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C-Peptide from Proinsulin

C-peptide is a 31-amino acid peptide cleaved from proinsulin as it is converted to insulin. Proinsulin consists of an A chain, a connecting peptide (C-peptide), and a B chain. After proinsulin is cleaved, C-peptide remains in the secretory granule of beta cells in the pancreas and is cosecreted with insulin in response to glucose stimulation. Recent studies have shown that systemic administration of C-peptide improves vascular, neural, and renal dysfunction in diabetic rats , decreases glomerular filtration, and increases renal plasma flow in type 1 diabetic patients . In addition, it has been shown that C-peptide promotes arteriolar dilation in skeletal muscle and inhibits leukocyte-endothelium interaction in the mesenteric microcirculation  by a NO-mediated mechanism.

C-Peptide from Prepro-Insulin-like Peptide

Stained rat testis tissue by Rabbit anti-Insulin-like peptide-5, C Peptide (H-035-47)

Stained rat testis tissue by Rabbit anti-Insulin-like peptide-3, C Peptide (H-035-48)

INSL 3, C Peptide Immunohistochemistry Protocol

 Slides from Phoenix Biotech (Beijing) Co., LTD., 

Qsinghua University, Beijing, P. R. China

C-Peptide (Human) EIA Kit (Catalog No.: EK-035-01) for Detection of C-Peptide (Human) Levels in plasma or serum

C-peptide exerts cardioprotective effects in myocardial ischemia-reperfusion
Ischemia followed by reperfusion in the presence of polymorphonuclear leukocytes (PMNs) results in cardiac dysfunction. C-peptide, a cleavage product of proinsulin to insulin processing, induces nitric oxide (NO)-mediated vasodilation. NO is reported to attenuate cardiac dysfunction caused by PMNs after ischemia-reperfusion (I/R). Therefore, we hypothesized that C-peptide could attenuate PMN-induced cardiac dysfunction. We examined the effects of C-peptide in isolated ischemic (20 min) and reperfused (45 min) rat hearts perfused with PMNs. C-peptide (70 nmol/kg iv) given 4 or 24 h before I/R significantly improved coronary flow (P < 0.05), left ventricular developed pressure (LVDP) (P < 0.01), and the maximal rate of development of LVDP (+dP/dt(max)) compared with I/R hearts obtained from rats given 0.9% NaCl (P < 0.01). N(G)-nitro-L-arginine methyl ester (L-NAME) (50 micromol/l) blocked these cardioprotective effects. In addition, C-peptide significantly reduced cardiac PMN infiltration from 183 +/- 24 PMNs/mm(2) in untreated hearts to 44 +/- 10 and 58 +/- 25 PMNs/mm(2) in hearts from 4- and 24-h C-peptide-treated rats, respectively. Rat PMN adherence to rat superior mesenteric artery exposed to 2 U/ml thrombin was significantly reduced in rats given C-peptide compared with rats given 0.9% NaCl (P < 0.001). Moreover, C-peptide enhanced basal NO release from rat aortic segments. These results provide evidence that C-peptide can significantly attenuate PMN-induced cardiac contractile dysfunction in the isolated perfused rat heart subjected to I/R at least in part via enhanced NO release.
Young LH, et al. Am J Physiol Heart Circ Physiol. 2000 Oct;279(4):H1453-9

Synergistic effects of C-peptide and insulin on coronary flow in early diabetic rats
The aims of the present study are (1) to examine whether coronary flow is increased and (2) to examine the role of C-peptide in relation to nitric oxide (NO) production and coronary flow in a rat heart (Wistar) during the early stages of type 1 diabetes. Coronary flow increased by 36.4% 10.6% (P <.05) during the early stages of streptozotocin-induced diabetes of isolated perfused rat hearts, but NO production increased without significance. C-peptide alone did not change coronary flow, but increased NO production in diabetes. In the presence of insulin, C-peptide reversed both flow and NO production to the control level of normal rats (P <.05). In conclusion, during the early stages of type 1 diabetes, coronary flow was increased, and C-peptide in the presence of insulin synergistically normalized the excessive flow and NO production induced by C-peptide to the control level of normal rats.
Nakamoto H, et al. Metabolism. 2004 Mar;53(3):335-9

