Endocrinopathies
Growth hormone excess (acromegaly)
Cushing syndrome
Hyperthyroidism
Pheochromocytoma
Glucagonoma
Infections
Cytomegalovirus infection
Coxsackievirus B
Drugs
Glucocorticoids
Thyroid hormone
-adrenergic agonists
Statins
[35]

The following is a comprehensive list of other causes of diabetes

Pathophysiology
Insulin is the principal hormone that regulates the uptake of glucose from the blood into most cells of
the body, especially liver, muscle, and adipose tissue. Therefore, deficiency of insulin or the insensitivity
of its receptors plays a central role in all forms of diabetes mellitus.[36]
The body obtains glucose from three main places: the intestinal absorption of food, the breakdown of
glycogen, the storage form of glucose found in the liver, and gluconeogenesis, the generation of glucose
from non-carbohydrate substrates in the body.[37] Insulin plays a critical role in balancing glucose levels
in the body. Insulin can inhibit the breakdown of glycogen or the process of gluconeogenesis, it can
stimulate the transport of glucose into fat and muscle cells, and it can stimulate the storage of glucose in
the form of glycogen.
Insulin is released into the blood by beta cells (-cells), found in the islets of Langerhans in the pancreas,
in response to rising levels of blood glucose, typically 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. Lower glucose levels result in decreased insulin release from the beta cells
and in the breakdown of glycogen to glucose. This process is mainly controlled by the hormone
glucagon, which acts in the opposite manner to insulin.[38]
If the amount of insulin available is insufficient, if cells respond poorly to the effects of insulin (insulin
insensitivity or insulin resistance), or if the insulin itself is defective, then glucose will not be absorbed
properly by the body cells that require it, and it will not be stored appropriately in the liver and muscles.
The net effect is persistently high levels of blood glucose, poor protein synthesis, and other metabolic
derangements, such as acidosis.
When the glucose concentration in the blood remains high over time, the kidneys will reach a threshold
of reabsorption, and glucose will be excreted in the urine (glycosuria).[39] This increases the osmotic
pressure of the urine and inhibits 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 and other body compartments, causing dehydration and increased thirst
(polydipsia).

Diagnosis
See also: Glycated hemoglobin and Glucose tolerance test
WHO diabetes diagnostic criteria
[40][41]
edit
Condition 2 hour glucose Fasting glucose HbA
1c

Unit mmol/l(mg/dl) mmol/l(mg/dl) %
Normal <7.8 (<140) <6.1 (<110) <6.0
Impaired fasting glycaemia <7.8 (<140) 6.1(110) & <7.0(<126) 6.06.4
Impaired glucose tolerance 7.8 (140) <7.0 (<126) 6.06.4
Diabetes mellitus 11.1 (200) 7.0 (126) 6.5
Diabetes mellitus is characterized by recurrent or persistent hyperglycemia, and is diagnosed by
demonstrating any one of the following:
[33]

Fasting plasma glucose level 7.0 mmol/l (126 mg/dl)
Plasma glucose 11.1 mmol/l (200 mg/dL) two hours after a 75 g oral glucose load as in
a glucose tolerance test
Symptoms of hyperglycemia and casual plasma glucose 11.1 mmol/l (200 mg/dl)
Glycated hemoglobin (Hb A1C) 6.5%.
[42]

A positive result, in the absence of unequivocal hyperglycemia, should be confirmed by a repeat of
any of the above methods on a different day. It is preferable 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.
[43]
According to the current definition, two fasting glucose measurements above
126 mg/dl (7.0 mmol/l) is considered diagnostic for diabetes mellitus.
Per the World Health Organization people with fasting glucose levels from 6.1 to 6.9 mmol/l (110 to
125 mg/dl) are considered to have impaired fasting glucose.
[44]
people with plasma glucose at or
above 7.8 mmol/L (140 mg/dL), but not over 11.1 mmol/L (200 mg/dL), two hours after a 75 g oral
glucose load are considered to have impaired glucose tolerance. Of these two prediabetic states, the
latter in particular is a major risk factor for progression to full-blown diabetes mellitus, as well as
cardiovascular disease.
[45]
The American Diabetes Association since 2003 uses a slightly different
range for impaired fasting glucose of 5.6 to 6.9 mmol/l (100 to 125 mg/dl).
[46]

Glycated hemoglobin is better than fasting glucose for determining risks of cardiovascular disease
and death from any cause.
[47]

The rare disease diabetes insipidus has similar symptoms to diabetes mellitus, but without
disturbances in the sugar metabolism (insipidus means "without taste" in Latin) and does not involve
the same disease mechanisms.

Prevention
There is no known preventive measure for type 1 diabetes.[3] Type 2 diabetes can often be prevented
by a person being a normal body weight, physical exercise, and following a healthy diet.[3] Dietary
changes known to be effective in helping to prevent diabetes include a diet rich in whole grains and
fiber, and choosing good fats, such as polyunsaturated fats found in nuts, vegetable oils, and fish.[48]
Limiting sugary beverages and eating less red meat and other sources of saturated fat can also help in
the prevention of diabetes.[48] Active smoking is also associated with an increased risk of diabetes, so
smoking cessation can be an important preventive measure as well.[49]

Management
Main article: Diabetes management
Diabetes mellitus is a chronic disease, for which there is no known cure except in very specific situations.
Management concentrates on keeping blood sugar levels as close to normal ("euglycemia") as possible,
without causing hypoglycemia. This can usually be accomplished with diet, exercise, and use of
appropriate medications (insulin in the case of type 1 diabetes; oral medications, as well as possibly
insulin, in type 2 diabetes).

Learning about the disease and actively participating in the treatment is vital for people with diabetes,
since the complications of diabetes are far less common and less severe in people who have well-
managed blood sugar levels.[50][51] The goal of treatment is an HbA1C level of 6.5%, but should not be
lower than that, and may be set higher.[52] Attention is also paid to other health problems that may
accelerate the deleterious effects of diabetes. These include smoking, elevated cholesterol levels,
obesity, high blood pressure, and lack of regular exercise.[52] Specialised footwear is widely used to
reduce the risk of ulceration, or re-ulceration, in at-risk diabetic feet. Evidence for the efficacy of this
remains equivocal, however.[53]

Lifestyle
See also: Diabetic diet
People with diabetes can benefit from education about the disease and treatment, good nutrition to
achieve a normal body weight, and sensible exercise, with the goal of keeping both short-term and long-
term blood glucose levels within acceptable bounds. In addition, given the associated higher risks of
cardiovascular disease, lifestyle modifications are recommended to control blood pressure.[54]

Medications
See also: Anti-diabetic medication
Metformin is generally recommended as a first line treatment for type 2 diabetes, as there is good
evidence that it decreases mortality.[55] Routine use of aspirin, however, has not been found to
improve outcomes in uncomplicated diabetes.[56] Angiotensin converting enzyme inhibitors (ACEIs)
improve outcomes in those with DM while the similar medications angiotensin receptor blockers (ARBs)
do not.[57]

Type 1 diabetes is typically treated with a combinations of regular and NPH insulin, or synthetic insulin
analogs. When insulin is used in type 2 diabetes, a long-acting formulation is usually added initially,
while continuing oral medications.[55] Doses of insulin are then increased to effect.[55]

In those with diabetes some recommend blood pressure levels below 120/80 mmHg;<[58][59] however,
evidence only supports less than or equal to somewhere between 140/90 mmHg to 160/100
mmHg.[60][61]

Pancreatic transplantation
A pancreas transplant is occasionally considered for people with type 1 diabetes who have severe
complications of their disease, including end stage renal disease requiring kidney transplantation.[62]

Support
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 in a team approach. Home telehealth support can be an effective management
technique.[63]

