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Insulin resistance



Insulin resistance
Classification & external resources
eMedicine med/1173 
MeSH C18.452.394.968.500

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.

Additional recommended knowledge

Contents

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. On occasion, 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.[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).

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. After 2 hours a Glycemia less than 7.8 mmol/L is considered normal, a glycaemia of between 7.8 to 11.0 is considered as Impaired Glucose Tolerance (IGT) and a glycaemia of greater than or equal to 11.1 is considered 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.[2] 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 (0.27microgm/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 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 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 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.[3]

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. An American study has shown that glucosamine (often prescribed for joint problems) may cause insulin resistance. [4]

Associated Conditions

Several associated conditions include

Insulin resistance may also be caused by the damage of liver cells having undergone a defect of insulin receptors in hepatocytes.

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. 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.[5]

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.[6]

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.[7][8][9]

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.[10]

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.[11]

References

  1. ^ McGarry J (2002). "Banting lecture 2001: dysregulation of fatty acid metabolism in the etiology of type 2 diabetes". Diabetes 51 (1): 7-18. PMID 11756317.
  2. ^ DeFronzo R, Tobin J, Andres R (1979). "Glucose clamp technique: a method for quantifying insulin secretion and resistance". Am J Physiol 237 (3): E214-23. PMID 382871.
  3. ^ Wallace T, Levy J, Matthews D (2004). "Use and abuse of HOMA modeling". Diabetes Care 27 (6): 1487-95. PMID 15161807.
  4. ^ Pham, T.; Cornea, A.; Blick, K.E.; Jenkins, A.; Scofield, R.H.M.D. (2007). "Oral Glucosamine in Doses Used to Treat Osteoarthritis Worsens Insulin Resistance". The American Journal of the Medical Sciences 333 (6): 333-339. Retrieved on 2007-11-11.
  5. ^ Bramnert M, Segerlantz M, Laurila E, Daugaard JR, Manhem P, Groop L (2003). "Growth hormone replacement therapy induces insulin resistance by activating the glucose-fatty acid cycle". THE JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM 88 (4): 1455-1463. PMID 12679422.
  6. ^ Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, Nathan DM; Diabetes Prevention Program Research Group (2002). "Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin". New England Journal of Medicine 346 (6): 393-403. PMID 11832527.
  7. ^ Lovejoy, JC (2002). "The influence of dietary fat on insulin resistance". Current Diabetes Reports 2 (5): 435–440. PMID 12643169.
  8. ^ Fukuchi S (2004). "Role of Fatty Acid Composition in the Development of Metabolic Disorders in Sucrose-Induced Obese Rats". Experimental Biology and Medicine 229 (6): 486–493. PMID 15169967.
  9. ^ Storlien LH (1996). "Dietary fats and insulin action". Diabetologica 39 (6): 621–631. PMID 8781757.
  10. ^ Harinantenaina L (2006). "Momordica charantia constituents and antidiabetic screening of the isolated major compounds". Chemical & Pharmaceutical Bulletin (Tokyo) 54 (7): 1017–21. PMID 16819222.
  11. ^ Himsworth HP (1936). "Diabetes mellitus: its differentiation into insulin-sensitive and insulin-insensitive types". Lancet 1: 127–130.

See also

 
This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Insulin_resistance". A list of authors is available in Wikipedia.
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