A Molecular Level Understanding of Zinc Activation of C-peptide and its Effects on Cellular Communication in the Bloodstream

Abstract

■ AbstractInspired by previous reports, our group has recently demonstrated that C-peptide exerts beneficial effects upon interactions with red blood cells (RBCs). These effects can be measured in RBCs obtained from animal models of both type 1 diabetes and type 2 diabetes, though to different extents. To date, the key metrics that have been measured involving C-peptide and RBCs include an increase in glucose uptake by these cells and a subsequent increase in adenosine triphosphate (ATP) release. Importantly, to date, our group has only been able to elicit these beneficial effects when the C-peptide is prepared in the presence of Zn 2+ . The C-peptide-induced release of ATP is of interest when considering that ATP is a purinergic signaling molecule known to stimulate the production of nitric oxide (NO) in the endothelium and in platelets. This NO production has been shown to participate in smooth muscle relaxation and subsequent vessel dilation. Furthermore, NO is a well-established platelet inhibitor. The objective of this review is to provide information pertaining to C-peptide activity on RBCs. Special attention is paid to the necessity of Zn 2+ activation, and the origin of that activation in vivo. Finally, a mechanism is proposed that explains how C-peptide is exerting its effects on other cells in the bloodstream, particularly on endothelial cells and platelets, via its ability to stimulate the release of ATP from RBCs.

Low O2-induced ATP release from erythrocytes of humans with type 2 diabetes is restored by physiological ratios of C-peptide and insulin

“…C-Peptide has been suggested to stimulate the uptake of glucose into erythrocytes, resulting in increased ATP release (28,29). However, glucose entry into the erythrocyte is not the rate-limiting step in ATP formation via glycolysis (48).…”

“…It was previously suggested that C-peptide-mediated increases in glucose entry into erythrocytes result in increased ATP release (28,29). We determined that when the concentration of glucose is elevated threefold (16.5 mM, ϳ300 mg/dl), a level that can be found in humans with type 2 diabetes, erythrocytes from healthy humans, and humans with type 2 diabetes demonstrated no change in low O 2 -induced ATP release compared with that observed at a more physiological glucose concentration (5.5 mM, 100 mg/dl).…”

The Beneficial Effects of C-Peptide on Diabetic Polyneuropathy

“…Hence, the replacement of insulinpromoting C-peptide in type 1 diabetes provides a unique opportunity to combat neuropathic and other complications, as outlined in this Special Issue of The Review of Diabetic Studies [24,[61][62][63][64].…”

“…Natural insulin exists in a hexameric form kept together by zinc-ions [22,23]. As shown in detail in an accompanying paper in this volume [24], C-peptide appears to regulate the dehexamirization of insulin by binding to Zn 2+ . It thereby enhances and prolongs the many direct nonhypoglycemic effects of insulin.…”

C-Peptide and its Intracellular Signaling

“…Alternative and more intensive approaches may well be successful. Also potentially relevant to this point are recent descriptions of a divalent metal ion dependency of Cpeptide activation [57]. We have often observed variable cell responses to C-peptide when Cpeptide is applied to cells in defined salt solutions lacking divalent metals.…”