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''The content of this chapter is largely taken from Wikipedia''
''Jonas de Jong and Alice Li''
{{DevelopmentPhase}}
__TOC__
 
==Preamble==
'''Diabetes mellitus''', or simply '''diabetes''', is a group of metabolic diseases in which a person has high blood sugar, either because the pancreas does not produce enough insulin, or because cells do not respond to the insulin that is produced.<cite>2</cite> This high blood sugar produces the classical symptoms of polyuria (frequent urination), polydipsia (increased thirst) and polyphagia (increased hunger).
Diabetes (diabetes mellitus) is one of the metabolic diseases with higher blood sugar level, either due to the pancreatic beta cells do not produce enough insulin, or the cells do not respond to the insulin that is produced.<cite>1</cite> Its clinical symptoms include three polies: polyuria (frequent urination), polydipsia (increased thirst) and polyphagia (increased hunger).  
 
There are three main types of diabetes mellitus (DM).
*'''Type 1 DM''' results from the body's failure to produce insulin, and presently requires the person to inject insulin or wear an insulin pump. This form was previously referred to as ''insulin-dependent diabetes mellitus'' (IDDM) or ''juvenile diabetes''.
*'''Type 2 DM''' results from insulin resistance, a condition in which cells fail to use insulin properly, sometimes combined with an absolute insulin deficiency. This form was previously referred to as non insulin-dependent diabetes mellitus (NIDDM) or ''adult-onset diabetes''.
*The third main form, gestational diabetes occurs when pregnant women without a previous diagnosis of diabetes develop a high blood glucose level. It may precede development of type 2 DM.
 
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.
 
All forms of diabetes have been treatable since insulin became available in 1921, and type 2 diabetes may be controlled with medications.  Both types 1 and 2 are chronic conditions that cannot be cured.  Pancreas transplants have been tried with limited success in type 1 DM; gastric bypass surgery has been successful in many with morbid obesity and type 2 DM.  Gestational diabetes usually resolves after delivery. Diabetes without proper treatments can cause many complications. Acute complications include hypoglycemia, diabetic ketoacidosis, or nonketotic hyperosmolar coma. Serious long-term complications include cardiovascular disease, chronic renal failure, and diabetic retinopathy (retinal damage).  Adequate treatment of diabetes is thus important, as well as blood pressure control and lifestyle factors such as smoking cessation and maintaining a healthy body weight.


Globally, as of 2012, an estimated 346 million people have type 2 diabetes.<cite>3</cite>
Diabetes is categorized as three types in the clinic: Type 1 diabetes (T1D, diabetes mellitus 1, DM1) results from pancreatic beta cell destruction and thus fails to produce insulin, and is insulin dependent which relies on insulin injection, it is also named insulin-dependent diabetes mellitus (''IDDM''). Since T1D happens mostly in juveniles it is also called juvenile-onset diabetes. Type 2 diabetes (T2D, diabetes mellitus 2, DM2) results from the reason that the beta cells do not respond to insulin (insulin resistance), and it may co-exist with the situation of partially or fully insulin-dependent, which is also named non-insulin-dependent diabetes mellitus (''NIDDM'') or adult-onset diabetes. In some type 2 diabetes, concomitant insulin therapy may be necessary (''IDDM2''). The third type is gestational diabetes occurs while pregnancy.  


==Classification==
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Diabetes mellitus is classified into four broad categories: Type 1, Type 2, gestational diabetes and ''other specific types''.<cite>2</cite> The ''other specific types'' are a collection of a few dozen individual causes.<cite>2</cite> The term ''diabetes'', without qualification, usually refers to diabetes mellitus.  The rare disease diabetes insipidus has similar symptoms as diabetes mellitus, but without disturbances in the sugar metabolism (''insipidus'' means ''without taste'' in Latin).
There is no cure for diabetes currently except that most of the gestational diabetes disappears when the pregnancy is ended, but it is treatable. The current therapies are insulin, other non-curing medications, and pancreatic replacement therapies like pancreatic islet transplantations which have been applied to severe T1D cases successfully since 1980s’.<cite>2</cite>Since both T1D and T2D are chronic diseases and the progresses of modern medicine, acute complications like hypoglycemia and ketoacidosis are under well controlled, and thus chronic and long-term complications like chronic renal failure, and diabetic retinopathy, especially cardiovascular diseases (''CVD''), are drawing attentions.  


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.
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|-
!colspan="2"|Basic treatment steps of diabetes:
|-
!width="60px"|Step 1
|Educate the patient


===Type 1 diabetes===
Treat concomittant risk factors (e.g. hypertension, obesity, hyperlipidemia)
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 beta cell loss is a T-cell-mediated autoimmune attack.<cite>6</cite> There is no known preventive measure against Type 1 diabetes, which 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 to dramatic and recurrent swings in glucose levels, often occurring for no apparent reason in insulin-dependent diabetes. This term, however, has no biologic basis and should not be used.<cite>7</cite> There are many reasons for Type 1 diabetes to be accompanied by irregular and unpredictable hyperglycemias, frequently with ketosis, and sometimes serious hypoglycemias, including an impaired counterregulatory response to hypoglycemia, occult infection, gastroparesis (which leads to erratic absorption of dietary carbohydrates), and endocrinopathies (e.g., Addison's disease).<cite>7</cite> These phenomena are believed to occur no more frequently than in 1% to 2% of persons with Type 1 diabetes.<cite>8</cite>
start met metformine (500 mg 1 dd, max. 1000 mg 3 dd)


===Type 2 diabetes===
start cholesterol lowering drug (e.g. simvastatine 40mg once daily)
Type 2 diabetes mellitus is characterized by insulin resistance, which may be combined with relatively reduced insulin secretion.<cite>2</cite> 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 and medications that improve insulin sensitivity or reduce glucose production by the liver.
start ACE inhibitor if no hypertension but with microalbuminuria (e.g. enalapril 10-20mg once daily)
|-
!Step 2
|''BMI <27:'' add sulfonylureumderivate (eg. tolbutamide 500 mg once daily, max. 1000 mg twice daily)


===Gestational diabetes===
''BMI =27:'' add sulfonylureumderivaat if no CVD or heart failure
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.


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 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.
If CVD but no increased risk of heart failure add  (pioglitazon 15 mg once daily, max. 45 mg once daily)
|-
!Step 3
|Add long acting insulin to oral treatment (stop pioglitazon if present)
|-
!Step 4a
|NPH-insuline or mix-insuline twice daily
|-
!Step 4b
|Insulin four times daily
|}


A 2008 study completed in the U.S. found the number of American women entering pregnancy with pre-existing diabetes is increasing. In fact, the rate of diabetes in expectant mothers has more than doubled in the past six years.<cite>9</cite> This is particularly problematic as diabetes raises the risk of complications during pregnancy, as well as increasing the potential for the children of diabetic mothers to become diabetic in the future.
===Case Report===
Rick is a 56-year-old plumber of a local firm, and his friends called him stocky since he is 7’8” and 260 lbs. He is married and was diagnosed with type 2 diabetes 14 months ago. He used to smoke 10 cigarettes a day and is currently not smoking, but he continued to eat fatty fast food seven to ten times per week due to his flow of work.  


===Other types===
He had followed lifestyle advice and lost some weight and was doing more exercises, but had now been diagnosed with hypertension (163/95 mmHg). His physician decided to offer Rick some treatments for his hypertension, and Rick attended for a further check-up 18 months after the diabetic diagnosis. It was found that Rick now has chest pain, and he had to start taking aspirin and a beta blocker.
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 which has been termed ''America's largest healthcare epidemic.''<cite>10</cite><cite>11</cite>


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.
===Introduction===
 
As per the World Health Organization (''WHO''), an estimated 347 million people world-wide have  diabetes in 2012.<cite>77</cite> The number of deaths attributed to diabetes was previously estimated at just over 800,000. However, it has long been known that the number of deaths related to diabetes is considerably underestimated. With regarding the causes of death of diabetes, one important factor contributing the increased morbidity and mortality in diabetic individuals is the development of cardiovascular disease, one of the chronic complications of diabetes. Several studies have demonstrated that diabetic patients have a risk of death that is two to three times higher than that among people without diabetes.<cite>4</cite>
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.<cite>11</cite>
 
==Signs and symptoms==
[[Image:Main symptoms of diabetes.png|thumb|300px|Overview of the most significant symptoms of diabetes.]]
 
The classic symptoms of untreated diabetes are loss of weight, polyuria (frequent urination), polydipsia (increased thirst) and polyphagia (increased hunger).<cite>12</cite> 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.
 
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. Blurred vision is a common complaint leading to a diabetes diagnosis; Type 1 should always be suspected in cases of rapid vision change, whereas with Type 2 change is generally more gradual, but should still be suspected. 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 present with diabetic ketoacidosis, a state of metabolic dysregulation characterized by the smell of acetone, a rapid, deep breathing known as Kussmaul breathing, nausea, vomiting and abdominal pain, and altered states of consciousness.
 
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===
All forms of diabetes increase the risk of long-term complications. These typically develop after many years (10–20), 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.<cite>13</cite> The main ''macrovascular'' diseases (related to atherosclerosis of larger arteries) are ischemic heart disease (angina and myocardial infarction), stroke and peripheral vascular disease.
 
