Insulin resistance
Insulin resistance(IR) is aphysiologicalcondition in which cells
fail to respond to the normal actions of the hormoneinsulin. The
body produces insulin, but the cells in the body become resistant
to insulin and are unable to use it as effectively, leading
tohyperglycemia. Beta cells in thepancreassubsequently increase
their production of insulin, further contributing
tohyperinsulinemia. This often remains undetected and can
contribute to a diagnosis ofType 2 Diabetes. 2Signs and symptoms
2.1Associated Risk Factors 3Causes 3.1Diet 3.2Sedentary lifestyle
3.3Protease inhibitors 3.4Cellular 3.5Molecular 3.6Disease 3.7HCV
and Insulin Resistance 4Pathophysiology 5Diagnosis 5.1Fasting
insulin levels 5.2Glucose tolerance testing (GTT) 5.3Measuring
insulin resistance 5.3.1Hyperinsulinemic euglycemic clamp
5.3.2Modified Insulin Suppression Test
5.4AlternativesExplanation[edit]One of insulin's functions is to
regulate delivery of glucose into cells to provide them with
energy.[1]Insulin resistant cells cannot take in glucose, amino
acids and fatty acids. Thus, glucose, fatty acids and amino acids
'leak' out of the cells. A decrease in insulin/glucagon ratio
inhibits glycolysis which in turn decreases energy production. The
resulting increase in blood glucose may raise levels outside the
normal range and cause adverse health effects, depending on dietary
conditions.[2]Certain cell types such asfatandmusclecells require
insulin to absorb glucose. When these cells fail to respond
adequately to circulating insulin, blood glucose levels rise.
Theliverhelps 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.[3]Insulin resistance in muscle and fat cells
reducesglucoseuptake (and also local storage of glucose
asglycogenandtriglycerides, 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 infat
cellsreduces the normal effects of insulin on lipids and results in
reduced uptake of circulating lipids and increasedhydrolysisof
storedtriglycerides. Increased mobilization of stored lipids in
these cells elevates freefatty acidsin theblood 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 themetabolic 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 andtype 2 diabetesoccurs.[2]Signs
and symptomsThese depend on poorly understood variations in
individual biology and consequently may not be found with all
people diagnosed with insulin resistance.1. Brain fogginess and
inability to focus.2. High blood sugar.3. Intestinal bloating most
intestinal gas is produced from carbohydrates in the diet, mostly
those that humans cannot digest and absorb.4. Sleepiness,
especially after meals.5. 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.6. Increased blood triglyceride levels.7. 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.8. Increased pro-inflammatory cytokines
associated with cardiovascular disease.9. Depression. Due to the
deranged metabolism resulting from insulin resistance,
psychological effects, including depression, are not uncommon.10.
Acanthosis nigricans.11. Increased hunger.Associated Risk
FactorsSeveral associated risk factors include: Genetic factors
(inherited component): Family history with type 2 diabetes; Insulin
receptormutations (Donohue Syndrome) LMNAmutations (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 (this is also cultural as diet varies with
race and class).[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] hightriglyceridelevel
(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 2.82 mmol / L); Hypertension (> 140/90 mmHg)
or arteriosclerosis;,no Liver pathologies; Infection (Hepatitis
C[6]); Haemochromatosis; Gastroparesis; Polycystic ovary
syndrome(PCOS); Hypercortisolism(e.g.,steroiduse orCushing's
disease);[7] manyantiretrovirals).,itCausesDietIt is well known
that insulin resistance commonly coexists withobesity. 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 (59% fat,
20% carb.)[8]Large quantities of saturated, monounsaturated, and
polyunsaturated (omega-6) fats all appear to be harmful to rats to
some degree, compared to large amounts of starch, 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 libitumhigh-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 polyunsaturatedomega-3fatty acids.[9][11][12]This
protective effect is most established with regard to the so-called
"marine long-chain omega-3 fatty acids",EPAandDHA, 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,[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 1.6grams/day, or less
than 2% of total fat; the actual average consumption of omega-3 in
the United States is around 1.3grams/day, almost all of it in the
form of ALA; EPA and DHA contributed less than
0.1grams/day.[18]Elevated levels offree fatty
acidsandtriglyceridesin 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 withtrans fatintake and strongly inversely
correlated with omega-3 intake. High-carbohydrate,low-fat dietswere
