Diabetes mellitus type 2 or type 2 diabetes (formerly called non-insulin-dependent diabetes mellitus (NIDDM), or adult-onset diabetes) is a disorder that is characterized by high blood glucose in the context of insulin resistance and relative insulin deficiency. While it is often initially managed by increasing exercise and dietary modification, medications are typically needed as the disease progresses. There are an estimated 23.6 million people in the U.S. (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.

Unlike type 1 diabetes, there is very little tendency toward ketoacidosis in type 2 diabetes, though it is not unknown. One effect that can occur is nonketonic hyperglycemia which also is quite dangerous, though it must be treated very differently. Complex and multifactorial metabolic changes very often lead to damage and function impairment of many organs, most importantly the cardiovascular system in both types. This leads to substantially increased morbidity and mortality in both type 1 and type 2 patients, but the two have quite different origins and treatments despite the similarity in complications.

Pathophysiology

Insulin resistance means that body cells do not respond appropriately when insulin is present. Unlike type 1 diabetes mellitus, insulin resistance is generally "post-receptor", meaning it is a problem with the cells that respond to insulin rather than a problem with the production of insulin.

Other important contributing factors:

• increased hepatic glucose production (e.g., from glycogen -> glucose conversion), especially at inappropriate times (typical cause is deranged insulin levels, as those levels control this function in liver cells)
• decreased insulin-mediated glucose transport in (primarily) muscle and adipose tissues (receptor and post-receptor defects)
• impaired beta-cell function—loss of early phase of insulin release in response to hyperglycemic stimuli

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. Type 2 may go unnoticed for years before diagnosis, since symptoms are typically milder (eg, no ketoacidosis, coma, etc) and can be sporadic. However, 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 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.

Diabetes mellitus type 2 is of unknown etiology (i.e., origin). 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).

According to CDC, about 23.613 million people in the United States, or 8% of the population, have diabetes. The total prevalence of diabetes increased 13.5% from 2005-2007. It is thought that only 24% of diabetes is now undiagnosed, down from an estimated 30% in 2005 and from the previously estimated 50% in ca 1995.

About 90–95% of all North American cases of diabetes are type 2, and about 20% of the population over the age of 65 has diabetes mellitus type 2. The fraction of type 2 diabetics in other parts of the world varies substantially, almost certainly for environmental and lifestyle reasons, though these are not known in detail. Diabetes affects over 150 million people worldwide and this number is expected to double by 2025. 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 very 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 are obese —chronic obesity leads to increased insulin resistance that can develop into diabetes, most likely because adipose tissue (especially that in the abdomen around internal organs) is a (recently identified) source of several chemical signals to other tissues (hormones and cytokines). 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, genetics play a relatively small role in the widespread occurrence of type 2 diabetes. This can be logically deduced from the huge increase in the occurrence of type 2 diabetes which has correlated with the significant change in western lifestyle.

Diabetes mellitus type 2 is often associated with 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). Secondary causes of Diabetes mellitus type 2 are: acromegaly, Cushing's syndrome, thyrotoxicosis, pheochromocytoma, chronic pancreatitis, cancer and drugs.

Drug induced hyperglycemia:

• Atypical Antipsychotics - Alter receptor binding characteristics, leading to increased insulin resistance.
• Beta-blockers - Inhibit insulin secretion.
• Calcium Channel Blockers - Inhibits secretion of insulin by interfering with cytosolic calcium release.
• Corticosteroids - Cause peripheral insulin resistance and gluconeogensis.
• Fluoroquinolones - Inhibits insulin secretion by blocking ATP sensitive potassium channels.
• Naicin - They cause increased insulin resistance due to increased free fatty acid mobilization.
• Phenothiazines - Inhibit insulin secretion.
• Protease Inhibitors - Inhibit the conversion of proinsulin to insulin.
• Thiazide Diuretics - Inhibit insulin secretion due to hypokalemia. They also cause increased insulin resistance due to increased free fatty acid mobilization.

