Insulin resistance

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Insulin resistance (IR) is a physiological condition where the natural hormone

insulin becomes less effective at lowering blood sugars. The resulting increase in
blood glucose may raise levels outside the normal range and cause adverse health
effects, depending on dietary conditions. [1] Certain cell types such as fat and muscle
cells require insulin to absorb glucose. When these cells fail to respond adequately
to circulating insulin, blood glucose levels rise. The liver helps regulate glucose
levels by reducing its secretion of glucose in the presence of insulin. This normal
reduction in the livers glucose production may not occur in people with insulin
resistance.[2]

Insulin resistance in muscle and fat cells reduces glucose uptake (and also local
storage of glucose as glycogen and triglycerides, respectively), whereas insulin
resistance in liver cells results in reduced glycogen synthesis and storage and a
failure to suppress glucose production and release into the blood. Insulin resistance
normally refers to reduced glucose-lowering effects of insulin. However, other
functions of insulin can also be affected. For example, insulin resistance in fat cells
reduces the normal effects of insulin on lipids and results in reduced uptake of
circulating lipids and increased hydrolysis of stored triglycerides. Increased
mobilization of stored lipids in these cells elevates free fatty acids in the blood
plasma. Elevated blood fatty-acid concentrations (associated with insulin resistance
and diabetes mellitus Type 2), reduced muscle glucose uptake, and increased liver
glucose production all contribute to elevated blood glucose levels. High plasma
levels of insulin and glucose due to insulin resistance are a major component of the
metabolic syndrome. If insulin resistance exists, more insulin needs to be secreted
by the pancreas. If this compensatory increase does not occur, blood glucose
concentrations increase and type 2 diabetes occurs.[3]

[edit] Signs and symptoms

These depend on poorly understood variations in individual biology and

consequently may not be found with all people diagnosed with insulin resistance.

1. Fatigue.
2. Brain fogginess and inability to focus.
3. High blood sugar.
4. Intestinal bloating most intestinal gas is produced from carbohydrates in the
diet, mostly those that humans cannot digest and absorb.
5. Sleepiness, especially after meals.
6. Weight gain, fat storage, difficulty losing weight for most people, excess
 weight is from high fat storage; the fat in IR is generally stored in and around
abdominal organs in both males and females. It is currently suspected that
hormones produced in that fat are a precipitating cause of insulin resistance.
7. Increased blood triglyceride levels.
8. Increased blood pressure. Many people with hypertension are either diabetic or
pre-diabetic and have elevated insulin levels due to insulin resistance. One of
insulin's effects is to control arterial wall tension throughout the body.
9. Increased pro-inflammatory cytokines associated with cardiovascular disease.
10. Depression. Due to the deranged metabolism resulting from insulin resistance,
psychological effects, including depression, are not uncommon.
11. Acanthosis nigricans.
12. Increased hunger.

[edit] Associated Risk Factors

Several associated risk factors include:

Genetic factors (inherited component):

Family history with type 2 diabetes;
Insulin receptor mutations (Donohue Syndrome)
LMNA mutations (Familial Partial Lipodystrophy) Insulin resistance
may also be caused by the damage of liver cells having undergone a
defect of insulin receptors in hepatocytes. [citation needed]
being Black, Hispanic, American Indian or Asian.[4][5]

Particular physiological conditions and environmental factors:

> 4045 years of age; [4][5]
obesity;[4][5]
your body storing fat predominantly in the abdomen, as opposed to
storing it in hips and thighs. [5]
sedentary lifestyle, lack of physical exercise [4][5]
hypertension;[4]
high triglyceride level (Hypertriglyceridemia);[4]
low level of "good cholesterol"; [4]
pre-diabetes, your sugar levels in blood have been too high in the past, i.e.
your body has previously shown slight problems with its production and
usage of insulin ("previous evidence of impaired glucose
homeostasis");[4][5]
having developed gestational diabetes during past pregnancies;[4][5]
giving birth to a baby weighing more than 9 pounds (a bit over 4
kilograms)[4][5]