Epidemiology
Main article: Epidemiology of diabetes mellitus


Prevalence of diabetes worldwide in 2000 (per 1,000 inhabitants) - world average was 2.8%.
no data
7.5
7.515
1522.5
22.530
3037.5
37.545
4552.5
52.560
6067.5
67.575
7582.5
82.5


Disability-adjusted life year for diabetes mellitus per 100,000 inhabitants in 2004
No data
<100
100200
200300
300400
400500
500600
600700
700800
800900
9001,000
1,0001,500
>1,500
As at 2013, 382 million people have diabetes worldwide.[12] Type 2 makes up about 90% of the
cases.[11][13] This is equal to 8.3% of the adult population[12] with equal rates in both women and
men.[13]

In 2012 it resulted in 1.5 million deaths worldwide making it the 8th leading cause of death.[7] More
than 80% of diabetic deaths occurring in low and middle-income countries.[64]

Its rate has increased, and by 2030, this number is estimated to almost double.[65] Diabetes mellitus
occurs throughout the world, but is more common (especially type 2) in more developed countries. The
greatest increase in rates is, however, expected to occur in Asia and Africa, where most people with
diabetes will probably be found by 2030.[65] The increase in rates 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.[65]

History
Main article: History of diabetes
Diabetes was one of the first diseases described,[66] with an Egyptian manuscript from c. 1500 BCE
mentioning "too great emptying of the urine".[67] The first described cases are believed to be of type 1
diabetes.[67] Indian physicians around the same time identified the disease and classified it as
madhumeha or "honey urine", noting the urine would attract ants.[67] The term "diabetes" or "to pass
through" was first used in 230 BCE by the Greek Appollonius of Memphis.[67] The disease was
considered rare during the time of the Roman empire, with Galen commenting he had only seen two
cases during his career.[67] This is possibly due the diet and life-style of the ancient people, or because
the clinical symptoms were observed during the advanced stage of the disease. Galen named the
disease "diarrhea of the urine" (diarrhea urinosa). The earliest surviving work with a detailed reference
to diabetes is that of Aretaeus of Cappadocia (2nd or early 3rd century CE). He described the symptoms
and the course of the disease, which he attributed to the moisture and coldness, reflecting the beliefs of
the "Pneumatic School". He hypothesized a correlation of diabetes with other diseases and he discussed
differential diagnosis from the snakebite which also provokes excessive thirst. His work remained
unknown in the West until the middle of the 16th century when, in 1552, the first Latin edition was
published in Venice.[68]

Type 1 and type 2 diabetes were identified as separate conditions for the first time by the Indian
physicians Sushruta and Charaka in 400-500 CE with type 1 associated with youth and type 2 with being
overweight.[67] The term "mellitus" or "from honey" was added by the Briton John Rolle in the late
1700s to separate the condition from diabetes insipidus, which is also associated with frequent
urination.[67] Effective treatment was not developed until the early part of the 20th century, when
Canadians Frederick Banting and Charles Herbert Best isolated and purified insulin in 1921 and 1922.[67]
This was followed by the development of the long-acting insulin NPH in the 1940s.[67]

Etymology
The word diabetes (/da.bitiz/ or /da.bits/) comes from Latin diabts, which in turn comes
from Ancient Greek (diabts) which literally means "a passer through; a siphon."*69+ Ancient
Greek physician Aretaeus of Cappadocia (fl. 1st century CE) used that word, with the intended meaning
"excessive discharge of urine", as the name for the disease.[70][71][72] Ultimately, the word comes
from Greek (diabainein), meaning "to pass through,"*69+ which is composed of - (dia-),
meaning "through" and (bainein), meaning "to go".*70+ The word "diabetes" is first recorded in
English, in the form diabete, in a medical text written around 1425.

The word mellitus (/mlats/ or /mlts/) comes from the classical Latin word melltus, meaning
"mellite"[73] (i.e. sweetened with honey;[73] honey-sweet[74]). The Latin word comes from mell-,
which comes from mel, meaning "honey";[73][74] sweetness;[74] pleasant thing,[74] and the suffix -
tus,*73+ whose meaning is the same as that of the English suffix "-ite".[75] It was Thomas Willis who in
1675 added "mellitus" to the word "diabetes" as a designation for the disease, when he noticed the
urine of a diabetic had a sweet taste (glycosuria).[71] This sweet taste had been noticed in urine by the
ancient Greeks, Chinese, Egyptians, Indians, and Persians.

Society and culture
Further information: List of films featuring diabetes
The 1989 "St. Vincent Declaration"[76][77] was the result of international efforts to improve the care
accorded to those with diabetes. Doing so is important not only in terms of quality of life and life
expectancy, but also economicallyexpenses due to diabetes have been shown to be a major drain on
healthand productivity-related resources for healthcare systems and governments.

Several countries established more and less successful national diabetes programmes to improve
treatment of the disease.[78]

People with diabetes who have neuropathic symptoms such as numbness or tingling in feet or hands are
twice as likely to be unemployed as those without the symptoms.[79]

In 2010, diabetes-related emergency department (ED) visit rates in the United States were higher among
people from the lowest income communities (526 per 10,000 population) than from the highest income
communities (236 per 10,000 population). Approximately 9.4% of diabetes-related ED visits were for the
uninsured.[80]

Naming
The term "type 1 diabetes" has replaced several former terms, including childhood-onset diabetes,
juvenile diabetes, and insulin-dependent diabetes mellitus (IDDM). Likewise, the term "type 2 diabetes"
has replaced several former terms, including adult-onset diabetes, obesity-related diabetes, and
noninsulin-dependent diabetes mellitus (NIDDM). Beyond these two types, there is no agreed-upon
standard nomenclature.

Other animals
Main articles: Diabetes in dogs and Diabetes in cats
In animals, diabetes is most commonly encountered in dogs and cats. Middle-aged animals are most
commonly affected. Female dogs are twice as likely to be affected as males, while according to some
sources, male cats are also more prone than females. In both species, all breeds may be affected, but
some small dog breeds are particularly likely to develop diabetes, such as Miniature Poodles.[81] The
symptoms may relate to fluid loss and polyuria, but the course may also be insidious. Diabetic animals
are more prone to infections. The long-term complications recognised in humans are much rarer in
animals. The principles of treatment (weight loss, oral antidiabetics, subcutaneous insulin) and
management of emergencies (e.g. ketoacidosis) are similar to those in humans.[81]

Research
Inhaled insulin has been developed.[82] The original products were withdrawn due to side effects.[82]
Afrezza, under development by pharmaceuticals company MannKind Corporation, was approved by the
FDA for general sale in June, 2014 [83] There are several advantages of inhaled insulin: they are
convenient and easy to use and provide a useful alternative therapy for patients who cannot use
intravenous insulin.






Insulin
From Wikipedia, the free encyclopedia
This article is about the insulin protein. For uses of insulin in treating diabetes, see insulin therapy.
Not to be confused with Inulin.
Insulin

High-resolution model of six insulin molecules assembled in a hexamer, highlighting the
threefoldsymmetry, the zinc ion holding it together (pink sphere), and the histidine residues (pink
sticks) involved in zinc binding. Inactive insulin is stored in the body as a hexamer, while the active
form is the monomer.
[1]

Available structures
PDB Ortholog search: PDBe, RCSB
[show]List of PDB id codes

Identifiers
Symbols INS ; IDDM2; ILPR; IRDN; MODY10
External IDs OMIM: 176730 MGI: 96573 HomoloGene: 173ChEMBL: 5881 GeneCards: INS
Gene
[show]Gene ontology
RNA expression pattern

More reference expression data
Orthologs
Species Human Mouse

Entrez 3630 16334

Ensembl ENSG00000254647 ENSMUSG00000000215

UniProt P01308 P01326

RefSeq (mRNA) NM_000207 NM_001185083

RefSeq (protein) NP_000198 NP_001172012

Location (UCSC) Chr 11:
2.18 2.18 Mb
Chr 7:
142.68 142.7 Mb

PubMedsearch [3] [4]

