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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 leads to the metabolic syndrome and type 2 diabetes.
Pathophysiology In patients who use insulin, "insulin resistance" is production of antibodies against insulin that lead 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 1980's and the decline in the use of animal insulins (e.g., pork, beef), this type of insulin resistance has become very uncommon. The most common type of insulin resistance is associated with metabolic syndrome. This was first described in the 1930's by H.P. (Harry) Himsworth (University College Hospital Medical School, London). He described results of experiments in an article in 1936, entitled, "Diabetes Mellitus: Its differentiation into insulin sensitive and insulin insensitive types." He found that those with diabetes can be differentiated into two types: those in whom injected insulin produces an immediate suppression of hyperglycemia; and those in whom the insulin has little or no effect. Hyperglycemia itself can lead to insulin resistance, but N-acetylcysteine and taurine can prevent this effect•. Insulin resistance denotes decreased sensitivity of target cells (muscle, adipose and hepatic cells) to insulin. The very common "metabolic syndrome" is the concomitant appearance of diabetes mellitus (type 2), hypertension, combined hyperlipidemia and central obesity. It is also associated with polycystic ovarian syndrome (PCOS). In some patients with excess body fat, compensatory hyperinsulinemia reduces the expression of the membrane insulin receptor (down regulation) which maintains the maximal response. More importantly, defects in processes within the cell itself (also called post-receptor defects) appear to play a much larger role in the development of insulin resistance. A relationship between leptin resistance and insulin resistance has been suggested. In a person with normal metabolism, insulin is released from the beta cells of the Islets of Langerhans located in the pancreas after eating ("postprandial"), and it signals the body to allow glucose to enter insulin-sensitive tissues (e.g., muscle, adipose) and maintain normal blood glucose levels. In an "insulin resistant" person the message does not get through to those cells until much more insulin is released in an attempt to compensate. Occasionally, this can lead to a steep drop in blood sugar and a hypoglycaemic reaction several hours after the meal. In some individuals, frank hyperglycemia develops as 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 hyperinsulinemia is what characterizes the transition from insulin resistance to type 2 diabetes•. Various disease states make the body tissues more resistant to the actions of insulin. Examples include infection (TNFα) and acidosis. Recent research involves the relative roles of adipokines (the cytokines produced by adipose tissue). 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. 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. 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. This was first reported by Andres and DeFronzo 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 5-10minutes. 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 signficantly 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 detemine 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). 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. Causes of insulin resistance The cause of the vast majority of cases of insulin resistance remains unknown. Several associated conditions include Therapy The primary treatment for insulin resistance is exercise and weight loss. In some individuals, a low glycemic index diet may also help. Both metformin and the thiazolidinediones improve insulin resistance, but are only approved therapies for type 2 diabetes, not insulin resistance, per se. By contrast, growth hormone replacement therapy may be associated with increased insulin resistance•. 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 •. Monounsaturated fatty acids (like unsaturated fats) promote insulin resistance, whereas polyunsaturated fatty acids can increase insulin sensitivity • • •. 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 sylvestra. There is little, if any, scientific support for any of these supplements. History The concept that insulin resistance may be the underlying cause of diabetes mellitus type 2 was first advanced by Sir Harold Percival Himsworth in 1936. Sources | |||||||||||||||||||
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