Pathology:
 Obesity and Overweight (BMI > 25);
Metabolic syndrome (Hyperlipidemia + HDL cholesterol level <
0.90 mmol/L or triglyceride level >2.82 mmol/L); Hypertension (>140/90
mmHg) or arteriosclerosis;
Liver pathologies;
Infection (Hepatitis C[6]);
Haemochromatosis;
Gastroparesis;
Polycystic ovary syndrome (PCOS);
Hypercortisolism (e.g., steroid use or Cushing's disease);[7]
Medication (e.g., glucosamine, rifampicin, isoniazid, olanzapine, risperidone,
progestogens, corticosteroids, glucocorticoids, methadone, many
antiretrovirals).

[edit] Causes

[edit] Diet

It is well known that insulin resistance commonly coexists with obesity. However,
causal links between insulin resistance, obesity, and dietary factors are complex and
controversial. It is possible that one of them arises first, and tends to cause the other;
or that insulin resistance and excess body weight might arise independently as a
consequence of a third factor, but end up reinforcing each other. Some population
groups might be genetically predisposed to one or the other.

Dietary fat has long been implicated as a driver of insulin resistance. Studies on
animals observed significant insulin resistance in rats after just 3 weeks on a high-
fat diet. [8] Large quantities of saturated, monounsaturated, and polyunsaturated
(omega-6) fats all appear to be harmful to rats to some degree, compared to high-
starch chow, but saturated fat appears to be the most effective at producing IR.[9]
This is partly caused by direct effects of a high-fat diet on blood markers, but, more
significantly, ad libitum high-fat diet has the tendency to result in caloric intake
that's far in excess of animals' energy needs, resulting in rapid weight gain. In
humans, statistical evidence is more equivocal. Being insensitive to insulin is still
positively correlated with fat intake, and negatively correlated with dietary fiber
intake.[10] But both these factors are also correlated with excess body weight.

The effect of dietary fat is largely or completely overridden if the high-fat diet is
modified to contain nontrivial quantities (in excess of 510% of total fat intake) of
polyunsaturated omega-3 fatty acids. [9][11][12] This protective effect is most
established with regard to the so-called "marine long-chain omega-3 fatty acids",
EPA and DHA, found in fish oil; evidence in favor of other omega-3's, in particular,
the most common vegetable-based omega-3 fatty acid, ALA, also exists (e.g.[13]), but
it is more limited; some studies find ALA only effective among people with
insufficient long-chain omega-3 intake,[14] and some studies fail to find any effect at
all[15] (ALA can be partially converted into EPA and DHA by the human body, but
the conversion rate is thought to be 10% or less, depending on diet and gender). The
effect is thought to explain relatively low incidence of IR, type 2 diabetes, and
obesity in polar foragers such as Alaskan Eskimos consuming their ancestral diet
(which is very high in fat, but contains substantial amounts of omega-3).[16][17]
However, it is not strong enough to prevent IR in the typical modern Western diet.
Unlike their omega-6 counterparts (which can be cheaply produced from a variety
of sources, such as corn and soybeans), major sources of omega-3 fatty acids remain
relatively rare and expensive. Consequently, the recommended average intake of
omega-3 for adult men in the United States is only 1.6 grams/day, or less than 2%
of total fat; the actual average consumption of omega-3 in the United States is
around 1.3 grams/day, almost all of it in the form of ALA; EPA and DHA
contributed less than 0.1 grams/day. [18]

Elevated levels of free fatty acids and triglycerides in the blood stream and tissues
have been found in many studies to contribute to diminished insulin
sensitivity.[9][19][20][21] Triglyceride levels are driven by a variety of dietary factors.
They are correlated with excess body weight.[22] They tend to rise due to overeating
and fall during fat loss.[23] At constant energy intake, triglyceride levels are
positively correlated with trans fat intake and strongly inversely correlated with
omega-3 intake. High-carbohydrate, low-fat diets were found by many studies to
result in elevated triglycerides, [24] in part due to higher production of VLDL from
fructose and sucrose, and in part because increased carbohydrate intake tends to
displace some omega-3 from the diet.