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edit
Insulin is a peptide hormone, produced by beta cells in the pancreas, and is central to
regulatingcarbohydrate and fat metabolism in the body. It causes cells in the skeletal muscles,
and fat tissue to absorbglucose from the blood.
Insulin is a very old protein that may have originated more than one billion years ago.
[2]
The
molecular origins of insulin go at least as far back as the simplest unicellular eukaryotes.
[3]
Apart
from animals, insulin-like proteins are also known to exist in Fungi and Protista kingdoms.
[2]

Insulin stops the use of fat as an energy source by inhibiting the release of glucagon. Except in the
presence of the metabolic disorder diabetes mellitus and metabolic syndrome, insulin is provided
within the body in a constant proportion to remove excess glucose from the blood, which otherwise
would be toxic. When blood glucose levels fall below a certain level, the body begins to use stored
sugar as an energy source throughglycogenolysis, which breaks down the glycogen stored in the
liver and muscles into glucose, which can then be utilized as an energy source. As a central
metabolic control mechanism, its status is also used as a control signal to other body systems (such
as amino acid uptake by body cells). In addition, it has several otheranabolic effects throughout the
body.
When control of insulin levels fails, diabetes mellitus can result. As a consequence, insulin is used
medically to treat some forms of diabetes mellitus. Patients with type 1 diabetes depend on external
insulin (most commonly injected subcutaneously) for their survival because the hormone is no longer
produced internally.
[4]
Patients with type 2 diabetes are often insulin resistant and, because of such
resistance, may suffer from a "relative" insulin deficiency. Some patients with type 2 diabetes may
eventually require insulin if dietary modifications or other medications fail to control blood glucose
levels adequately. Over 40% of those with Type 2 diabetes require insulin as part of their diabetes
management plan.
The human insulin protein is composed of 51 amino acids, and has a molecular weight of 5808 Da. It
is adimer of an A-chain and a B-chain, which are linked together by disulfide bonds.
Insulin's name is derived from the Latin insula for "island". Insulin's structure varies slightly
between species of animals. Insulin from animal sources differs somewhat in "strength"
(in carbohydrate metabolism control effects) from that in humans because of those
variations. Porcine insulin is especially close to the human

Gene[edit]
The preproinsulin precursor of insulin is encoded by the INS gene.
[5][6]

Alleles[edit]
A variety of mutant alleles with changes in the coding region have been identified. A read-through
gene, INS-IGF2, overlaps with this gene at the 5' region and with the IGF2 gene at the 3' region.
[5]

Regulation[edit]
Several regulatory sequences in the promoter region of the human insulin gene bind to transcription
factors. In general, the A-boxes bind to Pdx1 factors, E-boxesbind to NeuroD, C-boxes bind to MafA,
and cAMP response elements to CREB. There are also silencers that inhibit transcription.
Regulatory sequences and their transcription factors for the insulin gene.
[7]

Regulatory sequence binding transcription factors
ILPR Par1
A5 Pdx1
negative regulatory element (NRE)
[8]
glucocorticoid receptor, Oct1
Z (overlapping NRE and C2) ISF
C2 Pax4, MafA(?)
E2 USF1/USF2
A3 Pdx1
CREB RE -
CREB RE CREB, CREM
A2 -
CAAT enhancer binding (CEB) (partly overlapping A2 and C1) -
C1 -
E1 E2A, NeuroD1, HEB
A1 Pdx1
G1 -
Protein structure[edit]
See also: Insulin/IGF/Relaxin family and Insulin and its analog structure
Within vertebrates, the amino acid sequence of insulin is strongly conserved. Bovine insulin differs
from human in only three amino acid residues, and porcine insulin in one. Even insulin from some
species of fish is similar enough to human to be clinically effective in humans. Insulin in some
invertebrates is quite similar in sequence to human insulin, and has similar physiological effects. The
strong homology seen in the insulin sequence of diverse species suggests that it has been
conserved across much of animal evolutionary history. The C-peptide of proinsulin (discussed later),
however, differs much more among species; it is also a hormone, but a secondary one.


SS-linked insulin monomer
The primary structure of bovine insulin was first determined by Frederick Sanger in 1951.
[9]
After
that, this polypeptide was synthesized independently by several groups.
[10][11][12]
The 3-dimensional
structure of insulin was determined by X-ray crystallography in Dorothy Hodgkin's laboratory in 1969
(PDB file 1ins).
[13]

Insulin is produced and stored in the body as a hexamer (a unit of six insulin molecules), while the
active form is the monomer. The hexamer is an inactive form with long-term stability, which serves
as a way to keep the highly reactive insulin protected, yet readily available. The hexamer-monomer
conversion is one of the central aspects of insulin formulations for injection. The hexamer is far more
stable than the monomer, which is desirable for practical reasons; however, the monomer is a much
faster-reacting drug because diffusion rate is inversely related to particle size. A fast-reacting drug
means insulin injections do not have to precede mealtimes by hours, which in turn gives diabetics
more flexibility in their daily schedules.
[14]
Insulin can aggregate and form fibrillar interdigitatedbeta-
sheets. This can cause injection amyloidosis, and prevents the storage of insulin for long periods.
[15]


Synthesis, physiological effects, and degradation[edit]
Synthesis[edit]
Insulin is produced in the pancreas and released when any of several stimuli are detected. These
stimuli include ingested protein and glucose in the blood produced from digested food.
[citation
needed]
Carbohydrates can be polymers of simple sugars or the simple sugars themselves. If the
carbohydrates include glucose, then that glucose will be absorbed into the bloodstream and blood
glucose level will begin to rise. In target cells, insulin initiates a signal transduction, which has the
effect of increasing glucose uptake and storage. Finally, insulin is degraded, terminating the
response.


Insulin undergoes extensive posttranslational modification along the production pathway. Production and secretion
are largely independent; prepared insulin is stored awaiting secretion. Both C-peptide and mature insulin are
biologically active. Cell components and proteins in this image are not to scale.
In mammals, insulin is synthesized in the pancreas within the -cells of the islets of Langerhans.
One million to three million islets of Langerhans (pancreatic islets) form the endocrine part of the
pancreas, which is primarily an exocrine gland. The endocrine portion accounts for only 2% of the
total mass of the pancreas. Within the islets of Langerhans, beta cells constitute 6580% of all the
cells.
Insulin consists of two polypeptide chains, the A- and B- chains, linked together by disulfide bonds. It
is however first synthesized as a single polypeptide called preproinsulin in pancreatic -cells.
Preproinsulin contains a 24-residue signal peptide which directs the nascent polypeptide chain to the
rough endoplasmic reticulum (RER). The signal peptide is cleaved as the polypeptide is translocated
into lumen of the RER, forming proinsulin.
[16]
In the RER the proinsulin folds into the correct
conformation and 3 disulfide bonds are formed. About 510 min after its assembly in the
endoplasmic reticulum, proinsulin is transported to the trans-Golgi network (TGN) where immature
granules are formed. Transport to the TGN may take about 30 min.
Proinsulin undergoes maturation into active insulin through the action of cellular endopeptidases
known as prohormone convertases (PC1 and PC2), as well as the exoproteasecarboxypeptidase
E.
[17]
The endopeptidases cleave at 2 positions, releasing a fragment called the C-peptide, and
leaving 2 peptide chains, the B- and A- chains, linked by 2 disulfide bonds. The cleavage sites are
each located after a pair of basic residues (lysine-64 and arginine-65, and arginine-31 and -32). After
cleavage of the C-peptide, these 2 pairs of basic residues are removed by the
carboxypeptidase.
[18]
The C-peptide is the central portion of proinsulin, and the primary sequence of
proinsulin goes in the order "B-C-A" (the B and A chains were identified on the basis of mass and the
C-peptide was discovered later).
The resulting mature insulin is packaged inside mature granules waiting for metabolic signals (such
as leucine, arginine, glucose and mannose) and vagal nerve stimulation to be exocytosed from the
cell into the circulation.
[19]

