title: Low O2-induced ATP release from erythrocytes of humans with type 2 diabetes is restored by physiological ratios of C-peptide and insulin.
abstract: ATP release from erythrocytes in response to reduced oxygen (O2) tension stimulates local vasodilation, enabling these cells to direct perfusion to areas in skeletal muscle in need of O2. Erythrocytes of humans with type 2 diabetes do not release ATP in response to low O2. Both C-peptide and insulin individually inhibit low O2-induced ATP release from healthy human erythrocytes, yet when coadministered at physiological concentrations and ratios, no inhibition is seen. Here, we determined: that 1) erythrocytes of healthy humans and humans with type 2 diabetes possess a C-peptide receptor (GPR146), 2) the combination of C-peptide and insulin at physiological ratios rescues low O2-induced ATP release from erythrocytes of humans with type 2 diabetes, 3) residual C-peptide levels reported in humans with type 2 diabetes are not adequate to rescue low O2-induced ATP release in the presence of 1 nM insulin, and 4) the effects of C-peptide and insulin are neither altered by increased glucose levels nor explained by changes in erythrocyte deformability. These results suggest that the addition of C-peptide to the treatment regimen for type 2 diabetes could have beneficial effects on tissue oxygenation, which would help to ameliorate the concomitant peripheral vascular disease.
authors: Department of Pharmacological and Physiological Science, Saint Louis University, St. Louis, Missouri j.rich34@gmail.com.
authors: Jennifer P
authors: JP
authors: Richards
authors: Department of Pharmacological and Physiological Science, Saint Louis University, St. Louis, Missouri.
authors: Gina L C
authors: GL
authors: Yosten
authors: Department of Pharmacological and Physiological Science, Saint Louis University, St. Louis, Missouri.
authors: Grant R
authors: GR
authors: Kolar
authors: Department of Pharmacological and Physiological Science, Saint Louis University, St. Louis, Missouri.
authors: Cory W
authors: CW
authors: Jones
authors: Department of Pharmacological and Physiological Science, Saint Louis University, St. Louis, Missouri.
authors: Alan H
authors: AH
authors: Stephenson
authors: Department of Pharmacological and Physiological Science, Saint Louis University, St. Louis, Missouri.
authors: Mary L
authors: ML
authors: Ellsworth
authors: Department of Pharmacological and Physiological Science, Saint Louis University, St. Louis, Missouri.
authors: Randy S
authors: RS
authors: Sprague
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D002096:C-Peptide / Q000378:metabolism*; D002469:Cell Separation / Q000379:methods; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D004912:Erythrocytes / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism*
chemical_list: D002096:C-Peptide; D007328:Insulin; D000255:Adenosine Triphosphate; D010100:Oxygen
keywords: C-peptide receptor; GPR146; adenosine triphosphate; microcirculation; red blood cell