Diabetes mellitus type 2


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Diabetes mellitus type 2 is a "subclass of diabetes mellitus that is characterized initially by insulin resistance and hyperinsulinemia; and eventually by glucose intolerance; hyperglycemia; and overt diabetes. Type II diabetes mellitus is no longer considered a disease exclusively found in adults. Patients seldom develop ketosis but often exhibit obesity."

The U.S. Centers for Disease Control and Prevention provides a more expanded description:

Type 2 diabetes was previously called non–insulin-dependent diabetes mellitus (NIDDM) or adult-onset diabetes. In adults, type 2 diabetes accounts for about 90% to 95% of all diagnosed cases of diabetes. It usually begins as insulin resistance, a disorder in which the cells do not use insulin properly. As the need for insulin rises, the pancreas gradually loses its ability to produce it. Type 2 diabetes is associated with older age, obesity, family history of diabetes, history of gestational diabetes, impaired glucose metabolism, physical inactivity, and race/ethnicity. African Americans, Hispanic/Latino Americans, American Indians, and some Asian Americans and Native Hawaiians or Other Pacific Islanders are at particularly high risk for type 2 diabetes and its complications. Type 2 diabetes in children and adolescents, although still rare, is being diagnosed more frequently among American Indians, African Americans, Hispanic/Latino Americans, and Asians/Pacific Islanders. 

Impaired glucose metabolism refers to impaired fasting glucose and impaired glucose tolerance.

Etiology
Diabetes mellitus type 2 is characterized by insulin resistance, high insulin levels, and declining function of insulin-secreting cells of the pancreatic islets (beta-cells).

Diabetes mellitus type 2 is associated with the Metabolic syndrome X (Abdominal obesity-metabolic syndrome).

Genetics
Diabetes mellitus type 2 is genetically heterogeneous and variations are labeled NIDDM2, NIDDM3, NIDDM4.

Maturity-onset diabetes of the young (MODY)
Maturity-onset diabetes of the young (MODY) is "an autosomal dominant form of diabetes typically occurring before 25 years of age and caused by primary insulin secretion defects. Despite its low prevalence, MODY is not a single entity but represents genetic, metabolic, and clinical heterogeneity" Several mutations may cause MODY and these variations are labeled MODY1, MODY2, ... MODY9. Because these mutations may cause diabetes at a later ge and other conditions can cause early diabetes, it has been suggestions to label these mutations "autosomal dominant noninsulin-dependent."

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 ≥ 7.0mmol/l (126mg/dl)
 * or


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

An alternative algorithm that diagnoses diabetes with high sensitivity and specificity:
 * Fasting plasma glucose ≥ 7.0mmol/l (126mg/dl)
 * Diabetes is diagnosed
 * or


 * Glycosylated hemoglobin A (Hb A1c) ≥ 7.0
 * Refer for oral glucose tolerance test

Glycosylated hemoglobin A
A glycosylated hemoglobin A value of ≥ 6.5% may be used to diagnose.

Impaired fasting glucose
Impaired fasting glucose is defined as:
 * Fasting glucose level > 5.6 mmol/l (100 mg/dl) and <  6.9 mmol/l (125mg/dl).

Impaired glucose tolerance
Impaired glucose tolerance is defined as :
 * Two-hour glucose levels of 140 to 199 mg per dL (7.8 to 11.0 mmol) on the 75-g oral glucose tolerance test

Screening and prevention
A cost-benefit analysis suggests that screening should start between age 30 and 45 and be repeated every 3 to 5 years.

US Preventive Services Task Force
Regarding the mass screening for diabetes, in 2008 the US Preventive Services Task Force concluded:
 * "Screen for type 2 diabetes in asymptomatic adults with sustained blood pressure (either treated or untreated) greater than 135/80 mm Hg. (B recommendation)"
 * "Current evidence is insufficient to assess the balance of benefits and harms of routine screening in asymptomatic adults with blood pressure of 135/80 mm Hg or lower. (I statement)"

Screening obese patients may also be beneficial.

In 2003, US Preventive Services Task Force concluded that the benefits are: The USPSTF recommended:
 * In hypertensive patients, identifying diabetes would lower the goal diastolic pressure to ≤ 80 mm Hg.
 * In hypercholesterolemia patients, identifying diabetes would affect decision making due to changes in calculating cardiovascular risk in the ATP3 clinical practice guideline.
 * "The USPSTF recommends screening for type 2 diabetes in adults with hypertension or hyperlipidemia." This was a grade B recommendation
 * "The evidence is insufficient to recommend for or against routinely screening asymptomatic adults for type 2 diabetes, impaired glucose tolerance, or impaired fasting glucose" (italics by CZ), this was a grade I recommendation when published in 2003.

