Soluble receptors for advanced glycation endproducts are predictors of insulin sensitivity and affected by weight loss

Abstract

Background Mice experiments have underscored the efficacy of pharmacological inhibition of advanced glycation endproducts (AGEs) through the use of soluble receptors for advanced glycation endproducts (sRAGE) in mitigating obesity-linked metabolic disruptions and insulin resistance. However, human studies have presented conflicting findings regarding the correlation between circulating sRAGE levels and insulin resistance, as well as glucose tolerance. Here, we aimed to delve deeper into the relationship between sRAGE levels and systemic insulin sensitivity. Methods Plasma sRAGE levels, hyperinsulinemic-euglycemic clamp, and continuous glucose monitoring were measured in two independent cross-sectional case-control studies [cohort 1 (n = 180) and cohort 2 (n = 124)]. In addition, a subgroup of 42 participants with obesity were followed for 12 months. In 14 of these participants, weight loss was achieved through bariatric surgery intervention. Results Our results revealed a significant association between plasma sRAGE levels and both insulin sensitivity and glycemic control parameters, even after adjustments for age, sex, and BMI. Furthermore, longitudinal analysis demonstrated that interventions aimed at weight loss led to reductions in fasting glucose and HbA1c levels, concurrently with increases in sRAGE levels. Conclusions These findings underscore that sRAGE levels were strongly associated with insulin sensitivity and glycemic control, suggesting a possible role of sRAGE in preserving insulin sensitivity and maintaining glycemic control, which should be confirmed in further studies

This study was partially supported by research grants PID2022-143113OB-I00 (JMM-N) from the Ministerio de Ciencia e Innovación from Spain and Instituto de Salud Carlos III (ISCIII) through the projects PI15/01934, PI18/01022 and PI21/01361 and co-funded by the European Union to J.M.F-R, and Generalitat de Catalunya 2021 SGR 01263. MR-D is funded by the Horizon 2020 Framework Programme of the European Union under the Marie Skłodowska-Curie Innovative Training Network grant agreement No. 859890. IDIBGI is a CERCA center from the “CERCA Programme/Generalitat de Catalunya.” The CIBEROBN is an initiative from the Instituto de Salud Carlos III (ISCIII). Dexcom provided CGM systems at discounted research pricing under an unrestricted grant