Diabetes mellitus type 2

Diabetes mellitus type 2–formerly non-insulin-dependent diabetes mellitus (NIDDM) or adult-onset diabetes–is a metabolic disorder that is characterized by high blood glucose in the context of insulin resistance and relative insulin deficiency. Diabetes is often initially managed by increasing exercise and dietary modification. If the condition progresses, medications may be needed. Often affecting the obese, diabetes requires patients to routinely check their blood sugar.

Unlike type 1 diabetes, there is very little tendency toward ketoacidosis although it is not unheard of. One effect that can occur is nonketonic hyperglycemia. Long-term complications from high blood sugar can include increased risk of heart attacks, strokes, amputation, diabetic retinopathy where eye sight is affected, and kidney failure. For extreme cases, circulation of limbs is affected, potentially requiring amputation. Loss of hearing, eyesight, and cognitive ability has also been linked to this condition.

Signs and symptoms
The classic symptoms of diabetes are polyuria (frequent urination), polydipsia (increased thirst), polyphagia (increased hunger), fatigue and weight loss. Type II diabetes has been associated with an increased risk of cognitive dysfunction and dementia through disease processes such as Alzheimer's disease and vascular dementia. Researchers have shown that reduced glucose tolerance has deleterious effects on memory in the elderly, and concomitant hippocampal atrophy.

Cause
Type 2 diabetes is due to a combination of lifestyle and genetic factors. Recently, intrauterine growth restriction (IUGR) or prenatal undernutrition (macro- and micronutrient) was identified as another probable factor A clue for this concept was the Dutch Hunger Winter and the pioneering work of Professor Barker.

Lifestyle
A number of lifestyle factors are known to be important to the development of type 2 diabetes. In one study, those who had high levels of physical activity, a healthy diet, did not smoke, and consumed alcohol in moderation had an 82% lower rate of diabetes. When a normal weight was included, the rate was 89% lower. In this study, a healthy diet was defined as one high in fiber, with a high polyunsaturated to saturated fat ratio, and a lower mean glycemic index. Obesity has been found to contribute to approximately 55% of cases of type 2 diabetes, and decreasing consumption of saturated fats and trans fatty acids while replacing them with unsaturated fats may decrease the risk. The increased rate of childhood obesity between the 1960s and 2000s is believed to have led to the increase in type 2 diabetes in children and adolescents. Dietary fat intake is linked to diabetes risk.

Environmental toxins may contribute to recent increases in the rate of type 2 diabetes. A weak positive correlation has been found between the concentration in the urine of bisphenol A, a constituent of some plastics, and the incidence of type 2 diabetes.

Medical conditions
There are many factors which can potentially give rise to, or exacerbate, type 2 diabetes. These include obesity, hypertension, elevated cholesterol (combined hyperlipidemia), and with the condition often termed metabolic syndrome (it is also known as Syndrome X, Reavan's syndrome, or CHAOS). Other causes include acromegaly, Cushing's syndrome, thyrotoxicosis, pheochromocytoma, chronic pancreatitis, cancer, and drugs. Additional factors found to increase the risk of type 2 diabetes include aging, high-fat diets and a less active lifestyle.

Subclinical Cushing's syndrome (cortisol excess) may be associated with type 1 diabetes. The percentage of subclinical Cushing's syndrome in the diabetic population is about 9%. Diabetic patients with a pituitary microadenoma can improve insulin sensitivity by removal of these microadenomas.

Hypogonadism is often associated with cortisol excess, and testosterone deficiency is also associated with type 2 diabetes, even if the exact mechanism by which testosterone improves insulin sensitivity is still not known.

Genetics
There is also a strong inheritable genetic connection in type 2 diabetes: having relatives (especially first degree) with type 2 increases risks of developing type 2 diabetes substantially. In addition, there is also a mutation to the Islet Amyloid Polypeptide gene that results in an earlier onset, more severe, form of diabetes.

About 55 percent of type 2 diabetes patients are obese at diagnosis —chronic obesity leads to increased insulin resistance that can develop into type 2 diabetes, most likely because adipose tissue (especially that in the abdomen around internal organs) is a source of several chemical signals, hormones and cytokines, to other tissues. Inflammatory cytokines for example may activate the NF-κB pathway which has been linked to the development of insulin resistance.