Other practice guidelines
In 2005, an evidence report by the Agency for Healthcare Research and Quality (AHRQ) 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".

The American College of Endocrinology announced in 2008 clinical practice guidelines for the treatment of prediabetes.

Accuracy of tests for early detection
Various testing strategies are available, including a clinical prediction rule.

The fasting plasma glucose > 7.0 mmol/L (126 mg/dL), compared to a 2-hour postload glucose level of at least 11.1 mmol/L (≥ 200 mg/dL) as a reference standard, has :
 * Fasting plasma glucose
 * sensitivity about 50%
 * specificity greater than 95%

A random capillary blood glucose > 6.7 mmol/L (120 mg/dL) has:
 * Random capillary blood glucose
 * sensitivity of 40% to 75%
 * specificity of 93% to 88%

Glycosylated hemoglobin A (Hb A1c) 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 Hb A1c value less than 6% became diabetic within 5 years compared to 282 of 26281 patients with a Hb A1c value of 6.0% or more. This equates to a Hb A1c value of 6.0% or more having:
 * Glycosylated hemoglobin
 * sensitivity = 16.7%
 * specificity = 98.9%

A clinical prediction rule based on age, gender, family medical history, hypertension, body mass index, and physical activity predicted diabetes with accuracy of:
 * Clinical prediction rule
 * sensitivity = 79%
 * specificity = 67%

Remission
In selected patients, dieting to loose approximately 3% of body weight can remit mild, assymptomatic diabetes in approximately 50% of patients according to one trial.

Intensive insulin treatment with a goal of normoglycaemia can cause diabetes in newly diagnosed patients to remit in one of four patients after one year of follow-up. However, there was no control group that did not receive intensive therapy.

Prior uncontrolled cases series have reported similar results.

These studies have been summaried by Retnakaran.

Chronic care of outpatients
For most patients the goal of treatment should be a Hb A1c of 7.0%. Below is a summary of clinical practice guidelines and randomized controlled trials that support this recommendation.

In older patients with life expectancy of less than 5 years, the benefit of achieving a Hb A1c of 7.0% is small.

Practice guidelines
For most patients, clinical practice guidelines recommend a goal Hb A1c of 7.0%.

Previously the American Diabetic Association (ADA) clinical practice guideline suggested a goal of 6.0%: The current ADA recommendation is from a consensus statement of 7% following the results of the trials below that suggest no benefit from goals below 7%.
 * "The A1C goal for patients in general is an A1C goal of <7%."
 * "The A1C goal for the individual patient is an A1C as close to normal (<6%) as possible without significant hypoglycemia."

Clinical practice guidelines by the National Institute for Health and Clinical Excellence recommend starting metformin or a sulfonylurea is Hb A1c is more than 6.5%; however, a thiazolidinedione or insulin should not be added unless the Hb A1c is more than 7.5%. These guidelines have been summarized.

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 8% is appropriate."

Evidence from trials


A goal fasting blood glucose of below 108 mg/dl (6 mmol/L) over 10 years resulting in an Hb A1c of 7% over 10 years was found in the UK Prospective Diabetes Study (UKPDS 33) randomized controlled trial. Intensive control reduced diabetic complications in one out of every 20 patients (number needed to treat = 20).

A goal fasting blood glucose of below 108 mg/dl (6 mmol/L) over 10 years resulting in an Hb A1c of 7.4% over 10.7 years in the metformin group compared to 8.0% in the conventional group in the UK Prospective Diabetes Study (UKPDS 34) randomized controlled trial. Metformin reduced cardiovascular disease in one out of every 11 patients (number needed to treat = 11).

A Hb A1c of 6.9% over 6 years was found in the VA Diabetes Trial (VADT) randomized controlled trial to have no significant effect on diabetic complications. Although the treatment group averaged an Hb A1c of 6.9%, the goal was 6.0%.

A Hb A1c goal of 6.5% over 5 years was found in the ADVANCE randomized controlled trial not to reduce mortality. The intervention group had 0.9% less nephropathy, but more severe hypoglycemia.

A Hb A1c goal of 6% over 3.5 years was found in the ACCORD randomized controlled trial found to increase serious complications.

