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

Abstract

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.

• Authors: Samadhi Aparicio-Siegmund, Yvonne Garbers, Charlotte M Flynn, Georg H Waetzig, Ioanna Gouni-Berthold, Wilhelm Krone, Heiner K Berthold, Matthias Laudes, Stefan Rose-John, Christoph Garbers
• Journal: American journal of physiology. Endocrinology and metabolism (Am J Physiol Endocrinol Metab) Vol. 317 Issue 2 Pg. E411-E420 (08 01 2019) ISSN: 1522-1555 [Electronic] United States
• PMID: 31237452 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• IL6R protein, human
• Interleukin-6
• Receptors, Interleukin-6
• STAT3 Transcription Factor
• STAT3 protein, human
• Cytokine Receptor gp130

Topics

• Aged
• Amino Acid Substitution
• Atherosclerosis (blood, etiology)
• Case-Control Studies
• Cytokine Receptor gp130 (blood, metabolism)
• Diabetes Mellitus, Type 2 (blood, complications, genetics, metabolism)
• Female
• Hep G2 Cells
• Humans
• Interleukin-6 (antagonists & inhibitors, blood, pharmacology)
• Male
• Middle Aged
• Phosphorylation (drug effects)
• Polymorphism, Single Nucleotide
• Protein Binding
• Receptors, Interleukin-6 (blood, genetics, metabolism)
• STAT3 Transcription Factor (genetics, metabolism)
• Signal Transduction (drug effects, genetics)