Other research shows that type 2 diabetes causes obesity as an effect of the changes in metabolism and other deranged cell behavior attendant on insulin resistance.

However, environmental factors (almost certainly diet and weight) play a large part in the development of type 2 diabetes in addition to any genetic component. This can be seen from the adoption of the type 2 diabetes epidemiological pattern in those who have moved to a different environment as compared to the same genetic pool who have not. Immigrants to Western developed countries, for instance, as compared to lower incidence countries of origins. Such developments can also be found in environments which have had a recent increase in social wealth, increasingly common throughout Asia.

There is a stronger inheritance pattern for type 2 diabetes. Those with first-degree relatives with type 2 diabetes have a much higher risk of developing type 2 diabetes, increasing with the number of those relatives. Concordance among monozygotic twins is close to 100%, and about 25% of those with the disease have a family history of diabetes. Genes significantly associated with developing type 2 diabetes, include TCF7L2, PPARG, FTO, KCNJ11, NOTCH2, WFS1, CDKAL1, IGF2BP2, SLC30A8, JAZF1, and HHEX. KCNJ11 (potassium inwardly rectifying channel, subfamily J, member 11), encodes the islet ATP-sensitive potassium channel Kir6.2, and TCF7L2 (transcription factor 7–like 2) regulates proglucagon gene expression and thus the production of glucagon-like peptide-1. Moreover, obesity (which is an independent risk factor for type 2 diabetes) is strongly inherited.

Monogenic forms, e.g., MODY, constitute 1–5 % of all cases.

Various hereditary conditions may feature diabetes, for example myotonic dystrophy and Friedreich's ataxia. Wolfram's syndrome is an autosomal recessive neurodegenerative disorder that first becomes evident in childhood. It consists of diabetes insipidus, diabetes mellitus, optic atrophy, and deafness, hence the acronym DIDMOAD.

Gene expression promoted by a diet of fat and glucose, as well as high levels of inflammation related cytokines found in the obese, results in cells that "produce fewer and smaller mitochondria than is normal," and are thus prone to insulin resistance.

Pathophysiology
Insulin resistance means that body cells do not respond appropriately when insulin is present.

This is a more complex problem than type 1, but is sometimes easier to treat, especially in the early years when insulin is often still being produced internally. Severe complications can result from improperly managed type 2 diabetes, including renal failure, erectile dysfunction, blindness, slow healing wounds (including surgical incisions), and arterial disease, including coronary artery disease. The onset of type 2 diabetes has been most common in middle age and later life, although it is being more frequently seen in adolescents and young adults due to an increase in child obesity and inactivity. A type of diabetes called MODY is increasingly seen in adolescents, but this is classified as a diabetes due to a specific cause and not as type 2 diabetes.

In the 2008 Banting Lecture of the American Diabetes Association, DeFronzo enumerates eight main pathophysiological factors in the type 2 diabetic organism

Diabetes mellitus with a known etiology, such as secondary to other diseases, known gene defects, trauma or surgery, or the effects of drugs, is more appropriately called secondary diabetes mellitus or diabetes due to a specific cause. Examples include diabetes mellitus such as MODY or those caused by hemochromatosis, pancreatic insufficiencies, or certain types of medications (e.g., long-term steroid use).

Recent studies of pancreatic beta cells have indicated a molecular connection between diet, obesity that involves the role of fat in activating a pathway to type 2 diabetes. In this mechanism, loss of beta cell glucose sensing contributes substantially to the early manifestation of diabetes, and beta cell dysfunction is responsible for the onset and severity of multiple systemic disease signs including impaired glucose tolerance, hyperglycemia, hepatic steatosis and insulin resistance in muscle and adipose cells. Previous work published in past decades by the laboratories of Roger Unger, Jerrold Olefsky, and Bernard Thorens alluded to the possibility of the importance of beta cell function and glucose sensing in these disease signs. This mechanism of beta cell dysfunction may be contributing substantially to the current epidemic of type 2 diabetes.

