Thomas Forst

John Wahren

New Tricks by an Old Dog

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 stimulating <svg     style="vertical-align:-0.16379pt;width:27.387501px;" id="M1" height="14.3125" version="1.1" viewBox="0 0 27.387501 14.3125" width="27.387501"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
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</svg>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.

T. Forst

T. Kunt

B. Wilhelm

M. M. Weber

A. Pfützner

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

The C-peptide of proinsulin is important for the biosynthesis of insulin and has for a long time been considered to be biologically inert. Animal studies have shown that some of the renal effects of the C-peptide may in part be explained by its ability to stimulate the Na,K-ATPase activity. Precisely, the C-peptide reduces diabetes-induced glomerular hyperfiltration both in animals and humans, therefore, resulting in regression of fibrosis. The tubular function is also concerned as diabetic animals supplemented with C-peptide exhibit better renal function resulting in reduced urinary sodium waste and protein excretion together with the reduction of the diabetes-induced glomerular hyperfiltration. The tubular effectors of C-peptide were considered to be tubule transporters, but recent studies have shown that biochemical pathways involving cellular kinases and inflammatory pathways may also be important. The matter theory concerning the C-peptide effects is a metabolic one involving the effects of the C-peptide on lipidic metabolic status.This review concentrates on the most convincing data which indicate that the C-peptide is a biologically active hormone for renal physiology.

L. Rebsomen

A. Khammar

D. Raccah

M. Tsimaratos

C-Peptide Effects on Renal Physiology and Diabetes

Starting with the epoch-making discovery of proinsulin, C-peptide has played an important interdisciplinary role, both as part of  the single-chain precursor molecule and  as an individual entity. In the pioneering years, fundamental systematic experiments unravelled new biochemical mechanisms and chemical structures. After the first detection of C-peptide in human serum, it quickly became a most useful independent indicator of  insulin biosynthesis and secretion, finding application in a rapidly growing number of clinical investigations. A prerequisite was the development of specific immuno assays for proinsulin and C-peptide.
Further milestones were: the chemical synthesis of several C-peptides and the accomplishments in the synthesis of proinsulin; the detection of preproinsulin  with its bearings on understanding protein biosynthesis; the pioneering role of insulin, proinsulin, C-peptide, and mini-C-peptides in the development of recombinant DNA technology; and the discovery of the enzymes for the endoproteolytic processing of proinsulin into insulin and C-peptide, completing the pathway of biosynthesis.
Today, C-peptide continues to serve as a special diagnostic tool in Diabetology and related fields. Thus, its passive role is well established. Evidence for its active role in physiology and pathophysiology is more recent and is subject of the following contributions.