Diabetes also damages the capillaries (causes microangiopathy).<cite>14</cite> Diabetic retinopathy, which affects blood vessel formation in the retina of the eye, can lead to visual symptoms, reduced vision, and potentially blindness. Diabetic nephropathy, the impact of diabetes on the kidneys, can lead to scarring changes in the kidney tissue, loss of small or progressively larger amounts of protein in the urine, and eventually chronic kidney disease requiring dialysis. Diabetic neuropathy is the impact of diabetes on the nervous system, most commonly causing numbness, tingling and pain in the feet and also increasing the risk of skin damage due to altered sensation. Together with vascular disease in the legs, neuropathy contributes to the risk of diabetes-related foot problems (such as diabetic foot ulcers) that can be difficult to treat and occasionally require amputation.
 
==Causes==
The cause of diabetes depends on the type.
 
Type 1 diabetes is partly inherited, and then triggered by certain infections, with some evidence pointing at Coxsackie B4 virus. A genetic element in individual susceptibility to some of these triggers has been traced to particular HLA (Human leukocyte antigen) genotypes (i.e., the genetic ''self'' identifiers relied upon by the immune system). However, even in those who have inherited the susceptibility, Type 1 DM seems to require an environmental trigger.  The onset of Type 1 diabetes is unrelated to lifestyle.
 
Type 2 diabetes is due primarily to lifestyle factors and genetics.<cite>15</cite>


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==Pathophysiology==
Multiple epidemiologic studies have established diabetes as a major risk factor for the development of all manifestations of cardiovascular disease, including myocardial infarction, stroke, peripheral vascular disease, and heart failure,<cite>5</cite><cite>6</cite><cite>7</cite><cite>8</cite> and recent data suggest that the proportion of cardiovascular disease attributable to diabetes is increasing.<cite>6</cite> It is estimated that cardiovascular disease accounts for 65% of all deaths in persons with diabetes.<cite>9</cite> In a recent meta-analysis of nearly 700,000 people from 102 prospective studies, diabetes conferred an approximate two fold risk for coronary heart disease and stroke, independently from other conventional risk factors.<cite>8</cite> Thus, in order to reduce the health burden of diabetes, it is considered necessary to aggressively prevent and treat cardiovascular disease in these patients.  
[[Image:Suckale08 fig3 glucose insulin day.png|thumb|300px|right|The fluctuation of blood sugar (red) and the sugar-lowering hormone insulin (blue) in humans during the course of a day with three meals - one of the effects of a sugar-rich vs a starch-rich meal is highlighted.]]


[[Image:Glucose-insulin-release.png|thumb|right|300px|Mechanism of insulin release in normal pancreatic beta cells - insulin production is more or less constant within the beta cells. Its release is triggered by food, chiefly food containing absorbable glucose.]]
===Diabetes and pre-diabetic glucose abnormalities===
Type 1 diabetes is caused by the gradually decreasing of endogenous insulin production by pancreatic beta cells and thus loss of the control of blood glucose, whereas type 2 diabetes is caused by the rising blood glucose resulted from a combination of genetic predisposition, unhealthy diet, physical inactivity, and body weight-gain.<cite>10</cite> The higher than normal blood glucose level in both type 1 and type 2 diabetes results in pathophysiological processes, which are associated with the development of microvascular disease and atherosclerosis. Patients with diabetes are thus at a particularly high risk for cardiovascular, cerebrovascular, and peripheral artery disease.


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.
Diabetes is characterized by recurrent or persistent hyperglycemia (high blood glucose), and is diagnosed by demonstrating any one of the following:<cite>11</cite>


Humans are capable of digesting some carbohydrates, in particular those most common in food; starch, and some disaccharides such as sucrose, are converted within a few hours to simpler forms, most notably the monosaccharide glucose, the principal carbohydrate energy source used by the body. The rest are passed on for processing by gut flora largely in the colon. 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, 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.
*Fasting blood glucose level = 126 mg/dl (= 7.0 mmol/L)
*2 hours glucose tolerance test: Plasma glucose = 200 mg/dL (= 11.1 mmol/L)
*HbA<sub>1C IFCC</sub> = 48 mmol/mol (6.5%)


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 ß-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 the opposite manner to insulin. Glucose thus forcibly produced from internal liver cell stores (as glycogen) re-enters the bloodstream; muscle cells lack the necessary export mechanism. Normally, liver cells do this when the level of insulin is low (which normally correlates with low levels of blood glucose).
A positive result should be confirmed by a repeat on a different day. People with fasting glucose levels from 110 to 125 mg/dl (6.1 to 7.0 mmol/L) are considered to have impaired fasting glucose.<cite>12</cite> People with blood glucose at 140 mg/dL ~ 200 mg/dL (7.8 ~ 11.1 mmol/L) as glucose tolerance test result are considered to have impaired glucose tolerance, which in particular is a major risk for progression to diabetes, as well as cardiovascular disease.<cite>13</cite> HbA<sub>1C</sub> (glycated hemoglobin), which is an indicator of average blood glucose level, is better than fasting glucose for determining risks of cardiovascular disease and death from any cause.<cite>14</cite> Measuring HbA<sub>1C</sub> assesses the effectiveness of therapy by monitoring long-term serum glucose regulation, and patients with diabetes who manage to keep their HbA<sub>1C</sub> level below 53 mmol/mol (7%) are considered to have good glycemic control.


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 bi-directional 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).
===Epidemiology and cardiovascular risk of diabetes===
The age-specific prevalence of diabetes rises with age up to the seventh to eighth decades in both men and women.<cite>15</cite> The prevalence is less than 10% in subjects below the age of 60, and 10–20% between 60 ~ 69 years; 15–20% in the oldest groups have previously known diabetes; and a similar proportion have screen-detected asymptomatic diabetes. This suggests that the lifetime risk of diabetes in European people is 30–40%. The prevalence of impaired glucose tolerance increases linearly with age, but the prevalence of impaired fasting glycaemia does not. In middle aged people, the prevalence of impaired glucose homeostasis is about 15%, whereas it is 35–40% in the elderly. The prevalence of diabetes and impaired glucose tolerance defined by isolated post-load hyperglycemia is higher in women than in men, but the prevalence of diabetes and impaired fasting glucose diagnosed by isolated fasting hyperglycemia is higher in men than in women.  


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 have its usual effect, so it 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.
Several prospective studies have unequivocally confirmed that post-load hyperglycemia increases cardiovascular diseases morbidity and mortality, however, it remains to be demonstrated that lowering a high 2-hours post-load blood glucose will reduce the risk. Studies are underway but thus far data are scarce. A secondary endpoint analysis of the ''STOP-NIDDM'' (Study to Prevent Non-Insulin-Dependent Diabetes Mellitus) revealed statistically significant reductions in cardiovascular diseases event rates in impaired glucose tolerance subjects receiving acarbose compared with placebo.<cite>16</cite> Since acarbose specifically reduces post-prandial glucose excursions, this is the first demonstration that lowering post-prandial glucose and may lead to a reduction in cardiovascular diseases events, but it should be noted that the power in this analysis is low due to a small number of cases.


When the glucose concentration in the blood is raised to about 9-10 mmol/L (except certain conditions, such as pregnancy), beyond its renal threshold (i.e. when glucose level surpasses the transport maximum of glucose reabsorption), 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 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.
===Identification of subjects at high risk for CVD===
Predicting risk of cardiovascular disease in diabetics can be done with the risk score of the ''DECODE'' study. The Diabetes Epidemiology: Collaborative Analysis Of Diagnostic Criteria in Europe (''DECODE'') group developed a cardiovascular diseases risk score, which is presently the only one of its kind including impaired glucose tolerance or impaired fasting glucose in the risk function determination.<cite>17</cite> The large European ''DECODE'' study is a collaborative prospective study of 22 cohorts in Europe with baseline glucose measurements for 29714 subjects aged 30-89 years who were followed-up for 11 years, indicated that either fasting or 2-hours post-load blood glucose is an independent risk factor for all-cause and cardiovascular morbidity and mortality even in people without diagnosed diabetes.<cite>18</cite> 


==Diagnosis==
Predicting risk to develop diabetes is possible with the Finnish Diabetes Risk Score.<cite>19</cite> The Finnish Diabetes Risk Score predicts the 10 year risk for developing type 2 diabetes with 85% accuracy. It also detects asymptomatic diabetes and abnormal glucose tolerance with high reliability in other populations, which can be used as a self-administered test to screen subjects at high risk for type 2 diabetes, and can also be used in the general population and clinical practice to identify undetected type 2 diabetes, and the abnormal glucose tolerance. In addition, Finnish Diabetes Risk Score is a good predictor that can be used to predict coronary artery disease, stroke and total mortality.<cite>20</cite> Such a simple scoring system can be used to identify high-risk individuals. If under proper management, it can be applied to not only diabetes prevention, but also to cardiovascular diseases prevention.
 
