Dysregulated Erythroid Mg 2+ Efflux in Type 2 Diabetes.

Hyperglycemia is associated with decreased Mg ²⁺ content in red blood cells (RBC), but mechanisms remain unclear. We characterized the regulation of Mg ²⁺ efflux by glucose in ex vivo human RBC. We observed that hemoglobin A _1C (HbA _1C ) values correlated with Na ⁺ -dependent Mg ²⁺ efflux (Na ⁺ /Mg ²⁺ exchange) and inversely correlated with cellular Mg content. Treatment of cells with 50 mM D-glucose, but not with sorbitol, lowered total cellular Mg (2.2 ± 0.1 to 2.0 ± 0.1 mM, p < 0.01) and enhanced Na ⁺ /Mg ²⁺ exchange activity [0.60 ± 0.09 to 1.12 ± 0.09 mmol/10 ¹³ cell × h (flux units, FU), p < 0.05]. In contrast, incubation with selective Src family kinase inhibitors PP2 or SU6656 reduced glucose-stimulated exchange activation ( p < 0.01). Na ⁺ /Mg ²⁺ exchange activity was also higher in RBC from individuals with type 2 diabetes (T2D, 1.19 ± 0.13 FU) than from non-diabetic individuals (0.58 ± 0.05 FU, p < 0.01). Increased Na ⁺ /Mg ²⁺ exchange activity in RBC from T2D subjects was associated with lower intracellular Mg content. Similarly increased exchange activity was evident in RBC from the diabetic db / db mouse model as compared to its non-diabetic control ( p < 0.03). Extracellular exposure of intact RBC from T2D subjects to recombinant peptidyl-N-glycosidase F (PNGase F) reduced Na ⁺ /Mg ²⁺ exchange activity from 0.98 ± 0.14 to 0.59 ± 0.13 FU ( p < 0.05) and increased baseline intracellular Mg content (1.8 ± 0.1 mM) to normal values (2.1 ± 0.1 mM, p < 0.05). These data suggest that the reduced RBC Mg content of T2D RBC reflects enhanced RBC Na ⁺ /Mg ²⁺ exchange subject to regulation by Src family kinases and by the N-glycosylation state of one or more membrane proteins. The data extend our understanding of dysregulated RBC Mg ²⁺ homeostasis in T2D.
Competing Interests: Authors JW and JD were employed by the company Quest Diagnostics. Authors LS and SA were consultants to Quest Diagnostics. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2022 Ferreira, Rivera, Wohlgemuth, Dlott, Snyder, Alper and Romero.)