Metal-activated C-peptide facilitates glucose clearance and the release of a nitric oxide stimulus via the GLUT1 transporter

Meyer, Jennifer A.; Froelich, Jennifer M.; Reid, Gavin E.; Karunarathne, Ajith; Spence, Dana M.

doi:10.1007/s00125-007-0853-3

Cited by 60 publications

(84 citation statements)

References 25 publications

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“…Previous work from our laboratory has demonstrated a protective effect of C-peptide on the vasculature in hyperglycaemic conditions by decreasing inflammatory damage and the activation of nuclear factor (NF)-κB [13,15]. More recently, a physiological role in glucose clearance and the release of ATP from erythrocytes of diabetic patients has been suggested [27]. C-peptide has also been shown to improve erythrocyte deformability in diabetic people [28].…”

Section: Discussionmentioning

confidence: 98%

C-peptide is internalised in human endothelial and vascular smooth muscle cells via early endosomes

et al. 2009

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Aims/hypothesis There is increasing evidence that Cpeptide exerts intracellular effects in a variety of cells and could be beneficial in patients with type 1 diabetes. Exactly how C-peptide achieves these effects, however, is unknown. Recent reports showed that C-peptide internalised in the cytoplasm of HEK-293 and Swiss 3T3 cells, where it was not degraded for at least 1 h after uptake. In this study, we investigated the hypothesis that C-peptide is internalised via an endocytic pathway and traffics to classic endocytic organelles, such as endosomes and lysosomes. Methods We studied the internalisation of C-peptide in vascular endothelial and smooth muscle cells, two relevant targets of Cpeptide activity, by using Alexa Fluor-labelled C-peptide probes in living cells and immunohistochemistry employing confocal laser-scanning microscopy. To examine trafficking to subcellular compartments, we used fluorescent constructs tagged to RAB5A, member RAS oncogene family (RAB5A) to identify early endosomes, or to lysosomal-associated membrane protein 1 (LAMP1) to identify lysosomes.Results C-peptide internalised in the cytoplasm of cells within punctate structures identified as early endosomes. Internalisation was clearly detectable after 10 min of incubation and was blocked at 4°C as well as with excess of unlabelled C-peptide. A minor fraction of vesicles, which increased with culture time, co-localised with lysosomes. Uptake of C-peptide was reduced by monodansylcadaverine, a pharmacological compound that blocks clathrin-mediated endocytosis, and by nocodazole, which disrupts microtubule assembly. Conclusions/interpretation C-peptide internalises in the cytoplasm of cells by endocytosis, as demonstrated by its localisation in early endosomes. Endosomes might represent a signalling station, through which C-peptide might achieve its cellular effects.

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Section: Discussionmentioning

confidence: 98%

C-peptide is internalised in human endothelial and vascular smooth muscle cells via early endosomes

et al. 2009

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“…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).…”

Section: Discussionmentioning

confidence: 99%

“…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).…”

Section: Effect Of Acute Exposure To High Glucose In the Presence Of mentioning

confidence: 99%

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

Richards

Yosten

Kolar

et al. 2014

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Insulin-independent effects of Cpeptide and metal activation C-peptide has been shown by our group and other groups to interact with RBCs [15][16][17][18]. In the studies involving deformability [15][16], the RBC samples were incubated with C-peptide alone and, after an incubation period, improvements in deformability of the RBCs obtained from diabetic patients were measured.…”

Section: C-peptide Secretion From Pancreatic Beta-cellsmentioning

confidence: 99%

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

et al. 2009

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■ 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.

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Metal-activated C-peptide facilitates glucose clearance and the release of a nitric oxide stimulus via the GLUT1 transporter

Abstract: When complexed to Fe2+ or Cr3+, C-peptide has the ability to promote ATP release from erythrocytes. This release is due to an increase in glucose transport through GLUT1.

Cited by 60 publications

References 25 publications

C-peptide is internalised in human endothelial and vascular smooth muscle cells via early endosomes

C-peptide is internalised in human endothelial and vascular smooth muscle cells via early endosomes

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

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

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Metal-activated C-peptide facilitates glucose clearance and the release of a nitric oxide stimulus via the GLUT1 transporter

Abstract: When complexed to Fe2+ or Cr3+, C-peptide has the ability to promote ATP release from erythrocytes. This release is due to an increase in glucose transport through GLUT1.

Cited by 60 publications

References 25 publications

C-peptide is internalised in human endothelial and vascular smooth muscle cells via early endosomes

C-peptide is internalised in human endothelial and vascular smooth muscle cells via early endosomes

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

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

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Resources

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