Effects of C-peptide on Microvascular Blood Flow and Blood Hemorheology

Beside functional and structural changes in vascular biology, alterations in the rheologic properties of blood cells mainly determines to an impaired microvascular blood flow in patients suffering from diabetes mellitus. Recent investigations provide increasing evidence that impaired C-peptide secretion in type 1 diabetic patients might contribute to the development of microvascular complications. C-peptide has been shown to stimulate endothelial NO secretion by activation of theCa2+calmodolin regulated enzyme eNOS. NO himself has the potency to increase cGMP levels in smooth muscle cells and to activateNa+K+ATPase activity and therefore evolves numerous effects in microvascular regulation. In type 1 diabetic patients, supplementation of C-peptide was shown to improve endothelium dependent vasodilatation in an NO-dependent pathway in different vascular compartments. In addition, it could be shown that C-peptide administration in type 1 diabetic patients, results in a redistribution of skin blood flow by increasing nutritive capillary blood flow in favour to subpapillary blood flow. ImpairedNa+K+ATPase in another feature of diabetes mellitus in many cell types and is believed to be a pivotal regulator of various cell functions. C-peptide supplementation has been shown to restoreNa+K+ATPase activity in different cell types during in vitro and in vivo investigations. In type 1 diabetic patients, C-peptide supplementation was shown to increase erythrocyteNa+K+ATPase activity by about 100%. There was found a linear relationship between plasma C-peptide levels and erythrocyteNa+K+ATPase activity. In small capillaries, microvascular blood flow is increasingly determined by the rheologic properties of erythrocytes. Using laser-diffractoscopie a huge improvement in erythrocyte deformability could be observed after C-peptide administration in erythrocytes of type 1 diabetic patients. Inhibition of theNa+K+ATPase by Obain completely abolished the effect of C-peptide on erythrocyte deformability. In conclusion, C-peptide improves microvascular function and blood flow in type 1 diabetic patients by interfering with vascular and rheological components of microvascular blood flow.

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C-peptide increases forearm blood flow in patients with type 1 diabetes via a nitric oxide-dependent mechanism

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00001.2003 ◽

2003 ◽

Vol 285 (4) ◽

pp. E864-E870 ◽

Cited By ~ 28

Author(s):

Bo-Lennart Johansson ◽

John Wahren ◽

John Pernow

Keyword(s):

Nitric Oxide ◽

Blood Flow ◽

Forearm Blood Flow ◽

Muscle Blood Flow ◽

Underlying Mechanism ◽

Saline Infusion ◽

Diabetic Patients ◽

C Peptide ◽

Type 1 Diabetic Patients

Proinsulin C-peptide has been shown to increase muscle blood flow in type 1 diabetic patients. The underlying mechanism is not fully understood. The aim of this study was to evaluate if the vasodilator effect of C-peptide is mediated by nitric oxide (NO). Eleven type 1 diabetic patients were studied two times and randomized to administration of intravenous and intra-arterial infusion of C-peptide or saline. Forearm blood flow (FBF) was measured by venous occlusion plethysmography during infusion of C-peptide or saline before, during, and after NO synthase (NOS) blockade. Endothelium-dependent and -independent vasodilatation was evaluated by administration of acetylcholine and sodium nitroprusside, respectively. FBF increased by 35% during intravenous C-peptide ( P < 0.01) but not during saline infusion (–2%, not significant). NOS blockade resulted in a more pronounced reduction in FBF during intravenous C-peptide than during saline infusion (–41 vs. –26%, P < 0.05). Intra-arterial C-peptide failed to increase FBF during NOS blockade. However, when C-peptide was given after the recovery from NOS blockade, FBF rose by 30% ( P < 0.001). The vasodilator effects of acetylcholine and nitroprusside were not influenced by C-peptide. It is concluded that the stimulatory effect of C-peptide on FBF in type 1 diabetic patients is mediated via the NO system and that C-peptide increases basal endothelial NO levels.

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Cellular and physiological effects of C-peptide

Clinical Science ◽

10.1042/cs20080441 ◽

2009 ◽

Vol 116 (7) ◽

pp. 565-574 ◽

Cited By ~ 57

Author(s):

Claire E. Hills ◽

Nigel J. Brunskill

Keyword(s):

Surrogate Marker ◽

Cell Types ◽

Hormone Deficiency ◽

Glucose Disposal ◽

Cell Phenotype ◽

Diabetic Patients ◽

C Peptide ◽

Salutary Effect ◽

Type 1 Diabetic Patients

In recent years, accumulating evidence indicates a biological function for proinsulin C-peptide. These results challenge the traditional view that C-peptide is essentially inert and only useful as a surrogate marker of insulin release. Accordingly, it is now clear that C-peptide binds with high affinity to cell membranes, probably to a pertussis-toxin-sensitive G-protein-coupled receptor. Subsequently, multiple signalling pathways are potently and dose-dependently activated in multiple cell types by C-peptide with the resulting activation of gene transcription and altered cell phenotype. In diabetic animals and Type 1 diabetic patients, short-term studies indicate that C-peptide also enhances glucose disposal and metabolic control. Furthermore, results derived from animal models and clinical studies in Type 1 diabetic patients suggest a salutary effect of C-peptide in the prevention and amelioration of diabetic nephropathy and neuropathy. Therefore a picture of Type 1 diabetes as a dual-hormone-deficiency disease is developing, suggesting that the replacement of C-peptide alongside insulin should be considered in its management.