Dietrich Brandenburg

History and Diagnostic Significance of C-Peptide

<i>Aims/hypothesis</i>. 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.
<i>Methods</i>. 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. <i>Results</i>. 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 <svg style="vertical-align:-2.3205pt;width:91.050003px;" id="M1" height="15.0875" version="1.1" viewBox="0 0 91.050003 15.0875" width="91.050003" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg"><g transform="matrix(.017,-0,0,-.017,.062,12.138)"><path id="x28" d="M300 -147l-18 -23q-106 71 -159 185.5t-53 254.5v1q0 139 53 252.5t159 186.5l18 -24q-74 -62 -115.5 -173.5t-41.5 -242.5q0 -130 41.5 -242.5t115.5 -174.5z" /></g><g transform="matrix(.017,-0,0,-.017,5.944,12.138)"><path id="x1D443" d="M619 482q0 -69 -40.5 -119t-96 -72.5t-118.5 -26.5h-44l-70 20l-31 -151q-14 -67 0.5 -83t89.5 -22l-5 -28h-287l8 28q65 7 81.5 22t29.5 83l79 398q12 56 0.5 70.5t-78.5 20.5l7 28h255q108 0 164 -43t56 -125zM524 478q0 141 -146 141q-25 0 -47 -8q-16 -6 -20.5 -13.5&#xA;t-10.5 -39.5l-43 -241q37 -13 83 -13q67 0 125.5 45t58.5 129z" /></g><g transform="matrix(.017,-0,0,-.017,21.464,12.138)"><path id="x3C" d="M512 -3l-437 233v51l437 233v-58l-378 -200v-2l378 -199v-58z" /></g><g transform="matrix(.017,-0,0,-.017,36.168,12.138)"><path id="x2E" d="M113 -12q-24 0 -39.5 16t-15.5 42q0 24 16 40.5t40 16.5t40 -16.5t16 -40.5q0 -26 -16 -42t-41 -16z" /></g><g transform="matrix(.017,-0,0,-.017,40.044,12.138)"><path id="x30" d="M241 635q53 0 94 -28.5t63.5 -76t33.5 -102.5t11 -116q0 -58 -11 -112.5t-34 -103.5t-63.5 -78.5t-94.5 -29.5t-95 28t-64.5 75t-34.5 102.5t-11 118.5q0 58 11.5 112.5t34.5 103t64.5 78t95.5 29.5zM238 602q-32 0 -55.5 -25t-35.5 -68t-17.5 -91t-5.5 -105&#xA;q0 -76 10 -138.5t37 -107.5t69 -45q32 0 55.5 25t35.5 68.5t17.5 91.5t5.5 105t-5.5 105.5t-18 92t-36 68t-56.5 24.5z" /></g><g transform="matrix(.017,-0,0,-.017,48.203,12.138)"><path id="x31" d="M384 0h-275v27q67 5 81.5 18.5t14.5 68.5v385q0 38 -7.5 47.5t-40.5 10.5l-48 2v24q85 15 178 52v-521q0 -55 14.5 -68.5t82.5 -18.5v-27z" /></g><g transform="matrix(.017,-0,0,-.017,53.541,12.138)"><path id="x2D" d="M300 253l-14 -55h-229l14 55h229z" /></g><g transform="matrix(.017,-0,0,-.017,56.77,12.138)"><use xlink:href="#x2E" /></g><g transform="matrix(.017,-0,0,-.017,60.646,12.138)"><use xlink:href="#x30" /></g><g transform="matrix(.017,-0,0,-.017,68.805,12.138)"><use xlink:href="#x30" /></g><g transform="matrix(.017,-0,0,-.017,76.965,12.138)"><use xlink:href="#x31" /></g><g transform="matrix(.017,-0,0,-.017,85.124,12.138)"><path id="x29" d="M275 270q0 -296 -211 -440l-19 23q75 62 116.5 174t41.5 243t-42 243t-116 173l19 24q211 -144 211 -440z" /></g></svg>. 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. <i>Conclusion/interpretation</i>. 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 is <svg style="vertical-align:-0.20473pt;width:32.362499px;" id="M2" height="16.1" version="1.1" viewBox="0 0 32.362499 16.1" width="32.362499" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg"><g transform="matrix(.017,-0,0,-.017,.062,15.775)"><path id="x43" d="M614 175l29 -10q-33 -109 -57 -154q-121 -26 -184 -26q-90 0 -160.5 29t-112.5 77t-63.5 105.5t-21.5 119.5q0 157 108 253t277 96q36 0 71.5 -5t69 -13.5t36.5 -8.5q15 -102 20 -150l-29 -8q-20 79 -66.5 114t-128.5 35q-119 0 -187.5 -86t-68.5 -207&#xA;q0 -140 73.5 -227.5t188.5 -87.5q73 0 119.5 37.5t86.5 116.5z" /></g><g transform="matrix(.017,-0,0,-.017,11.503,15.775)"><path id="x61" d="M433 39l-85 -51q-27 0 -47 20q-16 16 -24 44q-5 -3 -24 -16.5t-27 -18.5t-23 -13.5t-25 -12t-19 -3.5q-52 0 -86 36.5t-34 85.5q0 71 81 99q128 43 155 65v17q0 54 -23 83.5t-62 29.5q-28 0 -45 -19t-29 -66q-7 -23 -29 -23q-15 0 -29 13t-14 30t31 40q25 19 68.5 40.5&#xA;t81.5 29.5q49 0 82 -27q45 -39 45 -123v-185q0 -60 35 -60q18 0 36 11zM275 84v156q-12 -6 -49 -23t-41 -19q-31 -14 -46 -31t-15 -43q0 -35 22.5 -55.5t48.5 -20.5q19 0 42 10.5t38 25.5z" /></g><g transform="matrix(.012,-0,0,-.012,18.987,7.613)"><path id="x32" d="M412 140l28 -9q0 -2 -35 -131h-373v23q112 112 161 170q59 70 92 127t33 115q0 63 -31 98t-86 35q-75 0 -137 -93l-22 20l57 81q55 59 135 59q69 0 118.5 -46.5t49.5 -122.5q0 -62 -29.5 -114t-102.5 -130l-141 -149h186q42 0 58.5 10.5t38.5 56.5z" /></g><g transform="matrix(.012,-0,0,-.012,24.699,7.613)"><path id="x2B" d="M535 230h-212v-233h-58v233h-213v50h213v210h58v-210h212v-50z" /></g></svg>-dependent and involves activation of red blood cell <svg style="vertical-align:-0.16379pt;width:27.387501px;" id="M3" height="14.3125" version="1.1" viewBox="0 0 27.387501 14.3125" width="27.387501" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg"><g transform="matrix(.017,-0,0,-.017,.062,14.05)"><path id="x4E" d="M719 650v-28q-43 -2 -62 -15t-22 -44q-6 -47 -6 -169v-403h-31l-426 524h-2v-251q0 -111 6 -169q4 -37 24 -50.5t72 -16.5v-28h-237v28q45 2 64.5 16t23.5 49q6 62 6 171v220q0 54 -3 68.5t-17 32.5q-16 19 -34.5 26.5t-54.5 10.5v28h147l418 -502h3v246q0 117 -7 166&#xA;q-4 34 -24.5 47t-73.5 15v28h236z" /></g><g transform="matrix(.017,-0,0,-.017,12.251,14.05)"><use xlink:href="#x61" /></g><g transform="matrix(.012,-0,0,-.012,19.713,5.887)"><use xlink:href="#x2B" /></g></svg>,<svg style="vertical-align:-0.0pt;width:19.174999px;" id="M4" height="14.1125" version="1.1" viewBox="0 0 19.174999 14.1125" width="19.174999" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg"><g transform="matrix(.017,-0,0,-.017,.062,14.05)"><path id="x4B" d="M667 0h-153l-248 291q-28 32 -54 27v-190q0 -65 14.5 -80t77.5 -20v-28h-260v28q58 5 71 20t13 80v392q0 48 -6 66.5t-22 25.5t-59 10v28h258v-28q-59 -5 -73 -20.5t-14 -81.5v-175q29 6 70 45q101 97 167 178q23 27 20 37t-36 14l-23 3v28h240v-28q-57 -5 -86 -18.5&#xA;t-76 -56.5q-40 -35 -177 -175q97 -124 235 -272q39 -41 61.5 -54t59.5 -18v-28z" /></g><g transform="matrix(.012,-0,0,-.012,11.5,5.887)"><use xlink:href="#x2B" /></g></svg>-ATPase.