Several recent authors suggested that the intake of simple sugars, and particularly
fructose, is also a factor that contributes to insulin resistance.[25][26] Fructose is
metabolized by the liver into triglycerides, and, as mentioned above, tends to raise
their levels in the blood stream. Therefore, it may contribute to insulin resistance
through the same mechanisms as the dietary fat. Just like fat, high levels of fructose
and/or sucrose induce insulin resistance in rats, [27][28] and, just like with fat, this
insulin resistance is ameliorated by fish oil supplementation.[29] One study observed
that a low-fat diet high in simple sugars (but not in complex carbohydrates and
starches) significantly stimulates fatty acid synthesis, primarily of the saturated fatty
acid palmitate, therefore, paradoxically, resulting in the plasma fatty acid pattern
that is similar to that produced by a high-saturated-fat diet. [30] It should be pointed
out that virtually all evidence of deleterious effects of simple sugars so far is limited
to their concentrated formulations and sweetened beverages. In particular, very little
is known about effects of simple sugars in whole fruit and vegetables. If anything,
epidemiological studies suggest that their high consumption is associated with
somewhat lower risk of IR and/or metabolic syndrome. [31][32]
Yet another proposed mechanism involves the phenomenon known as leptin
resistance. Leptin is a hormone that regulates long-term energy balance in many
mammals. An important role of leptin is long-term inhibition of appetite in response
to formation of body fat. This mechanism is known to be disrupted in many obese
individuals: even though their leptin levels are commonly elevated, this does not
result in reduction of appetite and caloric intake.[33] Leptin resistance can be
triggered in rats by ad libitum consumption of energy-dense, highly palatable foods
over a period of several days. [34] Chronic consumption of fructose in rats ultimately
results in leptin resistance (however, this has only been demonstrated in a diet
where fructose provided 60% of calories; [35] the actual consumption by humans in a
typical Western diet is several times lower.) Once leptin signalling has been
disrupted, the individual becomes prone to further overeating, weight gain, and
insulin resistance.

As elevated blood glucose levels are the primary stimulus for insulin secretion and
production, habitually excessive carbohydrate intake is another likely contributor.
This serves as a major motivation behind the low-carb family of diets. Furthermore,
carbohydrates are not created equal (for example, the blood glucose level response
to a fixed quantity of carbohydrates in baked potatoes is about twice the response to
the same quantity of carbohydrates in pumpernickel bread). Integrated blood
glucose response to a fixed quantity of carbohydrates in a meal is known as
glycemic index. Some diets are based on this concept; they assume that
consumption of low-GI foods is less likely to result in insulin resistance and obesity.
However, small to moderate amounts of simple sugars (i.e., sucrose, fructose, and
glucose) in the typical developed-world diet seem to not have a causative effect on
the development of insulin resistance.[36]

Once established, insulin resistance would result in increased circulating levels of

insulin. Since insulin is the primary hormonal signal for energy storage into fat cells,
which tend to retain their sensitivity in the face of hepatic and skeletal muscle
resistance, IR stimulates the formation of new fatty tissue and accelerates weight
gain. [37]

