'Insulin resistance' is the condition in which normal amounts of
insulin are inadequate to produce a normal insulin response from
fat,
muscle and
liver cells. Insulin resistance in fat cells results in
hydrolysis of stored
triglycerides, which elevates free
fatty acids in the
blood plasma. Insulin resistance in muscle reduces
glucose uptake whereas insulin resistance in liver reduces glucose storage, with both effects serving to elevate blood glucose. High plasma levels of insulin and glucose due to insulin resistance often lead to
metabolic syndrome and
type 2 diabetes.
Pathophysiology
In a person with normal metabolism, insulin is released from the beta (β) cells of the
Islets of Langerhans located in the
pancreas after eating ("postprandial"), and it signals insulin-sensitive tissues in the body (e.g.,
muscle,
adipose) to absorb
glucose to lower blood glucose to a normal level (approximately 5 mmol/L (mM), or 90 mg/dL). In an ''insulin resistant'' person, normal levels of insulin do not trigger the signal for
glucose absorption by muscle and adipose cells. To compensate for this, the pancreas in an insulin resistant individual releases much more insulin such that the cells are adequately triggered to absorb glucose. Occasionally, this can lead to a steep drop in blood sugar and a
hypoglycemic reaction several hours after the meal.
The most common type of
insulin resistance is associated with a disease state known as
metabolic syndrome. Insulin resistance can progress to full
type 2 diabetes. This is often seen when
hyperglycemia develops after a meal, when pancreatic β-cells are unable to produce adequate insulin to maintain normal blood sugar levels (
euglycemia). The inability of the β-cells to produce more insulin in a condition of hyperglycemia is what characterizes the transition from insulin resistance to type 2 diabetes.
[ Banting lecture 2001: dysregulation of fatty acid metabolism in the etiology of type 2 diabetes, McGarry J, , , Diabetes, 2002 ]
Various disease states make the body tissues more resistant to the actions of insulin. Examples include
infection (mediated by the cytokine
TNFα) 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).
Elevated blood levels of glucose regardless of cause leads to increased
glycation of
proteins.
Insulin resistance is often found in people with visceral adiposity (i.e., a high degree of fatty tissue underneath the abdominal muscle wall - as distinct from subcutaneous adiposity or fat between the skin and the muscle wall), hypertension, hyperglycemia and dyslipidemia involving elevated triglycerides, small dense low-density lipoprotein (sdLDL) particles, and decreased HDL cholesterol levels.
Insulin resistance is also often associated with a hypercoagulable state (impaired fibrinolysis) and increased inflammatory cytokine levels.
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 falls of glucose levels (glycemia) after a given 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 very uncommon.
Investigation
Fasting Insulin Levels
A fasting serum insulin level of greater than the upper limit of normal for the assay used (approximately 60pmol/L) is considered evidence of insulin resistance.
Glucose tolerance testing (GTT)
During a
glucose tolerance test, which may be used to diagnose diabetes mellitus, a fasted patient takes a 75 gram oral dose of glucose. Blood glucose levels are then measured over the following 2 hours.
Interpretation is based on WHO guidelines, but
glycemia greater than or equal to 11.1mmol/L at 2 hours or greater than or equal to 7.0mmol/L fasting is diagnostic for diabetes mellitus.
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 a
hypoglycemic "dip", which is a result of an overshoot in insulin production after the failure of the physiologic postprandial insulin response.
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.
[ Glucose clamp technique: a method for quantifying insulin secretion and resistance, DeFronzo R, Tobin J, Andres R, , , Am J Physiol, 1979 ] 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.
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 5-10 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.
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.
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).
'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.
Patients initially receive 25mcg of sandostatin in 5ml of normal saline over 3-5 min IV as an initial bolus and then will be infused continuously with an intravenous infusion of somatostatin (0.27microgm/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 1/2 hour of the test. These last 4 values are averaged to determine the steady state plasma glucose level. Subjects with an SSPG greater than 150mg/dl are considered to be insulin resistant.
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 QUICKI (quantitative insulin sensitivity check index). Both employ
fasting insulin and
glucose levels to calculate insulin resistance, and both correllate 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.