===Treatments to reduce cardiovascular risk===  
{| class="wikitable" border="0" cellpadding="0" cellspacing="0" width="600px"
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|-
|-
!colspan="4"|Diabetes diagnostic criteria<cite>18</cite><cite>19</cite>
!colspan="3"|Treatment to reduce cardiovascular risk <cite>34</cite>
|-
|-
!Condition
|bgcolor="#CCCCFF" colspan="3"|'''Lifestyle and comprehensive management'''
!2 Hour Glucose
!Fasting glucose
!HbA<sub>1c</sub>
|-
|-
|
!Recommendation
|mmol/l(mg/dl)
!Class<sup>a</sup>
|mmol/l(mg/dl)
!Level<sup>b</sup>
|%
|-
|-
|Normal
|Structured patient education improves metabolic and blood pressure control
|<7.8 (<140)
!I
|<6.1 (<110)
!A
|<6.0
|-
|-
|Impaired fasting glycaemia
|Non-pharmacological life style therapy improves metabolic control
|<7.8 (<140)
!I
|≥ 6.1(≥110) & <7.0(<126)
!A
|6.0–6.4
|-
|-
|Impaired glucose tolerance
|Self-monitoring improves glycaemic control
|≥7.8 (≥140)
!I
|<7.0 (<126)
!A
|6.0–6.4
|-
|-
!Diabetes mellitus
|Near normoglycaemic control (''HbA1c &le; 6.5%<sup>c</sup>'')
|≥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:<cite>11</cite>
 
* Fasting plasma glucose level ≥7.0 mmol/l (126 mg/dl)
* Plasma glucose ≥11.1 mmol/l (200&nbsp;mg/dL) two hours after a 75g oral glucose load as in a glucose tolerance test
* Symptoms of hyperglycemia and casual plasma glucose ≥11.1 mmol/l (200&nbsp;mg/dl)
* Glycated hemoglobin (Hb A1C) ≥6.5%<cite>20</cite>


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.<cite>21</cite> According to the current definition, two fasting glucose measurements above 126 mg/dl (7.0 mmol/l) is considered diagnostic for diabetes mellitus.
reduces microvascular complications


People with fasting glucose levels from 110 to 125 mg/dl (6.1 to 6.9 mmol/l) are considered to have impaired fasting glucose.<cite>22</cite> Patients with plasma glucose at or above 140 mg/dL (7.8 mmol/L), but not over 200 mg/dL (11.1 mmol/L), two hours after a 75 g oral glucose load are considered to have impaired glucose tolerance. Of these two prediabetic states, the latter in particular is a major risk factor for progression to full-blown diabetes mellitus, as well as cardiovascular disease.<cite>23</cite>
reduces macrovascular complications
 
!I
Glycated hemoglobin is better than fasting glucose for determining risks of cardiovascular disease and death from any cause.<cite>24</cite>
!A
 
==Management==
Diabetes mellitus is a chronic disease which cannot be cured 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).
 
Patient education, understanding, and participation is vital, since the complications of diabetes are far less common and less severe in people who have well-managed blood sugar levels.<cite>25</cite><cite>26</cite> The goal of treatment is an HbA1C level of 6.5%, but should not be lower than that, and may be set higher.<cite>27</cite> 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.<cite>27</cite>
 
===Lifestyle===
There are roles for patient education, dietetic support, 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.<cite>28</cite>
 
===Medications===
The following table compares some common anti-diabetic agents, generalizing classes, although there may be substantial variation in individual drugs of each class. When the table makes a comparison such as "lower risk" or "more convenient" the comparison is with the other drugs on the table.
 
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|-
|-
! colspan="4"|Comparison of anti-diabetic medication<cite>62</cite><cite>63</cite><cite>65</cite><cite>66</cite>
|Intensified insulin therapy in type 1 diabetes reduces morbidity and mortality
!I
!A
|-
|-
!Agent<cite>63</cite><cite>65</cite><cite>66</cite>
|Early escalation of therapy towards predefined treatment targets improves a composite of morbidity and mortality in type 2 diabetes
!Mechanism<cite>64</cite>
!IIa
!Advantages<cite>63</cite><cite>65</cite><cite>66</cite>
!B
!Disadvantages<cite>63</cite><cite>65</cite><cite>66</cite>
|-
|Sulfonylurea (glyburide, glimepiride, glipizide)
|Stimulating insulin release by pancreatic beta cells by inhibiting the K<sub>ATP</sub> channel
|
*Fast onset of action
*No effect on blood pressure
*No effect on low-density lipoprotein
*Inexpensive
*Lower risk of gastrointestinal problems than with metformin
*More convenient dosing
|
*Causes an average of 5-10 pounds weight gain
*Increased risk of hypoglycemia
*Glyburide has increases risk of hypoglycemia slightly more as compared with glimepiride and glipizide
*Higher risk of death compared with metformin<cite>64</cite>
|-
|-
|Metformin
|Early initiation of insulin should be considered in patients with type 2 diabetes failing glucose target
|Acts on liver to cause decrease in insulin resistance
!IIb
|
!C
*Not associated with weight gain
*Low risk of hypoglycemia as compared to alternatives
*Good effect on LDL cholesterol
*Decreases triglycerides
*No effect on blood pressure
*Inexpensive
|
*Increased risk of Human gastrointestinal tract|gastrointestinal problems
*Contraindicated for people with moderate or severe kidney disease or heart failure because of risk of lactic acidosis
*Increased risk of Vitamin B12 deficiency<cite>63</cite><cite>65</cite><cite>66</cite>
*Less convenient dosing
*Metallic taste<cite>63</cite><cite>65</cite><cite>66</cite>
|-
|-
|Alpha-glucosidase inhibitor (acarbose, miglitol)
|Metformin is recommended as first line drug in overweight type 2 diabetes
|Reduces glucose absorbance by acting on small intestine to cause decrease in production of enzymes needed to digest carbohydrates
!IIa
|
!B
*Slightly decreased risk of hypoglycemia as compared to sulfonylurea
*Not associated with weight gain
*Decreases triglycerides
*No effect on cholesterol
|
*Less effective than most other diabetes pills in decreasing glycated hemoglobin
*Increased risk of GI problems than other diabetes pills except metformin
*Inconvenient dosing
*Expensive
|-
|-
|Thiazolidinediones (Actos, Avandia)
|bgcolor="#CCCCFF" colspan="3"|'''<sup>a</sup>Class of recommendation.'''
|Reduce insulin resistance by activating (Peroxisome proliferator-activated receptor gamma) PPAR-γ in fat and muscle
|
*Lower risk of hypoglycemia
*Slight increase in high-density lipoprotein
*Actos linked to decreased triglycerides
*Convenient dosing
|
*Increased risk of heart failure
*Causes an average of 5-10 pounds weight gain
*Associated with higher risk of edema
*Associated with higher risk of anemia
*Increases low-density lipoprotein
*Avandia linked to increased triglycerides and risk of heart attack
*Actos linked to increased risk of bladder cancer
*Slower onset of action
*Requires monitoring for hepatoxicity
*Associated with increased risk of limb fractures
*Expensive
|}


Most anti-diabetic agents are contraindicated in pregnancy, in which insulin is preferred.<cite>63</cite>
'''<sup>b</sup>Level of evidence.'''
 
====Oral medications====
Metformin is generally recommended as a first line treatment for Type 2 diabetes, as there is good evidence that it decreases mortality.<cite>29</cite> Routine use of aspirin, however, has not been found to improve outcomes in uncomplicated diabetes.<cite>30</cite>
 
====Insulin====
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.<cite>29</cite> Doses of insulin are then increased to effect.<cite>29</cite>
 
===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 of a patient in a team approach. Optometrists, podiatrists/chiropodists, dietitians, Physical therapy|physiotherapists, nursing specialists (e.g., diabetic specialist nurses), nurse practitioners, or certified diabetes educators, may jointly provide multidisciplinary expertise. Home telehealth support can be an effective management technique.<cite>31</cite>
 
==Epidemiology==
{| class="wikitable" border="0" cellpadding="0" cellspacing="0" width="800px"
|-
|bgcolor="FFFFFF" align="center"|[[Image:Diabetes world map - 2000.png|400px]]
|bgcolor="FFFFFF" align="center"|[[Image:Diabetes mellitus world map - DALY - WHO2004.svg|400px]]
|-
!Prevalence of diabetes worldwide in 2000 (per 1,000 inhabitants) - world average was 2.8%.
!Disability-adjusted life year for diabetes mellitus per 100,000 inhabitants in 2004.
|-
|
{| class="wikitable" border="0" cellpadding="0" cellspacing="0" width="400px"
|-
|width="15px" bgcolor="#b3b3b3"|&nbsp;
|no data
|width="15px" bgcolor="#ff8400"|
|45–52.5
|-
|width="15px" bgcolor="#ffff65"|
|≤ 7.5
|width="15px" bgcolor="#ff6e00"|
|52.5–60
|-
|width="15px" bgcolor="#fff200"|
|7.5–15
|width="15px" bgcolor="#ff5800"|
|60–67.5
|-
|width="15px" bgcolor="#ffdc00"|
|15–22.5
|width="15px" bgcolor="#ff4200"|
|67.5–75
|-
|width="15px" bgcolor="#ffc600"|
|22.5–30
|width="15px" bgcolor="#ff2c00"|
|75–82.5
|-
|width="15px" bgcolor="#ffb000"|
|30–37.5
|width="15px" bgcolor="#cb0000"|
|≥ 82.5
|-
|width="15px" bgcolor="#ff9a00"|
|37.5–45
|}


|
'''<sup>c</sup>Diabetes Control and Complication Trial-standardized.'''
{| class="wikitable" border="0" cellpadding="0" cellspacing="0" width="400px"
|-
|width="15px" bgcolor="#b3b3b3"|
|no data
|width="15px" bgcolor="#ff8400"|
|600–700
|-
|width="15px" bgcolor="#ffff65"|
|<100
|width="15px" bgcolor="#ff6e00"|
|700–800
|-
|width="15px" bgcolor="#fff200"|
|100–200
|width="15px" bgcolor="#ff5800"|
|800–900
|-
|width="15px" bgcolor="#ffdc00"|
|200–300
|width="15px" bgcolor="#ff4200"|
|900–1,000
|-
|width="15px" bgcolor="#ffc600"|
|300–400
|width="15px" bgcolor="#ff2c00"|
|1,000–1,500
|-
|width="15px" bgcolor="#ffb000"|
|400–500
|width="15px" bgcolor="#cb0000"|
|>1,500
|-
|width="15px" bgcolor="#ff9a00"|
|500–600
|}
|}
|}


Globally, as of 2010, an estimated 285 million people had diabetes, with Type 2 making up about 90% of the cases.<cite>4</cite> Its incidence is increasing rapidly, and by 2030, this number is estimated to almost double.<cite>32</cite> 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 probably be found by 2030.<cite>32</cite> The increase in incidence 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.<cite>32</cite>
To reduce the risk of cardiovascular disease, the followings are needed to be considered:
 
===Australia===
Indigenous populations in first world countries have a higher prevalence and increasing incidence of diabetes than their corresponding nonindigenous populations. In Australia, the age-standardised prevalence of self-reported diabetes in indigenous Australians is almost four times that of nonindigenous Australians.<cite>33</cite> Preventative community health programs, such as Sugar Man (diabetes education), are showing some success in tackling this problem.
 
