4 ANÁLISIS E INTERPRETACIÓN DE RESULTADOS
6.6 Desarrollo de la Propuesta
2.2.6.1 Basis for surrogate measurement of insulin sensitivity
The two most important components of insulin sensitivity are glucose clearance in peripheral (mainly muscles) tissues (i.e. peripheral insulin sensitivity) and insulin mediated suppression of hepatic glucose production (i.e. hepatic insulin sensitivity) (802). The HEC mainly measures muscle insulin sensitivity, fasting indices mainly measure hepatic insulin sensitivity and the OGTT-based indices measure both types of insulin sensitivity (783;801). The reason behind moderate to high correlations (r>0.5) of fasting surrogate measures with the HEC is that, in most people, hepatic insulin sensitivity is closely related to peripheral insulin sensitivity (801). OGTT based surrogate markers are based on changes in insulin and glucose during the OGTT and incorporate both peripheral and hepatic insulin sensitivity. During the first hour of OGTT, changes in hepatic glucose production are dominant, while peripheral glucose uptake is best measured during the second hour (801).
Measurement of insulin resistance is very complex when considering whole body glucose metabolism. The surrogate markers are based on blood levels of glucose, insulin and/or non- esterified fatty acids (NEFA), which in turn are influenced by following important biological processes: dietary glucose absorption, renal
glucose loss, insulin clearance, lipolysis, lipids re- esterification, hepatic glucose production, insulin secretion rate, β-cell glucose sensitivity, muscle cells or peripheral insulin sensitivity and muscle cells activity or glucose utilization. Each of these components influences circulating glucose and insulin concentrations and at any moment of blood sampling; the blood glucose and insulin level are the product of all of these components.
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Resistance to insulin-mediated peripheral glucose disposal or insulin resistance (measured by HEC) is just one component of glucose metabolism and refers mainly to muscle cells. Hepatic insulin sensitivity or hepatic glucose production is largely suppressed during the clamp procedure and so the term insulin
sensitivity in this context refers mainly to muscles glucose disposal. The
measurement of interest when measuring insulin sensitivity is only muscle cells insulin sensitivity and not the combined effect of all measurements and thus surrogate markers can only provide an approximation of a true value.
Although OGTT derived indices take at least 2-3 hours, they have the additional advantage of evaluating other parameters apart from insulin sensitivity, such as glucose tolerance and insulin secretion.
The HEC is considered the gold standard for measuring peripheral insulin
sensitivity as it is not influenced by changing glucose and insulin levels (and the factors influencing blood glucose and insulin), the hepatic insulin extraction or clearance, β-cells insulin secretion and feedback mechanism between glucose and insulin (777).
2.2.6.2 Correlations between surrogate markers and HEC in relation to blood glucose status
Surrogate measures of insulin sensitivity exhibit weaker correlations with the HEC in healthy normal weight individuals as compared to people having insulin resistance (776). This finding is further supported by a recent meta-analysis showing that surrogate measures like Matsuda, Stumvoll MCR, Stumvoll ISI and revised QUICKI were more strongly correlated with HEC in individuals with IGT than in those with NGT or type 2 diabetic patients (802). However OGIS, QUICKI and HOMA showed almost equal correlations in individuals with NGT, IGT and type 2 diabetes (802).
The strength of the correlations between HEC and surrogate measures in individuals with different levels of insulin sensitivity (NGT, IGT and T2DM) depends on the insulin dose used during the clamp (806). Lower insulin doses show strong correlations for healthy NGT people, and higher insulin doses show higher correlation for insulin resistant individuals (802). The studies of fasting surrogate measures showing higher correlations with HEC in which low dose
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insulin is used, may be due to the fact that it may be measuring hepatic insulin sensitivity instead of peripheral glucose uptake (807) as low dose insulin does not suppress HGP. In OGTT based surrogate measures insulin levels around 120 min exhibit a strong correlation with HEC in a healthy population, but not in a population with diabetes as it is strongly influenced by islet dysfunction (802).
2.2.6.3 Other potential errors associated with surrogate measures
In a healthy individual fasting glucose is tightly regulated by other factors apart from insulin sensitivity, such as islet cells function and insulin release and HGP. So there will be minimal variation in fasting glucose in healthy subjects with various degrees of insulin sensitivity. In addition insulin levels at any point are also regulated by β-cell insulin secretion and insulin clearance by liver; in addition to insulin sensitivity (802). On the other hand measuring insulin concentration is one of the most important components of many surrogate indices but there are several sources of error in insulin measurement. Some insulin assays show cross reactivity with pro-insulin and partially processed proinsulin products: this can be a source of error when using some
radioimmunoassys. Newer and more specific assays have reduced this cross reactivity (808). Another issue with inulin assays is that many show more
variability at low insulin levels and may be a possible cause of lower correlation coefficients in healthy individuals vs type 2 diabetic patients (806). The OGTT based surrogate markers are also influenced by inter individual variability of gastric emptying, glucose absorption, insulin secretion and incretin hormones (802).
Closing the discussion, surrogate markers have an importance in large scale studies and can be used in place of HEC when it is desired to check insulin sensitivity at one point in time. However, surrogate markers are less reliable for analysing change in insulin sensitivity in response to metabolic factors or the relationship of insulin sensitivity with other risk factors (inflammation, BP, hypertension etc). The main reason why surrogate markers are not used in mechanistic and physiological studies is that their validity is dependent upon intact function of other biological processes; normal pancreatic βcell function, normal liver glucose and fat metabolism and normal insulin clearance.
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For measuring insulin sensitivity surrogate markers depend upon detecting insulin and glucose concentration. The glucose concentration can be low or high depending on many factors specially β-cell insulin secretion. In insulin resistant states, if β-cells are functioning normally they will secrete extra insulin to compensate for insulin resistance leading to ‘compensatory hyperinsulinaemia’. This is true for obese insulin resistant people having normal blood glucose. On the other side some people have weak or more prone β-cells of pancreas and develop dysfunction with slight metabolic stress and may show abnormal plasma glucose in insulin sensitive or mild insulin resistant individual. In HEC,
physiological feedback between glucose and insulin concentrations is disrupted and HEC is not influenced by β-cell insulin secretion capacity and insulin
clearance etc (802).
In a recent meta- analysis comparing correlations of all surrogate markers with HEC, Otten et al found that the OGTT-based surrogate measures (Stumvoll metabolic clearance rate r=0.70, OGIS r=0.70, the Matsuda index r=0.67, the Stumvoll insulin sensitivity index r=0.67) had highest correlation with HEC. The non-OGTT surrogate measure which exhibited the highest correlation coefficient with HEC was ‘revised QUICKI’ r=0.68) (802). It was further concluded that surrogate indices derived from fasting measurements, are valid measures of insulin resistance, and that OGTT with multiple sampling is not necessary for estimating insulin sensitivity in both clinical and epidemiological studies (802).
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Figure 2.1 Basis of surrogate markers of insulin sensitivity and hyperinsulinaemic euglycaemic clamp
Reproduced with permission from Petrie JR 2014 (809).
Whole body glucose metabolism, blood glucose, insulin levels and peripheral insulin sensitivity in relation to measurement of insulin sensitivity.