Another possible explanation is that both insulin resistance and obesity often have
the same cause - systematic overeating - which has the potential to lead to insulin
resistance and obesity, due to repeated administration of excess levels of glucose,
which stimulate insulin secretion; excess levels of fructose, which raise triglyceride
levels in the bloodstream; and fats, which can be easily absorbed by the adipose
cells, and tend to end up as fatty tissue in a hypercaloric diet. Some scholars go as
far as to claim that neither insulin resistance, nor obesity are really metabolic
disorders per se, but simply adaptive responses to sustained caloric surplus,
intended to protect bodily organs from lipotoxicity (unsafe levels of lipids in the
bloodstream and tissues): "Obesity should therefore not be regarded as a pathology
or disease, but rather as the normal, physiologic response to sustained caloric
surplus ... As a consequence of the high level of lipid accumulation in insulin target
tissues including skeletal muscle and liver, it has been suggested that exclusion of
glucose from lipid-laden cells is a compensatory defense against further
accumulation of lipogenic substrate." [38]Fast food meals typically possess several
characteristics, all of which have independently been linked to IR: they are energy-
dense, palatable, and cheap, increasing risk of overeating and leptin resistance; they
are simultaneously high in dietary fat and fructose, and low in omega-3; and they
usually have high glycemic indices. Consumption of fast food has been proposed as
a fundamental factor behind the metabolic syndrome epidemic and all its
constituents.[37]

An American study has shown that glucosamine (often prescribed for joint
problems) may cause insulin resistance.[39]

Several studies show that high levels of cortisol within the bloodstream from the
digestion of animal protein can contribute to the development of insulin
resistance.[40][41] Additionally animal protein because of its high content of purine
causes blood pH to become acidic. Several studies conclude that high uric acid level
apart from other contributing factors by itself may be a significant cause of insulin
resistance.[42]

Vitamin D deficiency is also associated with insulin resistance.[43]

[edit] Sedentary lifestyle

Sedentary lifestyle increases the likelihood of development of insulin

resistance.[44][45] It's been estimated that each 500 kcal/week increment in physical
activity related energy expenditure reduces the lifetime risk of type 2 diabetes by
6%.[46] A different study found that vigorous exercise at least once a week reduced
the risk of type 2 diabetes in women by 33%.[47]

[edit] Protease inhibitors

Protease inhibitors found in HIV drugs are linked to insulin resistance.[48]

[edit] Cellular

At the cellular level, much of the variance in insulin sensitivity between untrained,
non-diabetic humans is explained by two mechanisms: differences in phospholipid
profiles of skeletal muscle cell membranes, and in intramyocellular lipid (ICML)
stores within these cells. [49] High levels of lipids in the bloodstream have the
potential to result in accumulation of triglycerides and their derivatives within
muscle cells, which activate proteins Kinase C- and C-, ultimately reducing the
glucose uptake at any given level of insulin.[19][50] This mechanism is quite fast-
acting and can induce insulin resistance within days or even hours in response to a
large lipid influx.[51] Draining the intracellular reserves, on the other hand, is more
challenging: moderate caloric restriction alone, even over a period of several
months, appears to be ineffective, [52][53] and it must be combined with physical
exercise to have any effect. (However, a 2011 study found that a severe ultra-low-
calorie diet, limiting patients to 600 calories/day for a period of 2 months, without
explicit exercise targets, was capable of reversing insulin resistance and type 2
diabetes. [54])

In the long term, diet has the potential to change the ratio of polyunsaturated to
saturated phospholipids in cell membranes, correspondingly changing cell
membrane fluidity; full impact of such changes is not fully understood, but it is
known that the percentage of polyunsaturated phospholipids is strongly correlated
with insulin resistance.[55] It is hypothesized that increasing cell membrane fluidity
by increasing PUFA concentration might result in an enhanced number of insulin
receptors, an increased affinity of insulin to its receptors and a reduced insulin
resistance, and vice versa. [56]

Many stressing factors can lead to increased cortisol in the bloodstream. Cortisol
counteracts insulin, and contributes to hyperglycemia-causing hepatic
gluconeogenesis [57] and inhibits the peripheral utilization of glucose which
eventually leads to insulin resistance.[57] It does this by decreasing the translocation
of glucose transporters (especially GLUT4) to the cell membrane. [58][59]

Although inflammation is often caused by cortisol, inflammation by itself also seems

to be implicated in causing insulin resistance. Mice without JNK1-signaling do not
develop insulin resistance under dietary conditions that normally produce it.[60][61]