found by many studies to result in elevated triglycerides,[24]in
part due to higher production ofVLDLfrom 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 particularlyfructose, 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 acidpalmitate, 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 asleptin resistance.Leptinis 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
thelow-carbfamily of diets. Furthermore, carbohydrates are not
equally absorbed (for example, the blood glucose level response to
a fixed quantity of carbohydrates in bakedpotatoesis about twice
the response to the same quantity of carbohydrates
inpumpernickelbread). Integrated blood glucose response to a fixed
quantity of carbohydrates in a meal is known asglycemic index. Some
diets are based on this concept, assuming 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 intofat 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, a 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 theadipose cellsand 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 disordersper
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 foodmeals 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
thatglucosamine(often prescribed for joint problems) may cause
insulin resistance.[39]Studies show that high levels
ofcortisolwithin 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 ofpurine, causes blood pH to become acidic. Several
studies conclude that highuric acidlevels, apart from other
contributing factors, by itself may be a significant cause of
insulin resistance.[42]Vitamin Ddeficiency is also associated with
insulin resistance.[43]Sedentary lifestyleSedentary 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]Protease inhibitorsProtease
inhibitorsfound in HIV drugs are linked to insulin
resistance.[48]CellularAt the cellular level, much of the variance
in insulin sensitivity between untrained, non-diabetic humans is
explained by two mechanisms: differences inphospholipidprofiles of
skeletal musclecell 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 inversely 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
counteractsinsulin, and contributes to hyperglycemia-causing
hepaticgluconeogenesis[57]and inhibits the peripheral utilization
of glucose which eventually leads to insulin resistance.[57]It does
this by decreasing the translocation ofglucose
transporters(especiallyGLUT4) 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
withoutJNK1-signaling do not develop insulin resistance under
dietary conditions that normally produce it.[60][61]Rare type 2
diabetes 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]MolecularInsulin resistance has been proposed at a molecular
level to be a reaction to excess nutrition bysuperoxide dismutasein
cellmitochondriathat 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 tomitochondrial uncouplers,electron
transport chaininhibitors, or mitochondrial superoxide dismutase
mimetics.[62]DiseaseRecent 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 ofbariatric surgeryhave increased insulin
sensitivity and even remission of type 2 diabetes. It was
discovered that diabetic/insulin resistant non obese rats
whoseduodenumhas 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 toPCOS(polycysticovarysyndrome) as
either causing it or being caused by it. Further studies are in
progress.[citation needed]HCV and Insulin ResistanceHepatitis 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]PathophysiologyAny food or drink containing glucose (or the
digestible carbohydrates that contain it, such assucrose,starch,
etc.) causesblood glucose levelsto increase. In a normal
metabolism, the elevated blood glucose level instructs beta ()
cells in theIslets of Langerhans, located in thepancreas, to
release insulin into the blood. The insulin, in turn, makes
insulin-sensitive tissues in the body (primarily
skeletalmusclecells,adiposetissue, andliver) absorbglucose, 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 5mmol/L(mM)
(90mg/dL). In aninsulin-resistantperson, 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 (seeinsulin) that
cause further abnormal biological effects throughout the
body.[citation needed]The most common type ofinsulinresistance is
associated with overweight and obesity in a condition known
asmetabolic syndrome. Insulin resistance often progresses to
fullType 2 diabetes mellitus(T2DM). This is often seen
whenhyperglycemiadevelops 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 T2DM.[63]Various disease states make
body tissues more resistant to the actions of insulin. Examples
includeinfection(mediated by the cytokineTNF) andacidosis. Recent
research is investigating the roles
ofadipokines(thecytokinesproduced byadipose 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 ofGLUT4(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 increasedglycationofproteinswith
