Insulin resistance/ja: Difference between revisions

感染症などの急性または慢性の炎症は、インスリン抵抗性を引き起こす可能性がある。[[tumor necrosis factor-alpha/ja|腫瘍壊死因子α|TNF-α]]は、[[lipolysis/ja|脂肪分解]]を促進し、インスリンシグナル伝達を阻害し、GLUT4の発現を低下させることにより、インスリン抵抗性を促進する可能性のあるサイトカインである。

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=== Molecular mechanism ===

At the molecular level, a cell senses insulin through insulin receptors, with the signal propagating through a signaling cascade collectively known as [[PI3K/AKT/mTOR pathway|PI3K/Akt/mTOR signaling pathway]]. Recent studies suggested that the pathway may operate as a [[Bistability#In biological and chemical systems|bistable]] switch under physiologic conditions for certain types of cells, and insulin response may well be a threshold phenomenon. The pathway's sensitivity to insulin may be blunted by many factors such as lipolysis of free fatty acids, causing insulin resistance. From a broader perspective, however, sensitivity tuning (including sensitivity reduction) is a common practice for an organism to adapt to the changing environment or metabolic conditions. Pregnancy, for example, is a prominent change of metabolic conditions, under which the mother has to reduce her muscles' insulin sensitivity to spare more glucose for the brains (the mother's brain and the fetal brain). This can be achieved through raising the response threshold (i.e., postponing the onset of sensitivity) by secreting placental growth factor to interfere with the interaction between insulin receptor substrate (IRS) and PI3K, which is the essence of the so-called ''adjustable threshold hypothesis'' of insulin resistance.

Insulin resistance has been proposed to be a reaction to excess nutrition by [[superoxide dismutase]] in cell [[mitochondria]] that acts as an antioxidant defense mechanism. This link seems to exist under diverse causes of insulin resistance. It also is based on the finding that insulin resistance may be reversed rapidly by exposing cells to mitochondrial uncouplers, [[electron transport chain]] inhibitors, or mitochondrial [[superoxide dismutase mimetics]].

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==Diagnosis==

===Fasting insulin levels===

A fasting serum insulin level greater than 29 microIU/mL or 174 pmol/L indicates insulin resistance. The same levels apply three hours after the last meal.

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===Glucose tolerance testing===

During a [[glucose tolerance test]] (GTT), which may be used to diagnose diabetes mellitus, a fasting patient takes a 75&nbsp;gram oral dose of glucose. Then blood glucose levels are measured over the following two hours.

Interpretation is based on [[WHO]] guidelines. After two hours a [[blood sugar|glycemia]] less than 7.8&nbsp;mmol/L (140&nbsp;mg/dL) is considered normal, a glycemia of between 7.8 and 11.0&nbsp;mmol/L (140 to 197&nbsp;mg/dL) is considered as [[impaired glucose tolerance]] (IGT), and a glycemia of greater than or equal to 11.1&nbsp;mmol/L (200&nbsp;mg/dL) is considered [[diabetes mellitus]].

An [[oral glucose tolerance test]] (OGTT) may 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 peak (after the meal) in insulin production. Extension of the testing (for several more hours) may reveal a [[hypoglycemia|hypoglycemic]] "dip," that is a result of an overshoot in insulin production after the failure of the physiologic postprandial insulin response.

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===Hyperinsulinemic euglycemic clamp===

The [[gold standard (test)|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]]. It is a type of [[glucose clamp technique]]. 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 commonly is referred to in diabetes literature as the GINF value.

The procedure takes about two hours. Through a [[peripheral vein]], [[insulin]] is infused at 10–120 mU per m² per [[minute]]. In order to compensate for the insulin [[intravenous|infusion]], [[glucose]] 20% is infused to maintain blood sugar levels between 5 and 5.5&nbsp;mmol/L. The rate of glucose infusion is determined by checking the [[blood sugar]] levels every five to ten minutes.

The rate of glucose infusion during the last thirty minutes of the test determines insulin sensitivity. If high levels (7.5&nbsp;mg/min or higher) are required, the patient is insulin-sensitive. Very low levels (4.0&nbsp;mg/min or lower) indicate that the body is resistant to insulin action. Levels between 4.0 and 7.5&nbsp;mg/min are not definitive, and suggest "impaired glucose tolerance," an early sign of insulin resistance.

This basic technique may be enhanced significantly by the use of glucose tracers. Glucose may 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).

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===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 μg of [[octreotide]] (Sandostatin) in 5 mL of normal saline over 3 to 5 minutes via intravenous infusion (IV) as an initial bolus, and then, are infused continuously with an intravenous infusion of [[somatostatin]] (0.27 μg/m²/min) to suppress endogenous insulin and glucose secretion. Next, insulin and 20% glucose are infused at rates of 32 and 267&nbsp;mg/m²/min, respectively. Blood glucose is checked at zero, 30, 60, 90, and 120 minutes, and thereafter, every 10 minutes for the last half-hour of the test. These last four values are averaged to determine the steady-state plasma glucose level (SSPG). Subjects with an SSPG greater than 150&nbsp;mg/dL are considered to be insulin-resistant.

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===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|Homeostatic Model Assessment]] (HOMA), and more recent methods include the [[Quantitative insulin sensitivity check index]] (QUICKI) and [[SPINA-GR]], a measure for insulin sensitivity. All of these calculated markers employ [[fasting]] [[insulin]] and [[glucose]] levels to calculate insulin resistance, and all correlate reasonably with the results of clamping studies.

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==Prevention and management==

The primary treatment for insulin resistance is [[exercise]] and [[weight loss]]. Both [[metformin]] and [[thiazolidinedione]]s improve insulin sensitivity. Metformin is approved for prediabetes and type 2 diabetes and has become one of the more commonly prescribed medications for insulin resistance.

The ''Diabetes Prevention Program'' (DPP) showed that exercise and diet were nearly twice as effective as [[metformin]] at reducing the risk of progressing to type 2 diabetes. However, the participants in the DPP trial regained about 40% of the weight that they had lost at the end of 2.8 years, resulting in a similar incidence of diabetes development in both the lifestyle intervention and the control arms of the trial. In epidemiological studies, higher levels of physical activity (more than 90 minutes per day) reduce the risk of diabetes by 28%.

[[Resistant starch]] from high-amylose corn, [[amylomaize]], has been shown to reduce insulin resistance in healthy individuals, in individuals with insulin resistance, and in individuals with type 2 diabetes.

Some types of [[Polyunsaturated fat|polyunsaturated fatty acids]] ([[omega-3]]) may moderate the progression of insulin resistance into type 2 diabetes, however, omega-3 fatty acids appear to have limited ability to reverse insulin resistance, and they cease to be efficacious once type 2 diabetes is established.