Molecular Effects of C-Peptide in Microvascular Blood Flow Regulation

Forst, Thomas; Hach, Thomas; Kunt, T.; Weber, Matthias M.; Pfützner, Andreas

doi:10.1900/rds.2009.6.159

Cited by 12 publications

(10 citation statements)

References 65 publications

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“…This defect may be exacerbated further by the administration of insulin that results in supraphysiological concentrations in the absence of C-peptide in the treatment of DM2. Although C-peptide was initially thought to be a biologically inert by-product of insulin production, more recently C-peptide has been shown to have physiological function in a variety of tissues (3,16,24,45). Importantly, coincubation of C-peptide and insulin at physiological ratios and concentrations rescues insulin-induced inhibition of low O 2 -induced ATP release from healthy human erythrocytes, resulting in compensation for the inherent defect in the low O 2 pathway in DM2 (37).…”

Section: Discussionmentioning

confidence: 99%

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

Richards

Bowles

Gordon

et al. 2015

American Journal of Physiology-Regulatory, Integrative and Comp

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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.

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Section: Discussionmentioning

confidence: 99%

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

Richards

Bowles

Gordon

et al. 2015

American Journal of Physiology-Regulatory, Integrative and Comp

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“…The use of C-peptide therapy, for the treatment of diabetic neuropathy and also nephropathy, reached clinical trials in T1DM patients [40]. It was shown that the replacement of a physiological amount of C-peptide could improve microvascular blood flow in several tissues of diabetic animals and humans (myocardium, nerve tissue, kidney and skeletal muscle) [48]. A review of the multiple cell signalling pathways of human proinsulin C-peptide in vasculopathy protection is here proposed, discussing the approaches to move beyond the state of the art in the development of innovative and effective therapeutic options of diabetic neuropathy and nephropathy.…”

Section: Functions and Features Of Human Proinsulin C-peptidementioning

confidence: 99%

“…In macrovascular complications, it is suggested that C-peptide avoids smooth muscle cell proliferation and neointima formation, being anti-atherogenic but other studies showed a pro-atherogenic effect [45,[52][53][54]. In some tissues in diabetic animals and patients, the replacement of an amount of C-peptide has shown to improve microvascular blood flow [48,55]. C-peptide prevents endothelial dysfunction in vasculature through activation of Erk-1/-2 and endothelial NO synthase, production of NO or inhibition of nuclear factor kappa light-chain enhancer of activated β cells pathway [56,57].…”

Section: Cell Signalling Pathways Of Human Proinsulin C-peptide In Vamentioning

confidence: 99%

Multiple Cell Signalling Pathways of Human Proinsulin C-Peptide in Vasculopathy Protection

Souto

Campos

Fangueiro

et al. 2020

IJMS

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A major hallmark of diabetes is a constant high blood glucose level (hyperglycaemia), resulting in endothelial dysfunction. Transient or prolonged hyperglycemia can cause diabetic vasculopathy, a secondary systemic damage. C-Peptide is a product of cleavage of proinsulin by a serine protease that occurs within the pancreatic β-cells, being secreted in similar amounts as insulin. The biological activity of human C-peptide is instrumental in the prevention of diabetic neuropathy, nephropathy and other vascular complications. The main feature of type 1 diabetes mellitus is the lack of insulin and of C-peptide, but the progressive β-cell loss is also observed in later stage of type 2 diabetes mellitus. C-peptide has multifaceted effects in animals and diabetic patients due to the activation of multiple cell signalling pathways, highlighting p38 mitogen-activated protein kinase and extracellular signal–regulated kinase ½, Akt, as well as endothelial nitric oxide production. Recent works highlight the role of C-peptide in the prevention and amelioration of diabetes and also in organ-specific complications. Benefits of C-peptide in microangiopathy and vasculopathy have been shown through conservation of vascular function, and also in the prevention of endothelial cell death, microvascular permeability, neointima formation, and in vascular inflammation. Improvement of microvascular blood flow by replacing a physiological amount of C-peptide, in several tissues of diabetic animals and humans, mainly in nerve tissue, myocardium, skeletal muscle, and kidney has been described. A review of the multiple cell signalling pathways of human proinsulin C-peptide in vasculopathy protection is proposed, where the approaches to move beyond the state of the art in the development of innovative and effective therapeutic options of diabetic neuropathy and nephropathy are discussed.

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“…However, there is also evidence for concomitant control by the smooth muscle cells [72] and more work should be done to distinguish between endothelial and muscle cells. Finally, it should be noted that other substances/ receptors can be involved: C-peptide is also able to increase microflow, which may be one explanation for the long-lasting vasodilations observed in humans after administration of high levels of insulin [77,78]; inhibition of angiotensin II type 1 receptor increases microflow and glucose uptake [79]; the antianginal compound ranolazine recruits capillaries and potentiates insulin's metabolic action [80]; relaxin dilates second and third order muscle arterioles but not terminal A4 arterioles [81]. The sympathoexcitatory effect is involved, at least at high hormone concentrations.…”

Section: Insulin and Microflowmentioning

confidence: 99%

Microcirculation

Wiernsperger

2015

Glucose Intake and Utilization in Pre-Diabetes and Diabetes

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Molecular Effects of C-Peptide in Microvascular Blood Flow Regulation

Cited by 12 publications

References 65 publications

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

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

Multiple Cell Signalling Pathways of Human Proinsulin C-Peptide in Vasculopathy Protection

Microcirculation

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Molecular Effects of C-Peptide in Microvascular Blood Flow Regulation

Cited by 12 publications

References 65 publications

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

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

Multiple Cell Signalling Pathways of Human Proinsulin C-Peptide in Vasculopathy Protection

Microcirculation

Contact Info

Product

Resources

About

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

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