===China===
Almost one Chinese adult in ten has diabetes. A 2010 study estimated that more than 92 million Chinese adults have the disease, with another 150 million showing early symptoms.<cite>34</cite> The incidence of the disease is increasing rapidly; a 2009 study found a 30% increase in 7 years.<cite>35</cite>
 
===India===
India has more diabetics than any other country in the world, according to the International Diabetes Foundation,<cite>36</cite> although more recent data suggest that China has even more.<cite>34</cite> The disease affects more than 50 million Indians - 7.1% of the nation's adults - and kills about 1 million Indians a year.<cite>36</cite> The average age on onset is 42.5 years.<cite>36</cite> The high incidence is attributed to a combination of genetic susceptibility plus adoption of a high-calorie, low-activity lifestyle by India's growing middle class.<cite>37</cite>
 
===United Kingdom===
About 3.8 million people in the United Kingdom have diabetes mellitus, but the charity Diabetes U.K. have made predictions that that could become high as 6.2 million by 2035/2036. Diabetes U.K. have also predicted that the National Health Service could be spending as much as 16.9 billion pounds on diabetes mellitus by 2035, a figure that means the NHS could be spending as much as 17% of its budget on diabetes treatment by 2035.<cite>38</cite><cite>39</cite><cite>40</cite>


===United States===
a) the prevention of the progression of diabetes;
[[Image:Diabetes County level estimates 2004-2009.gif|thumb|300px|Diabetes rates at county levels 2004 - 2009.]]


For at least 20 years, diabetes rates in North America have been increasing substantially. In 2010, nearly 26 million people have diabetes in the United States, of whom 7 million people remain undiagnosed. Another 57 million people are estimated to have prediabetes.<cite>41</cite><cite>42</cite>
b) the prevention of cardiovascular disease by physical activity; and


The Centers for Disease Control and Prevention (CDC) has termed the change an epidemic.<cite>43</cite> The National Diabetes Information Clearinghouse estimates 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. Most of this difference is not currently understood. The American Diabetes Association (ADA) cites the 2003 assessment of the National Center for Chronic Disease Prevention and Health Promotion (Centers for Disease Control and Prevention) that one in three Americans born after 2000 will develop diabetes in their lifetimes.<cite>44</cite><cite>45</cite>
c) the treatments to reduce cardiovascular risk.  


According to the ADA, about 18.3% (8.6 million) of Americans age 60 and older have diabetes.<cite>46</cite> 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, 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.<cite>47</cite>
With regarding the first treatment – the prevention of the progression of diabetes, clinical studies have demonstrated that effective lifestyle intervention strategies and drug treatments can prevent or at least delay the progression to type 2 diabetes in high-risk individuals. For instance, the Finnish Diabetes Prevention Study found that a 5% reduction in bodyweight, achieved through an intensive diet and exercise program was associated with a 58% reduction in the risk of developing type 2 diabetes in overweight subjects with impaired glucose tolerance;<cite>21</cite>  and the US Diabetes Prevention Program found that lifestyle modification reduced the incidence of type 2 diabetes by 58% in overweight adults with impaired glucose tolerance.<cite>22</cite>   
 
==References==
<biblio>
#1 ''Diabetes Blue Circle Symbol''. International Diabetes Federation. 17 March 2006.
#2 Shoback, edited by David G. Gardner, Dolores (2011). Greenspan's basic & clinical endocrinology (9th ed.). New York: McGraw-Hill Medical. pp. Chapter 17. ISBN 0-07-162243-8.
#3 [http://www.npr.org/blogs/health/2012/06/21/155505445/how-to-spot-a-neglected-tropical-disease How to spot a neglected tropical disease]
#4 Williams textbook of endocrinology (12th ed.). Philadelphia: Elsevier/Saunders. pp. 1371–1435. ISBN 978-1-4377-0324-5.
#5 Lambert, P.; Bingley, P. J. (2002). ''What is Type 1 Diabetes?''. Medicine 30: 1–5. doi:10.1383/medc.30.1.1.28264. Diabetes Symptoms edit
#6 pmid=17429082.
#7 ''Diabetes Mellitus (DM): Diabetes Mellitus and Disorders of Carbohydrate Metabolism: Merck Manual Professional''. Merck Publishing. April 2010. Retrieved 2010-07-30.
#8 pmid=406527.
#9 pmid=18223030.
#10 Handelsman Y, MD. ''A Doctor's Diagnosis: Prediabetes''. Power of Prevention 1 (2).
#11 ''Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications'' (PDF). World Health Organisation. 1999.
#12 pmid=18977856.
#13 pmid=20609967.
#14 pmid=21791495.
#15 pmid=19032965.
#16 Unless otherwise specified, reference is: Table 20-5 in Mitchell, Richard Sheppard; Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson. Robbins Basic Pathology. Philadelphia: Saunders. ISBN 1-4160-2973-7. 8th edition.
#17 pmid=20167359.
#18 Definition and diagnosis of diabetes mellitus and intermediate hyperglycemia: report of a WHO/IDF consultation. Geneva: World Health Organization. 2006. p. 21. ISBN 978-92-4-159493-6.
#19 pmid=20194231.
#20 ''Diabetes Care'' January 2010''. American Diabetes Association. Retrieved 2010-01-29.
#21 pmid=11473076.
#22 Definition and diagnosis of diabetes mellitus and intermediate hyperglycemia : report of a WHO/IDF consultation. World Health Organization. 2006. p. 21. ISBN 978-92-4-159493-6.
#23 Santaguida PL, Balion C, Hunt D, Morrison K, Gerstein H, Raina P, Booker L, Yazdi H. ''Diagnosis, Prognosis, and Treatment of Impaired Glucose Tolerance and Impaired Fasting Glucose''. Summary of Evidence Report/Technology Assessment, No. 128. Agency for Healthcare Research and Quality. Retrieved 2008-07-20.
#24 pmid=20200384.
#25 pmid=16371630.
#26 pmid=7887548.
#27 National Institute for Health and Clinical Excellence. Clinical guideline 66: Type 2 diabetes. London, 2008.
#28 pmid=10938049.
#29 pmid=19145963.
#30 pmid=20508233.
#31 pmid=19531058.
#32 pmid=15111519.
#33 Australian Institute for Health and Welfare. ''Diabetes, an overview''. Archived from the original on 2008-06-17. Retrieved 2008-06-23.
#34 ''China faces 'diabetes epidemic', research suggests''. BBC. March 25, 2010. Retrieved 8 June 2012.
#35 Grens, Kerry (April 4, 2012). ''Diabetes continuing to spike in China''. Reuters. Retrieved 8 June 2012.
#36 Gale, Jason (November 7, 2010). ''India’s Diabetes Epidemic Cuts Down Millions Who Escape Poverty''. Bloomberg. Retrieved 8 June 2012.
#37 Kleinfield, N. R. (September 13, 2006). ''Modern Ways Open India’s Doors to Diabetes''. New York Times. Retrieved 8 June 2012.
#38 ''NHS spending on diabetes 'to reach £16.9 billion by 2035'''. 2012-04-25. Retrieved 2012-04-26.
#39 [http://managingdiabetes.co.uk/articles/diabetesnhsspending.php Diabetes NHS Spending]
#40 [http://www.nhs.uk/news/2012/04april/Pages/nhs-diabetes-costs-cases-rising.aspx NHS Diabetes Costs Cases Rising]
#41 ''Number of Americans with Diabetes Rises to Nearly 26 Million'' (Press release). Centers for Disease Control and Prevention. 2011-01-26. Retrieved 2012-05-27.
#42 ''National diabetes fact sheet: national estimates and general information on diabetes and prediabetes in the United States, 2011''. Centers for Disease Control and Prevention. 2011. Retrieved 2012-05-31.
#43 ''Diabetes Rates Rise Another 6 Percent in 1999 — January 26, 2001''. Retrieved 2008-06-23.
#44 pmid=14532317.
#45 ''Total Prevalence of Diabetes & Pre-diabetes''. American Diabetes Association. 2005. Archived from the original on 2006-02-08. Retrieved 2006-03-17.
#46 ''Seniors and Diabetes''. Elderly And Diabetes-Diabetes and Seniors. LifeMed Media. 2006. Retrieved 2007-05-14.
#47 pmid=9571335.
</biblio>
----
----
 
 
''The content of this chapter is largely taken from Wikipedia''
{{DevelopmentPhase}}
__TOC__
 
==Preamble==
Diabetes (diabetes mellitus) is one of the metabolic diseases with higher blood sugar level, either due to the pancreatic beta cells do not produce enough insulin, or the cells do not respond to the insulin that is produced.<cite>1</cite> Its clinical symptoms include three polies: polyuria (frequent urination), polydipsia (increased thirst) and polyphagia (increased hunger). Diabetes is categorized as three types in the clinic: Type 1 diabetes (T1D, diabetes mellitus 1, DM1) results from pancreatic beta cell destruction and thus fails to produce insulin, and is insulin dependent which relies on insulin injection, it is also named insulin-dependent diabetes mellitus (''IDDM''). Since T1D happens mostly in juveniles it is also called juvenile-onset diabetes. Type 2 diabetes (T2D, diabetes mellitus 2, DM2) results from the reason that the beta cells do not respond to insulin (insulin resistance), and it may co-exist with the situation of partially or fully insulin-dependent, which is also named non-insulin-dependent diabetes mellitus (''NIDDM'') or adult-onset diabetes. In some type 2 diabetes, concomitant insulin therapy may be necessary (''IDDM2''). The third type is gestational diabetes occurs while pregnancy.
 