Additional factors found to increase risk of type 2 diabetes include aging, high-fat diets and a less active lifestyle..

Symptoms

• Early symptoms may be nothing more than chronic fatigue, generalised weakness and malaise (feeling of unease)
• Excessive urine production
• Excessive thirst and increased fluid intake
• Blurred vision (typically from lens shape alterations, due to osmotic effects, e.g., high blood glucose levels)
• Unexplained weight loss
• Lethargy
• Itching of external genitalia

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)

Screening and prevention

Prevention

Onset of type 2 diabetes can often be delayed through proper nutrition and regular exercise.

Interest has arisen in preventing diabetes due to research on the benefits of treating patients before overt diabetes. Although the U.S. Preventive Services Task Force concluded that "the evidence is insufficient to recommend for or against routinely screening asymptomatic adults for type 2 diabetes, impaired glucose tolerance, or impaired fasting glucose," this was a grade I recommendation when published in 2003. However, the USPSTF does recommend screening for diabetics in adults with hypertension or hyperlipidemia ( grade B recommendation).

In 2005, an evidence report by the Agency for Healthcare Research and Quality concluded that "there is evidence that combined diet and exercise, as well as drug therapy (metformin, acarbose), may be effective at preventing progression to DM in IGT subjects".

Milk has also been associated with the prevention of diabetes. A questionnaire study was done by Choi et al. of 41,254 men which including a 12 year follow up showed this association. In this study, it was found that diets high in low-fat dairy might lower the risk of type 2 diabetes in men. Even though these benefits are being considered linked to milk consumption, the effect of diet is only one factor that is affecting the body’s overall health.

Accuracy of tests for 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%

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

• sensitivity = 16.7%
• specificity = 98.9%

Benefit of early detection

Since publication of the USPSTF statement, a randomized controlled trial of prescribing acarbose to patients with "high-risk population of men and women between the ages of 40 and 70 years with a body mass index (BMI), calculated as weight in kilograms divided by the square of height in meters, between 25 and 40. They were eligible for the study if they had IGT according to the World Health Organization criteria, plus impaired fasting glucose (a fasting plasma glucose concentration of between 100 and 140 mg/dL or 5.5 and 7.8 mmol/L) found a number needed to treat of 44 (over 3.3 years) to prevent a major cardiovascular event.

Other studies have shown that lifestyle changes, xenical and metformin can delay the onset of diabetes.

Treatment

Diabetes mellitus type 2 is a chronic, progressive disease that has no established cure, but does have well-established treatments which can delay or prevent entirely the formerly inevitable consequences of the condition. Often, the disease is viewed as progressive since poor management of blood sugar leads to a myriad of steadily worsening complications. However, if blood sugar is properly maintained, then the disease is effectively cured - that is, patients are at no heightened risk for neuropathy, blindness, or any other high blood sugar complication. There are two main goals of treatment:

1. reduction of mortality and concomitant morbidity (from assorted diabetic complications)
2. preservation of quality of life

The first goal can be achieved through close glycemic control (i.e., to near 'normal' blood glucose levels); the reduction in severity of diabetic side effects has been very well demonstrated in several large clinical trials and is established beyond controversy. The second goal is often addressed (in developed countries) by support and care from teams of diabetic health workers (usually physician, PA, nurse, dietitian or a certified diabetic educator). Endocrinologists, family practitioners, and general internists are the physician specialties most likely to treat people with diabetes. Knowledgeable patient participation is vital to clinical success, and so patient education is a crucial aspect of this effort.

Type 2 is initially treated by adjustments in diet and exercise, and by weight loss, most especially in obese patients. The amount of weight loss which improves the clinical picture is sometimes modest (2–5 kg or 4.4-11 lb); this is almost certainly due to currently poorly understood aspects of fat tissue activity, for instance chemical signaling (especially in visceral fat tissue in and around abdominal organs). In many cases, such initial efforts can substantially restore insulin sensitivity. In some cases strict diet can adequately control the glycemic levels.

