Mechanisms of C-peptide-mediated rescue of low O 2 -induced ATP release from erythrocytes of humans with Type 2 diabetes

• Published in: American journal of physiology. Regulatory, integrative and comparative physiology integrative and comparative physiology, 2015-03, Vol.308 (5), p.R411-R418
• Main Authors: Richards, Jennifer P., Bowles, Elizabeth A., Gordon, Weston R., Ellsworth, Mary L., Stephenson, Alan H., Sprague, Randy S.
• Format: Article
• Language: English
• ISSN: 0363-6119; 1522-1490
• DOI: 10.1152/ajpregu.00420.2014

The circulating erythrocyte, by virtue of the regulated release of ATP in response to reduced oxygen (O 2 ) tension, plays a key role in maintaining appropriate perfusion distribution to meet tissue needs. Erythrocytes from individuals with Type 2 diabetes (DM2) fail to release ATP in response to this stimulus. However, the administration of C-peptide and insulin at a 1:1 ratio was shown to restore this important physiological response in humans with DM2. To begin to investigate the mechanisms by which C-peptide influences low O 2 -induced ATP release, erythrocytes from healthy humans and humans with DM2 were exposed to reduced O 2 in a thin-film tonometer, and ATP release under these conditions was compared with release during normoxia. We determined that 1) low O 2 -induced ATP release from DM2 erythrocytes is rescued by C-peptide in the presence and absence of insulin, 2) the signaling pathway activated by C-peptide in human erythrocytes involves PKC, as well as soluble guanylyl cyclase (sGC) and 3) inhibitors of cGMP degradation rescue low O 2 -induced ATP release from DM2 erythrocytes. These results provide support for the hypothesis that both PKC and sGC are components of a signaling pathway activated by C-peptide in human erythrocytes. In addition, since both C-peptide and phosphodiesterase 5 inhibitors rescue low O 2 -induced ATP release from erythrocytes of humans with DM2, their administration to humans with DM2 could aid in the treatment and/or prevention of the vascular disease associated with this condition.