Rare Type 2 cases sometimes use high levels of exogenous insulin. As short term
overdosing of insulin causes short term insulin resistance, it has been hypothesized
that chronic high dosing contributes to more permanent insulin resistance.[citation
needed]

[edit] Molecular

Insulin resistance has been proposed at a molecular level to be a reaction to excess

nutrition by superoxide dismutase in cell mitochondria that acts as an antioxidant
defense mechanism. This link seems to exist under diverse causes of insulin
resistance. It is also based on the finding that insulin resistance can be rapidly
reversed by exposing cells to mitochondrial uncouplers, electron transport chain
inhibitors, or mitochondrial superoxide dismutase mimetics.[62]

[edit] Disease
Recent research and experimentation has uncovered a non-obesity related
connection to insulin resistance and Type 2 diabetes. It has long been observed that
patients who have had some kinds of bariatric surgery have increased insulin
sensitivity and even remission of Type 2 diabetes. It was discovered that diabetic /
insulin resistant non obese rats whose duodenum has been surgically removed also
experienced increased insulin sensitivity and remission of Type 2 diabetes. This
suggested similar surgery in humans, and early reports in prominent medical
journals (January 8) are that the same effect is seen in humans, at least the small
number who have participated in the experimental surgical program. The
speculation is that some substance is produced in that portion of the small intestine
that signals body cells to become insulin resistant. If the producing tissue is
removed, the signal ceases and body cells revert to normal insulin sensitivity. No
such substance has been found as yet, so its existence remains speculative.[citation
needed]

Insulin resistance has also been linked to PCOS (polycystic ovary syndrome) as
either causing it or being caused by it. Further studies are in progress. [citation needed]

[edit] HCV and Insulin Resistance

Hepatitis C also makes people three to four times more likely to develop Type 2
diabetes and insulin resistance.[6] In addition, "people with Hepatitis C who
develop diabetes probably have susceptible insulin-producing cells, and would
probably get it anyway -- but much later in life.[6] The extra insulin resistance
caused by Hepatitis C apparently brings on diabetes at 35 or 40, instead of 65 or
70." [6]

[edit] Pathophysiology

Any food or drink containing glucose (or the digestible carbohydrates that contain
it, such as sucrose, starch, etc.) causes blood glucose levels to increase. In a normal
metabolism, the elevated blood glucose level makes beta () cells in the Islets of
Langerhans, located in the pancreas, release insulin into the blood. The insulin, in
turn, makes insulin-sensitive tissues in the body (primarily skeletal muscle cells,
adipose tissue, and liver) absorb glucose, and thereby lower the blood glucose level.
The beta cells reduce insulin output as the blood glucose level falls, allowing blood
glucose to settle at a constant of approximately 5 mmol/L (mM) (90 mg/dL). In an
insulin-resistant person, normal levels of insulin do not have the same effect in
controlling blood glucose levels. During the compensated phase on insulin
resistance insulin levels are higher, and blood glucose levels are still maintained. If
compensatory insulin secretion fails, then either fasting (impaired fasting glucose)
or postprandial (impaired glucose tolerance) glucose concentrations increase.
Eventually, type 2 diabetes occurs when glucose levels become higher throughout
the day as the resistance increases and compensatory insulin secretion fails. The
elevated insulin levels have additional effects (see insulin) that cause further
abnormal biological effects throughout the body. [citation needed]

The most common type of insulin resistance is associated with overweight and
obesity in a condition known as metabolic syndrome. Insulin resistance often
progresses to full Type 2 diabetes mellitus (T2DM). This is often seen when
hyperglycemia develops after a meal, when pancreatic -cells are unable to produce
sufficient insulin to maintain normal blood sugar levels (euglycemia) in the face of
insulin resistance. The inability of the -cells to produce sufficient insulin in a
condition of hyperglycemia is what characterizes the transition from insulin
resistance to Type 2 diabetes mellitus.[63]