Diagnosis
The World Health Organization definition of diabetes is for a single raised glucose reading with symptoms, otherwise raised values on two occasions, of either:
 * fasting plasma glucose ≥ 7.0 mmol/l (126 mg/dl)
 * or


 * With a glucose tolerance test, two hours after the oral dose a plasma glucose ≥ 11.1 mmol/l (200 mg/dl)

Early detection
If a 2-hour postload glucose level of at least 11.1 mmol/L (≥ 200 mg/dL) is used as the reference standard, the fasting plasma glucose > 7.0 mmol/L (126 mg/dL) diagnoses current diabetes with :
 * sensitivity about 50%
 * specificity greater than 95%

A random capillary blood glucose > 6.7 mmol/L (120 mg/dL) diagnoses current diabetes with :
 * sensitivity = 75%
 * specificity = 88%

Glycated hemoglobin values that are elevated (over 5%), but not in the diabetic range (not over 7.0%) are predictive of subsequent clinical diabetes in United States female health professionals. In this study, 177 of 1061 patients with glycated hemoglobin value less than 6% became diabetic within 5 years compared to 282 of 26281 patients with a glycated hemoglobin value of 6.0% or more. This equates to a glycated hemoglobin value of 6.0% or more having:
 * sensitivity = 16.7%
 * specificity = 98.9%

Screening
No major organization recommends universal screening for diabetes as there is no evidence that such a program would improve outcomes. Screening is recommended by the United States Preventive Services Task Force in adults without symptoms whose blood pressure is greater than 135/80 mmHg. For those whose blood pressure is less, the evidence is insufficient to recommend for or against screening. The World Health Organization recommends only testing those groups at high risk. Based on a survey conducted in 2011 on 70,000 average persons, the Hungarian Diabetes Society recommends the introduction of a general screening of the adult population for Diabetes Type II.

Prevention
Onset of type 2 diabetes can be delayed or prevented through proper nutrition and regular exercise. Intensive lifestyle measures may reduce the risk by over half. Evidence for the benefit of dietary changes alone however is limited. In those with impaired glucose tolerance, diet and exercise and/or metformin or acarbose may decrease the risk of developing diabetes. Lifestyle interventions are more effective than metformin.

Management
Management of type 2 diabetes focuses on lifestyle interventions, lowering other cardiovascular risk factors, and maintaining blood glucose levels in the normal range. Self-monitoring of blood glucose for people with newly diagnosed type 2 diabetes was recommended by the National Health Services in 2008 however the benefit of self monitoring in those not using multi-dose insulin is questionable. Managing other cardiovascular risk factors including hypertension, high cholesterol, and microalbuminuria improves a person's life expectancy. Intensive blood sugar lowering as opposed to standard blood sugar lowering does not appear to change mortality.

Lifestyle
Aerobic exercise is beneficial in diabetes with a greater amount of exercise yielding better results. It leads to a decrease in HbA1C, improved insulin sensitivity, and a better V02 max. Resistance training is also useful and the combination of both types of exercise may be most effective. A diabetic diet that promotes weight loss is important. While the best diet type to achieve this is controversial a low glycemic index diet has been found to improve blood sugar control. Culturally appropriate education may help people with type 2 diabetes control their blood sugar levels, for up to six months at least.

Medications


There are several classes of medications available. Metformin is generally recommended as a first line treatment as there is good evidence that it decreases mortality. Injections of insulin may either be added to oral medication or used alone. Other classes of medications used to treat type 2 diabetes are sulfonylureas, nonsulfonylurea secretagogues, alpha glucosidase inhibitors, and thiazolidinediones.

Insulin
When insulin is used, a long-acting formulation is usually added initially, while continuing oral medications. Doses of insulin are increased to effect.

The initial insulin regimen is often chosen based on the patient's blood glucose profile. Initially, adding nightly insulin to patients failing oral medications may be best. Nightly insulin combines better with metformin than with sulfonylureas.

