Human proinsulin C-peptide prevents proliferation of rat aortic smooth muscle cells cultured in high-glucose conditions

Kobayashi, Yasuko; Naruse, Keiko; Hamada, Yoji; Nakashima, Eitaro; Kato, Kenichi; Akiyama, N; Kawanishi, Hideki; Watarai, Atsuko; Nakae, Mika; Oiso, Yutaka; Nakamura, Jiro

doi:10.1007/s00125-005-1942-9

Cited by 50 publications

(40 citation statements)

References 31 publications

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“…Some studies have demonstrated the beneficial effects of C-peptide on vessels by inhibiting smooth muscle cell proliferation and migration and antiinflammatory activity in endothelial cells (2,27,28). Other studies have revealed C-peptide deposition in the arteriosclerotic lesions of diabetic patients, chemotactic activity towards monocytes and CD4C lymphocytes and the induction of vascular smooth muscle cell proliferation (24,25).…”

Section: Discussionmentioning

confidence: 99%

C-peptide and the risk for incident complications and mortality in type 2 diabetic patients: a retrospective cohort study after a 14-year follow-up

Gentile

Castiglione

et al. 2012

European Journal of Endocrinology

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Objective: C-peptide, a cleavage product of insulin, exerts biological effects in patients with type 1 diabetes mellitus, but its role in type 2 diabetes mellitus is controversial. Our aim was to examine the associations between fasting C-peptide levels and all-cause mortality, specific-cause mortality and the incidence of chronic complications in patients with type 2 diabetes. Design: Retrospective cohort study with a median follow-up of 14 years. Methods: A representative cohort of 2113 patients with type 2 diabetes mellitus and a subgroup of 931 individuals from this cohort without chronic complications at baseline from a diabetic clinic were studied. Results: Patients with higher C-peptide levels had higher baseline BMI and triglyceride and lower HDL-cholesterol values. During the follow-up, 46.1% of the patients died. In a Cox proportional hazard model, after multiple adjustments, no significant association was found between the C-peptide tertiles and all-cause mortality or mortality due to cancer, diabetes or cardiovascular diseases. In the subgroup of 931 patients without chronic complications at baseline, the incidence of microvascular complications decreased from the first to the third C-peptide level tertile, while the incidence of cardiovascular disease did not differ. The risks for incident retinopathy (hazard ratio (HR)Z0.33; 95% confidence interval (CI) 0.23-0.47), nephropathy (HRZ0.27; 95% CI 0.18-0.38) and neuropathy (HRZ0.39; 95% CI 0.25-0.61) were negatively associated with the highest C-peptide tertile, after adjusting for multiple confounders. Conclusions: Higher baseline C-peptide levels were associated with a reduced risk of incident microvascular complications but imparted no survival benefit to patients with type 2 diabetes mellitus.

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Section: Discussionmentioning

confidence: 99%

C-peptide and the risk for incident complications and mortality in type 2 diabetic patients: a retrospective cohort study after a 14-year follow-up

Gentile

Castiglione

et al. 2012

European Journal of Endocrinology

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“…The few studies available on the topic have tested the effect of C-peptide on low and high glucose-induced proliferative activities of vascular smooth muscle cells, one major component involved in the formation of atherosclerotic plaque [33,34]. Here, we wanted to expand upon these studies by evaluating the potential effects of C-peptide on the endothelial cell component of the vessel wall during hyperglycaemia.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to endothelial cells, vascular smooth muscle cells also appear to be the target of beneficial effects of C-peptide on the vasculature in conditions of hyperglycaemia [33,44]. Physiological concentrations of C-peptide attenuate glucoseinduced hyperproliferation of vascular smooth muscle cells [33,44], a phenomenon associated, at least in part, with a specific inhibitory effect on NF-κB [44].…”

Section: Discussionmentioning

confidence: 99%

Human C-peptide antagonises high glucose-induced endothelial dysfunction through the nuclear factor-κB pathway

et al. 2008

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Aims/hypothesis Endothelial dysfunction in diabetes is predominantly caused by hyperglycaemia leading to vascular complications through overproduction of oxidative stress and activation of the transcription factor nuclear factor-κB (NF-κB). Many studies have suggested that decreased circulating levels of C-peptide may play a role in diabetic vascular dysfunction. To date, the possible effects of C-peptide on endothelial cells and intracellular signalling pathways are largely unknown. We therefore investigated the effect of C-peptide on several biochemical markers of endothelial dysfunction in vitro. To gain insights into potential intracellular signalling pathways affected by C-peptide, we tested NF-κB activation, since it is known that inflammation, secondary to oxidative stress, is a key component of vascular complications and NF-κB is a redox-dependent transcription factor. Methods Human aortic endothelial cells (HAEC) were exposed to 25 mmol/l glucose in the presence of C-peptide (0.5 nmol/l) for 24 h and tested for expression of the gene encoding vascular cell adhesion molecule-1 (VCAM-1) by RT-PCR and flow cytometry. Secretion of IL-8 and monocyte chemoattractant protein-1 (MCP-1) was measured by ELISA. NF-κB activation was analysed by immunoblotting and ELISA. Results Physiological concentrations of C-peptide affect high glucose-induced endothelial dysfunction by: (1) decreasing VCAM-1 expression and U-937 cell adherence to HAEC; (2) reducing secretion of IL-8 and MCP-1; and (3) suppressing NF-κB activation. Conclusions/interpretation During hyperglycaemia, Cpeptide directly affects VCAM-1 expression and both MCP-1 and IL-8 HAEC secretion by reducing NF-κB activation. These effects suggest a physiological anti-inflammatory (and potentially anti-atherogenic) activity of C-peptide on endothelial cells.

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“…The internalisation of C-peptide was explored in human aortic endothelial cells (HAEC) and umbilical artery smooth muscle cells (UASMC), two important targets of C-peptide activity, especially in the context of vascular dysfunction leading to vascular complications in type 1 diabetes [13][14][15][16]. We found that in these cells C-peptide internalises from the cellular surface within punctate structures, most of them co-localizing with early endosomes.…”

Section: Introductionmentioning

confidence: 99%

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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Human proinsulin C-peptide prevents proliferation of rat aortic smooth muscle cells cultured in high-glucose conditions

Cited by 50 publications

References 31 publications

C-peptide and the risk for incident complications and mortality in type 2 diabetic patients: a retrospective cohort study after a 14-year follow-up

C-peptide and the risk for incident complications and mortality in type 2 diabetic patients: a retrospective cohort study after a 14-year follow-up

Human C-peptide antagonises high glucose-induced endothelial dysfunction through the nuclear factor-κB pathway

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

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