The immune-opioid axis in prediabetes: prediction of prediabetes with insulin resistance by plasma interleukin-10 and Endomorphin-2 to kappa-opioid receptors ratio

Abstract

BackgroundPrediabetes is characterized by a hemoglobin A1c of 5.7%–6.4% and fasting blood glucose of 100–125 mg/dl. A high percentage of prediabetes subjects develops into type 2 diabetes mellitus in the following years. The effect of opioid peptides and their receptors, in addition to immunological cytokines on prediabetes, is not well understood.ObjectiveWe hypothesize that opioid peptides and their receptors affect the insulin and the insulin resistance (IR) in patients with prediabetes and that the immune cytokines, IL-6 (inflammatory factor) and IL-10 (anti-inflammatory factor), influence the opioid system.MethodsA total of 60 patients with prediabetes and IR (prediabetes+IR), 60 patients with prediabetes without IR (prediabetes-IR), and 60 controls participated in the study. The IR state was HOMAIR > 2.5. The enzyme linked immunosorbent assay was used to measure interleukin (IL)-6, IL-10, μ- and κ-opioid receptors (MOR and KOR), endomorphin-2 (EM2), and β- endorphin (βEP).ResultsThe subjects with prediabetes had dyslipidemia, and not all of them underwent the IR state. The IL-6, IL-10, β-endorphin, MOR, and endomorphin-2 were higher in the prediabetes subgroups compared with the control group. MOR was correlated with IL-10 and KOR. Prediabetes+IR can be predicted by the increased levels of the combination of IL-10, βEP, and EM2 and by the combination of IL-10 and endomorphin-2/KOR with good sensitivity and specificity.ConclusionOpioid peptides and their receptors were upregulated in patients with prediabetes depending on the significance of IR. These changes in the opioid system depend on the immune cytokines. Both systems need to be normalized to prevent further development into diabetes mellitus.