Insulin resistance

Insulin resistance (IR) 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 reduces the effects of insulin and results in elevated hydrolysis of stored triglycerides in the absence of measures which either increase insulin sensitivity or which provide additional insulin. Increased mobilization of stored lipids in these cells elevates free fatty acids in the blood plasma. Insulin resistance in muscle cells reduces glucose uptake (and so local storage of glucose as glycogen), whereas insulin resistance in liver cells results in impaired glycogen synthesis and a failure to suppress glucose production. 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 concentration. High plasma levels of insulin and glucose due to insulin resistance are believed to be the origin of metabolic syndrome and type 2 diabetes, including its complications.

Symptoms of IR

1. Fatigue.
2. Brain fogginess and inability to focus. Sometimes the fatigue is physical, but often it is mental.
3. High blood sugar.
4. Intestinal bloating. Most intestinal gas is produced from carbohydrates in the diet. Insulin resistance sufferers who eat carbohydrates sometimes suffer from gas.
5. Sleepiness. Many people with insulin resistance get sleepy immediately after eating a meal containing more than 20% or 30% carbohydrates.
6. Weight gain, fat storage, difficulty losing weight. For most people, too much weight is too much fat. The fat in IR is generally stored in and around abdominal organs in both males and females. It is currently suspected that hormonal effects from such 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 on arterial walls throughout the body.
9. Depression. Because of the deranged metabolism resulting from insulin resistance, psychological effects are not uncommon. Depression is said to be the prevalent psychological symptom.

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. This lowers blood glucose levels. The beta cells reduce their insulin output as blood glucose levels fall, with the result that blood glucose is maintained at approximately 5 mmol/L (mM) (90 mg/dL). In an insulin-resistant person, normal levels of insulin do not have the same effect on muscle and adipose cells, with the result that glucose levels stay higher than normal. To compensate for this, the pancreas in an insulin-resistant individual is stimulated to release more insulin. The elevated insulin levels have additional effects (see insulin) which cause further biological effects throughout the body.

The most common type of insulin resistance is associated with a collection of symptoms known as metabolic syndrome. Insulin resistance can progress to full Type 2 diabetes mellitus (T2DM). This is often seen when hyperglycemia develops after a meal, when pancreatic β-cells are unable to produce sufficient insulin to maintain normal blood sugar levels (euglycemia). The inability of the β-cells to produce sufficient insulin in a condition of hyperglycemia is what characterizes the transition from insulin resistance to Type 2 diabetes mellitus.^[1]

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).

Insulin itself can lead to insulin resistance; every time a cell is exposed to insulin, the production of GLUT4 (type four glucose receptors) on the cell's membrane is decreased.^[2] This leads to a greater need for insulin, which again leads to fewer glucose receptors. Exercise reverses this process in muscle tissue,^[3] but if left unchecked, it can spiral into insulin resistance.

Elevated blood levels of glucose — regardless of cause — leads to increased glycation of proteins with changes (only a few of which are understood in any detail) in protein function throughout the body.

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, 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 proinfammatory cytokines profoundly 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. A great deal of attention into the production of proinflammatory cytokines has focused on the IKK-beta/NF-kappa-B pathway, a protein network that enhances transcription of cytokine genes. 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.

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 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 uncommon.

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 by several factors. Among them, 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 the 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.

Investigation

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.

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. After 2 hours a Glycemia less than 7.8 mmol/L (140 mg/dl) is considered normal, a glycaemia of between 7.8 to 11.0 mmol/dl (140 to 197 mg/dl) is considered as Impaired Glucose Tolerance (IGT) and a glycaemia of greater than or equal to 11.1 mmol/dl (200 mg/dl) is considered Diabetes Mellitus.

An 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.^[4] 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 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.

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 25 mcg of octreotide (Sandostatin) in 5 ml of normal saline over 3 to 5 min IV as an initial bolus, and then will be infused continuously with an intravenous infusion of somatostatin (0.27 μgm/m²/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. Subjects with an SSPG greater than 150 mg/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 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.^[5]

Causes of insulin resistance

There are several levels of insulin resistence causation including diet, cellular, molecular, genetic, and disease.

Diet

Grounds exist for linking insulin resistance to a high-carbohydrate diet. An American study has shown that glucosamine (often prescribed for joint problems) may cause insulin resistance.^[6] 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. Other studies have also linked to the increased amounts of fructose (e.g., in HFCS — high fructose corn syrup, currently the least expensive nutritive sweetener available in industrial quantities); in humans, fructose causes changes in blood lipid profiles, among other things, mostly due to its effects on liver function. The high amounts of ordinary sucrose (i.e., table sugar) in the typical developed-world diet is also suspected of having some causative effect on the development of insulin resistance (sucrose is 1/2 fructose, which may account for the effect, if any). Insulin resistance has certainly risen in step with the increase in sugar consumption and the substantial commercial usage of HFCS since its introduction to the food trades; the effect may also be due to other parallel diet changes however. Further research may distinguish between candidate causes. .