Treatment goals

Treatment goals for type 2 diabetic patients are related to effective control of blood glucose, blood pressure and lipids to minimize the risk of long-term consequences associated with diabetes. They are suggested in clinical practice guidelines released by various national and international diabetes agencies.

The targets are:

• Hb_A1c of 6% to 7.0%
• Preprandial blood glucose: 4.0 to 6.0 mmol/L (72 to 108 mg/dl)
• 2-hour postprandial blood glucose: 5.0 to 8.0 mmol/L (90 to 144 mg/dl)

In older patients, clinical practice guidelines by the American Geriatrics Society states "for frail older adults, persons with life expectancy of less than 5 years, and others in whom the risks of intensive glycemic control appear to outweigh the benefits, a less stringent target such as [Hb_A1c of] 8% is appropriate".

Self monitoring of blood glucose

Self-monitoring of blood glucose may not improve outcomes in some cases, that is among "reasonably well controlled non-insulin treated patients with type 2 diabetes". Nevertheless, it is very strongly recommended for patients in whom it can assist in maintaining proper glycemic control, and is well worth the cost (sometimes considerable) if it does. It is the only source of current information on the glycemic state of the body, as changes are rapid and frequent, depending on food, exercise, and medication (dosage and timing with respect to both diet and exercise), and secondarily, on time of day, stress (mental and physical), infection, etc.

The National Institute for Health and Clinical Excellence (NICE), UK released updated diabetes recommendations on 30 May 2008. They indicate that self-monitoring of blood glucose levels for people with newly diagnosed type 2 diabetes should be part of a structured self-management education plan. However, a recent study found that a treatment strategy of intensively lowering blood sugar levels (below 6%) in patients with additional cardiovascular disease risk factors poses more harm than benefit, and so there appear to be limits to benefit of intensive blood glucose control in some patients.

Dietary management

Modifying the diet to limit and control glucose (or glucose equivalent, e.g., starch) intake, and in consequence, blood glucose levels, is known to assist type 2 patients, especially early in the course of the disease's progression. Additionally, weight loss is recommended and is often helpful in persons suffering from type 2 diabetes for the reasons discussed above.

Several dietary modifications using dietary supplements are sometimes recommended to those with type 2; there are studies suggesting that there is some beneficial effect for some of these. See the discussion below.

Self management

Diabetes self-management education is an integral component of medical care. Among adults with diagnosed diabetes, 12% take both insulin and oral medications,19% take insulin only, 53% take oral medications only, and 15% do not take either insulin or oral medications.

Traditionally, information regarding diabetes would be obtained from a family physician. However, with access to the internet so widely available now, people are able to educate themselves through websites. This information can be beneficial, but care must be taken to ensure the information is medically sound. Several of the external links below provide information about diabetes and its management, including self-management.

Exercise

In September 2007, a joint randomized controlled trial by the University of Calgary and the University of Ottawa found that "Either aerobic or resistance training alone improves glycemic control in type 2 diabetes, but the improvements are greatest with combined aerobic and resistance training than either alone." The combined program reduced the HbA1c by 0.5 percentage point. Other studies have established that the amount of exercise needed is not large or extreme, but must be consistent and continuing. Examples might include a brisk 45 minute walk every other day.

Theoretically, exercise does have benefits in that exercise would stimulate the release of certain ligands that cause GLUT4 to be released from internal endosomes to the cell membrane. Insulin though, which no longer works effectively in those afflicted with type 2 diabetes, causes GLUT1 to be placed into the membrane. Though they have different structures, they both perform the same function of increasing intake of glucose into the cell from the blood serum . Exercise also allows for the uptake of glucose independently of insulin, ie by adrenaline .

Antidiabetic drugs

There are several drugs available for type 2 diabetics—most are unsuitable or even dangerous for use by type 1 diabetics. They fall into several classes and are not equivalent, nor can they be simply substituted one for another. All are prescription drugs.

