Abstract
Insulin resistance (IR), currently called prediabetes (PD), affects more than half of the adult population worldwide. Type 2 diabetes (T2D), which often follows in the absence of treatment, affects more than 475 million people and represents 10–20% of the health budget in industrialized countries. A preventive public health policy is urgently needed in order to stop this constantly progressing epidemic. Indeed, early management of prediabetes does not only strongly reduce its evolution toward T2D but also strongly reduces the appearance of cardiovascular comorbidity as well as that of associated cancers. There is however currently no simple and reliable test available for the diagnosis or screening of prediabetes and it is generally estimated that 20–60% of diabetics are not diagnosed. We therefore developed an ELISA for the quantitative determination of serum Insulin-Regulated AminoPeptidase (IRAP). IRAP is associated with and translocated in a stoechiometric fashion to the plasma membrane together with GLUT4 in response to insulin in skeletal muscle and adipose tissue which are the two major glucose storage sites. Its extracellular domain (IRAPs) is subsequently cleaved and secreted in the blood stream. In T2D, IRAP translocation in response to insulin is strongly decreased. Our patented sandwich ELISA is highly sensitive (≥10.000-fold “normal” fasting concentrations) and specific, robust and very cost-effective. Dispersion of fasting plasma concentration values in a healthy population is very low (101.4 ± 15.9 μg/ml) as compared to those of insulin (21–181 pmol/l) and C-peptide (0.4–1.7 nmol/l). Results of pilot studies indicate a clear correlation between IRAPs levels and insulin sensitivity. We therefore think that plasma IRAPs may be a direct marker of insulin sensitivity and that the quantitative determination of its plasma levels should allow large-scale screening of populations at risk for PD and T2D, thereby allow the enforcement of a preventive health policy aiming at efficiently reducing this epidemic.
Highlights
Candice Trocmé 1, Nicolas Gonnet 2, Margaux Di Tommaso 3, Hanen Samouda 3, Jean-Luc Cracowski, 2,4,5 Claire Cracowski 2, Stéphanie Lambert-Porcheron 6,7, Martine Laville, 6,7,8 Estelle Nobécourt 9, Chiraz Gaddhab 10, Allan Le Lay 11, Torsten Bohn 3, Christine Poitou, 12,13 Karine Clément, 12,13 Fahd Al-Mulla 14, Milad S
Insulin-Regulated AminoPeptidase (IRAP), Biomarker of Insulin-Resistance think that plasma IRAPs may be a direct marker of insulin sensitivity and that the quantitative determination of its plasma levels should allow large-scale screening of populations at risk for PD and Type 2 diabetes (T2D), thereby allow the enforcement of a preventive health policy aiming at efficiently reducing this epidemic
The use of glycemia to screen for T2D and even more so for PD, has proven delusive probably due to its complex regulation and so are HbA1c and insulinemia
Summary
Our approach has been to shift from an integrative parameter, glycemia, to a specific and exclusively insulindependent parameter, glucose uptake. The mechanism through which insulin stimulates cellular glucose uptake, is by inducing the translocation of the vesicles which contain the glucose transporter GLUT4, from the cytoplasm to the plasma membrane (Bryant et al, 2002). Determining plasma membrane vs vesicular GLUT4, is complex and invasive as it requires muscle or adipose tissue biopsies Such an approach is obviously not suitable for routine and large-scale screening or diagnosis of insulin resistance. Its sensitivity is 10 ng/ml for reference values around 100 μg/ml in healthy volunteers under fasting conditions This assay and the diagnostic applications of IRAP. The dispersion of the IRAP concentrations determined in healthy volunteers under fasting conditions using this assay is low (101.4 ± 15.9 μg/ml) as compared to glycemia, insulinemia (21–181 pmol/l) or C-peptide (0.4–1.7 nmol/l), adding to its potential clinical value as a biomarker
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