[ Use and abuse of HOMA modeling, Wallace T, Levy J, Matthews D, , , Diabetes Care, 2004 ]
Causes of insulin resistance
The cause of the vast majority of cases of insulin resistance remains unknown. However, insulin resistance might be caused by a high carbohydrate diet. [NIRC ED: While technically correct in the absence of proof from replicable scientific studies, one factor is highly implicated by epidemiological evidence: insulin resistance is coded in the genetics of about 10% of the population. This is inferred from the genetic risk inherent in indisputable family patterns of diabetes and heart disease occurrence, two of insulin resistance's bad outcomes. Further, there is scientific evidence that insulin resistance is probably triggered, and certainly enhanced, by excess weight.] Some physicians also believe that
glucosamine (often prescribed for joint problems) may cause insulin resistance.
Associated Conditions
Several associated conditions include
★ Abnormally Sedentary Lifestyle, whether the result of the effects of
aging on the body or lack of physical exercise (both of which can also produce
obesity)
★
Haemochromatosis
★
Polycystic ovarian syndrome (PCOS)
★
Hypercortisolism (e.g.
steroid use or
Cushing's disease)
★
Drugs (e.g.
rifampicin,
isoniazid,
olanzapine,
risperidone,
progestogens, many antiretrovirals, possibly
alcohol,
methadone)
★ Genetic causes
★
★
Insulin receptor mutations (
Donohue Syndrome)
★
★
LMNA mutations (
Familial Partial Lipodystrophy)
Therapy
The primary treatment for insulin resistance is
exercise and
weight loss. In some individuals, a low
glycemic index or a low carbohydrate diet may also help. Fasting might also help. Both
metformin and the
thiazolidinediones improve insulin resistance, but are only approved therapies for type 2 diabetes, not insulin resistance, per se. [NIRC ED: Nevertheless, metformin, the 8th most often prescribed drug in the US, is often prescribed for pre-diabetes and insulin resistance, despite FDA instructions.] By contrast,
growth hormone replacement therapy may be associated with increased insulin resistance.
[ Growth hormone replacement therapy induces insulin resistance by activating the glucose-fatty acid cycle, Bramnert M, Segerlantz M, Laurila E, Daugaard JR, Manhem P, Groop L, , , THE JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 2003 ]
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.
[ Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin, Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, Nathan DM; Diabetes Prevention Program Research Group, , , New England Journal of Medicine, 2002 ] [NIRC ED: However, the same study showed that combining exercise, improved diet and metformin produced the most dramatic results.]
Some types of
Monounsaturated fatty acids and saturated fats appear to promote insulin resistance, whereas some types of
polyunsaturated fatty acids (omega 3) can increase insulin sensitivity.
[ The influence of dietary fat on insulin resistance, Lovejoy, JC, , , Current Diabetes Reports, 2002 ][ Role of Fatty Acid Composition in the Development of Metabolic Disorders in Sucrose-Induced Obese Rats, Fukuchi S, , , Experimental Biology and Medicine, 2004 ][ Dietary fats and insulin action, Storlien LH, , , Diabetologica, 1996 ]
There are scientific studies showing that
chromium picolinate can increase insulin sensitivity, especially in type 2 diabetics, but other studies show no effect. The results are controversial.
Naturopathic approaches to insulin resistance have been advocated including supplementation of vanadium, bitter melon (momordica) and
Gymnema sylvestre.
[ Momordica charantia constituents and antidiabetic screening of the isolated major compounds, Harinantenaina L, , , Chemical & Pharmaceutical Bulletin (Tokyo), 2006 ]
History
The concept that insulin resistance may be the underlying cause of
diabetes mellitus type 2 was first advanced by Sir
Harold Percival Himsworth of the University College Hospital Medical Center in London in
1936.
[ Diabetes mellitus: its differentiation into insulin-sensitive and insulin-insensitive types, Himsworth HP, , , Lancet, 1936 ]
References
See also
★
Chronic Somogyi rebound
External links
★
The National Insulin Resistance Council
★
Insulin resistance at the
Open Directory Project
★
Insulin Resistance Information
★
Bitter Melon, Prickly Pear Cactus, Address Insulin Resistance
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