The endogenous production of insulin is regulated in several steps along the synthesis pathway:
At transcription from the insulin gene
In mRNA stability
At the mRNA translation
In the posttranslational modifications
Insulin and its related proteins have been shown to be produced inside the brain, and reduced levels
of these proteins are linked to Alzheimer's disease.
[20][21][22]

Release[edit]
See also: Blood glucose regulation
Beta cells in the islets of Langerhans release insulin in two phases. The first phase release is rapidly
triggered in response to increased blood glucose levels. The second phase is a sustained, slow
release of newly formed vesicles triggered independently of sugar. The description of first phase
release is as follows:
Glucose enters the -cells through the glucose transporter, GLUT2.
Glucose goes into glycolysis and the Krebs cycle, where multiple, high-energy ATP molecules
are produced by oxidation, leading to a rise in the ATP:ADP ratio within the cell.
An increased intracellular ATP:ADP ratio closes the ATP-sensitive SUR1/Kir6.2 potassium
channel (see sulfonylurea receptor). This prevents potassium ions (K
+
) from leaving the cell by
facilitated diffusion, leading to a buildup of potassium ions. As a result, the inside of the cell
becomes more positive with respect to the outside, leading to the depolarisation of the cell
surface membrane.
On depolarisation, voltage-gated calcium ion (Ca
2+
) channels open which allows calcium ions to
move into the cells by facilitated diffusion.
An increased intracellular calcium ion concentration causes the activation of phospholipase C,
which cleaves the membrane phospholipid phosphatidyl inositol 4,5-bisphosphate into inositol
1,4,5-trisphosphate and diacylglycerol.
Inositol 1,4,5-trisphosphate (IP3) binds to receptor proteins in the plasma membrane of
the endoplasmic reticulum (ER). This allows the release of Ca
2+
ions from the ER via IP3-gated
channels, and further raises the intracellular concentration of calcium ions.
Significantly increased amounts of calcium ions in the cells causes the release of previously
synthesized insulin, which has been stored in secretory vesicles.
This is the primary mechanism for release of insulin. Other substances known to stimulate insulin
release include the amino acids arginine and leucine, parasympathetic release of acetylcholine (via
phospholipase C), sulfonylurea, cholecystokinin (CCK, via phospholipase C),
[23]
and the
gastrointestinally derivedincretins glucagon-like peptide-1 (GLP-1) and glucose-dependent
insulinotropic peptide (GIP).
Release of insulin is strongly inhibited by the stress hormone norepinephrine (noradrenaline), which
leads to increased blood glucose levels during stress. It appears that release of catecholamines by
the sympathetic nervous system has conflicting influences on insulin release by beta cells, because
insulin release is inhibited by
2
-adrenergic receptors
[24]
and stimulated by
2
-adrenergic
receptors.
[25]
The net effect of norepinephrine from sympathetic nerves and epinephrine from adrenal
glands on insulin release is inhibition due to dominance of the -adrenergic receptors.
[26]

When the glucose level comes down to the usual physiologic value, insulin release from the -cells
slows or stops. If blood glucose levels drop lower than this, especially to dangerously low levels,
release of hyperglycemic hormones (most prominently glucagon from islet of Langerhans alpha
cells) forces release of glucose into the blood from cellular stores, primarily liver cell stores of
glycogen. By increasing blood glucose, the hyperglycemic hormones prevent or correct life-
threatening hypoglycemia.
Evidence of impaired first-phase insulin release can be seen in the glucose tolerance test,
demonstrated by a substantially elevated blood glucose level at 30 minutes, a marked drop by 60
minutes, and a steady climb back to baseline levels over the following hourly time points.
Oscillations[edit]
Main article: Insulin oscillations


Insulin release from pancreas oscillates with a period of 36 minutes.
[27]

Even during the digestion, in general, one or two hours following a meal, insulin release from the
pancreas is not continuous, but oscillates with a period of 36 minutes, changing from generating a
blood insulin concentration more than about 800 pmol/l to less than 100 pmol/l.
[27]
This is thought to
avoid downregulation of insulin receptors in target cells, and to assist the liver in extracting insulin
from the blood.
[27]
This oscillation is important to consider when administering insulin-stimulating
medication, since it is the oscillating blood concentration of insulin release, which should, ideally, be
achieved, not a constant high concentration.
[27]
This may be achieved by delivering insulin
rhythmically to the portal vein or by islet cell transplantation to the liver.
[27]
It is hoped that future
insulin pumps will address this characteristic. (See also Pulsatile Insulin.)
Blood content[edit]


The idealized diagram shows the fluctuation of blood sugar (red) and the sugar-lowering hormone insulin (blue) in
humans during the course of a day containing three meals. In addition, the effect of a sugar-rich versus astarch-rich
meal is highlighted.
The blood content of insulin can be measured in international units, such as IU/mL or in molar
concentration, such as pmol/L, where 1 IU/mL equals 6.945 pmol/L.
[28]
A typical blood level
between meals is 811 IU/mL (5779 pmol/L).
[29]

Signal transduction[edit]
Special transporter proteins in cell membranes allow glucose from the blood to enter a cell. These
transporters are, indirectly, under blood insulin's control in certain body cell types (e.g., muscle
cells). Low levels of circulating insulin, or its absence, will prevent glucose from entering those cells
(e.g., in type 1 diabetes). More commonly, however, there is a decrease in the sensitivity of cells to
insulin (e.g., the reduced insulin sensitivity characteristic of type 2 diabetes), resulting in decreased
glucose absorption. In either case, there is 'cell starvation' and weight loss, sometimes extreme. In a
few cases, there is a defect in the release of insulin from the pancreas. Either way, the effect is the
same: elevated blood glucose levels.
Activation of insulin receptors leads to internal cellular mechanisms that directly affect glucose
uptake by regulating the number and operation of protein molecules in the cell membrane that
transport glucose into the cell. The genes that specify the proteins that make up the insulin receptor
in cell membranes have been identified, and the structures of the interior, transmembrane section,
and the extra-membrane section of receptor have been solved.
Two types of tissues are most strongly influenced by insulin, as far as the stimulation of glucose
uptake is concerned: muscle cells (myocytes) and fat cells (adipocytes). The former are important
because of their central role in movement, breathing, circulation, etc., and the latter because they
accumulate excess food energy against future needs. Together, they account for about two-thirds of
all cells in a typical human body.
Insulin binds to the extracellular portion of the alpha subunits of the insulin receptor. This, in turn,
causes a conformational change in the insulin receptor that activates the kinase domain residing on
the intracellular portion of the beta subunits. The activated kinase domain autophosphorylates
tyrosine residues on the C-terminus of the receptor as well as tyrosine residues in the IRS-1 protein.
phosphorylated IRS-1, in turn, binds to and activates phosphoinositol 3 kinase (PI3K)
PI3K catalyzes the reaction PIP2 + ATP PIP3 + ADP
PIP3 activates protein kinase B (PKB)
PKB phosphorylates glycogen synthase kinase (GSK) and thereby inactivates GSK
[30]

GSK can no longer phosphorylate glycogen synthase (GS)
unphosphorylated GS makes more glycogen
PKB also facilitates vesicle fusion, resulting in an increase in GLUT4 transporters in the
plasma membrane
[31]

After the signal has been produced, termination of signaling is then needed. As mentioned below in
the section on degradation, endocytosis and degradation of the receptor bound to insulin is a main
mechanism to end signaling. In addition, signaling can be terminated by dephosphorylation of the
tyrosine residues by tyrosine phosphatases. Serine/Threonine kinases are also known to reduce the
activity of insulin. Finally, with insulin action being associated with the number of receptors on the
plasma membrane, a decrease in the amount of receptors also leads to termination of insulin
signaling.
[19]