Thomas Hach

Thomas Kunt

Karin Ekberg

Andreas Pfützner

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

Diabetic polyneuropathy (DPN) occurs more frequently in type 1 diabetes resulting in a more severe DPN.  The differences in DPN between the two types of diabetes are due to differences in the availability of insulin and C-peptide.  Insulin and C-peptide provide gene regulatory effects on neurotrophic factors with effects on axonal cytoskeletal proteins and nerve fiber integrity.  A significant abnormality in type 1 DPN is nodal degeneration.  In the type 1 BB/Wor-rat, C-peptide replacement corrects metabolic abnormalities ameliorating the acute nerve conduction defect.  It corrects abnormalities of neurotrophic factors and the expression of neuroskeletal proteins with improvements of axonal size and function. C-peptide corrects the expression of nodal adhesive molecules with prevention and repair of the functionally significant nodal degeneration.
    Cognitive dysfunction is a recognized complication of type 1 diabetes, and is associated with impaired neurotrophic support and apoptotic neuronal loss. C-peptide prevents hippocampal apoptosis and cognitive deficits.  It is therefore clear that substitution of C-peptide in type 1 diabetes has a multitude of effects on DPN and cognitive dysfunction.
Here the effects of C-peptide replenishment will be extensively described as they pertain to DPN and diabetic encephalopathy, underpinning its beneficial effects on neurological complications in type 1 diabetes.

