Mechanisms of C-peptide-mediated rescue of low O2-induced ATP release from erythrocytes of humans with type 2 diabetes.

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  • Additional Information
    • Source:
      Publisher: American Physiological Society Country of Publication: United States NLM ID: 100901230 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1522-1490 (Electronic) Linking ISSN: 03636119 NLM ISO Abbreviation: Am J Physiol Regul Integr Comp Physiol Subsets: MEDLINE
    • Publication Information:
      Original Publication: Bethesda, Md. : American Physiological Society
    • Subject Terms:
      Adenosine Triphosphate/*blood ; C-Peptide/*pharmacology ; Diabetes Mellitus, Type 2/*drug therapy ; Erythrocytes/*drug effects ; Hypoglycemic Agents/*pharmacology ; Oxygen/*blood; 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
    • 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.)
    • Contributed Indexing:
      Keywords: G protein-coupled receptor 146; adenosine triphosphate; microcirculation; red blood cell; soluble guanylyl cyclase
    • Accession Number:
      0 (C-Peptide)
      0 (Hypoglycemic Agents)
      0 (Insulin)
      0 (Phosphodiesterase 5 Inhibitors)
      0 (Protein Kinase Inhibitors)
      0 (Receptors, Cytoplasmic and Nuclear)
      8L70Q75FXE (Adenosine Triphosphate)
      EC 2.7.11.13 (Protein Kinase C)
      EC 4.6.1.2 (Guanylate Cyclase)
      EC 4.6.1.2 (Soluble Guanylyl Cyclase)
      H2D2X058MU (Cyclic GMP)
      S88TT14065 (Oxygen)
    • Publication Date:
      Date Created: 20150102 Date Completed: 20150429 Latest Revision: 20200930
    • Publication Date:
      20221213
    • Accession Number:
      10.1152/ajpregu.00420.2014
    • Accession Number:
      25552662