The older University Group Diabetes Program (UGDP) also found no benefit in a controversial randomized controlled trial. The UGDP randomized approximately 1000 patients to one of five treatment groups and followed from 1962 to 1975: phenformin, tolbutamide, small fixed-dose insulin (ISTD) based on body surface area (averaged 14 units per day), variable-dose insulin (ISTD) (averaged 45 units per day), n (IVAR), or placebo. The trial found statistically significant increase in cardiovascular deaths among the patients treated with tolbutamide and so this group was stopped in 1969. The phenformin group was also stopped early due to increased mortality. The ISTD group had no reduction in blood glucose. The IVAR group had a reduction in the IVAR group of about 2.0 mmol/L (36 mg/dL) which correlates to a 1% difference in the level of Hb A1c. Problems in the trial include: 1) "25% of placebo and tolbutamide-treated subjects dropped out or changed medication during the trial, 2) glucose values were only checked quarterly , 3) smoking history was not measured 4) reduced fraction of males in the IVAR group (IVAR=22%; placebo=31%).

Intensive care
Two clinical practice guidelines are available; however, both of these guidelines were developed without broad representation of stakeholders. This may lead to overly aggressive clinical recommendations.

A clinical practice guideline from the American Association of Clinical Endocrinologists (AACE) recommends the following target blood glucose levels:
 * "Critically ill patients, between 80 to 110 mg/dL (grade A recommendation)"

A clinical practice guideline from the American Diabetes Association (ADA) states
 * "Critically ill patients: blood glucose levels should be kept as close to 110 mg/dl (6.1 mmol/l) as possible and generally <140 mg/dl (7.8 mmol/l). (A) These patients require an intravenous insulin protocol that has demonstrated efficacy and safety in achieving the desired glucose range without increasing risk for severe hypoglycemia. (E)"

Randomized controlled trials of tight glucose control in the critical care and perioperative care settings have produced mixed results. A meta-analysis of trials in the critical care setting concludes there is no benefit to tight control.

Since the meta-analysis, two negative randomized controlled trials have been published.

Non-intensive care
Two clinical practice guidelines are available; however, both of these guidelines were developed without broad representation of stakeholders. This may lead to overly aggressive clinical recommendations.

A clinical practice guideline from the American Association of Clinical Endocrinologists (AACE) recommends the following target blood glucose levels:
 * "Preprandial, less than 110 mg/dL (grade C recommendation)"
 * "Peak postprandial, less than 180 mg/dL (grade B recommendation)"

A clinical practice guideline from the American Diabetes Association (ADA) states
 * "Non–critically ill patients: there is no clear evidence for specific blood glucose goals. Since cohort data suggest that outcomes are better in hospitalized patients with fasting glucose <126 mg/dl and all random glucoses <180–200, these goals are reasonable if they can be safely achieved. Insulin is the preferred drug to treat hyperglycemia in most cases. (E)"
 * "Due to concerns regarding the risk of hypoglycemia, some institutions may consider these blood glucose levels to be overly aggressive for initial targets. Through quality improvement, glycemic goals should systematically be reduced to the recommended levels. (E)"

Older versions (2007) of these clinical practice guidelines were more aggressive regarding non-critically ill patients:
 * "Non-critically ill patients: premeal blood glucose levels should be kept as close to 90 to 130 mg/dL (5.0 to 7.2 mmol/L; midpoint of range 110 mg/dL) as possible given the clinical situation and postprandial blood glucose levels <180 mg/dL. Insulin should be used as necessary. (E)"

Intraoperative care
Regarding intraoperative control of glucose, a [[randomized controlled trial concluded "the increased incidence of death and stroke in the intensive treatment group raises concern about routine implementation of this intervention."

Pediatrics
Lower blood sugars may be beneficial in the intensive care of children.

Self monitoring of blood glucose
It is unclear if self-monitoring of blood glucose improves outcomes among "reasonably well controlled non-insulin treated patients with type 2 diabetes." Self-monitoring may reduce quality of life.

Diet
A low glycemic index diet may reduce the HbA1c.

Sulfonylureas
Sulfonylureas are insulin secretagogues.

Biguanides
Biguanides are insulin sensitizers and include metformin and phenformin.

Thiazolidinediones
Thiazolidinediones (TZDs) are insulin sensitizers and include rosiglitazone, pioglitazone, and troglitazone.

α-glucosidase inhibitors
α-glucosidase inhibitors reduce carbohydrate absorption and include acarbose and miglitol.

Meglitinides
Meglitinides stimulate insulin release. Examples include nateglinide, repaglinide, and their analogs. These are associated with weight gain.

Peptide analogs
In general, these do not cause weight gain.