Various disease states make body tissues more resistant to the actions of insulin.
Examples include infection (mediated by the cytokine TNF) and acidosis. Recent
research is investigating the roles of adipokines (the cytokines produced by adipose
tissue) in insulin resistance. Certain drugs may also be associated with insulin
resistance (e.g., glucocorticoids).[citation needed]

Insulin itself leads to a kind of insulin resistance; every time a cell is exposed to
insulin, the production of GLUT4 (type four glucose receptors) on the cell's
membrane decreases somewhat.[64] In the presence of a higher than usual level of
insulin (generally caused by insulin resistance), this down-regulation acts as a kind
of positive feedback, increasing the need for insulin. Exercise reverses this process in
muscle tissue, [65] but if it is left unchecked, it can contribute to insulin resistance.

Elevated blood levels of glucose regardless of cause lead to increased glycation

of proteins with changes, only a few of which are understood in any detail, in
protein function throughout the body. [66][67]

Insulin resistance is often found in people with visceral adiposity (i.e., a high degree
of fatty tissue within the abdomen as distinct from subcutaneous adiposity or fat
between the skin and the muscle wall, especially elsewhere on the body, such as
hips or thighs), hypertension, hyperglycemia and dyslipidemia involving elevated
triglycerides, small dense low-density lipoprotein (sdLDL) particles, and decreased
HDL cholesterol levels. With respect to visceral adiposity, a great deal of evidence
suggests two strong links with insulin resistance. First, unlike subcutaneous adipose
tissue, visceral adipose cells produce significant amounts of proinflammatory
cytokines such as tumor necrosis factor-alpha (TNF-a), and Interleukins-1 and -6,
etc. In numerous experimental models, these proinflammatory cytokines disrupt
normal insulin action in fat and muscle cells, and may be a major factor in causing
the whole-body insulin resistance observed in patients with visceral adiposity.
Much of the attention on production of proinflammatory cytokines has focused on
the IKK-beta/NF-kappa-B pathway, a protein network that enhances transcription
of inflammatory markers and mediators that can cause insulin resistance. Second,
visceral adiposity is related to an accumulation of fat in the liver, a condition known
as nonalcoholic fatty liver disease (NAFLD). The result of NAFLD is an excessive
release of free fatty acids into the bloodstream (due to increased lipolysis), and an
increase in hepatic glucose production, both of which have the effect of exacerbating
peripheral insulin resistance and increasing the likelihood of Type 2 diabetes
mellitus.[citation needed]

Insulin resistance is also often associated with a hypercoagulable state (impaired

fibrinolysis) and increased inflammatory cytokine levels. [68]

Insulin resistance is also occasionally found in patients who use insulin. In this case,
the production of antibodies against insulin leads to lower-than-expected glucose
level reductions (glycemia) after a specific dose of insulin. With the development of
human insulin and analogues in the 1980s and the decline in the use of animal
insulins (e.g., pork, beef), this type of insulin resistance has become less common.
This form of insulin resistance is not what is being referred to in the metabolic
syndrome. [citation needed]

Magnesium (Mg) is present in living cells and its plasma concentration is

remarkably constant in healthy subjects. Plasma and intracellular Mg concentrations
are tightly regulated. Among the controlling mechanisms, insulin seems to be one of
the most important. In vitro and in vivo studies have demonstrated that insulin may
modulate the shift of Mg from extracellular to intracellular space. Intracellular Mg
concentration has also been shown to be effective in modulating insulin action
(mainly oxidative glucose metabolism), offset calcium-related excitation-contraction
coupling, and decrease smooth cell responsiveness to depolarizing stimuli. Poor
intracellular Mg concentrations, as found in Type 2 diabetes mellitus and in
hypertensive patients, may result in a defective tyrosine-kinase activity at the
insulin receptor level and exaggerated intracellular calcium concentration. Both
events are responsible for impairment in insulin action, and a worsening of insulin
resistance in noninsulin-dependent diabetic and hypertensive patients. By contrast,
in T2DM patients daily Mg administration, restoring a more appropriate
intracellular Mg concentration, contributes to improve insulin-mediated glucose
uptake. The benefits deriving- from daily Mg supplementation in T2DM patients are
further supported by epidemiological studies showing that high daily Mg intake are
predictive of a lower incidence of T2DM.[citation needed]

