The IL-6-neutralizing sIL-6R-sgp130 buffer system is disturbed in patients with type 2 diabetes

• Published in: American journal of physiology: endocrinology and metabolism Vol. 317; no. 2; pp. E411 - E420
• Main Authors: Aparicio-Siegmund, Samadhi, Garbers, Yvonne, Flynn, Charlotte M., Waetzig, Georg H., Gouni-Berthold, Ioanna, Krone, Wilhelm, Berthold, Heiner K., Laudes, Matthias, Rose-John, Stefan, Garbers, Christoph
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.08.2019
• Subjects: Aged; Amino Acid Substitution; Arteriosclerosis; Atherosclerosis; Atherosclerosis - blood; Atherosclerosis - etiology; Buffers; Case-Control Studies; Cytokine Receptor gp130 - blood; Cytokine Receptor gp130 - metabolism; Diabetes; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - complications; Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - metabolism; Female; Glycoprotein gp130; Glycoproteins; Hep G2 Cells; Humans; Interleukin 6; Interleukin 6 receptors; Interleukin-6 - antagonists & inhibitors; Interleukin-6 - blood; Interleukin-6 - pharmacology; Male; Middle Aged; Neutralizing; Nucleotides; Phosphorylation - drug effects; Polymorphism; Polymorphism, Single Nucleotide; Protein Binding; Receptors, Interleukin-6 - blood; Receptors, Interleukin-6 - genetics; Receptors, Interleukin-6 - metabolism; Serum levels; Signal Transduction - drug effects; Signal Transduction - genetics; Single-nucleotide polymorphism; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism; gp130; interleukin-6 receptor; type 2 diabetes; interleukin-6
• ISSN: 0193-1849; 1522-1555; 1522-1555
• DOI: 10.1152/ajpendo.00166.2019

Serum levels of interleukin-6 (IL-6) are increased in patients with type 2 diabetes (T2D). IL-6 exerts its pleiotropic effects via the IL-6 α-receptor (IL-6R), which exists in membrane-bound and soluble (sIL-6R) forms and activates cells via the β-receptor glycoprotein 130 (gp130). The nonsynonymous single-nucleotide polymorphism (SNP) rs2228145 (Asp358Ala) within the IL6R locus is associated with T2D. The aim of this study was to determine whether sIL-6R in combination with soluble gp130 (sgp130) is able to form an IL-6-neutralizing buffer in healthy subjects and whether this is disturbed in T2D. We found that sIL-6R-sgp130 indeed forms an IL-6-neutralizing buffer in the serum of healthy humans, whose capacity is controlled by the SNP of the IL-6R. Circulating sIL-6R-sgp130 levels were lower in T2D subjects ( P < 0.001), whereas IL-6 was high and inversely correlated with sIL-6R ( r = −0.57, P < 0.001), indicating a severe disturbance of the buffer. This phenomenon is also observed in sex- and age-matched patients with both T2D and atherosclerosis but not in patients with atherosclerosis alone. In conclusion, sIL-6R and sgp130 serum levels were significantly lower in T2D patients compared with healthy subjects or atherosclerosis patients, although IL-6 levels were high. These data suggest that disturbance of the protective buffer may be closely associated with T2D pathophysiology.