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C-peptide improves adenosine-induced myocardial vasodilation in type 1 diabetes patients

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00236.2003 ◽

2004 ◽

Vol 286 (1) ◽

pp. E14-E19 ◽

Cited By ~ 34

Author(s):

Bo-Lennart Johansson ◽

Jan Sundell ◽

Karin Ekberg ◽

Cathrine Jonsson ◽

Marko Seppänen ◽

...

Keyword(s):

Skeletal Muscle ◽

Blood Flow ◽

Type 1 Diabetes ◽

Muscle Blood Flow ◽

Left Ventricular ◽

Diabetic Patients ◽

Skeletal Muscle Blood Flow ◽

C Peptide ◽

Type 1 Diabetic Patients

Patients with type 1 (insulin-dependent) diabetes show reduced skeletal muscle blood flow and coronary vasodilatory function despite intensive insulin therapy and good metabolic control. Administration of proinsulin C-peptide increases skeletal muscle blood flow in these patients, but a possible influence of C-peptide on myocardial vasodilatory function in type 1 diabetes has not been investigated. Ten otherwise healthy young male type 1 diabetic patients (Hb A1c 6.6%, range 5.7-7.9%) were studied on two consecutive days during normoinsulinemia and euglycemia in a double-blind, randomized, crossover design, receiving intravenous infusion of C-peptide (5 pmol·kg-1·min-1) for 120 min on one day and saline infusion on the other day. Myocardial blood flow (MBF) was measured at rest and during adenosine administration (140 μg·kg-1·min-1) both before and during the C-peptide or saline infusions by use of positron emission tomography and [15O]H2O administration. Basal MBF was not significantly different in the patients compared with an age-matched control group, but adenosine-induced myocardial vasodilation was 30% lower ( P < 0.05) in the patients. During C-peptide administration, adenosine-stimulated MBF increased on average 35% more than during saline infusion ( P < 0.02) and reached values similar to those for the healthy controls. Moreover, as evaluated from transthoracal echocardiographic measurements, C-peptide infusion resulted in significant increases in both left ventricular ejection fraction (+5%, P < 0.05) and stroke volume (+7%, P < 0.05). It is concluded that short-term C-peptide infusion in physiological amounts increases the hyperemic MBF and left-ventricular function in type 1 diabetic patients.

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C-Peptide and Its C-Terminal Fragments Improve Erythrocyte Deformability in Type 1 Diabetes Patients

Experimental Diabetes Research ◽

10.1155/2008/730594 ◽

2008 ◽

Vol 2008 ◽

pp. 1-6 ◽

Cited By ~ 17

Author(s):

Thomas Hach ◽

Thomas Forst ◽

Thomas Kunt ◽

Karin Ekberg ◽

Andreas Pfützner ◽

...

Keyword(s):

Signal Transduction ◽

Type 1 Diabetes ◽

Signal Transduction Pathway ◽

Erythrocyte Deformability ◽

Diabetic Patients ◽

Transduction Pathway ◽

Stress Range ◽

C Peptide ◽

Type 1 Diabetic Patients

Aims/hypothesis. Data now indicate that proinsulin C-peptide exerts important physiological effects and shows the characteristics of an endogenous peptide hormone. This study aimed to investigate the influence of C-peptide and fragments thereof on erythrocyte deformability and to elucidate the relevant signal transduction pathway.Methods. Blood samples from 23 patients with type 1 diabetes and 15 matched healthy controls were incubated with 6.6 nM of either human C-peptide, C-terminal hexapeptide, C-terminal pentapeptide, a middle fragment comprising residues 11–19 of C-peptide, or randomly scrambled C-peptide. Furthermore, red blood cells from 7 patients were incubated with C-peptide, penta- and hexapeptides with/without addition of ouabain, EDTA, or pertussis toxin. Erythrocyte deformability was measured using a laser diffractoscope in the shear stress range 0.3–60 Pa.Results. Erythrocyte deformability was impaired by 18–25% in type 1 diabetic patients compared to matched controls in the physiological shear stress range 0.6–12 Pa(P<.01–.001). C-peptide, penta- and hexapeptide all significantly improved the impaired erythrocyte deformability of type 1 diabetic patients, while the middle fragment and scrambled C-peptide had no detectable effect. Treatment of erythrocytes with ouabain or EDTA completely abolished the C-peptide, penta- and hexapeptide effects. Pertussis toxin in itself significantly increased erythrocyte deformability.Conclusion/interpretation. C-peptide and its C-terminal fragments are equally effective in improving erythrocyte deformability in type 1 diabetes. The C-terminal residues of C-peptide are causally involved in this effect. The signal transduction pathway isCa2+-dependent and involves activation of red blood cellNa+,K+-ATPase.