The structure of the insulininsulin receptor complex has been determined using the techniques
of X-ray crystallography.
[32]

Physiological effects[edit]


Effect of insulin on glucose uptake and metabolism. Insulin binds to its receptor (1), which starts many protein
activation cascades (2). These include translocation of Glut-4 transporter to the plasma membrane and influx of
glucose (3), glycogen synthesis (4), glycolysis (5) and triglyceride (6).
The actions of insulin on the global human metabolism level include:
Control of cellular intake of certain substances, most prominently glucose in muscle andadipose
tissue (about two-thirds of body cells)
Increase of DNA replication and protein synthesis via control of amino acid uptake
Modification of the activity of numerous enzymes.
The actions of insulin (indirect and direct) on cells include:
Increased glycogen synthesis insulin forces storage of glucose in liver (and muscle) cells in
the form of glycogen; lowered levels of insulin cause liver cells to convert glycogen to glucose
and excrete it into the blood. This is the clinical action of insulin, which is directly useful in
reducing high blood glucose levels as in diabetes.
Increased lipid synthesis insulin forces fat cells to take in blood lipids, which are converted
to triglycerides; lack of insulin causes the reverse.
[33][clarification needed (see talk)]

Increased esterification of fatty acids forces adipose tissue to make fats (i.e., triglycerides)
from fatty acid esters; lack of insulin causes the reverse.
Decreased proteolysis decreasing the breakdown of protein
Decreased lipolysis forces reduction in conversion of fat cell lipid stores into blood fatty acids;
lack of insulin causes the reverse.
Decreased gluconeogenesis decreases production of glucose from nonsugar substrates,
primarily in the liver (the vast majority of endogenous insulin arriving at the liver never leaves the
liver); lack of insulin causes glucose production from assorted substrates in the liver and
elsewhere.
Decreased autophagy - decreased level of degradation of damaged organelles. Postprandial
levels inhibit autophagy completely.
[34]

Increased amino acid uptake forces cells to absorb circulating amino acids; lack of insulin
inhibits absorption.
Increased potassium uptake forces cells to absorb serum potassium; lack of insulin inhibits
absorption. Insulin's increase in cellular potassium uptake lowers potassium levels in blood. This
possibly occurs via insulin-induced translocation of the Na+/K+-ATPase to the surface of
skeletal muscle cells.
[35][36]

Arterial muscle tone forces arterial wall muscle to relax, increasing blood flow, especially in
microarteries; lack of insulin reduces flow by allowing these muscles to contract.
Increase in the secretion of hydrochloric acid by parietal cells in the stomach
Decreased renal sodium excretion.
[37]

Insulin also influences other body functions, such as vascular compliance and cognition. Once
insulin enters the human brain, it enhances learning and memory and benefits verbal memory in
particular.
[38]
Enhancing brain insulin signaling by means of intranasal insulin administration also
enhances the acute thermoregulatory and glucoregulatory response to food intake, suggesting that
central nervous insulin contributes to the control of whole-body energy homeostasis in
humans.
[39]
Insulin also has stimulatory effects on gonadotropin-releasing hormone from
the hypothalamus, thus favoring fertility.
[40]

Degradation[edit]

Once an insulin molecule has docked onto the receptor and effected its action, it may be released
back into the extracellular environment, or it may be degraded by the cell. The two primary sites for
insulin clearance are the liver and the kidney. The liver clears most insulin during first-pass transit,
whereas the kidney clears most of the insulin in systemic circulation. Degradation normally
involves endocytosis of the insulin-receptor complex, followed by the action of insulin-degrading
enzyme. An insulin molecule produced endogenously by the pancreatic beta cells is estimated to be
degraded within about one hour after its initial release into circulation (insulin half-life ~ 4
6 minutes).
[41][42]

Hypoglycemia[edit]
Main article: Hypoglycemia
Although other cells can use other fuels (most prominently fatty acids), neurons depend on glucose
as a source of energy in the nonstarving human. They do not require insulin to absorb glucose,
unlike muscle and adipose tissue, and they have very small internal stores of glycogen. Glycogen
stored in liver cells (unlike glycogen stored in muscle cells) can be converted to glucose, and
released into the blood, when glucose from digestion is low or absent, and the glycerol backbone in
triglycerides can also be used to produce blood glucose.
Sufficient lack of glucose and scarcity of these sources of glucose can dramatically make itself
manifest in the impaired functioning of the central nervous system: dizziness, speech problems, and
even loss of consciousness. Low blood glucose level is known as hypoglycemia or, in cases
producing unconsciousness, "hypoglycemic coma" (sometimes termed "insulin shock" from the most
common causative agent). Endogenous causes of insulin excess (such as an insulinoma) are very
rare, and the overwhelming majority of insulin excess-induced hypoglycemia cases
are iatrogenic and usually accidental. A few cases of murder, attempted murder, or suicide using
insulin overdoses have been reported, but most insulin shocks appear to be due to errors in dosage
of insulin (e.g., 20 units instead of 2) or other unanticipated factors (did not eat as much as
anticipated, or exercised more than expected, or unpredicted kinetics of the subcutaneously injected
insulin itself).
Possible causes of hypoglycemia include:
External insulin (usually injected subcutaneously)
Oral hypoglycemic agents (e.g., any of the sulfonylureas, or similar drugs, which increase insulin
release from -cells in response to a particular blood glucose level)
Ingestion of low-carbohydrate sugar substitutes in people without diabetes or with type 2
diabetes. Animal studies show these can trigger insulin release, albeit in much smaller quantities
than sugar, according to a report in Discover magazine, August 2004, p 18. (This can never be a
cause of hypoglycemia in patients with mature type 1 diabetes, since there is no endogenous
insulin production to stimulate. It can occur during the honeymoon period, a period up to several
years after a type 1 diabetes diagnosis during which endogenous insulin production still occurs.)
Diseases and syndromes[edit]
There are several conditions in which insulin disturbance is pathologic:
Diabetes mellitus general term referring to all states characterized by hyperglycemia
Type 1 autoimmune-mediated destruction of insulin-producing -cells in the pancreas,
resulting in absolute insulin deficiency
Type 2 multifactoral syndrome with combined influence of genetic susceptibility and
influence of environmental factors, the best known being obesity, age, and physical
inactivity, resulting in insulin resistance in cells requiring insulin for glucose absorption.
Other types of impaired glucose tolerance (see the Diabetes)
Insulinoma - a tumor of pancreatic -cells producing excess insulin or reactive hypoglycemia.
Metabolic syndrome a poorly understood condition first called Syndrome X by Gerald Reaven,
Reaven's Syndrome after Reaven, CHAOS in Australia (from the signs that seem to travel
together). It is currently not clear whether these signs have a single, treatable cause, or are the
result of body changes leading to type 2 diabetes. It is characterized by elevated blood pressure,
dyslipidemia (disturbances in blood cholesterol forms and other blood lipids), and increased
waist circumference (at least in populations in much of the developed world). The basic
underlying cause may be the insulin resistance that precedes type 2 diabetes, which is a
diminished capacity for insulin response in some tissues (e.g., muscle, fat). It is common that
morbidities, such as essential hypertension, obesity, type 2 diabetes, and cardiovascular
disease (CVD) develop.
Polycystic ovary syndrome a complex syndrome in women in the reproductive years
where anovulation and androgen excess are commonly displayed ashirsutism. In many cases of
PCOS, insulin resistance is present.
Medication uses[edit]
Main article: Insulin therapy


