Beneficial effects of C‐peptide on incipient nephropathy and neuropathy in patients with Type 1 diabetes mellitus

Johansson, Bo‐Lennart; Borg, Kristian; Fernqvist‐Forbes, E.; Kernell, A; Odergren, Tomas; Wahren, John

doi:10.1046/j.1464-5491.2000.00274.x

Cited by 248 publications

(214 citation statements)

References 29 publications

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“…However, over the last decade, several reports have suggested that C-peptide may exert a number of physiological effects, which are probably mediated by stimulation of Na + ,K + -ATPase and endothelial nitric oxide synthetase activities in several tissues [23]. In the early stage of type 1 diabetes, C-peptide replacement results in diminished UAE rate and ameliorates nerve dysfunction [24]. Based on these findings, lack of Cpeptide itself might be one of the causal factors in the development of microangiopathy in fulminant type 1 diabetic patients.…”

Section: Discussionmentioning

confidence: 99%

Fulminant type 1 diabetes as a high risk group for diabetic microangiopathy—a nationwide 5-year-study in Japan

et al. 2007

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Aims/hypothesis The aim of the present study was to assess the development of microangiopathy in patients with fulminant type 1 diabetes, a novel subtype of type 1B diabetes. Materials and methods In a nationwide survey, we followed 41 patients with fulminant type 1 diabetes and 76 age-and sex-matched patients with type 1A diabetes for 5 years. The following data were recorded every 12 months after the onset of diabetes: seven-point blood glucose concentrations, HbA 1c level, urinary albumin excretion, serum C-peptide level, blood pressure, daily dosages of insulin, frequency of severe hypoglycaemic episodes, and neurological and fundoscopic examination. ResultsThe 5-year cumulative incidence of microangiopathy was 24.4% in fulminant type 1 diabetes and 2.6% in type 1A diabetes. In longitudinal studies using the KaplanMeier method, the cumulative incidence of each form of microangiopathy was significantly higher in fulminant type 1 diabetes than in type 1A diabetes; retinopathy was 9.8% vs 0% (p=0.014), nephropathy 12.2% vs 2.6% (p=0.015) and neuropathy 12.2% vs 1.3% (p=0.010), respectively. Mean HbA 1c levels were similar in the fulminant and type 1A diabetes groups during the follow-up periods. However, the mean M-value, mean insulin dosages and the frequency of severe hypoglycaemic episodes were significantly higher, and the mean postprandial C-peptide level was significantly lower in the fulminant type 1 diabetes group.

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Section: Discussionmentioning

confidence: 99%

Fulminant type 1 diabetes as a high risk group for diabetic microangiopathy—a nationwide 5-year-study in Japan

et al. 2007

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“…In recent years, C-peptide has been shown to exert insulin-independent biological effects on a variety of cells, where it affects the activation of several intracellular pathways, such as, but not limited to, those involved in cellular proliferation and inflammation [2][3][4]. Importantly, C-peptide has been demonstrated to be beneficial when administered as replacement therapy to type 1 diabetes patients who suffer from some diabetic complications [5][6][7][8]. How exactly C-peptide achieves its intracellular effects in target cells, however, is unknown.…”

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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“…Activation of these enzyme systems is of particular interest in diabetes, since both are reported to be deficient in this disorder [9][10][11][12]. Studies in animal models of diabetes and in patients with type 1 diabetes demonstrate that administration of Cpeptide, to yield physiological concentrations, results in a substantial improvement of diabetes-induced functional and structural changes in peripheral nerves [13][14][15]. In addition, there is evidence to indicate that C-peptide prevents diabetes-induced deficits in nerve fibre regeneration [16], protects against glucose-induced apoptosis of nerve cells and stimulates cellular proliferation [17,18].…”

Section: Introductionmentioning

confidence: 99%

“…In addition, there is evidence to indicate that C-peptide prevents diabetes-induced deficits in nerve fibre regeneration [16], protects against glucose-induced apoptosis of nerve cells and stimulates cellular proliferation [17,18]. Moreover, C-peptide in replacement doses corrects the characteristic glomerular hyperfiltration seen in the early stages of diabetic nephropathy, reduces urinary excretion of albumin and prevents the development of glomerular hypertrophy in type 1 diabetes [13,19,20]. In addition, recent studies have established that C-peptide given in replacement doses to type 1 patients augments skeletal muscle and myocardial blood flow and increases the rate of contraction and the stroke volume of the left ventricle [21][22][23].…”

Section: Introductionmentioning

confidence: 99%

C-peptide stimulates ERK1/2 and JNK MAP kinases via activation of protein kinase C in human renal tubular cells

et al. 2004

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Beneficial effects of C‐peptide on incipient nephropathy and neuropathy in patients with Type 1 diabetes mellitus

Abstract: These results indicate that combined treatment with C-peptide and insulin for 3 months may improve renal function by diminishing urinary albumin excretion and ameliorate autonomic and sensory nerve dysfunction in patients with Type 1 diabetes mellitus.

Cited by 248 publications

References 29 publications

Fulminant type 1 diabetes as a high risk group for diabetic microangiopathy—a nationwide 5-year-study in Japan

Fulminant type 1 diabetes as a high risk group for diabetic microangiopathy—a nationwide 5-year-study in Japan

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

C-peptide stimulates ERK1/2 and JNK MAP kinases via activation of protein kinase C in human renal tubular cells

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