Anders A. F. Sima

Weixian Zhang

Zhen-guo Li

Hideki Kamiya

The Effects of C-peptide on Type 1 Diabetic Polyneuropathies and Encephalopathy in the BB/Wor-rat

Patients with fulminant type 1 diabetes almost completely lack C-peptide even soon after the onset of the disease, and the deficiency continues for the rest of their life. Thus, fulminant type 1 diabetes could serve as a good model of nature to explore the physiological role of C-peptide. For example, patients with fulminant type 1 diabetes have diabetic chronic complications more frequently than those with classical autoimmune type 1 diabetes 5 years after the onset of diabetes, and the higher prevalence could be partly attributable to the complete lack of C-peptide in fulminant type 1 diabetes.

Yuko Murase-Mishiba

A. Imagawa

Toshiaki Hanafusa

Fulminant Type 1 Diabetes as a Model of Nature to Explore the Role of C-Peptide

Patients with insulin resistance and early type 2 diabetes exhibit an increased propensity to develop a diffuse and extensive pattern of arteriosclerosis. Typically, these patients show increased levels of C-peptide and over the last years various groups examined the effect of C-peptide in vascular cells as well as its potential role in lesion development.  While some studies demonstrated beneficial effects of C-peptide, for example, by showing an inhibition of smooth muscle cell proliferation, others suggested proatherogenic mechanisms in patients with type 2 diabetes. Among them, C-peptide may facilitate the recruitment of inflammatory cells into early lesions and promote lesion progression by inducing smooth muscle cell proliferation. The following review will summarize the effects of C-peptide in vascular cells and discuss the potential role of C-peptide in atherogenesis in patients with type 2 diabetes.

Nikolaus Marx

Daniel Walcher

C-Peptide and Atherogenesis: C-Peptide as a Mediator of Lesion Development in Patients with Type 2 Diabetes Mellitus?

During the recent years, multiple studies demonstrated that C-peptide is not an inert peptide, but exerts important physiological effects. C-peptide binds to cell membranes, stimulates the Na,K-ATPase and the endothelial nitric oxide (NO) synthase. Moreover, there is evidence that C-peptide decreases glomerular hyperfiltration and increases glucose utilisation. Nevertheless, there is still limited knowledge concerning mechanisms leading to an increased glucose utilisation either in rats or in humans. The aim of this paper is to give an overview over the published studies regarding C-peptide and glucose metabolism from in vitro studies to longer lasting studies in humans.

P. Kann

A. Pf&#xFC;tzner

Influence of C-Peptide on Glucose Utilisation

C-peptide, a cleavage product of the proinsulin molecule, has long been regarded as biologically inert, serving merely as a surrogate marker for insulin release. Recent findings demonstrate both a physiological and protective role of C-peptide when administered to individuals with type I diabetes.  Data indicate that C-peptide appears to bind in nanomolar concentrations to a cell surface receptor which is most likely to be G-protein coupled. Binding of C-peptide initiates multiple cellular effects, evoking a rise in intracellular calcium, increased PI-3-kinase activity, stimulation of the Na<sup>+</sup>/K<sup>+</sup> ATPase, increased eNOS transcription, and activation of  the MAPK signalling pathway. These cell signalling effects have been studied in multiple cell types from multiple tissues. Overall these observations raise the possibility that C-peptide may serve as a potential therapeutic agent for the treatment or prevention of long-term complications associated with diabetes.

Claire E. Hills

Nigel J. Brunskill

Intracellular Signalling by C-Peptide

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<p><em>Journal of Diabetes Research</em> publishes articles related to type 1 and type 2 diabetes. Topics include etiology, pathogenesis, management, and prevention of diabetes, as well as associated complications such as nephropathy.</p>


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<p>Chief Editor Dr Mark Yorek, from the University of Iowa, is currently researching vascular and neural disease related to obesity and diabetes. His active research studies focus on etiology, treatment and prevention of nerve damage.</p>


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Journal of Diabetes Research publishes articles related to type 1 and type 2 diabetes. Topics include etiology, pathogenesis, management, and prevention of diabetes, as well as associated complications such as nephropathy.

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Journal of Diabetes Research

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