Insulin vial
Biosynthetic human insulin (insulin human rDNA, INN)for clinical use is manufactured
by recombinant DNA technology.
[43]
Biosynthetic human insulin has increased purity when compared
with extractive animal insulins, enhanced purity reducing antibody formation. Researchers have
succeeded in introducing the gene for human insulin into plants as another method of producing
insulin ("biopharming") in safflower.
[44][45]
This technique is anticipated to reduce production costs.
Several analogs of human insulin are available for clinical therapy. These insulin analogs are closely
related to the human insulin structure, they were developed for specific aspects of glycemic control
in terms of fast action (prandial insulins) and long action (basal insulins).
[46]
The first biosynthetic
insulin analog was developed for clinical use at mealtime (prandial insulin), Humalog (insulin lispro),it
is more rapidly absorbed after subcutaneous injection than regular insulin, with an effect 15 minutes
after injection. Other rapid-acting analogues are NovoRapid and Apidra, with similar profiles. All are
rapidly absorbed due to sequence that will reduce formation of dimers and hexamers (monomeric
insulins are more rapidly absorbed). Fast acting insulins do not require the injection-to-meal interval
previously recommended for human insulin and animal insulins. The other type is long acting insulin;
the first of these was Lantus (insulin glargine). These have a steady effect for an extended period
from 18 to 24 hours. Likewise, another protracted insulin analogue (Levemir) is based on a fatty acid
acylation approach. A myristyric acid molecule is attached to this analogue, which in turn associates
the insulin molecule to the abundant serum albumin, which in turn extends the effect and reduces
the risk of hypoglycemia. Both protracted analogues need to be taken only once daily, and are used
for type 1 diabetics as the basal insulin. A combination of a rapid acting and a protracted insulin is
also available, making it more likely for patients to achieve an insulin profile that mimics that of the
bodys own insulin release.
Insulin is usually taken as subcutaneous injections by single-use syringes with needles, via
an insulin pump, or by repeated-use insulin pens with disposable needles.
Unlike many medicines, insulin currently cannot be taken orally because, like nearly all other
proteins introduced into the gastrointestinal tract, it is reduced to fragments (even single amino acid
components), whereupon all activity is lost. There has been some research into ways to protect
insulin from the digestive tract, so that it can be administered orally or sublingually. While
experimental, several companies now have various formulations in human clinical trials, and one,
the India-based Biocon, has formed an agreement with BMS to produce an oral-insulin alternative.
[47]

History[edit]
Discovery[edit]
In 1869, while studying the structure of the pancreas under a microscope, Paul Langerhans, a
medical student in Berlin, identified some previously unnoticed tissue clumps scattered throughout
the bulk of the pancreas. The function of the "little heaps of cells", later known as the islets of
Langerhans, initially remained unknown, but Edouard Laguesse later suggested they might produce
secretions that play a regulatory role in digestion. Paul Langerhans' son, Archibald, also helped to
understand this regulatory role. The term "insulin" originates from insula, the Latin word for
islet/island.
In 1889, the Polish-German physician Oscar Minkowski, in collaboration with Joseph von Mering,
removed the pancreas from a healthy dog to test its assumed role in digestion. Several days after
the removal of the dog's pancreas, Minkowski's animal-keeper noticed a swarm of flies feeding on
the dog's urine. On testing the urine, they found sugar, establishing for the first time a relationship
between the pancreas and diabetes. In 1901 Eugene Lindsay Opie took another major step forward
when he clearly established the link between the islets of Langerhans and diabetes: "Diabetes
mellitus . . . is caused by destruction of the islets of Langerhans and occurs only when these bodies
are in part or wholly destroyed". Before Opie's work, medical science had clearly established the link
between the pancreas and diabetes, but not the specific role of the islets.


The structure of insulin. The left side is a space-filling model of the insulin monomer, believed to be biologically
active. Carbon is green, hydrogen white, oxygen red, andnitrogen blue. On the right side is a ribbon diagram of the
insulin hexamer, believed to be the stored form. A monomer unit is highlighted with the A chain in blue and the B
chain in cyan. Yellow denotes disulfide bonds, and magenta spheres are zinc ions.
Over the next two decades researchers made several attempts to isolate - as a potential treatment -
whatever the islets produced. In 1906 George Ludwig Zuelzer achieved partial success in treating
dogs with pancreatic extract, but he was unable to continue his work. Between 1911 and 1912, E.L.
Scott at the University of Chicago used aqueous pancreatic extracts, and noted "a slight diminution
of glycosuria", but was unable to convince his director of his work's value; it was shut down. Israel
Kleiner demonstrated similar effects at Rockefeller University in 1915, but World War I interrupted
his work and he did not return to it.
[48]

In 1916 Nicolae Paulescu, a Romanian professor of physiology at the University of Medicine and
Pharmacy in Bucharest, developed an aqueous pancreatic extract which, when injected into
a diabetic dog, had a normalizing effect on blood-sugar levels. He had to interrupt his experiments
because of World War I, and in 1921 he wrote four papers about his work carried out
in Bucharest and his tests on a diabetic dog. Later that year, he published "Research on the Role of
thePancreas in Food Assimilation".
[49][50]

Extraction and purification[edit]
In October 1920, Canadian Frederick Banting concluded that it was the very digestive secretions
that Minkowski had originally studied that were breaking down the islet secretion(s), thereby making
it impossible to extract successfully. He jotted a note to himself: "Ligate pancreatic ducts of the dog.
Keep dogs alive till acini degenerate leaving islets. Try to isolate internal secretion of these and
relieve glycosurea."
The idea was the pancreas's internal secretion, which, it was supposed, regulates sugar in the
bloodstream, might hold the key to the treatment of diabetes. A surgeon by training, Banting knew
certain arteries could be tied off that would lead to atrophy of most of the pancreas, while leaving the
islets of Langerhans intact. He theorized a relatively pure extract could be made from the islets once
most of the rest of the pancreas was gone.
In the spring of 1921, Banting traveled to Toronto to explain his idea to J.J.R. Macleod, who was
Professor of Physiology at the University of Toronto, and asked Macleod if he could use his lab
space to test the idea. Macleod was initially skeptical, but eventually agreed to let Banting use his
lab space while he was on holiday for the summer. He also supplied Banting with ten dogs on which
to experiment, and two medical students, Charles Best and Clark Noble, to use as lab assistants,
before leaving for Scotland. Since Banting required only one lab assistant, Best and Noble flipped a
coin to see which would assist Banting for the first half of the summer. Best won the coin toss, and
took the first shift as Banting's assistant. Loss of the coin toss may have proved unfortunate for
Noble, given that Banting decided to keep Best for the entire summer, and eventually shared half his
Nobel Prize money and a large part of the credit for the discovery of insulin with the winner of the
toss. Had Noble won the toss, his career might have taken a different path.
[51]
Banting's method was
to tie a ligature around the pancreatic duct; when examined several weeks later, the pancreatic
digestive cells had died and been absorbed by the immune system, leaving thousands of islets.
They then isolated an extract from these islets, producing what they called "isletin" (what we now
know as insulin), and tested this extract on the dogs starting July 27.
[52]
Banting and Best were then
able to keep a pancreatectomized dog named Marjorie alive for the rest of the summer by injecting
her with the crude extract they had prepared. Removal of the pancreas in test animals in essence
mimics diabetes, leading to elevated blood glucose levels. Marjorie was able to remain alive
because the extracts, containing isletin, were able to lower her blood glucose levels.
Banting and Best presented their results to Macleod on his return to Toronto in the fall of 1921, but
Macleod pointed out flaws with the experimental design, and suggested the experiments be
repeated with more dogs and better equipment. He then supplied Banting and Best with a better
laboratory, and began paying Banting a salary from his research grants. Several weeks later, the
second round of experiments was also a success; and Macleod helped publish their results privately
in Toronto that November. However, they needed six weeks to extract the isletin, which forced
considerable delays. Banting suggested they try to use fetal calf pancreas, which had not yet
developed digestive glands; he was relieved to find this method worked well. With the supply
problem solved, the next major effort was to purify the extract. In December 1921, Macleod invited
the biochemist James Collip to help with this task, and, within a month, the team felt ready for a
clinical test.
On January 11, 1922, Leonard Thompson, a 14-year-old diabetic who lay dying at the Toronto
General Hospital, was given the first injection of insulin.
[53]
However, the extract was so impure,
Thompson suffered a severe allergic reaction, and further injections were canceled. Over the next
12 days, Collip worked day and night to improve the ox-pancreas extract, and a second dose was
injected on January 23. This was completely successful, not only in having no obvious side-effects
but also in completely eliminating the glycosuria sign of diabetes. The first American patient
was Elizabeth Hughes Gossett, the daughter of the governor of New York.
[54]
The first patient treated
in the U.S. was future woodcut artist James D. Havens; Dr. John Ralston Williams imported insulin
from Toronto to Rochester, New York, to treat Havens.
[55]

