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.
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. This leads to a greater need for insulin, which again leads to fewer glucose receptors. Exercise reverses this process in muscle tissue, 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.
Further Reading
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