There is no cure for diabetes currently except that most of the gestational diabetes disappears when the pregnancy is ended, but it is treatable. The current therapies are insulin, other non-curing medications, and pancreatic replacement therapies like pancreatic islet transplantations which have been applied to severe T1D cases successfully since 1980s’.<cite>2</cite>Since both T1D and T2D are chronic diseases and the progresses of modern medicine, acute complications like hypoglycemia and ketoacidosis are under well controlled, and thus chronic and long-term complications like chronic renal failure, and diabetic retinopathy, especially cardiovascular diseases (''CVD''), are drawing attentions.
 
{| class="wikitable" border="0" cellpadding="0" cellspacing="0" width="600px"
|-
!colspan="2"|Basic treatment steps of diabetes:
|-
!width="60px"|Step 1
|Educate the patient
 
Treat concomittant risk factors (e.g. hypertension, obesity, hyperlipidemia)
 
start met metformine (500 mg 1 dd, max. 1000 mg 3 dd)
 
start cholesterol lowering drug (e.g. simvastatine 40mg once daily)
 
start ACE inhibitor if no hypertension but with microalbuminuria (e.g. enalapril 10-20mg once daily)
|-
!Step 2
|''BMI <27:'' add sulfonylureumderivate (eg. tolbutamide 500 mg once daily, max. 1000 mg twice daily)
 
''BMI =27:'' add sulfonylureumderivaat if no CVD or heart failure
 
If CVD but no increased risk of heart failure add  (pioglitazon 15 mg once daily, max. 45 mg once daily)
|-
!Step 3
|Add long acting insulin to oral treatment (stop pioglitazon if present)
|-
!Step 4a
|NPH-insuline or mix-insuline twice daily
|-
!Step 4b
|Insulin four times daily
|}
 
===Case Report===
Rick is a 56-year-old plumber of a local firm, and his friends called him stocky since he is 7’8” and 260 lbs. He is married and was diagnosed with type 2 diabetes 14 months ago. He used to smoke 10 cigarettes a day and is currently not smoking, but he continued to eat fatty fast food seven to ten times per week due to his flow of work.
 
He had followed lifestyle advice and lost some weight and was doing more exercises, but had now been diagnosed with hypertension (163/95 mmHg). His physician decided to offer Rick some treatments for his hypertension, and Rick attended for a further check-up 18 months after the diabetic diagnosis. It was found that Rick now has chest pain, and he had to start taking aspirin and a beta blocker.
 
===Introduction===
As per the World Health Organization (''WHO''), an estimated 347 million people world-wide have  diabetes in 2012.<cite>77</cite> The number of deaths attributed to diabetes was previously estimated at just over 800,000. However, it has long been known that the number of deaths related to diabetes is considerably underestimated. With regarding the causes of death of diabetes, one important factor contributing the increased morbidity and mortality in diabetic individuals is the development of cardiovascular disease, one of the chronic complications of diabetes. Several studies have demonstrated that diabetic patients have a risk of death that is two to three times higher than that among people without diabetes.<cite>4</cite> 
 
Multiple epidemiologic studies have established diabetes as a major risk factor for the development of all manifestations of cardiovascular disease, including myocardial infarction, stroke, peripheral vascular disease, and heart failure,<cite>5</cite><cite>6</cite><cite>7</cite><cite>8</cite> and recent data suggest that the proportion of cardiovascular disease attributable to diabetes is increasing.<cite>6</cite> It is estimated that cardiovascular disease accounts for 65% of all deaths in persons with diabetes.<cite>9</cite> In a recent meta-analysis of nearly 700,000 people from 102 prospective studies, diabetes conferred an approximate two fold risk for coronary heart disease and stroke, independently from other conventional risk factors.<cite>8</cite> Thus, in order to reduce the health burden of diabetes, it is considered necessary to aggressively prevent and treat cardiovascular disease in these patients.
 
===Diabetes and pre-diabetic glucose abnormalities===
Type 1 diabetes is caused by the gradually decreasing of endogenous insulin production by pancreatic beta cells and thus loss of the control of blood glucose, whereas type 2 diabetes is caused by the rising blood glucose resulted from a combination of genetic predisposition, unhealthy diet, physical inactivity, and body weight-gain.<cite>10</cite> The higher than normal blood glucose level in both type 1 and type 2 diabetes results in pathophysiological processes, which are associated with the development of microvascular disease and atherosclerosis. Patients with diabetes are thus at a particularly high risk for cardiovascular, cerebrovascular, and peripheral artery disease.
 
Diabetes is characterized by recurrent or persistent hyperglycemia (high blood glucose), and is diagnosed by demonstrating any one of the following:<cite>11</cite>
 
*Fasting blood glucose level = 126 mg/dl (= 7.0 mmol/L)
*2 hours glucose tolerance test: Plasma glucose = 200 mg/dL (= 11.1 mmol/L)
*HbA<sub>1C IFCC</sub> = 48 mmol/mol (6.5%)
 
A positive result should be confirmed by a repeat on a different day. People with fasting glucose levels from 110 to 125 mg/dl (6.1 to 7.0 mmol/L) are considered to have impaired fasting glucose.<cite>12</cite> People with blood glucose at 140 mg/dL ~ 200 mg/dL (7.8 ~ 11.1 mmol/L) as glucose tolerance test result are considered to have impaired glucose tolerance, which in particular is a major risk for progression to diabetes, as well as cardiovascular disease.<cite>13</cite> HbA<sub>1C</sub> (glycated hemoglobin), which is an indicator of average blood glucose level, is better than fasting glucose for determining risks of cardiovascular disease and death from any cause.<cite>14</cite> Measuring HbA<sub>1C</sub> assesses the effectiveness of therapy by monitoring long-term serum glucose regulation, and patients with diabetes who manage to keep their HbA<sub>1C</sub> level below 53 mmol/mol (7%) are considered to have good glycemic control.
 
===Epidemiology and cardiovascular risk of diabetes===
The age-specific prevalence of diabetes rises with age up to the seventh to eighth decades in both men and women.<cite>15</cite> The prevalence is less than 10% in subjects below the age of 60, and 10–20% between 60 ~ 69 years; 15–20% in the oldest groups have previously known diabetes; and a similar proportion have screen-detected asymptomatic diabetes. This suggests that the lifetime risk of diabetes in European people is 30–40%. The prevalence of impaired glucose tolerance increases linearly with age, but the prevalence of impaired fasting glycaemia does not. In middle aged people, the prevalence of impaired glucose homeostasis is about 15%, whereas it is 35–40% in the elderly. The prevalence of diabetes and impaired glucose tolerance defined by isolated post-load hyperglycemia is higher in women than in men, but the prevalence of diabetes and impaired fasting glucose diagnosed by isolated fasting hyperglycemia is higher in men than in women.
 
Several prospective studies have unequivocally confirmed that post-load hyperglycemia increases cardiovascular diseases morbidity and mortality, however, it remains to be demonstrated that lowering a high 2-hours post-load blood glucose will reduce the risk. Studies are underway but thus far data are scarce. A secondary endpoint analysis of the ''STOP-NIDDM'' (Study to Prevent Non-Insulin-Dependent Diabetes Mellitus) revealed statistically significant reductions in cardiovascular diseases event rates in impaired glucose tolerance subjects receiving acarbose compared with placebo.<cite>16</cite> Since acarbose specifically reduces post-prandial glucose excursions, this is the first demonstration that lowering post-prandial glucose and may lead to a reduction in cardiovascular diseases events, but it should be noted that the power in this analysis is low due to a small number of cases.
 
