Diabetes mellitus type 2

Diabetes mellitus type 2 or Type 2 Diabetes (formerly called non-insulin-dependent diabetes (NIDDM), obesity-related diabetes, or adult-onset diabetes) is a metabolic disorder that is primarily characterized by insulin resistance, relative insulin deficiency and hyperglycemia. It is often managed by engaging in exercise and modifying one's diet. It is rapidly increasing in the developed world, and there is some evidence that this pattern will be followed in much of the rest of the world in coming years. The CDC has characterized the increase as an epidemic.^[1] In addition, whereas this disease used to be seen primarily in adults over age 45, in contrast to Diabetes mellitus type 1, it is now increasingly seen in children and adolescents, an increase thought to be linked to rising rates of obesity in this age group. ^[2]

Unlike Type 1 diabetes, there is little tendency toward ketoacidosis in Type 2 diabetes, though it is not unknown. One effect that can occur is nonketonic hyperglycemia which also 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.

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Pathophysiology

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

Other important contributing factors:

• increased hepatic glucose production (e.g., from glycogen degradation), especially at inappropriate times
• 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
• Cancer survivors who received allogenic Hematopoietic Cell Transplantation (HCT) are 3.65 times more likely to report type 2 diabetes than their siblings. Total body irradiation (TBI) is also associated with a higher risk of developing diabetes.

This is a more complex problem than type 1, but is sometimes easier to treat, especially in the initial years when insulin is often still being produced internally. Type 2 may go unnoticed for years in a patient before diagnosis, since the symptoms are typically milder (no ketoacidosis) and can be sporadic. However, severe complications can result from improperly managed Type 2 diabetes, including renal failure, blindness, wounds that are slow to heal (including surgical incision), and arterial disease, including coronary artery disease. The onset of Type 2 is most common in middle age and later life, though a form of it, called MODY is being much more frequently seen in adolescents.

Diabetes mellitus type 2 is presently 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. Examples include diabetes mellitus caused by hemochromatosis, pancreatic insufficiencies, or certain types of medications (e.g. long-term steroid use).

About 90–95% of all North American cases of diabetes are type 2^[3], 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^[3]. 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^[4],[5]. About 55 percent of type 2 are obese^[6] —chronic obesity leads to increased insulin resistance that can develop into diabetes, most likely because adipose tissue is a (recently identified) source of several chemical signals to other tissues (hormones and cytokines). Other research shows that type 2 diabetes causes obesity.^[7]

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). It is also associated with acromegaly, Cushing's syndrome and a number of other endocrinological disorders. Additional factors found to increase risk of type 2 diabetes include aging^[8], high-fat diets^[9] and a less active lifestyle^[10].

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^[11]:

• 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

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 (USPSTF) 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"^[12][13], 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".^[14]

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^[13]:

• sensitivity about 50%
• specificity greater than 95%

A random capillary blood glucose > 6.7 mmol/L (120 mg/dL) diagnoses current diabetes with^[15]:

• 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.^[16] 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^[17].

Other studies have shown that life-style changes^[18] and metformin^[19] can delay the onset of diabetes.

Treatment

Diabetes mellitus type 2 is a chronic, progressive disease that has no clearly established cure. There are two main goals of treatment of the disease:

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., blood glucose levels); the reduction effect in diabetic complications has been well demonstrated in several large clinical trials and is well established beyond controversy. The second goal is often addressed (in developed countries) by support and care from teams of diabetic health workers (physician, PA, nurse, dietitian or a certified diabetic educator). Endocrinologists, family practitioners, and general internists are the types of physicians most likely to treat people with diabetes. Knowledgeable patient participation is vital and so patient education is a crucial aspect of this effort.

Type 2 is initially treated by adjustment in diet and exercise, and by weight loss, 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.

Treatment goals

Treatment goals for 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 6.0%^[20] to 7.0%^[21]

• Preprandial blood glucose: 4.0 to 6.0 mmol/L^[22]

• 2-hour postprandial blood glucose: 5.0 to 8.0 mmol/L^[22]

Self monitoring of blood glucose

Main article: Blood glucose monitoring

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".^[23] Nevertheless, it is strongly recommended for patients in whom it can assist in maintaining proper glycemic control, and is well worth the (sometimes considerable) if it does.