One of the most widely used drugs now used for type 2 diabetes is the biguanide metformin; it works primarily by reducing liver release of blood glucose from glycogen stores and secondarily by provoking some increase in cellular uptake of glucose in body tissues. Both historically, and currently, the most commonly used drugs are in the Sulfonylurea group, of which several members (including glibenclamide and gliclazide) are widely used; these increase glucose stimulated insulin secretion by the pancreas and so lower blood glucose even in the face of insulin resistance.

Newer drug classes include:

• Testosterone treatment is very efficient to reduce insulin resistance without digestive problems (a very common side effect of other anti-diabetes drugs)
• Thiazolidinediones (TZDs) (rosiglitazone, pioglitazone, and troglitazone -- the last, as Rezulin, was withdrawn from the US market because of an increased risk of systemic acidosis). These increase tissue insulin sensitivity by affecting gene expression
• α-glucosidase inhibitors (acarbose and miglitol) which interfere with absorption of some glucose containing nutrients, reducing (or at least slowing) the amount of glucose absorbed
• Meglitinides which stimulate insulin release (nateglinide, repaglinide, and their analogs) quickly; they can be taken with food, unlike the sulfonylureas which must be taken prior to food (sometimes some hours before, depending on the drug)
• Peptide analogs which work in a variety of ways:
  • Incretin mimetics which increase insulin output from the beta cells among other effects. These includes the Glucagon-like peptide (GLP) analog exenatide, sometimes referred to as lizard spit as it was first identified in Gila monster saliva
  • Dipeptidyl peptidase-4 inhibitors increase Incretin levels (sitagliptin) by decreasing their deactivation rates
  • Amylin agonist analog, which slows gastric emptying and suppresses glucagon (pramlintide)

Oral drugs

Diabetes mellitus type 2 is tightly associated with hypogonadism.

A systematic review of randomized controlled trials found that metformin and second-generation sulfonylureas are the preferred choices for most with type 2 diabetes, especially those early in the course of the disease. Failure of response after a time is not unknown with most of these agents: the initial choice of anti-diabetic drug has been compared in a randomized controlled trial which found "cumulative incidence of monotherapy failure at 5 years to be 15% with rosiglitazone, 21% with metformin, and 34% with glyburide". Of these, rosiglitazone users showed more weight gain and edema than did non-users. Rosiglitazone may increase risk of death from cardiovascular causes though the causal connection is unclear.

Pioglitazone and rosiglitazone may also increase the risk of fractures.



For patients who also have heart failure, metformin may be the best tolerated drug.

The variety of available agents can be confusing, and the clinical differences among type 2 diabetics compounds the problem. At present, choice of drugs for type 2 diabetics is rarely straightforward and in most instances has elements of repeated trial and adjustment.

Injectable peptide analogs

DPP-4 inhibitors lowered A1c by 0.74%, comparable to other antidiabetic drugs. GLP-1 analogs resulted in weight loss and had more gastrointestinal side effects, while DPP-4 inhibitors were weight neutral and increased risk for infection and headache, but both classes appear to present an alternative to other antidiabetic drugs.

Insulin preparations

If antidiabetic drugs fail (ie, the clinical benefit stops), insulin therapy may be necessary – usually in addition to oral medication therapy – to maintain normal or near normal glucose levels.

Typical total daily dosage of insulin is 0.6 U/kg. But, of course, best timing and indeed total amounts depend on diet (composition, amount, and timing) as well the degree of insulin resistance. More complicated estimations to guide initial dosage of insulin are:

• For men, [(fasting plasma glucose [mmol/liter]–5)x2] x (weight [kg]÷(14.3xheight [m])–height [m])
• For women, [(fasting plasma glucose [mmol/liter]–5)x2] x (weight [kg]÷(13.2xheight [m])–height [m])

The initial insulin regimen are 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. The initial dose of nightly insulin (measured in IU/d) should be equal to the fasting blood glucose level (measured in mmol/L). If the fasting glucose is reported in mg/dl, multiply by 0.05551 to convert to mmol/L.

