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 slightly 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. 

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).

Insulin resistance (HOMA-IR) can be measured by:
 * $$\text{HOMA-IR} = \frac{\text{fasting plasma glucose} * \text{fasting insulin}}{22.5}$$

Beta cell function (HOMA-B) can be measured by:
 * $$\text{HOMA-IR} = \frac{20 * \text{fasting insulin}}{\text{fasting plasma glucose} - 3.5}$$

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 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

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
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.

Prior guidelines
In 2003, US Preventive Services Task Force concluded:
 * "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.

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%

Benefit of early detection
According to the US Preventive Services Task Force, the benefits are:
 * 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 American College of Endocrinology recently announced guidelines for the treatment of prediabetes.

Since publication of the USPSTF statement, a randomized controlled trial of prescribing acarbose to patients who do not have overt diabetes, but are a "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.

Subsequently 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".

Life-style changes can delay the onset of diabetes. Life-style changes can reduce cardiovascular risk factors.

Metformin can improve "weight, lipid profiles, and insulin resistance, and reduces new-onset diabetes by 40%." according to a meta-analysis. The meta-analysis also concluded that "the long-term effect on morbidity and mortality should be assessed in future trials." This meta-analysis includes an earlier randomized controlled trial that found that metformin can delay the onset of diabetes.

The DREAM study has reported that rosiglitazone but not ramipril can delay the onset of diabetes. Although the DREAM study performed carotid ultrasounds on 20% of patients, these results have not been reported.

Remission
An initial randomized controlled trial found that intensive insulin treatment with a goal of normoglycaemia can cause diabetes to remit in one of four patients after one year of follow-up.

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.

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 a goal Hb A1c of 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 Hb A1c goal of 7% over 10 years was found in the UK Prospective Diabetes Study (UKPDS 33) randomized controlled trial to reduce diabetic complications in one out of every 20 patients (number needed to treat = 20).

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.

Practice guidelines
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)"
 * "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)"
 * "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)"

Evidence from trials
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.
 * Adults

Since the meta-analysis, an additional negative randomized controlled trial has been published.

Regarding surgical patients in a critical care setting, a large randomized controlled trial (1548 patients) concluded "intensive insulin therapy to maintain blood glucose at or below 110 mg per deciliter reduces morbidity and mortality among critically ill patients in the surgical intensive care unit." However, other trials have not found this benefit according to a meta-analysis. This trial has been criticized for the following reasons:
 * 1) "The trial was stopped early for an unexpectedly large treatment effect, which can overestimate the efficacy of treatment or result in a false-positive finding;"
 * 2) "The relative reduction in mortality for a decrease of 50 mg/dL in morning glucose levels seems biologically implausible and exceeds that for any other intervention in critically ill patients;"
 * 3) "The mortality rate in the control group was much higher than that noted in tertiary care medical centers in the United States. On admission to the ICU, all patients received 200 to 300 g/d of intravenous dextrose followed by enteral or parenteral nutrition, an unusual practice considering the deleterious effects of parenteral nutrition; at least in part, the difference in outcomes between the 2 arms in this study might have reflected the harm of maintaining the control group as hyperglycemic rather than the benefit of strict glucose control in the intervention group."

Regarding medical patients in a critical care setting, a large randomized controlled trial that compared a goal blood glucose level of 80 to 110 mg per deciliter (4.4 to 6.1 mmol per liter) to a goal blood glucose level of between 180 and 200 mg per deciliter (10 and 11 mmol per liter) concluded "intensive insulin therapy significantly reduced morbidity but not mortality among all patients in the medical ICU. Although the risk of subsequent death and disease was reduced in patients treated for three or more days, these patients could not be identified before therapy." Tight control may protect renal function.

Among medical patients with septic shock, intensive insulin therapy and pentastarch increased adverse events in a randomized controlled trial.

A meta-analysis was published in 2006 that did not include the two trials above that were published later that did not reduce mortality. This meta-analysis concluded that tight control was beneficial in surgical critical care. However, in addition to not including the two more recent negative trials, this meta-analysis overlooked the problems with the largest trial

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

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.

Peptide analogs

 * Incretin mimetics. Incretin is an insulin secretagogue.
 * Glucagon-like peptide (GLP) analogs (subcutaneous administration)
 * exenatide
 * liraglutide (not FDA approved)
 * Gastric inhibitory peptide (GIP) analogs
 * None are FDA approved
 * Incretin enhancement by dipeptidyl peptidase-4 (DPP-4) inhibitors
 * sitagliptin is an oral inhibitor of DPP-4
 * 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 pratice 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 recently, a randomized controlled trial found that although long acting insulins were less effective, they were associated 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 intial media thickness in a randomized controlled trial.

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
When treating hypertension in the diabetic patients, the goal blood pressure is 130/80 which is lower than in non-diabetic patients.

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 intial 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.