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 anddyslipidemiainvolving 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
proinflammatorycytokinessuch as tumor necrosis factor-alpha
(TNF-a), andInterleukins-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-Bpathway, 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 asnon-alcoholic
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 glycogenolysis and hepatic
glucose production, both of which have the effect of exacerbating
peripheral insulin resistance and increasing the likelihood ofType
2 diabetes mellitus.[citation needed]Insulin resistance is also
often associated with ahypercoagulable state(impairedfibrinolysis)
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 (such as pork or 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 inType 2 diabetes mellitus(T2DM) 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
T2DMDiagnosisFasting insulin levelA 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.Glucose tolerance testing (GTT)During aglucose tolerance
test, which may be used to diagnose diabetes mellitus, a fasting
patient takes a 75gram oral dose of glucose. Blood glucose levels
are then measured over the following 2 hoursInterpretation is based
on WHO guidelines. After 2 hours aglycemialess than 7.8mmol/L
(140mg/dl) is considered normal, a glycemia of between 7.8 to
11.0mmol/L (140 to 197mg/dl) is considered asimpaired glucose
tolerance(IGT) and a glycemia of greater than or equal to
11.1mmol/L (200mg/dl) is considereddiabetes mellitus.Anoral glucose
tolerance test(OGTT) 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 ahypoglycemic"dip," which is a
result of an overshoot in insulin production after the failure of
the physiologic postprandial insulin responseMeasuring insulin
resistanceHyperinsulinemic euglycemic clampThegold standardfor
investigating and quantifying insulin resistance is the
"hyperinsulinemic euglycemic clamp," so-called because it measures
the amount ofglucosenecessary to compensate for an
increasedinsulinlevel without causinghypoglycemia.[69]It is a type
ofglucose 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 aperipheral
vein,insulinis infused at 10120 mU per m2perminute. In order to
compensate for the insulininfusion,glucose20% is infused to
maintain blood sugar levels between 5 and 5.5mmol/l. The rate of
glucose infusion is determined by checking theblood sugarlevels
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 (7.5mg/min or higher) are required, the patient is
insulin-sensitive. Very low levels (4.0mg/min or lower) indicate
that the body is resistant to insulin action. Levels between 4.0
and 7.5mg/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),
6,62H-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 TestAnother 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 (0.27gm/m2/min) to suppress
endogenous insulin and glucose secretion. Insulin and 20% glucose
is then infused at rates of 32 and 267mg/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 150mg/dl
are considered to be insulin-resistant.AlternativesGiven the
complicated nature of the "clamp" technique (and the potential
dangers ofhypoglycemiain some patients), alternatives have been
sought to simplify the measurement of insulin resistance. The first
was theHomeostatic Model Assessment(HOMA), and a more recent method
is theQuantitative insulin sensitivity check index(QUICKI). Both
employfastinginsulinandglucoselevels to calculate insulin
resistance, and both correlate reasonably with the results of
clamping studies. Wallaceet al.point out that QUICKI is
thelogarithmof the value from one of the HOMA
equations.[71]ManagementThe primary treatment for insulin
resistance isexerciseandweight loss. Low-carb diet has also been
shown to help.[72]Bothmetforminand thethiazolidinedionesimprove
insulin resistance, but are only approved therapies for type 2
diabetes, not insulin resistance. By contrast,growth hormone
replacement therapymay 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]TheDiabetes
Prevention Programshowed that exercise and diet were nearly twice
as effective asmetforminat reducing the risk of progressing to type
2 diabetes.One 2009 study has found that carbohydrate deficit after
exercise, but not energy deficit, contributed to insulin
sensitivity increaseResistant starch from high amylose corn has
been shown to reduce insulin resistance in healthy individuals, and
in individuals with type 2 diabetes.Animal studies demonstrate that
it cannot reverse insulin resistance, but that it reduces the
development of insulin resistance. Some types ofmonounsaturated
fatty acids, saturated, and trans fats promote insulin resistance.
Some types ofpolyunsaturated fatty acids(omega-3) can moderate the
progression of insulin resistance into type 2 diabetesHowever,
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 21/2cups of coffee per day.[89]