Children dying from diabetic ketoacidosis were kept in large wards, often with 50 or more patients in
a ward, mostly comatose. Grieving family members were often in attendance, awaiting the (until
then, inevitable) death.
In one of medicine's more dramatic moments, Banting, Best, and Collip went from bed to bed,
injecting an entire ward with the new purified extract. Before they had reached the last dying child,
the first few were awakening from their coma, to the joyous exclamations of their families.
[56]

Banting and Best never worked well with Collip, regarding him as something of an interloper, and
Collip left the project soon after.
Over the spring of 1922, Best managed to improve his techniques to the point where large quantities
of insulin could be extracted on demand, but the preparation remained impure. The drug firm Eli Lilly
and Company had offered assistance not long after the first publications in 1921, and they took Lilly
up on the offer in April. In November, Lilly made a major breakthrough and was able to produce
large quantities of highly refined insulin. Insulin was offered for sale shortly thereafter.
Synthesis[edit]
Purified animal-sourced insulin was the only type of insulin available to diabetics until genetic
advances occurred later with medical research. The amino acid structure of insulin was
characterized in the early 1950s by Frederick Sanger,
[57]
and the first synthetic insulin was produced
simultaneously in the labs of Panayotis Katsoyannis at the University of Pittsburgh and Helmut
Zahn at RWTH Aachen University in the early 1960s.
[58][59]

The first genetically engineered, synthetic "human" insulin was produced using E. coli in 1978
by Arthur Riggs and Keiichi Itakura at the Beckman Research Instituteof the City of Hope in
collaboration with Herbert Boyer at Genentech.
[60][61]
Genentech, founded by Swanson, Boyer
and Eli Lilly and Company, went on in 1982 to sell the first commercially available biosynthetic
human insulin under the brand name Humulin.
[61]
The vast majority of insulin currently used
worldwide is now biosynthetic recombinant "human" insulin or its analogues.
[62]

Recombinant insulin is produced either in yeast (usually saccharomyces cerevisiae) or E. coli.
[63]
In
yeast, insulin may be engineered as a single-chain protein with a KexII endoprotease (a yeast
homolog of PCI/PCII) site that separates the insulin A chain from a c-terminally truncated insulin B
chain. A chemically synthesized c-terminal tail is then grafted onto insulin by reverse proteolysis
using the inexpensive protease trypsin; typically the lysine on the c-terminal tail is protected with a
chemical protecting group to prevent proteolysis. The ease of modular synthesis and the relative
safety of modifications in that region accounts for common insulin analogs with c-terminal
modifications (e.g. lispro, aspart, glulisine). The Genentech synthesis and completely chemical
synthesis such as that by Bruce Merrifield are not preferred because the efficiency of recombining
the two insulin chains is low, primarily due to competition with the precipitation of insulin B chain.
Nobel Prizes[edit]


Frederick Banting joined by Charles Best in office, 1924
The Nobel Prize committee in 1923 credited the practical extraction of insulin to a team at
the University of Toronto and awarded the Nobel Prize to two men: Frederick Banting and J.J.R.
Macleod.
[64]
They were awarded the Nobel Prize in Physiology or Medicine in 1923 for the discovery
of insulin. Banting, insulted that Best was not mentioned, shared his prize with him, and Macleod
immediately shared his with James Collip. The patent for insulin was sold to the University of
Torontofor one half-dollar.
The primary structure of insulin was determined by British molecular biologist Frederick Sanger.
[57]
It
was the first protein to have its sequence be determined. He was awarded the 1958 Nobel Prize in
Chemistry for this work.
In 1969, after decades of work, Dorothy Hodgkin determined the spatial conformation of the
molecule, the so-called tertiary structure, by means of X-ray diffraction studies. She had been
awarded a Nobel Prize in Chemistry in 1964 for the development of crystallography.
Rosalyn Sussman Yalow received the 1977 Nobel Prize in Medicine for the development of
the radioimmunoassay for insulin.
George Minot, co-recipient of the 1934 Nobel Prize for the development of the first effective
treatment for pernicious anemia, had diabetes mellitus. Dr. William Castleobserved that the 1921
discovery of insulin, arriving in time to keep Minot alive, was therefore also responsible for the
discovery of a cure for pernicious anemia.
[65]

Nobel Prize controversy[edit]


Nicolae Paulescu
The work published by Banting, Best, Collip and Macleod represented the preparation of purified
insulin extract suitable for use on human patients.
[66]
Although Paulescu discovered the principles of
the treatment his saline extract could not be used on humans, and he was not mentioned in the 1923
Nobel Prize. Professor Ian Murray was particularly active in working to correct "the historical wrong"
against Nicolae Paulescu. Murray was a professor of physiology at the Anderson College of
Medicine in Glasgow, Scotland, the head of the department of Metabolic Diseases at a leading
Glasgow hospital, vice-president of the British Association of Diabetes, and a founding member of
theInternational Diabetes Federation. Murray wrote:
Insufficient recognition has been given to Paulesco, the distinguished Roumanian scientist, who at
the time when the Toronto team were commencing their research had already succeeded in
extracting the antidiabetic hormone of the pancreas and proving its efficacy in reducing the
hyperglycaemia in diabetic dogs.
[67]

In a recent private communication Professor Tiselius, head of the Nobel Institute, has expressed his
personal opinion that Paulescu was equally worthy of the award in 1923.
[68]


Hyperglycemia
From Wikipedia, the free encyclopedia
Hyperglycemia
Classification and external resources
ICD-10 R73.9
ICD-9 790.29
DiseasesDB 6234
MedlinePlus 007228
MeSH D006943
Hyperglycemia, or high blood sugar (also spelled hyperglycaemia or hyperglycmia, not to be
confused withhypoglycemia) is a condition in which an excessive amount of glucose circulates in
the blood plasma. This is generally a glucose level higher than 11.1 mmol/l (200 mg/dl), but
symptoms may not start to become noticeable until even higher values such as 1520 mmol/l
(~250300 mg/dl). A subject with a consistent range between 100 and 126 (American Diabetes
Association guidelines) is considered hyperglycemic, while above 126 mg/dl or 7 mmol/l is generally
held to have diabetes. Chronic levels exceeding 7 mmol/l (125 mg/dl) can produce organ damage.
[1]

The origin of the term is Greek: hyper-, meaning excessive; -glyc-, meaning sweet; and -emia,
meaning of the blood.
Contents
[hide]
1 Definition
2 Signs and symptoms
3 Causes
3.1 Diabetes mellitus
3.2 Drugs
3.3 Critical illness
4 Complications
5 Treatment
6 See also
7 References
8 External links
Definition[edit]
It is critical for patients who monitor glucose levels at home to be aware of which units of
measurement their testing kit uses. Glucose levels are measured in either:
Millimoles per litre (mmol/l) is the SI standard unit used in most countries around the world.
Milligrams per decilitre (mg/dl) is used in some countries such as the United States, Japan,
France, Egypt and Colombia. It can be acquired by multiplying mmol/L by 18.
Scientific journals are moving towards using mmol/l; some journals now use mmol/l as the primary
unit but quote mg/dl in parentheses.
[2]