When nightly insulin is insufficient, choices include:
 * Premixed insulin with a fixed ratio of short and intermediate acting insulin; this tends to be more effective than long acting insulin, but is associated with increased hypoglycemia.  Initial total daily dosage of biphasic insulin can be 10 units if the fasting plasma glucose values are less than 180 mg/dl or 12 units when the fasting plasma glucose is above 180 mg/dl". A guide to titrating fixed ratio insulin is available.
 * Long acting insulins include insulin glargine and insulin detemir. A meta-analysis of randomized controlled trials by the Cochrane Collaboration found "only a minor clinical benefit of treatment with long-acting insulin analogues for patients with diabetes mellitus type 2". More recently, a randomized controlled trial found that although long acting insulins were less effective, they were associated with reduced hypoglycemic episodes.

Surgery
Gastric Bypass procedures are currently considered an elective procedure with no universally accepted algorithm to decide who should have the surgery. In the diabetic patient, certain types result in 99-100% prevention of insulin resistance and 80-90% clinical resolution or remission of type 2 diabetes. In 1991, the NIH (National Institutes of Health) Consensus Development Conference on Gastrointestinal Surgery for Obesity proposed that the body mass index (BMI) threshold to consider surgery should drop from 40 to 35 in the appropriate patient. More recently, the American Society for Bariatric Surgery (ASBS) and the ASBS Foundation suggested that the BMI threshold be lowered to 30 in the presence of severe co-morbidities. Debate has flourished about the role of gastric bypass surgery in type 2 diabetics since the publication of The Swedish Obese Subjects Study. The largest prospective series showed a large decrease in the occurrence of type 2 diabetes in the post-gastric bypass patient at both 2 years (odds ratio was 0.14) and at 10 years (odds ratio was 0.25).

A study of 20-years of Greenville (US) gastric bypass patients found that 80% of those with type 2 diabetes before surgery no longer required insulin or oral agents to maintain normal glucose levels. Weight loss occurred rapidly in many people in the study who had had the surgery. The 20% who did not respond to bypass surgery were, typically, those who were older and had had diabetes for over 20 years.

Progression
The way type 2 diabetes is managed may change with age. Insulin production decreases because of age-related impairment of pancreatic beta cells. Additionally, insulin resistance increases because of the loss of lean tissue and the accumulation of fat, particularly intra-abdominal fat, and the decreased tissue sensitivity to insulin. Glucose tolerance progressively declines with age, leading to a high prevalence of type 2 diabetes and postchallenge hyperglycemia in the older population. Age-related glucose intolerance is often accompanied by insulin resistance, but circulating insulin levels are similar to those of younger people. Treatment goals for older patients with diabetes vary with the individual, and take into account health status, as well as life expectancy, level of dependence, and willingness to adhere to a treatment regimen.

Prognosis
Even if properly and carefully managed, type 2 diabetes is currently a chronic disease, which is, in most cases, compatible with an otherwise full life. Some cases, for reasons obscure, cannot be reasonably managed and lead to damage or even death sooner than later. Non-compliance with management is a contributor in some cases (unwillingness to monitor blood glucose, take prescribed medication, or reliance on unusual or exotic treatment regimes without credible track record), but not all. Much of the damage is due to the complications of diabetes, not directly to diabetes' acute effects. For example, in the developed world, and increasingly elsewhere, type 2 diabetes is the largest cause of non-traumatic blindness and kidney failure.

Research continues and several potential treatments may result in "cures". Examples include resection surgery of the upper small intestine, and very stringent restricted calorie diets. None is, as of 2011, sufficiently well understood, or adequately tested, to be of clinical significance. One or more might, possibly, become clinically significant for some cases, or even all, but this is some years away in the most fortunate instance.

Epidemiology
Globally in 2003 it was estimated that there were 150 million people with type 2 diabetes. The incidence varies substantially in different parts of the world, almost certainly because of environmental and lifestyle factors, though these are not known in detail. In the United States there are 23.6 million people (7.8% of the population) with diabetes with 17.9 million being diagnosed, 90% of whom are type 2. With prevalence rates doubling between 1990 and 2005, CDC has characterized the increase as an epidemic. Traditionally considered a disease of adults, type 2 diabetes is increasingly diagnosed in children in parallel to rising obesity rates due to alterations in dietary patterns as well as in life styles during childhood.