title: Mechanisms of C-peptide-mediated rescue of low O2-induced ATP release from erythrocytes of humans with type 2 diabetes.
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.
authors.affiliation: Department of Pharmacological and Physiological Science, Saint Louis University, St. Louis, Missouri.
authors.forename: Jennifer P
authors.initials: JP
authors.lastname: Richards
authors.affiliation: Department of Pharmacological and Physiological Science, Saint Louis University, St. Louis, Missouri.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Bowles
authors.affiliation: Department of Pharmacological and Physiological Science, Saint Louis University, St. Louis, Missouri.
authors.forename: Weston R
authors.initials: WR
authors.lastname: Gordon
authors.affiliation: Department of Pharmacological and Physiological Science, Saint Louis University, St. Louis, Missouri.
authors.forename: Mary L
authors.initials: ML
authors.lastname: Ellsworth
authors.affiliation: Department of Pharmacological and Physiological Science, Saint Louis University, St. Louis, Missouri.
authors.forename: Alan H
authors.initials: AH
authors.lastname: Stephenson
authors.affiliation: Department of Pharmacological and Physiological Science, Saint Louis University, St. Louis, Missouri spraguer@slu.edu.
authors.forename: Randy S
authors.identifier: http://orcid.org/0000-0001-6404-6073
authors.initials: RS
authors.lastname: Sprague
mesh_terms: D000255:Adenosine Triphosphate / Q000097:blood*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002096:C-Peptide / Q000494:pharmacology*; D016022:Case-Control Studies; D015687:Cell Hypoxia; D006152:Cyclic GMP / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D004912:Erythrocytes / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D006162:Guanylate Cyclase / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D010100:Oxygen / Q000097:blood*; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000071756:Soluble Guanylyl Cyclase
chemical_list: D002096:C-Peptide; D007004:Hypoglycemic Agents; D007328:Insulin; D058986:Phosphodiesterase 5 Inhibitors; D047428:Protein Kinase Inhibitors; D018160:Receptors, Cytoplasmic and Nuclear; D000255:Adenosine Triphosphate; D011493:Protein Kinase C; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP; D010100:Oxygen
keywords: G protein-coupled receptor 146; adenosine triphosphate; microcirculation; red blood cell; soluble guanylyl cyclase