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
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
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:
A
random capillary blood glucose > 6.7 mmol/L
(120 mg/dL) diagnoses
current diabetes with:
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:
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:
- reduction of mortality and concomitant morbidity (from assorted
diabetic complications)
- 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:
- HbA1c 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.

Metformin 500mg tablets
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 :
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
References
- Robbins and Cotran, Pathologic Basis of Disease, 7th Ed. pp
1194-1195.
- American Diabetes Association title =Total Prevalence of
Diabetes and Pre-diabetes url
=http://www.diabetes.org/diabetes-statistics/prevalence.jsp |
accessdate =2008-11-29
- Inzucchi SE, Sherwin RS, The Prevention of Type 2 Diabetes
Mellitus. Endocrinol Metab Clin N Am 34 (2205) 199-219.
- Diabetes rates are increasing among youth
NIH, November 13, 2007
- 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
- Cotran, Kumar, Collins; Robbins Pathologic Basis of
Disease, Saunders Sixth Edition, 1999; 913-926.
- [[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 }}
- http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2007.pdf
- Non-technical summary
- Bolen S et al. Systematic Review: Comparative Effectiveness and Safety of Oral
Medications for Type 2 Diabetes Mellitus. Ann Intern Med
2007;147:6
- Gastric Bypass Surgery - Diabetes Health
External links
Organizations
Authorities
Further reading