===Identification of subjects at high risk for CVD===
Predicting risk of cardiovascular disease in diabetics can be done with the risk score of the ''DECODE'' study. The Diabetes Epidemiology: Collaborative Analysis Of Diagnostic Criteria in Europe (''DECODE'') group developed a cardiovascular diseases risk score, which is presently the only one of its kind including impaired glucose tolerance or impaired fasting glucose in the risk function determination.<cite>17</cite> The large European ''DECODE'' study is a collaborative prospective study of 22 cohorts in Europe with baseline glucose measurements for 29714 subjects aged 30-89 years who were followed-up for 11 years, indicated that either fasting or 2-hours post-load blood glucose is an independent risk factor for all-cause and cardiovascular morbidity and mortality even in people without diagnosed diabetes.<cite>18</cite> 
 
Predicting risk to develop diabetes is possible with the Finnish Diabetes Risk Score.<cite>19</cite> The Finnish Diabetes Risk Score predicts the 10 year risk for developing type 2 diabetes with 85% accuracy. It also detects asymptomatic diabetes and abnormal glucose tolerance with high reliability in other populations, which can be used as a self-administered test to screen subjects at high risk for type 2 diabetes, and can also be used in the general population and clinical practice to identify undetected type 2 diabetes, and the abnormal glucose tolerance. In addition, Finnish Diabetes Risk Score is a good predictor that can be used to predict coronary artery disease, stroke and total mortality.<cite>20</cite> Such a simple scoring system can be used to identify high-risk individuals. If under proper management, it can be applied to not only diabetes prevention, but also to cardiovascular diseases prevention.
 
===Treatments to reduce cardiovascular risk===
(Insert Table: ‘Treatment to reduce cardiovascular risk’, PMID17220161, p11) <cite>34</cite>
 
To reduce the risk of cardiovascular disease, the followings are needed to be considered: a) the prevention of the progression of diabetes; b) the prevention of cardiovascular disease by physical activity; and c) the treatments to reduce cardiovascular risk. With regarding the first treatment – the prevention of the progression of diabetes, clinical studies have demonstrated that effective lifestyle intervention strategies and drug treatments can prevent or at least delay the progression to type 2 diabetes in high-risk individuals. For instance, the Finnish Diabetes Prevention Study found that a 5% reduction in bodyweight, achieved through an intensive diet and exercise program was associated with a 58% reduction in the risk of developing type 2 diabetes in overweight subjects with impaired glucose tolerance;<cite>21</cite>  and the US Diabetes Prevention Program found that lifestyle modification reduced the incidence of type 2 diabetes by 58% in overweight adults with impaired glucose tolerance.<cite>22</cite>   


As the second treatment, the prevention of cardiovascular disease by physical activity, The International Diabetes Federation (''European Region'') have recommended physical activity for the prevention of cardiovascular disease complications among diabetic patients,<cite>23</cite> since studies found that physical activity was associated with reduced risk of cardiovascular disease, cardiovascular death, and total mortality in men with type 2 diabetes. People physically active at their work had a 40% lower cardiovascular mortality compared with people with lower physical activity at work. A high level of leisure-time physical activity like walking and walking pace was associated with a 33% drop in cardiovascular mortality, and moderate physical activity was linked to a 17% drop in cardiovascular mortality compared with the most sedentary group.<cite>24</cite>   
As the second treatment, the prevention of cardiovascular disease by physical activity, The International Diabetes Federation (''European Region'') have recommended physical activity for the prevention of cardiovascular disease complications among diabetic patients,<cite>23</cite> since studies found that physical activity was associated with reduced risk of cardiovascular disease, cardiovascular death, and total mortality in men with type 2 diabetes. People physically active at their work had a 40% lower cardiovascular mortality compared with people with lower physical activity at work. A high level of leisure-time physical activity like walking and walking pace was associated with a 33% drop in cardiovascular mortality, and moderate physical activity was linked to a 17% drop in cardiovascular mortality compared with the most sedentary group.<cite>24</cite>   
Line 560: Line 227:
The most common cause of death in European diabetic adults is coronary artery disease (''CAD''). Studies have demonstrated that the risk is two to three times higher than that among people without diabetes.<cite>30</cite> The prevalence of coronary artery disease in patients with type 1 or 2 diabetes are widely different.<cite>31</cite><cite>32</cite> In the ''EURODIAB IDDM'' Complication Study which involved 3250 type 1 diabetic patients from 16 countries, the prevalence of cardiovascular disease was 9% in men and 10% in women; and it is increasing with age that it is 6% in the age group of 15–29 years and 25% in the age group of 45–59 years.  In men, duration of diabetes was longer, waist-to-hip ratio greater, and hypertension more common in patients with cardiovascular disease, while in women, a greater body mass index was associated with increased prevalence of cardiovascular disease. The risk of coronary artery disease in type 1 diabetic patients increases dramatically when they have the onset of diabetic nephropathy.  
The most common cause of death in European diabetic adults is coronary artery disease (''CAD''). Studies have demonstrated that the risk is two to three times higher than that among people without diabetes.<cite>30</cite> The prevalence of coronary artery disease in patients with type 1 or 2 diabetes are widely different.<cite>31</cite><cite>32</cite> In the ''EURODIAB IDDM'' Complication Study which involved 3250 type 1 diabetic patients from 16 countries, the prevalence of cardiovascular disease was 9% in men and 10% in women; and it is increasing with age that it is 6% in the age group of 15–29 years and 25% in the age group of 45–59 years.  In men, duration of diabetes was longer, waist-to-hip ratio greater, and hypertension more common in patients with cardiovascular disease, while in women, a greater body mass index was associated with increased prevalence of cardiovascular disease. The risk of coronary artery disease in type 1 diabetic patients increases dramatically when they have the onset of diabetic nephropathy.  


[[Image:RCA atherosclerosis.jpg|thumb|right|300px|Coronary Artery Diseases<cite>78</cite>]]
[[Image:RCA atherosclerosis.jpg|thumb|right|300px|Coronary Artery Diseases<cite>78</cite> ]]


Diabetic men and women had comparable mortality rates, whereas coronary mortality among men was significantly higher.<cite>33</cite> Further evidences of the important relations between diabetes and myocardial infarction were obtained from the INTERHEART study in Canada. Diabetes increased the risk of myocardial infarction by more than two times in men and women, and independent of ethnicity. And thus a history of diabetes and myocardial infarction increased cardiovascular disease and mortality markedly. Diabetes or hyperglycemia itself and its complications are very important for the increased risk for coronary artery disease and related mortality.  
Diabetic men and women had comparable mortality rates, whereas coronary mortality among men was significantly higher.<cite>33</cite> Further evidences of the important relations between diabetes and myocardial infarction were obtained from the INTERHEART study in Canada. Diabetes increased the risk of myocardial infarction by more than two times in men and women, and independent of ethnicity. And thus a history of diabetes and myocardial infarction increased cardiovascular disease and mortality markedly. Diabetes or hyperglycemia itself and its complications are very important for the increased risk for coronary artery disease and related mortality.  
Line 575: Line 242:


===Treatments and outcomes===
===Treatments and outcomes===
(Insert Table 12: ‘Treatment options based on accumulated evidence’, PMID17220161, p20) <cite>34</cite>  
{| class="wikitable" border="0" cellpadding="0" cellspacing="0" width="600px"
|-
!Treatment options based on accumulated evidence <cite>34</cite>
|-
|
*Revascularization
*Anti-ischaemic medication
*Anti-platelet agents
*Anti-thrombin agents
*Secondary prevention by means of
**Lifestyle habits including food and physical activity
**Smoking cessation
**Blocking the renin–angiotensin system
**Blood pressure control (target < 140/85 mmHg)<cite>ESCEADS</cite>
**Lipid-lowering medication (target LDL < 1.8 mmol/L or < 70 mg/dL)<cite>ESCEADS</cite>
**Blood glucose control (target HbA1c < 53 mmol/mol or < 7%)
|}


The preventive modalities include doctors counsel exercise, the “diabetes with CAD meal plan” aiming at long-term weight loss, aspirin in doses of 75 to 81 mg/d,<cite>37</cite> (in patients who do not tolerate or have a contra-indication to aspirin, clopidogrel can be used as an alternative antiplatelet agent <cite>38</cite>), antihypertensive therapy and glycemic control.
The preventive modalities include doctors counsel exercise, the “diabetes with CAD meal plan” aiming at long-term weight loss, aspirin in doses of 75 to 81 mg/d,<cite>37</cite> (in patients who do not tolerate or have a contra-indication to aspirin, clopidogrel can be used as an alternative antiplatelet agent <cite>38</cite>), antihypertensive therapy and glycemic control.
Line 590: Line 273:


===Introduction===
===Introduction===
[[Image:Heartfailure.jpg|thumb|right|300px|The major signs and symptoms of heart failure.]]
Prevalence of diabetes and heart failure are increasing exponentially worldwide <cite>40</cite>. Diabetes is well-known to increase the risk of heart failure independent of other traditional risk factors and ischemia. Most heart failure in people with diabetes results from coronary artery disease, and diabetic cardiomyopathy is only said to exist if there is no coronary artery disease to explain the heart muscle disorder.<cite>41</cite> Little is known about the prevalence of the combination of diabetes and heart failure. The most recent and extensive data on the prevalence of diabetes and heart failure are from the Reykjavi´k Study, showing that the prevalence of the combination of heart failure and diabetes is 0.5% in men and 0.4% in women, increasing with increasing age. Heart failure was found in 12% of those with diabetes compared with only 3% in individuals without diabetes.<cite>42</cite> Thus, there was a strong association between diabetes and heart failure. In the Framingham study, the incidence of heart failure was double among males and five times higher in females with diabetes during 18 years of follow-up, compared with patients free from diabetes,  
Prevalence of diabetes and heart failure are increasing exponentially worldwide <cite>40</cite>. Diabetes is well-known to increase the risk of heart failure independent of other traditional risk factors and ischemia. Most heart failure in people with diabetes results from coronary artery disease, and diabetic cardiomyopathy is only said to exist if there is no coronary artery disease to explain the heart muscle disorder.<cite>41</cite> Little is known about the prevalence of the combination of diabetes and heart failure. The most recent and extensive data on the prevalence of diabetes and heart failure are from the Reykjavi´k Study, showing that the prevalence of the combination of heart failure and diabetes is 0.5% in men and 0.4% in women, increasing with increasing age. Heart failure was found in 12% of those with diabetes compared with only 3% in individuals without diabetes.<cite>42</cite> Thus, there was a strong association between diabetes and heart failure. In the Framingham study, the incidence of heart failure was double among males and five times higher in females with diabetes during 18 years of follow-up, compared with patients free from diabetes,  


