Pathophysiology
Any food or drink containing glucose (or the digestible carbohydrates that contain it, such as sucrose, starch, etc.) causes blood glucose levels to increase. In a normal metabolism, the elevated blood glucose level makes beta (β) cells in the Islets of Langerhans, located in the pancreas, release insulin into the blood. The insulin, in turn, makes insulin-sensitive tissues in the body (primarily skeletal muscle cells, adipose tissue, and liver) absorb glucose, and thereby lower the blood glucose level. The beta cells reduce insulin output as the blood glucose level falls, allowing blood glucose to settle at a constant of approximately 5 mmol/L (mM) (90 mg/dL). In an insulin-resistant person, normal levels of insulin do not have the same effect in controlling blood glucose levels. During the compensated phase on insulin resistance insulin levels are higher, and blood glucose levels are still maintained. If compensatory insulin secretion fails, then either fasting (impaired fasting glucose) or postprandial (impaired glucose tolerance) glucose concentrations increase. Eventually, type 2 diabetes occurs when glucose levels become higher throughout the day as the resistance increases and compensatory insulin secretion fails. The elevated insulin levels have additional effects (see insulin) that cause further abnormal biological effects throughout the body.
The most common type of insulin resistance is associated with overweight and obesity in a condition known as metabolic syndrome. Insulin resistance often progresses 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) in the face of insulin resistance. 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 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 leads to a kind of insulin resistance; every time a cell is exposed to insulin, the production of GLUT4 (type four glucose receptors) on the cell's membrane decreases somewhat. In the presence of a higher than usual level of insulin (generally caused by insulin resistance), this down-regulation acts as a kind of positive feedback, increasing the need for insulin. Exercise reverses this process in muscle tissue, but if it is left unchecked, it can contribute to insulin resistance.
Elevated blood levels of glucose – regardless of cause – lead 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 within the abdomen – 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 proinflammatory cytokines 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. Much of the attention on production of proinflammatory cytokines has focused on the IKK-beta/NF-kappa-B pathway, a protein network that enhances transcription of inflammatory markers and mediators that can cause insulin resistance. 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 less common. This form of insulin resistance is not what is being referred to in the metabolic syndrome.
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. Among the controlling mechanisms, 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 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.
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