Definition and measurement of insulin resistance in humans
المؤلف:
Holt, Richard IG, and Allan Flyvbjerg
المصدر:
Textbook of diabetes (2024)
الجزء والصفحة:
6th ed , page 238-240
2025-12-01
59
The sensitivity to insulin results from its biological effects in the insulin- responsive tissues, predominantly skeletal muscle, liver, and adipose tissue. Impaired insulin sensitivity, also termed insulin resistance, is generally defined as reduced glucose clearance in skeletal muscle, impaired suppression of glucose production by the liver, and decreased rates of lipolysis in adipose tissue or by decreased combined action on whole- body glucose disposal (Figures 1 and 2).
Fig1. Cellular mechanism of insulin resistance in human skeletal muscle. Augmented lipid availability, mainly increased fatty acid flux, raises the intramyocellular pool of the long- chain fatty acyl (CoA) pool, which fuels mitochondrial oxidation or serves to synthesize diacylglycerols (DAGs) for storage as triglyceride (TAG) lipid droplets. When fatty acid delivery and uptake exceed the rates of mitochondrial long- chain fatty acyl- CoA oxidation and incorporation of DAGs into TAGs, the intramyocellular DAG content transiently or chronically increases. Specifically, increases in plasma membrane sn- 1,2- DAGs lead to activation of novel protein kinase C (nPKC) isoforms (PKCε and PKCθ). Translocation of the PKCε to the membrane leads to phosphorylation of the insulin receptor on threonine1160 (T1160), leading to inhibition of insulin receptor kinase (IRK) activity, whereas activation of PKCθ leads to increased serine phosphorylation of insulin receptor substrate 1 (IRS- 1) on critical sites (e.g. Ser1101), which in turn blocks insulin- stimulated tyrosine phosphorylation of IRS- 1 and the binding and activation of phosphatidylinositol 3- kinase (PI3K). Both of these events result in reduced insulin- stimulated recruitment of glucose transporter type 4 (GLUT 4) units to the membrane, leading to impaired insulin- stimulated glucose uptake and phosphorylation to glucose- 6- phosphate and ultimately decreased insulin- stimulated glycogen synthesis. Source: Shulman 2014. Copyright © 2014 Massachusetts Medical Society. Reprinted with permission.
Fig2. Cellular mechanism of insulin resistance in the human liver. An imbalance of intrahepatocellular fluxes gives rise to increases in plasma membrane sn- 1,2- diacylglyerols (sn- 1,2- DAGs), when DAG synthesis, from both fatty acid re- esterification and de novo lipogenesis, exceeds the rates of mitochondrial oxidation of long- chain fatty acyl- coenzyme A (CoA) and/or the rates of sn- 1,2- DAG incorporation into triglycerides (TAGs) and lipid droplets. Increases in plasma membrane sn- 1,2- DAGs leads to translocation and activation of protein kinase Cε (PKCε) to the plasma membrane, where it binds to the insulin receptor and phosphorylates it on threonine1160 (threonine1150 in mice), which in turn leads to inhibition of IRK activity and downstream insulin signalling events. In turn, phosphorylation of glycogen synthase kinase 3 (GSK3) increases, while that of forkhead box subgroup O (FOXO) decreases. This results in inhibition of glycogen synthase activity and thereby lowering insulin- stimulated glycogen storage, and in FOXO- mediated gene transcription of the gluconeogenic enzymes (e.g. phosphoenolpyruvate carboxykinase [PEP- CK] and glucose- 6- phosphate), with decreased insulin suppression of hepatic gluconeogenesis. It is also important to note that untargeted phosphoproteomic studies have identified many other proteins that are phosphorylated by activation of PKCε besides the insulin receptor, such as p70S6K, which will also cause insulin resistance downstream of the insulin receptor. Source: Shulman 2014. Copyright © 2014 Massachusetts Medical Society. Reprinted with permission.
In 1936, Himsworth provided the first protocol for the standardized in vivo determination of insulin sensitivity from the glycaemic response on intravenous insulin application. Decades later, the hyperinsulinaemic–euglycaemic clamp test became the gold standard for measuring whole- body insulin sensitivity in vivo and for identifying insulin- resistant people. This steady- state method relies on constant insulin and glucose concentrations, which disrupt the physiological feedback loop between blood glucose concentrations and insulin secretion. The glucose infusion rates required to maintain a defined level of glycaemia will then reflect whole- body insulin sensitivity, given as the M- value. Combined with other techniques, including indirect calorimetry, isotopic tracer dilution, and nuclear magnetic resonance (NMR) spectroscopy of muscle, liver, and brain, the clamp allows the assessment of oxidative and non- oxidative glucose metabolism, systemic, and even tissue- specific fluxes of glucose and other metabolites under in vivo conditions. In contrast to the steady- state clamp test, other techniques such as the intravenous or oral glucose tolerance tests describe parameters of insulin action, such as the Si or oral glucose insulin sensitivity (OGIS) values, from modelling of the dynamic changes of plasma glucose and insulin concentrations over time. These tests can also provide measures of insulin secretion and kinetics during the same experiment.
As these techniques are time consuming and laborious and require experienced personnel, simpler tests have been developed for assessing insulin sensitivity in epidemiological studies. The commonest indices, homeostasis model assessment (HOMA- IR, HOMA- B) and QUICKI, are calculated from fasting plasma glucose and insulin or C- peptide concentrations. The general limitation of this approach results from the fact that the liver is responsible for providing fasting plasma glucose. Under these conditions, 60% of glucose is utilized in non- insulin- dependent tissues, such as the brain, and to a lesser extent in insulin- sensitive tissues, such as muscle and liver. The insulin resistance indices obtained during fasting therefore do not correlate closely with clamp- derived glucose disposal. Finally, these indices can be used for describing insulin sensitivity in recent- onset diabetes, but may not be valid in long- standing diabetes when the physiological relationship between circulating glucose and insulin or C- peptide is disrupted.
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