Insulin resistance pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Dayana Davidis, M.D. [2]
Overview
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.[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.
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)
Insulin resistance may also be caused by the damage of liver cells which result in defect of insulin receptors in hepatocytes.