1. Mechanisms of C-peptide-mediated rescue of low O2-induced ATP release from erythrocytes of humans with type 2 diabetes.
- Author
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Richards JP, Bowles EA, Gordon WR, Ellsworth ML, Stephenson AH, and Sprague RS
- Subjects
- Adult, Aged, Aged, 80 and over, Case-Control Studies, Cell Hypoxia, Cyclic GMP metabolism, Diabetes Mellitus, Type 2 blood, Erythrocytes metabolism, Female, Guanylate Cyclase metabolism, Humans, Insulin pharmacology, Male, Middle Aged, Phosphodiesterase 5 Inhibitors pharmacology, Protein Kinase C antagonists & inhibitors, Protein Kinase C metabolism, Protein Kinase Inhibitors pharmacology, Receptors, Cytoplasmic and Nuclear metabolism, Signal Transduction drug effects, Soluble Guanylyl Cyclase, Adenosine Triphosphate blood, C-Peptide pharmacology, Diabetes Mellitus, Type 2 drug therapy, Erythrocytes drug effects, Hypoglycemic Agents pharmacology, Oxygen blood
- Abstract
The circulating erythrocyte, by virtue of the regulated release of ATP in response to reduced oxygen (O2) 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 O2-induced ATP release, erythrocytes from healthy humans and humans with DM2 were exposed to reduced O2 in a thin-film tonometer, and ATP release under these conditions was compared with release during normoxia. We determined that 1) low O2-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 O2-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 O2-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., (Copyright © 2015 the American Physiological Society.)
- Published
- 2015
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