Insulin resistance

In medicine, insulin resistance denotes a decompensation of glucose homeostasis where the tissues appear to be less responsive to insulin.

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.

Insulin resistance denotes decreased sensitivity of target cells (muscle, fat cells) to insulin. It is the metabolic cause of the very common "metabolic syndrome", which is the clustering of diabetes mellitus (type 2), hypertension, combined hyperlipidemia and central obesity in patients. It also underlies most processes behind the metabolic complications of polycystic ovarian syndrome (PCOS).

In a normal person, a small amount of insulin is produced after eating ("postprandial"), and it signals the body to absorb the sugars from the food at a steady rate. In an "insulin resistant" person the message does not get to the cells so the sugar remains in the blood for long periods of time while ever more insulin is released in an attempt to trigger the sugar-uptake. The sugar circulates in the blood for several hours and then is taken into the cells very rapidly, leading to a steep drop in blood sugar and a hypoglycaemic reaction several hours after the meal.

At a later stage, frank hyperglycemia develops as pancreatic &beta;-cells are unable to produce adequate insulin to maintain normal blood sugar levels ("euglycemia").

Various disease states make the body tissues more resistant to the actions of insulin. Example include infection (TNF&alpha;) and acidosis. Recent research involves the relative roles of adipokines (the cytokines produced by adipose tissue) in modifying insulin resistance.

Insulin resistance and atherosclerosis often appear together. Insulin resistance in these patients can be detected not only by sophisticated tests but by some simple observations of hypertension, hyperglycaemia and dyslipidemia involving small dense low-density lipoprotein (sdLDL) particles.

These patients also have slightly decreased high-density lipoprotein (HDL) levels, impaired fibrinolysis, a hypercoagulable state and increased inflammatory cytokine levels.

Glucose tolerance testing (GTT)
During a glucose tolerance test (GTT), which is generally used to diagnose diabetes mellitus type 2, the patient (who has been fasting) takes a fixed oral dose of glucose, and glucose levels are measured by fingerprick testing every 30 minutes of the following hours.

Interpretation depends on local guidelines, but glycemia exceeding 10 mmol/l is often considered diagnostic for diabetes.

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) will often 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 DeFronzo et al in 1979. The test is rarely performed in clinical care, but is sometimes used in medical research - for example, to assess the effects of different medications.

The procedure takes about 2 hours. Through a peripheral vein, insulin is infused at 0.06 units per kg body weight 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 minutes.

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) suggest that the body is resistant to insulin action. Levels between 4.1 and 7.4 mg/min are indetermined and might point at "impaired glucose tolerance", considered an early form of insulin resistance.

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

 * 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)
 * Genes

Therapy
Both metformin and the thiazolidinediones improve insulin resistance. Exercise, weight loss, and a low glycemic index diet may help.

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 (Knowler et al 2002).

Naturopathic approaches to insulin resistance include: supplementation of chromium and vanadium have been shown to potentiate the effects of insulin at receptor cells, bitter melon (momordica) and gymnema sylvestra are two common herbs used as hypoglycemic agents. Additionally, Essential Fatty Acids, EFA, have been shown to improve insulin receptor sensitivity.

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.