Glucose levels vary before and after meals, and at various times of day; the definition of "normal"
varies among medical professionals. In general, the normal range for most people (fasting adults) is
about 80 to 110 mg/dl or 4 to 6 mmol/l. (where 80 mg/dl is "optimal".) A subject with a consistent
range above 126 mg/dl or 7 mmol/l is generally held to have hyperglycemia, whereas a consistent
range below 70 mg/dl or 4 mmol/l is considered hypoglycemic. In fasting adults, blood plasma
glucose should not exceed 126 mg/dL. Sustained higher levels of blood sugar cause damage to the
blood vessels and to the organs they supply, leading to the complications of diabetes.
[3]

Chronic hyperglycemia can be measured via the HbA1c test. The definition of acute hyperglycemia
varies by study, with mmol/l levels from 8 to 15.
[4]

Signs and symptoms[edit]
Temporary hyperglycemia is often benign and asymptomatic. Blood glucose levels can rise well
above normal for significant periods without producing any permanent effects or symptoms.
However, chronic hyperglycemia at levels more than slightly above normal can produce a very wide
variety of serious complications over a period of years, including kidney damage, neurological
damage, cardiovascular damage, damage to the retina or damage to feet and legs. Diabetic
neuropathy may be a result of long-term hyperglycemia.
In diabetes mellitus (by far the most common cause of chronic hyperglycemia), treatment aims at
maintaining blood glucose at a level as close to normal as possible, in order to avoid these serious
long-term complications. This is done by a combination of proper diet, regular exercise, and insulin
or other medication such asMetformin, etc.
Acute hyperglycemia involving glucose levels that are extremely high is a medical emergency and
can rapidly produce serious complications (such as fluid loss through osmotic diuresis). It is most
often seen in persons who have uncontrolled insulin-dependent diabetes.
The following symptoms may be associated with acute or chronic hyperglycemia, with the first three
composing the classic hyperglycemic triad:
Polyphagia - frequent hunger, especially pronounced hunger
Polydipsia - frequent thirst, especially excessive thirst
Polyuria - increased volume of urination (not an increased frequency for urination)
Blurred vision
Fatigue (sleepiness)
Weight loss
Poor wound healing (cuts, scrapes, etc.)
Dry mouth
Dry or itchy skin
Tingling in feet or heels
Erectile dysfunction
Recurrent infections, external ear infections (swimmer's ear)
Cardiac arrhythmia
Stupor
Coma
Seizures
Frequent hunger without other symptoms can also indicate that blood sugar levels are too low. This
may occur when people who have diabetes take too much oral hypoglycemic medication or insulin
for the amount of food they eat. The resulting drop in blood sugar level to below the normal range
prompts a hunger response. This hunger is not usually as pronounced as in Type I diabetes,
especially the juvenile onset form, but it makes the prescription of oral hypoglycemic medication
difficult to manage.
Polydipsia and polyuria occur when blood glucose levels rise high enough to result in excretion of
excess glucose via the kidneys (glycosuria), producing osmotic diuresis.
Symptoms of diabetic ketoacidosis may include:
Ketoacidosis
Kussmaul hyperventilation: deep, rapid breathing
Confusion or a decreased level of consciousness
Dehydration due to glycosuria and osmotic diuresis
Acute hunger and/or thirst
'Fruity' smelling breath odor
Impairment of cognitive function, along with increased sadness and anxiety
[5][6]

Causes[edit]
Diabetes mellitus[edit]
Chronic hyperglycemia that persists even in fasting states is most commonly caused by diabetes
mellitus. In fact, chronic hyperglycemia is the defining characteristic of the disease. Intermittent
hyperglycemia may be present in prediabetic states. Acute episodes of hyperglycemia without an
obvious cause may indicate developing diabetes or a predisposition to the disorder.
In diabetes mellitus, hyperglycemia is usually caused by low insulin levels (Diabetes mellitus type 1)
and/or by resistance to insulin at the cellular level (Diabetes mellitus type 2), depending on the type
and state of the disease. Low insulin levels and/or insulin resistance prevent the body from
converting glucose into glycogen(a starch-like source of energy stored mostly in the liver), which in
turn makes it difficult or impossible to remove excess glucose from the blood. With normal glucose
levels, the total amount of glucose in the blood at any given moment is only enough to provide
energy to the body for 20-30 minutes, and so glucose levels must be precisely maintained by the
body's internal control mechanisms. When the mechanisms fail in a way that allows glucose to rise
to abnormal levels, hyperglycemia is the result.
Drugs[edit]
Certain medications increase the risk of hyperglycemia, including corticosteroids, octreotide, beta
blockers, epinephrine, thiazide diuretics, niacin, pentamidine,protease inhibitors, L-
asparaginase,
[7]
and some antipsychotic agents.
[8]
The acute administration of stimulants such
as amphetamine typically produces hyperglycemia; chronic use, however, produces hypoglycemia.
Some of the newer psychotropic medications, such as Zyprexa (Olanzapine)
and Cymbalta(Duloxetine), can also cause significant hyperglycemia.
Critical illness[edit]
A high proportion of patients suffering an acute stress such as stroke or myocardial infarction may
develop hyperglycemia, even in the absence of a diagnosis of diabetes. (Or perhaps stroke or
myocardial infarction was caused by hyperglycemia and undiagnosed diabetes.) Human and animal
studies suggest that this is not benign, and that stress-induced hyperglycemia is associated with a
high risk of mortality after both stroke and myocardial infarction.
[9]

The following conditions can also cause hyperglycemia in the absence of diabetes. 1) Dysfunction of
the thyroid, adrenal, and pituitary glands 2) Numerous diseases of the pancreas 3) Severe increases
in blood glucose may be seen in sepsis and certain infections 4) Intracranial diseases (frequently
overlooked) can also cause hyperglycemia. Encephalitis, brain tumors (especially those located near
the pituitary gland), brain bleeds, and meningitis are prime examples. 5) Mid to high blood sugar
levels are often seen in convulsions and terminal stages of many diseases. Prolonged, major
surgeries can temporarily increase glucose levels. Certain forms of severe stress and physical
trauma can increase levels for a brief time as well yet rarely exceeds 120 mg/dl.
Complications[edit]
Hyperglycemia can be a serious problem if not treated in time. In untreated hyperglycemia, a
condition called ketoacidosis (contrast ketosis) could occur. Ketoacidosis develops when the body
does not have enough insulin. Without insulin, the body isn't able to utilize the glucose for fuel, so
the body starts to break down fats for energy.
Ketoacidosis is a life-threatening condition which needs immediate treatment. Symptoms include:
shortness of breath, breath that smells fruity (such as pear drops), nausea and vomiting, and very
dry mouth. Chronic hyperglycemia (high blood sugar) injures the heart in patients without a history of
heart disease or diabetes and is strongly associated with heart attacks and death in subjects with no
coronary heart disease or history of heart failure.
[10]

Treatment[edit]
Treatment of hyperglycemia requires elimination of the underlying cause, such as diabetes. Acute
hyperglycemia can be treated by direct administration of insulin in most cases. Severe
hyperglycemia can be treated with oral hypoglycemic therapy and lifestyle modification.
[11]








Management of Type 2 Diabetes
Treatment should be aimed at alleviating symptoms and minimising the risk of long-term
complications. Optimal control of glucose and other cardiovascular risk factors (eg, smoking,
sedentary lifestyle, hypertension, dyslipidaemia and obesity) is essential.
Management of type 2 diabetes has to be tailored to the individual needs and circumstances of each
patient - eg, the benefits of tight glucose control must be weighed against any potential
complications such as recurrent hypoglycaemia.
[
1
][
2
]

Patient education