Insulin resistance in obesity: metabolic mechanisms and measurement methods.
In obesity several mechanisms contribute to produce insulin resistance. Elevation of plasma FFA increases the concentration of cytoplasmic long-chain-CoA (LC-CoA) and mitochondrial acetyl-CoA. The latter inhibits pyruvate dehydrogenase (PDH) and, therefore, glucose oxidation. LC-CoA exerts an array of effects, some mediated by peroxisome proliferator-activated receptors, including modulation of gene expression of enzymes of glycolipid metabolism, thus inhibiting glucose utilization and potentiating FFA oxidation. Enhanced availability of glucose plus insulin forces glucose utilization (activation of PDH and glycogen synthase) and leads to increased production of malonyl-CoA (via citrate), which inhibits carnitine palmitoyl transferase 1 and therefore FFA beta-oxidation. In obesity there is often enhanced availability of both FFA and glucose plus insulin. The latter, by increasing malonyl-CoA, may limit FFA beta-oxidation. This, however, leads to further increases in LC-CoA, which worsens insulin resistance. All these mechanisms occur through both short-term and long-term effects. Therefore, when insulin sensitivity is measured with the hyperinsulinemic clamp, which artificially suppresses FFA levels, the FFA short-term effects are lost. More physiological methods are those utilizing OGTT data, allowing calculation of an Insulin Sensitivity Index for glycemia, or ISI(gly), through the formula: 2/((INSp x GLYp)+1), where INSp and GLYp are the measured insulin and glycemic areas expressed by taking mean normal value as 1. The corresponding Insulin Resistance Index, or IRI(gly), can be obtained through the formula: 2/((1/(INSp x GLYp))+1). Substitution of glycemic (GLYp) with FFA (FFAp) values allows the calculation of indices of insulin sensitivity and resistance for FFA, i.e., ISI(ffa) and IRI(ffa).
Belfiore
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Chair of Internal Medicine, University of Catania Medical School, Catania, 95123, Italy. francesco.belfiore@iol.it
Iannello
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D000818:Animals; D003920:Diabetes Mellitus / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology*; D008954:Models, Biological; D009765:Obesity / Q000378:metabolism*
D005227:Fatty Acids; D005230:Fatty Acids, Nonesterified; D005947:Glucose