[edit] Diagnosis

[edit] Fasting insulin levels

A fasting serum insulin level of greater than the upper limit of normal for the assay
used (approximately 60 pmol/L) is considered evidence of insulin resistance.[citation
needed]
[edit] Glucose tolerance testing (GTT)

During a glucose tolerance test, which may be used to diagnose diabetes mellitus, a
fasting patient takes a 75 gram oral dose of glucose. Blood glucose levels are then
measured over the following 2 hours. [citation needed]

Interpretation is based on WHO guidelines. After 2 hours a Glycemia less than

7.8 mmol/L (140 mg/dl) is considered normal, a glycemia of between 7.8 to
11.0 mmol/L (140 to 197 mg/dl) is considered as Impaired Glucose Tolerance (IGT)
and a glycemia of greater than or equal to 11.1 mmol/L (200 mg/dl) is considered
Diabetes Mellitus.[citation needed]

An OGTT[clarification needed] (Oral Glucose Tolerance Test) can be normal or mildly

abnormal in simple insulin resistance. Often, there are raised glucose levels in the
early measurements, reflecting the loss of a postprandial (after the meal) peak in
insulin production. Extension of the testing (for several more hours) may reveal a
hypoglycemic "dip," which is a result of an overshoot in insulin production after the
failure of the physiologic postprandial insulin response. [citation needed]

[edit] Measuring insulin resistance

Hyperinsulinemic euglycemic clamp

The gold standard for investigating and quantifying insulin resistance is the
"hyperinsulinemic euglycemic clamp," so-called because it measures the amount of
glucose necessary to compensate for an increased insulin level without causing
hypoglycemia.[69] It is a type of glucose clamp technique. The test is rarely
performed in clinical care, but is used in medical research, for example, to assess the
effects of different medications. The rate of glucose infusion is commonly referred to
in diabetes literature as the GINF value. [70]

The procedure takes about 2 hours. Through a peripheral vein, insulin is infused at
10-120 mU per m2 per minute. In order to compensate for the insulin infusion,
glucose 20% is infused to maintain blood sugar levels between 5 and 5.5 mmol/l.
The rate of glucose infusion is determined by checking the blood sugar levels every
5 to 10 minutes. Low-dose insulin infusions are more useful for assessing the
response of the liver, whereas high-dose insulin infusions are useful for assessing
peripheral (i.e., muscle and fat) insulin action.[70]

The rate of glucose infusion during the last 30 minutes of the test determines insulin
sensitivity. If high levels (7.5 mg/min or higher) are required, the patient is insulin-
sensitive. Very low levels (4.0 mg/min or lower) indicate that the body is resistant
to insulin action. Levels between 4.0 and 7.5 mg/min are not definitive and suggest
"impaired glucose tolerance," an early sign of insulin resistance.[70]

This basic technique can be significantly enhanced by the use of glucose tracers.
Glucose can be labeled with either stable or radioactive atoms. Commonly-used
tracers are 3-3H glucose (radioactive), 6,6 2H-glucose (stable) and 1-13C Glucose
(stable). Prior to beginning the hyperinsulinemic period, a 3h tracer infusion enables
one to determine the basal rate of glucose production. During the clamp, the plasma
tracer concentrations enable the calculation of whole-body insulin-stimulated
glucose metabolism, as well as the production of glucose by the body (i.e.,
endogenous glucose production).[70]

Modified Insulin Suppression Test

Another measure of insulin resistance is the modified insulin suppression test

developed by Gerald Reaven at Stanford University. The test correlates well with
the euglycemic clamp with less operator-dependent error. This test has been used to
advance the large body of research relating to the metabolic syndrome. [70]