C-peptide and captopril are equally effective in lowering glomerular hyperfiltration in diabetic rats
BACKGROUND: C-peptide has been shown to reduce glomerular hyperfiltration, glomerular hypertrophy and urinary albumin excretion in type 1 diabetes, but its effect has not been compared with that of an angiotensin-converting enzyme inhibitor (ACEI) in the early stage of renal involvement in diabetes. METHODS: Glomerular filtration rate (GFR) was measured in terms of inulin clearance and renal blood flow, using ultrasound technique, in four groups of streptozotocin-induced diabetic rats before and after a 60 min infusion of C-peptide (D-Cp), captopril (D-ACEI), C-peptide and captopril (D-Cp-ACEI) or placebo (D-placebo). In addition, a non-diabetic control group was studied before and after captopril infusion (C-ACEI). RESULTS: GFR was 37-51% higher in the diabetic groups than in the control animals. GFR decreased after treatment in the D-Cp, D-ACEI and D-Cp-ACEI groups, but did not change in the D-placebo group. Blood flow increased by 26-32% in the three groups receiving captopril and by 5% in the diabetic groups treated with C-peptide alone or placebo. The increase in blood flow in the three ACEI-treated groups was significantly greater than in the D-placebo group. Filtration fraction fell significantly in all groups, but only in the combined D-Cp-ACEI group did it fall significantly more than in the D-placebo group. CONCLUSIONS: C-peptide and captopril lower diabetes-induced glomerular hyperfiltration to a similar extent, but the influence of captopril on blood flow is greater than that of C-peptide, suggesting different mechanisms of action. No statistically significant additive effects of C-peptide and captopril were shown in this acute infusion study.
Samnegard B, et al. Nephrol Dial Transplant. 2004 Mar 5 [Epub ahead of print]

Role of C-peptide in human physiology
The C-peptide of proinsulin is important for the biosynthesis of insulin but has for a long time been considered to be biologically inert. Data now indicate that C-peptide in the nanomolar concentration range binds specifically to cell surfaces, probably to a G protein-coupled surface receptor, with subsequent activation of Ca(2+)-dependent intracellular signaling pathways. The association rate constant, K(ass), for C-peptide binding to endothelial cells, renal tubular cells, and fibroblasts is approximately 3. 10(9) M(-1). The binding is stereospecific, and no cross-reaction is seen with insulin, proinsulin, insulin growth factors I and II, or neuropeptide Y. C-peptide stimulates Na(+)-K(+)-ATPase and endothelial nitric oxide synthase activities. Data also indicate that C-peptide administration is accompanied by augmented blood flow in skeletal muscle and skin, diminished glomerular hyperfiltration, reduced urinary albumin excretion, and improved nerve function, all in patients with type 1 diabetes who lack C-peptide, but not in healthy subjects. The possibility exists that C-peptide replacement, together with insulin administration, may prevent the development or retard the progression of long-term complications in type 1 diabetes.
Wahren J, et al. Am J Physiol Endocrinol Metab. 2000 May;278(5):E759-68