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 such as 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.
• Insulin Pump therapy in Type 2 diabetes is gradualy becoming popular.In an original published study, in addition to reduction of blood sugars, there is evidence of profound benefits in resistant neuropathic pain and also improvements in sexual performance.

Antihypertensive agents

The goal blood pressure is 130/80 which is lower than in non-diabetic patients.

ACE inhibitors

The HOPE study suggests that diabetics should be treated with ACE inhibitors (specifically ramipril 10 mg/d) if they have one of the following :

• hypertension
• hypercholesterolemia or reduced low high-density lipoprotein cholesterol levels
• cigarette smoking
• microalbuminuria

After treatment with ramipril for 5 years the number needed to treat was 50 patients to prevent one cardiovascular death. Other ACE inhibitors may not be as effective.

Hypolipidemic agents

Gastric bypass 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 Institute 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. More 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.

In January 2008, The Journal of the American Medical Association (JAMA) published the first randomized controlled trial comparing the efficacy of laparoscopic adjustable gastric banding against conventional medical therapy in the obese patient with type 2 diabetes. Laparoscopic Adjustable Gastric Banding results in remission of type 2 diabetes among affected patients diagnosed within the previous two years according to a randomized controlled trial. The relative risk reduction was 69.0%. For patients at similar risk to those in this study (87.0% had type 2), this leads to an absolute risk reduction of 60%. 1.7 patients must be treated for one to benefit (number needed to treat = 1.7). Click here to adjust these results for patients at higher or lower risk of type 2 diabetics.

These results have not yet produced a clinical standard for surgical treatment of diabetic patients, as the mechanism, if any, is currently obscure. Surgical cure of Type 2 diabetes must be, as a result, considered currently experimental.

See also

• Low glycemic index diet
• Low carb diet
• Diabetic diet
• Dipeptidyl peptidase-4 inhibitors and their development

References

1. Robbins and Cotran, Pathologic Basis of Disease, 7th Ed. pp 1194-1195.
2. American Diabetes Association title =Total Prevalence of Diabetes and Pre-diabetes url =http://www.diabetes.org/diabetes-statistics/prevalence.jsp | accessdate =2008-11-29
3. Inzucchi SE, Sherwin RS, The Prevention of Type 2 Diabetes Mellitus. Endocrinol Metab Clin N Am 34 (2205) 199-219.
4. Diabetes rates are increasing among youth NIH, November 13, 2007
5. Steinberger J, Moran A, Hong CP, Jacobs DR Jr, Sinaiko AR: Adiposity in childhood predicts obesity and insulin resistance in young adulthood. J Pediatr 138:469–473, 2001
6. Cotran, Kumar, Collins; Robbins Pathologic Basis of Disease, Saunders Sixth Edition, 1999; 913-926.
7. [[cite journal |author = Choi HK, Willett WC, Stampfer P, Vasson MP, Maubois JL, Beaufrere B |title = Dairy consumption and risk of type 2 diabetes mellitus in men |journal = Archives of Internal Medicine |volume = 165 |pages = 997-1003 |year = 2005 |accessdate = 2009-10-29 }}
8. http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2007.pdf
9. Non-technical summary
10. Bolen S et al. Systematic Review: Comparative Effectiveness and Safety of Oral Medications for Type 2 Diabetes Mellitus. Ann Intern Med 2007;147:6
11. Gastric Bypass Surgery - Diabetes Health

External links

Organizations

• IDF Diabetes Atlas
• International Diabetes Federation
• World Diabetes Day (International Diabetes Federation)
• Diabetes UK - Largest organisation in the UK working for people with diabetes
• American Diabetes Association

Authorities

• National Diabetes Information Clearinghouse
• Centers for Disease Control (Endocrine pathology)

Further reading

• Diabetes Symptoms Revisited: Are They Too Vague and Too Late?
• ABC Radio National transcript on hypothesised aetiology involving gut hormone
• Does what we eat manage Type 2 Diabetes effectively?