Cellular

At the cellular level, excessive circulating insulin appears to be a contributor to insulin resistance via down-regulation of insulin receptors. This occurs due to prolonged and repeated elevations of circulating insulin.^[7] Since the usual instances of Type 2 insulin resistance are distinct from pathological over production of insulin, this does not seem to be the typical cause of the insulin resistance leading to Type 2 diabetes mellitus, the largest clinical issue connected with insulin resistance. The presence of insulin resistance typically precedes the diagnosis of Types 2 diabetes mellitus, however, and as elevated blood glucose levels are the primary stimulus for insulin secretion and production, habitually excessive carbohydrate intake is a likely contributor. Additionally, some Type 2 cases require so much external insulin that this down-regulation contributes to total insulin resistance.

Inflammation 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.^[8][9]

Vitamin D deficiency is also associated with insulin resistance.^[10]

Some research has shed light on a complex interaction between elevated free fatty acids and inflammatory cytokines seen in obesity activating Protein Kinase C isoform theta. PKC Theta inhibits Insulin Receptor Substrate (IRS) activation and hence prevents glucose up-take in response to insulin.

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 a antixidant 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.^[11]

Genetic

Individual variability is a cause with an inherited component, as sharply increased rates of insulin resistance and Type 2 diabetes are found in those with close relatives who have developed Type 2 diabetes.

Disease

Sub-clinical Cushing's syndrome and hypogonadism (low testosterone levels) seem to be the major insulin resistance causes ^[12][13].

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 proximal small intestine and 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 which 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 speculation.

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^{[citation needed]})
• Haemochromatosis
• Gastroparesis
• Tobacco Smoking^{[citation needed]}
• Coffee (A Canadian study has found that consumption of caffeine makes insulin more resistant to alterations in blood sugar in patients with and without diabetes.)
• Polycystic ovarian syndrome (PCOS)
• Hypercortisolism (e.g., steroid use or Cushing's disease)
• Drugs (e.g., rifampicin, isoniazid, olanzapine, risperidone, progestogens, corticosteroids, glucocorticoids, many antiretrovirals, possibly alcohol^[14], methadone)
• Genetic causes
  • 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.

Treatment

The primary treatment for insulin resistance is exercise and weight loss. Low-glycemic index or low-carbohydrate diets have also been shown to help.^[15] 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.^[16] 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 except for use in diabetics, but often improves insulin resistance by the same mechanism as it does diabetes. It also has been used to aid in weight loss for diabetics and those with insulin resistance, and is being studied for this use as well as for weight loss in people who have gained weight while on antidepressants.

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.^[17]

Many people with insulin resistance currently follow the lead of some diabetics, and add cinnamon in therapeutic doses to their diet to help control blood sugar. This has the danger of increasing the risk of bleeding, since most commercial cinnamon preparations are actually from Cassia (Cinnamomum aromaticum), which also contains anticoagulants; whereas "true cinnamon" (Cinnamomum zeylanicum or sp. verum) does not.^{[citation needed]}

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.^[18][19][20]

There are scientific studies showing that vanadium (e.g., as vanadyl sulfate) and chromium (e.g., in chromium picolinate and GTF formulations) in reasonable doses have reportedly also shown some efficacy in improving IR sensitivity, but these effects are controversial.

Naturopathic approaches to insulin resistance have been advocated including supplementation of vanadium (but see preceding paragraph), bitter melon (Momordica, but reportedly dangerous if not used with care), and Gymnema sylvestre.^[21]

One study found that chromium is necessary for maintaining normal glucose tolerance.^[22]

Daily Mg administration, restoring an appropriate intracellular Mg concentration, contributes to improve insulin-mediated glucose uptake. High daily Mg intake are predictive of a lower incidence of NIDDM.

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,^[23] and confirmed by Sir Harold Percival Himsworth of the University College Hospital Medical Centre in London in 1936.^[24]

See also

• Chronic Somogyi rebound

References

• Symptoms list was quoted in part from various websites that are trying to educate the public about the illness, but were edited for accuracy.

^{[12] [13]}

External links

• Insulin resistance review from American Association of Family Physicians
• Insulin resistance at the Open Directory Project
• The National Insulin Resistance Council