Dietary management

Main article: Diabetic diet

Modifying the diet is known to help control glucose (or glucose equivalnet, eg starch) intake, and in consequence, blood glucose levels. Additionally, weight loss is often recommended in persons suffering from type 2 diabetes for the reasons discussed above.

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."^[24][25] The combined program reduced the HbA1c by 0.5 percentage point. Other studies have established that the amount of exercise needed is not excessive, but must be consistent and continuing. Examples might include a brisk 45 minute walk every other day.

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 simple substituted one for another. All are prescription drugs.  

Main article: anti-diabetic drug

The most important drug now in use for Type 2 Diabetes is the Biguanide metformin which works primarily by reducing liver release of blood glucose from glycogen stores as well as provoking some increase in cellular uptake of glucose in body tissues. Both historically, and currently, commonly used are the Sulfonylurea group, of which several members (including glibenclamide and gliclazide) are widely used; these increase glucose stimulated insulin secretion by the pancreas.

Newer drug classes include:

• Thiazolidinediones (TZDs) (rosiglitazone, pioglitazone, and troglitazone) (withdrawn from the US market) which increase tissue insulin response
• α-glucosidase inhibitors (acarbose and miglitol) which interfere with absorption of some nutrients
• Meglitinides which stimulate insulin release (nateglinide, repaglinide, and their analogs) quickly; they can be taken with food, unlike the sulfonylureas
• 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
  • Dipeptidyl peptidase-4 (DPP-4) inhibitors increase Incretin levels (sitagliptin) by decreasing their deactivation rates
  • Amylin agonist analog, which slows gastric emptying and suppresses glucagon (pramlintide)

Oral drugs

A systematic review of randomized controlled trials found that metformin and second-generation sulfonylureas are the preferred choices for most with type 2.^[26] 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 of 15% with rosiglitazone, 21% with metformin, and 34% with glyburide".^[27] Of these, rosiglitazone users showed more weight gain and edema than did non-users.^[27] Rosiglitazone may increase risk of death from cardiovascular causes.^[28] Pioglitazone and rosiglitazone may also increase the risk of fractures.^[29][30]

For patients who also have heart failure, metformin may be the best available drug.^[31]

Insulin preparations

If antidiabetic drugs fail (or stop helping), insulin therapy may be necessary – usually in addition to oral medication therapy – to maintain normal glucose levels.

Typical total daily dosage of insulin is 0.6 U/kg.^[32] More complicated estimations to guide initial dosage of insulin are:^[33]

• 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 can be chosen based on the patient's blood glucose profile.^[34] Initially, adding nightly insulin to patients failing oral medications may be best.^[35] Nightly insulin combines better with metformin that with sulfonylureas.^[32] 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.^[36]

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 more hypoglycemia.^[37][38][39]. 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".^[38] A guide to titrating fixed ratio insulin is available (http://www.annals.org/cgi/content/full/145/2/125/T4).^[34]

• 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".^[40] More recently, a randomized controlled trial found that although long acting insulins were less effective, they were associated with less hypoglycemia.^[37]

Alternative medicines

Carnitine has been shown to increase insulin sensitivity and glucose storage in humans. ^[41]. It is important to note that this was with a constant blood infusion, not an oral dose, and that the clinical significance of this result is unclear.

Taurine has also shown significant improvement in insulin sensitivity and hyperlipidemia in rats.^[42]

Neither of these have shown permanent positive effects, nor a complete restoration to pre-diabetes conditions, only improvement. Their clinical importance in humans remains unclear.

Antihypertensive agents

Main article: Antihypertensive

The goal blood pressure is 130/80 which is lower than in non-diabetic patients.^[43]

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 ^[44]:

• 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.^[45]

Hypolipidemic agents

Main article: Hypercholesterolemia#Diabetic_patients