Incretin therapy can reduce the glycosylated hemoglobin but may increase cancer and pancreatitis.
 * Incretin mimetics. Incretin is an insulin secretagogue.
 * Glucagon-like peptide (GLP) analogs (subcutaneous administration)
 * Exenatide (Byetta®)
 * Liraglutide (Victoza®)
 * Gastric inhibitory peptide (GIP) analogs
 * None are FDA approved
 * Incretin enhancement by dipeptidyl peptidase-4 (DPP-4) inhibitors
 * Sitagliptin (Januvia®) is an oral inhibitor of DPP-4
 * Alogliptin (SYR-322) is an oral inhibitor of DPP-4

Amylin therapy
 * Amylin agonist analog (slows gastric emptying and suppresses glucagon)
 * Pramlintide

Oral drugs
If dietary changes are not successful, medication is needed.

Metformin is usually the first drug according to clinical practice guidelines. Metformin and second-generation sulfonylureas and are excellent choices according to a systematic review of randomized controlled trials. Confirming the role of metformin, 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 of 15% with rosiglitazone, 21% with metformin, and 34% with glyburide." While thiazolidinediones such as rosiglitazone are effective, they may increase drug toxicity such as heart failure and fractures.

For patients with heart failure, metformin may be the best choice.

Insulin regimens
If antidiabetic drugs fail, insulin therapy may be necessary. The initial insulin regimen can be chosen based on the patient's blood glucose profile. When insulin is started, "insulin secretagogues (sulfonylurea or glinides) should be discontinued, or tapered and then discontinued, since they are not considered to be synergistic."

Bedtime insulin
Initially, adding bedtime insulin to patients failing oral medications is more effective and with less weight gain than using multiple dose insulin. Nightly insulin combines better with metformin that 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, multiple by 0.05551 (or divided by 18) to convert to mmol/L.

Multiple dose insulin
When nightly insulin is insufficient, multiple doses are required.

Typical total daily dosage of insulin is 0.6 U/kg with starting doses of 0.25 U/kg. 4 units can be added for each 18 mg/dl over 180 mg/dl. A typical final dose is about 45 units per day. 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])


 * 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 more 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 (http://www.annals.org/cgi/content/full/145/2/125/T4).


 * Long acting insulins such as insulin glargine and insulin detemir (shorter half-life). 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 recent randomized controlled trials have found no differences with glargine. The 4T study reported at 1 year and have found that although long acting insulins were less effective, they were associated with less hypoglycemia. After three years, improved control occurred with the newer insulins with less hypoglycemia.

Treatment of associated diseases
Treating to a goal of LDL-C < 70 mg/dl and systolic blood pressure to < 115 mm Hg may cause regression of carotid initial media thickness in a randomized controlled trial.

Aspirin
Aspirin may not be justified just because a patients had diabetes.

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 : 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.
 * hypertension
 * hypercholesterolemia or reduced low high-density lipoprotein cholesterol levels
 * cigarette smoking
 * microalbuminuria

Hypertension
According to clinical practice guidelines, when treating hypertension in the diabetic patients, the goal blood pressure is 130/80 which is lower than in non-diabetic patients. However, a subsequent randomized controlled trial found no benefit in treating to a level of 120 mm Hg.

Hypercholesterolemia
Various clinical practice guidelines have addressed the treatment of hypercholesterolemia. The American College of Physicians has addressed hypercholesterolemia in patients with diabetes. Their recommendations are:
 * Recommendation 1: Lipid-lowering therapy should be used for secondary prevention of cardiovascular mortality and morbidity for all patients (both men and women) with known coronary artery disease and type 2 diabetes.
 * Recommendation 2: Statins should be used for primary prevention against macrovascular complications in patients (both men and women) with type 2 diabetes and other cardiovascular risk factors.
 * Recommendation 3: Once lipid-lowering therapy is initiated, patients with type 2 diabetes mellitus should be taking at least moderate doses of a statin (the accompanying evidence report states "simvastatin, 40 mg/d; pravastatin, 40 mg/d; lovastatin, 40 mg/d; atorvastatin, 20 mg/d; or an equivalent dose of another statin").
 * Recommendation 4: For those patients with type 2 diabetes who are taking statins, routine monitoring of liver function tests or muscle enzymes is not recommended except in specific circumstances.

Statin therapy prevents major vascular events in about 1 of every 24 patients with [diabetes who use the treatment for 5 years if they are similar to the patients in the meta-analysis by Kearney et al (Number needed to treat is 24).

Treating to a goal of LDL-C < 70 mg/dl and systolic blood pressure to < 115 mm Hg may cause regression of carotid initial media thickness in a randomized controlled trial.

Obesity
Bariatric surgery remits diabetes mellitus type 2 in more than 1 of every two people after 2 years if they are similar to the patients in the randomized controlled trial / meta-analysis by Dixon et al (Number needed to treat is 1.74). In this trial 73% of the patients who remitted their diabetes versus 13% of the patients in the control group.