Patients initially receive 25 mcg of octreotide (Sandostatin) in 5 ml of normal saline

over 3 to 5 min IV as an initial bolus, and then are infused continuously with an
intravenous infusion of somatostatin (0.27 gm/m 2/min) to suppress endogenous
insulin and glucose secretion. Insulin and 20% glucose is then infused at rates of 32
and 267 mg/m2/min, respectively. Blood glucose is checked at zero, 30, 60, 90, and
120 minutes, and then every 10 minutes for the last half-hour of the test. These last 4
values are averaged to determine the steady-state plasma glucose level (SSPG).
Subjects with an SSPG greater than 150 mg/dl are considered to be insulin-
resistant.[70]

[edit] Alternatives

Given the complicated nature of the "clamp" technique (and the potential dangers of
hypoglycemia in some patients), alternatives have been sought to simplify the
measurement of insulin resistance. The first was the Homeostatic Model Assessment
(HOMA), and a more recent method is the Quantitative insulin sensitivity check
index (QUICKI). Both employ fasting insulin and glucose levels to calculate insulin
resistance, and both correlate reasonably with the results of clamping studies.
Wallace et al. point out that QUICKI is the logarithm of the value from one of the
HOMA equations. [71]

[edit] Management

The primary treatment for insulin resistance is exercise and weight loss.
Low-glycemic load diet has also been shown to help.[72] Both metformin and the
thiazolidinediones improve insulin resistance, but are only approved therapies for
type 2 diabetes, not insulin resistance. By contrast, growth hormone replacement
therapy may be associated with increased insulin resistance.[73]

Metformin has become one of the more commonly prescribed medications for
insulin resistance, and currently a newer drug, exenatide (marketed as Byetta), is
being used. Exenatide has not been approved in the UK except for use in diabetics,
but often improves insulin resistance in healthy individuals by the same mechanism
as it does in diabetics. [citation needed]

The Diabetes Prevention Program showed that exercise and diet were nearly twice as
effective as metformin at reducing the risk of progressing to type 2 diabetes. [74] One
2009 study has found that carbohydrate deficit after exercise, but not energy deficit,
contributed to insulin sensitivity increase. [75]

Resistant starch from high amylose corn has been shown to reduce insulin
resistance in healthy individuals, and in individuals with type 2
diabetes. [76][77][78][79][80][81] Animal studies demonstrate that it cannot reverse
insulin resistance, but that it reduces the development of insulin resistance.[82][83][84]

Some types of Monounsaturated fatty acids, saturated, and trans fats promote
insulin resistance. Some types of polyunsaturated fatty acids (omega-3) can
moderate the progression of insulin resistance into type 2 diabetes. [85][86][87]
However, omega-3 fatty acids appear to have limited ability to reverse insulin
resistance, and they cease to be efficacious once type 2 diabetes is established.[88]

Caffeine intake limits insulin action, but not enough to increase blood sugar levels
in healthy persons. People who already have diabetes II can see a small increase in
levels if they take 2 or 21/2 cups of coffee per day.[89]

[edit] History

The concept that insulin resistance may be the underlying cause of diabetes mellitus
type 2 was first advanced by Prof. Wilhelm Falta and published in Vienna in
1931,[90] and confirmed as contributary by Sir Harold Percival Himsworth of the
University College Hospital Medical Centre in London in 1936.[91] However, type 2
diabetes does not occur unless there is concurrent failure of compensatory insulin
secretion.[92]

[edit] See also

Chronic Somogyi rebound

Hyperinsulinemia

[edit] References
 1. "Insulin resistance".
2. "www.sciencedaily.com".
3. "www.medicinenet.com".
4. ^ a b c d e f g h i j Jennifer Mayfield (October 15, 1998). Diagnosis and
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[edit] External links

Rao, Goutham (2001). "Insulin resistance syndrome". American Family Physician
63 (6): 115963, 11656. PMID 11277552.
Insulin resistance at the Open Directory Project
The National Insulin Resistance Council