Several clinical and experimental studies have shown that diabetes mellitus leads to functional, biochemical, and morphological abnormalities of the heart, independent of promoting myocardial ischemia, and some of these changes happen earlier in the natural history of diabetes.<cite>40</cite> Diabetes is an independent risk factor for heart failure, and promotes myocardial remodeling (a precursor of heart failure), and the mechanisms beyond ischemia that lead to the development of heart failure in individuals with varying degrees of impaired glucose homeostasis. The most common abnormality observed in asymptomatic diabetics is left ventricular diastolic dysfunction, likely resulting from greater left ventricular myocardial and vascular stiffness. There is also growing evidence that some, if not all, of these structural and biochemical myocardial abnormalities start at the pre-diabetic stage.
Several clinical and experimental studies have shown that diabetes mellitus leads to functional, biochemical, and morphological abnormalities of the heart, independent of promoting myocardial ischemia, and some of these changes happen earlier in the natural history of diabetes.<cite>40</cite> Diabetes is an independent risk factor for heart failure, and promotes myocardial remodeling (a precursor of heart failure), and the mechanisms beyond ischemia that lead to the development of heart failure in individuals with varying degrees of impaired glucose homeostasis. The most common abnormality observed in asymptomatic diabetics is left ventricular diastolic dysfunction, likely resulting from greater left ventricular myocardial and vascular stiffness. There is also growing evidence that some, if not all, of these structural and biochemical myocardial abnormalities start at the pre-diabetic stage.
(Insert Figure ‘Heart Failure’ from: http://en.wikipedia.org/wiki/Heart_failure )


===Evaluation===  
===Evaluation===  
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===Treatments and outcomes===  
===Treatments and outcomes===  
(Insert Table: ‘Heart failure and diabetes’, PMID17220161, p25) <cite>34</cite>  
{| class="wikitable" border="0" cellpadding="0" cellspacing="0" width="600px"
|-
!colspan="3"|Heart failure and diabetes<cite>34</cite>
|-
|bgcolor="#CCCCFF" colspan="3"|
|-
!Recommendation
!Class<sup>a</sup>
!Level<sup>b</sup>
|-
|ACE-inhibitors are recommended as first-line therapy in diabetic patients with reduced left ventricular dysfunction with or without symptoms of heart failure
!I
!C
|-
|Angiotensin-II receptor blockers have similar effects in heart failure as ACE-inhibitors and can be used as an alternative or even as added treatment to ACE-inhibitors
!I
!C
|-
|Beta blockers (metoprolol, bisoprolol, and carvedilol) are recommended as first-line therapy in diabetic patients with heart failure
!I
!C
|-
|Diuretics, in particular loop diuretics, are important for symptomatic treatment of diabetic patients with fluid overload owing to heart failure
!IIa
!C
|-
|Aldosterone antagonists may be added to ACE-inhibitors, BBs, and diuretics in diabetic patients with severe heart failure
!IIb
!C
|-
|bgcolor="#CCCCFF" colspan="3"|'''<sup>a</sup>Class of recommendation.'''
 
'''<sup>b</sup>Level of evidence.'''
|}


According to the European Society of Cardiology (ESC) and the European Association for the Study of Diabetes (EASD) Guidelines,<cite>31</cite> there are very few clinical trials on heart failure treatment specifically for diabetic patients. Information on treatment efficacy of various drugs is therefore based on diabetic subgroups included in various heart failure trials. A disadvantage of this is that the subgroups are not always well defined as regards the diabetic state and treatment. Most data favor a proportionately similar efficacy in patients with and without diabetes. Traditional treatment of heart failure in diabetic patients is based on diuretics, ACE-inhibitors, and Beta-blockades, as outlined in other guidelines.<cite>44</cite> Moreover, it is assumed that meticulous metabolic control should be beneficial in heart failure patients with diabetes.
According to the European Society of Cardiology (ESC) and the European Association for the Study of Diabetes (EASD) Guidelines,<cite>31</cite> there are very few clinical trials on heart failure treatment specifically for diabetic patients. Information on treatment efficacy of various drugs is therefore based on diabetic subgroups included in various heart failure trials. A disadvantage of this is that the subgroups are not always well defined as regards the diabetic state and treatment. Most data favor a proportionately similar efficacy in patients with and without diabetes. Traditional treatment of heart failure in diabetic patients is based on diuretics, ACE-inhibitors, and Beta-blockades, as outlined in other guidelines.<cite>44</cite> Moreover, it is assumed that meticulous metabolic control should be beneficial in heart failure patients with diabetes.


Diuretics are mandatory for relief of symptoms that are due to fluid overload. These drugs should, however, not be used in excess since they induce neuro-hormonal activation.<cite>44</cite> ACE-inhibitors are beneficial in moderate-to-severe heart failure with and without diabetes, they inhibit angiotensin-converting enzyme, thereby decreasing the tension of blood vessels and blood volume, thus lowering blood pressure. Frequently prescribed ACE inhibitors include perindopril, captopril, enalapril, lisinopril, and ramipril. Hypoglycaemia has been reported following the institution of ACE-inhibitors in patients with diabetes on glucose-lowering treatment.<cite>45</cite> It is therefore recommended to monitor blood glucose carefully in the early phase of the institution of an ACE-inhibitor in such patients. Beta-blockade decreases myocardial free fatty acid exposure, thereby changing that metabolic pathway in type 2 diabetes.<cite>46</cite> The addition of eplerenone, a selective aldosterone blocker, to optimal medical therapy reduces morbidity and mortality among patients with acute myocardial infarction complicated by left ventricular dysfunction and heart failure.<cite>47</cite>  
Diuretics are mandatory for relief of symptoms that are due to fluid overload. These drugs should, however, not be used in excess since they induce neuro-hormonal activation.<cite>44</cite> ACE-inhibitors are beneficial in moderate-to-severe heart failure with and without diabetes, they inhibit angiotensin-converting enzyme, thereby decreasing the tension of blood vessels and blood volume, thus lowering blood pressure. Frequently prescribed ACE inhibitors include perindopril, captopril, enalapril, lisinopril, and ramipril. Hypoglycaemia has been reported following the institution of ACE-inhibitors in patients with diabetes on glucose-lowering treatment.<cite>45</cite> It is therefore recommended to monitor blood glucose carefully in the early phase of the institution of an ACE-inhibitor in such patients. Beta-blockade decreases myocardial free fatty acid exposure, thereby changing that metabolic pathway in type 2 diabetes.<cite>46</cite> The addition of eplerenone, a selective aldosterone blocker, to optimal medical therapy reduces morbidity and mortality among patients with acute myocardial infarction complicated by left ventricular dysfunction and heart failure.<cite>47</cite>


==Atrial fibrillation and diabetes==
==Atrial fibrillation and diabetes==
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===Treatments and outcomes===  
===Treatments and outcomes===  
(Insert Table: ‘Arrhythmias: atrial fibrillation…’, PMID17220161, p26) <cite>34</cite>  
{| class="wikitable" border="0" cellpadding="0" cellspacing="0" width="600px"
|-
!colspan="3"|Arrhythmias: atrial fibrillation and sudden cardiac death<cite>34</cite>
|-
|bgcolor="#CCCCFF" colspan="3"|
|-
!Recommendation
!Class<sup>a</sup>
!Level<sup>b</sup>
|-
|Aspirin and anticoagulant use as recommended for patients with atrial fibrillation should be rigorously applied in diabetic patients with atrial fibrillation to prevent stroke
!I
!C
|-
|Chronic oral anticoagulant therapy in a dose adjusted to achieve a target international normalized ratio (INR) of 2–3 should be considered in all patients with atrial fibrillation and diabetes, unless contraindicated
!IIa
!C
|-
|Control of glycaemia even in the pre-diabetic stage is important to prevent the development of the alterations that predispose to sudden cardiac death
!I
!C
|-
|Microvascular disease and nephropathy are indicators of increased risk of sudden cardiac death in diabetic patients
!IIa
!B
|-
|bgcolor="#CCCCFF" colspan="3"|
'''<sup>a</sup>Class of recommendation.
 