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Decreased distensibility of resistance vessels of the skin in type 1 (insulin-dependent) diabetic patients with microangiopathy

Clinical Science ◽

10.1042/cs0720123 ◽

1987 ◽

Vol 72 (1) ◽

pp. 123-130 ◽

Cited By ~ 15

Author(s):

J. Kastrup ◽

T. Nørgaard ◽

H.-H. Parving ◽

N. A. Lassen

Keyword(s):

Blood Flow ◽

Inverse Correlation ◽

Diabetic Patients ◽

Resistance Vessels ◽

Head Up Tilt ◽

Insulin Dependent ◽

Insulin Dependent Diabetic ◽

Type 1 Diabetic Patients ◽

Term Type

1. The distensibility of the resistance vessels of the skin at the dorsum of the foot was determined in 11 long-term type 1 (insulin-dependent) diabetic patients with nephropathy and retinopathy, nine short-term type 1 diabetic patients without clinical microangiopathy and in nine healthy non-diabetic subjects. 2. Blood flow was measured by the local 133Xexenon washout technique in a vascular bed locally paralysed by the injection of histamine. Blood flow was measured before, during and after a 40 mmHg increase of the vascular transmural pressure, induced by head-up tilt. 3. The mean increase in blood flow during headup tilt was only 24% in diabetic subjects with and 48% in diabetic patients without clinical microangiopathy, compared with 79% in normal non-diabetic subjects (P < 0.0005 and P < 0.05, respectively). 4. An inverse correlation between microvascular distensibility and degree of hyalinosis of the terminal arterioles in biopsies from the skin was demonstrated (r = − 0.57, P < 0.001). 5. Our results suggest that terminal arteriolar hyalinosis reduces the microvascular distensibility and probably increases the minimal vascular resistance, thereby impeding hyperaemic responses.

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Increased forearm blood flow in longstanding Type 1 diabetic patients without microvascular complications

Diabetic Medicine ◽

10.1111/j.1464-5491.2006.02020.x ◽

2007 ◽

Vol 24 (2) ◽

pp. 208-210 ◽

Cited By ~ 2

Author(s):

P. J. van Gurp ◽

J. W. M. Lenders ◽

C. J. Tack

Keyword(s):

Blood Flow ◽

Forearm Blood Flow ◽

Microvascular Complications ◽

Diabetic Patients ◽

Type 1 Diabetic Patients

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Blood flow in the skin of type 1 diabetic patients before and after combined pancreas/kidney transplantation

Diabetes/Metabolism Research and Reviews ◽

10.1002/dmrr.555 ◽

2005 ◽

Vol 21 (6) ◽

pp. 525-532 ◽

Cited By ~ 6

Author(s):

Nicola Eberl ◽

Wolfgang Piehlmeier ◽

Stefan Dachauer ◽

August König ◽

Walter Land ◽

...

Keyword(s):

Blood Flow ◽

Kidney Transplantation ◽

Diabetic Patients ◽

Before And After ◽

Pancreas Kidney Transplantation ◽

Type 1 Diabetic Patients

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Higher post-absorptive C-peptide levels in Type 1 diabetic patients without renal complications

Diabetic Medicine ◽

10.1046/j.1464-5491.1999.00181.x ◽

1999 ◽

Vol 16 (12) ◽

pp. 1048-1048 ◽

Cited By ~ 18

Author(s):

G. Zerbini ◽

R. Mangili ◽

L. Luzi

Keyword(s):

Diabetic Patients ◽

C Peptide ◽

Renal Complications ◽

Type 1 Diabetic Patients

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Role of C-Peptide in the Regulation of Microvascular Blood Flow

Experimental Diabetes Research ◽

10.1155/2008/176245 ◽

2008 ◽

Vol 2008 ◽

pp. 1-8 ◽

Cited By ~ 7

Author(s):

T. Forst ◽

T. Kunt ◽

B. Wilhelm ◽

M. M. Weber ◽

A. Pfützner

Keyword(s):

Blood Flow ◽

Beta Cell ◽

Cell Function ◽

Pancreatic Beta Cell ◽

Microvascular Blood Flow ◽

Diabetic Patients ◽

C Peptide ◽

Glucose Levels ◽

Peptide Secretion

During the recent years, the role of C-peptide, released from the pancreatic beta cell, in regulating microvascular blood flow, has received increasing attention. In type 1 diabetic patients, intravenous application of C-peptide in physiological concentrations was shown to increase microvascular blood flow, and to improve microvascular endothelial function and the endothelial release of NO. C-peptide was shown to impact microvascular blood flow by several interactive pathways, like stimulatingNa+K+ATPase or the endothelial release of NO. There is increasing evidence, that in patients with declining beta cell function, the lack of C-peptide secretion might play a putative role in the development of microvascular blood flow abnormalities, which go beyond the effects of declining insulin secretion or increased blood glucose levels.

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