'''<sup>b</sup>Level of evidence.
|}


Aspirin and anticoagulant use as recommended for patients with atrial fibrillation should be rigorously applied in diabetic patients with atrial fibrillation to prevent heart stroke. Oral anticoagulation is most beneficial for patients at higher risk for stroke, whereas the risks outweigh the benefit in patients at low risk.<cite>50</cite> Thus, quantifying the risk of stroke is crucial for determining which atrial fibrillation patients would benefit most from anticoagulant therapy.
Aspirin and anticoagulant use as recommended for patients with atrial fibrillation should be rigorously applied in diabetic patients with atrial fibrillation to prevent heart stroke. Oral anticoagulation is most beneficial for patients at higher risk for stroke, whereas the risks outweigh the benefit in patients at low risk.<cite>50</cite> Thus, quantifying the risk of stroke is crucial for determining which atrial fibrillation patients would benefit most from anticoagulant therapy.
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===Introduction===  
===Introduction===  
[[Image:Bluthirnschranke nach Infarkt nativ und KM.png|thumb|right|400px|Defect of the blood-brain barrier after stroke shown in MRI.]]
Diabetes related peripheral and cerebrovascular diseases are peripheral vascular disease and stroke. Peripheral vascular disease (PVD, also known as peripheral artery disease, PAD) is a term used to refer to atherosclerotic blockages found in the lower extremity, and it causes either acute or chronic ischemia (lack of blood supply). It has a two- to four-fold increased incidence in subjects with diabetes, which is present in 15% of diabetic patients. The ankle/brachial systolic blood pressure index, a noninvasive measure of peripheral vascular disease, is widely used in epidemiological studies.<cite>57</cite><cite>58</cite> The symptomatic manifestations of peripheral vascular disease are intermittent claudication and limb ischemia. Impairment of the circulation in the foot owing to diabetic macro- and microvascular diseases is the most common non-traumatic reason for limb amputation. The prevalence of peripheral vascular disease increases with advancing age, duration of diabetes, and peripheral neuropathy. The latter condition may mask the symptoms of limb ischemia and thus disease progression may be advanced before patients and healthcare providers realize that peripheral vascular disease is present. About 20% of patients with mild peripheral vascular disease may be asymptomatic; other symptoms include:<cite>59</cite>
Diabetes related peripheral and cerebrovascular diseases are peripheral vascular disease and stroke. Peripheral vascular disease (PVD, also known as peripheral artery disease, PAD) is a term used to refer to atherosclerotic blockages found in the lower extremity, and it causes either acute or chronic ischemia (lack of blood supply). It has a two- to four-fold increased incidence in subjects with diabetes, which is present in 15% of diabetic patients. The ankle/brachial systolic blood pressure index, a noninvasive measure of peripheral vascular disease, is widely used in epidemiological studies.<cite>57</cite><cite>58</cite> The symptomatic manifestations of peripheral vascular disease are intermittent claudication and limb ischemia. Impairment of the circulation in the foot owing to diabetic macro- and microvascular diseases is the most common non-traumatic reason for limb amputation. The prevalence of peripheral vascular disease increases with advancing age, duration of diabetes, and peripheral neuropathy. The latter condition may mask the symptoms of limb ischemia and thus disease progression may be advanced before patients and healthcare providers realize that peripheral vascular disease is present. About 20% of patients with mild peripheral vascular disease may be asymptomatic; other symptoms include:<cite>59</cite>


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Cerebrovascular mortality rates have been shown to be raised in patients with type 2 diabetes and have been reported that it is at least as great a risk factor in type 1 diabetes as in type 2. It is found that cerebrovascular mortality is raised at all ages in these patients.<cite>61</cite> Typical brain strokes can be classified into two categories: ischemic and hemorrhagic strokes.<cite>60</cite> Ischemic strokes are those that are caused by vessel occlusion mostly by embolism, while hemorrhagic strokes (intracerebral hemorrhage) are the ones which result from rupture of a blood vessel due to hypertension. About 80% of strokes are caused by ischemia, and the remainder by hemorrhage. Some hemorrhages develop inside the areas of ischemia, and thus it is unknown how many hemorrhages actually start as ischemic stroke.
Cerebrovascular mortality rates have been shown to be raised in patients with type 2 diabetes and have been reported that it is at least as great a risk factor in type 1 diabetes as in type 2. It is found that cerebrovascular mortality is raised at all ages in these patients.<cite>61</cite> Typical brain strokes can be classified into two categories: ischemic and hemorrhagic strokes.<cite>60</cite> Ischemic strokes are those that are caused by vessel occlusion mostly by embolism, while hemorrhagic strokes (intracerebral hemorrhage) are the ones which result from rupture of a blood vessel due to hypertension. About 80% of strokes are caused by ischemia, and the remainder by hemorrhage. Some hemorrhages develop inside the areas of ischemia, and thus it is unknown how many hemorrhages actually start as ischemic stroke.
(image: http://commons.wikimedia.org/wiki/File:Bluthirnschranke_nach_Infarkt_nativ_und_KM.png)


===Evaluation===
===Evaluation===
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===Treatments and outcomes===  
===Treatments and outcomes===  
(Insert Table: ‘Peripheral vascular disease’, PMID17220161, p29) <cite>34</cite>
{| class="wikitable" border="0" cellpadding="0" cellspacing="0" width="600px"
|-
!colspan="3"|Peripheral vascular disease<cite>34</cite>
|-
|bgcolor="#CCCCFF" colspan="3"|
|-
!Recommendation
!Class<sup>a</sup>
!Level<sup>b</sup>
|-
|All patients with type 2 diabetes and CVD are recommended treatment with low-dose aspirin
!IIa
!B
|-
|In diabetic patients with peripheral vascular disease, treatment with clopidogrel or low molecular weight heparin may be considered in certain cases
!IIa
!B
|-
|Patients with critical limb ischaemia should, if possible, undergo revascularization procedures
!I
!B
|-
|An alternative treatment for patients with critical limb ischaemia, not suited for revascularization, is prostacyclin infusion
!I
!A
|-
|bgcolor="#CCCCFF" colspan="3"|
'''<sup>a</sup>Class of recommendation.'''


(Insert Table: ‘Stroke’, PMID17220161, p31) <cite>34</cite>
'''<sup>b</sup>Level of evidence.'''
|}


Peripheral vascular diseases: Preventions are most important strategies, such as regular exercises, the optimization of glycemic control, management of hypertension, smoking cessation, antiplatelet and anti-cholesterol medications like aspirin, clopidogrel and statins.  
Peripheral vascular diseases: Preventions are most important strategies, such as regular exercises, the optimization of glycemic control, management of hypertension, smoking cessation, antiplatelet and anti-cholesterol medications like aspirin, clopidogrel and statins.  
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If anatomically possible, a revascularization procedure should be attempted in all patients with critical limb ischemia,<cite>65</cite> such as an angioplasty or a  bypass grafting can be done on solitary lesions in large arteries like the femoral artery, but the revascularization may not have sustained benefits. A synthetic prostacyclin (Ilomedin, Iloprost) is the only pharmacological agent so far convincingly shown to have significant beneficial effects on ulcer healing and pain relief on patients with critical limb ischemia, which is given intravenously daily for a period of 2–4 weeks.<cite>66</cite>
If anatomically possible, a revascularization procedure should be attempted in all patients with critical limb ischemia,<cite>65</cite> such as an angioplasty or a  bypass grafting can be done on solitary lesions in large arteries like the femoral artery, but the revascularization may not have sustained benefits. A synthetic prostacyclin (Ilomedin, Iloprost) is the only pharmacological agent so far convincingly shown to have significant beneficial effects on ulcer healing and pain relief on patients with critical limb ischemia, which is given intravenously daily for a period of 2–4 weeks.<cite>66</cite>
{| class="wikitable" border="0" cellpadding="0" cellspacing="0" width="600px"
|-
!colspan="3"|Stroke<cite>34</cite>
|-
|bgcolor="#CCCCFF" colspan="3"|
|-
!Recommendation
!Class<sup>a</sup>
!Level<sup>b</sup>
|-
|For stroke prevention, blood pressure lowering is more important than the choice of drug. Inhibition of the renin–angiotensin–aldosterone system may have additional benefits beyond blood pressure lowering ''per se''
|IIa
|B
|-
|Patients with acute stroke and diabetes should be treated according to the same principles as stroke patients without diabetes
|IIa
|C
|-
|bgcolor="#CCCCFF" colspan="3"|
'''<sup>a</sup>Class of recommendation.'''
'''<sup>b</sup>Level of evidence.'''
|}


Cerebrovascular diseases: Stroke prevention should be based on a multifactorial strategy aimed at the treatment of hypertension, hyperlipidemia, microalbuminuria, hyperglycemia and the use of antiplatelet medications. Antiplatelet therapy reduces the incidence of stroke in diabetic patients and is indicated for both primary and secondary prevention.<cite>67</cite> Low dose Aspirin (75–250 mg daily) should be the initial choice, but in case of intolerance, clopidogrel 75 mg once daily should be given.<cite>68</cite> In patients with recurrent stroke, a combination of aspirin and dipyridamol should be a better option.
Cerebrovascular diseases: Stroke prevention should be based on a multifactorial strategy aimed at the treatment of hypertension, hyperlipidemia, microalbuminuria, hyperglycemia and the use of antiplatelet medications. Antiplatelet therapy reduces the incidence of stroke in diabetic patients and is indicated for both primary and secondary prevention.<cite>67</cite> Low dose Aspirin (75–250 mg daily) should be the initial choice, but in case of intolerance, clopidogrel 75 mg once daily should be given.<cite>68</cite> In patients with recurrent stroke, a combination of aspirin and dipyridamol should be a better option.
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#77 [http://www.who.int/mediacentre/factsheets/fs312/en/index.html World Health Organization (''WHO''), an estimated 347 million people world-wide have  diabetes in 2012]
#77 [http://www.who.int/mediacentre/factsheets/fs312/en/index.html World Health Organization (''WHO''), an estimated 347 million people world-wide have  diabetes in 2012]
#78 pmid=16399854
#78 pmid=16399854
#ESCEADS pmid=23996285
</biblio>
</biblio>
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