Prevention of vascular and neural dysfunction in diabetic rats by C-peptide
C-peptide, a cleavage product from the processing of proinsulin to insulin, has been considered to possess little if any biological activity other than its participation in insulin synthesis. Injection of human C-peptide prevented or attenuated vascular and neural (electrophysiological) dysfunction and impaired Na+ and K+dependent adenosine triphosphate activity in tissues of diabetic rats. Nonpolar amino acids in the midportion of the peptide were required for these biological effects. Synthetic reverse sequence (retro) and all-D-amino acid (enantio) C-peptides were equipotent to native C-peptide, which indicates that the effects of C-peptide on diabetic vascular and neural dysfunction were mediated by nonchiral interactions instead of stereospecific receptors or binding sites.
Ido Y, et al. Science. 1997 Jul 25;277(5325):563-6
Specific binding of proinsulin C-peptide to human cell membranes
Recent reports have demonstrated beneficial effects of proinsulin C-peptide in the diabetic state, including improvements of kidney and nerve function. To examine the background to these effects, C-peptide binding to cell membranes has been studied by using fluorescence correlation spectroscopy. Measurements of ligand-membrane interactions at single-molecule detection sensitivity in 0.2-fl confocal volume elements show specific binding of fluorescently labeled C-peptide to several human cell types. Full saturation of the C-peptide binding to the cell surface is obtained at low nanomolar concentrations. Scatchard analysis of binding to renal tubular cells indicates the existence of a high-affinity binding process with K(ass) > 3.3 x 10(9) M(-1). Addition of excess unlabeled C-peptide is accompanied by competitive displacement, yielding a dissociation rate constant of 4.5 x 10(-4) s(-1). The C-terminal pentapeptide also displaces C-peptide bound to cell membranes, indicating that the binding occurs at this segment of the ligand. Nonnative D-C-peptide and a randomly scrambled C-peptide do not compete for binding with the labeled C-peptide, nor were crossreactions observed with insulin, insulin-like growth factor (IGF)-I, IGF-II, or proinsulin. Pretreatment of cells with pertussis toxin, known to modify receptor-coupled G proteins, abolishes the binding. It is concluded that C-peptide binds to specific G protein-coupled receptors on human cell membranes, thus providing a molecular basis for its biological effects.
Rigler R, et al. Proc Natl Acad Sci U S A. 1999 Nov 9;96(23):13318-23.

Human proinsulin with its C-peptide. Insulin A chain (purple), B chain (yellow), and C-peptide (blue). The CA and BC junctions, the dibasic processing sites (R31-R32 and K64-R65), are shown suitably poised for interaction with the prohormone convertases . Pro48 (P48) corresponds to Pro16

Supersecondary structures of native human C-peptide (Human), reverse sequence human C-peptide (Rev-human), and rat C-peptide 1 (Rat) depicted by MolScript (16), based on predictions by LINUS (14). A turn-like structure in the midportion of the peptides (from C13 to C19) is shown in red.
Ido Y, et al. Science. 1997 Jul 25;277(5325):563-6


Summary of effects of C-peptides and fragments on 30 mM glucose-induced vascular dysfunction (blood flow) in the skin chamber granulation tissue model. All peptides were coadministered at a concentration of 100 nM with 30 mM glucose. Efficacy is expressed as an average percent of the effect of 100 nM human C-peptide. Because the reductions (by the peptides) in 30 mM glucose-induced increases in 125I-albumin permeation and blood flow were the same, only the blood flow data are shown. The number in parentheses to the right of each bar is the number of chambers assessed. Scheffe's interval test was used to assess differences (12). Significantly different for 30 mM glucose: *P < 0.05.
Ido Y, et al. Science. 1997 Jul 25;277(5325):563-6

Effects of human C-peptide on body weight and metabolic parameters in rats with streptozotocin-induced diabetes of 5 weeks duration.


Control Control + C-peptide Diabetes Diabetes + C-peptide

Number of rats 7 6 8 8
Body weight (g)
Initial 216  ?nbsp; 17* 217  ?nbsp; 21  224   ?nbsp; 23  212   ?nbsp; 21
Final 359  ?nbsp; 34 357  ?nbsp; 41  333   ?nbsp; 26||  307   ?nbsp; 21||
Food consumption (g/day) 19.4  ?nbsp; 1.4 20.3  ?nbsp; 3.4   30.0 ?nbsp;  6.8   31.1 ?nbsp;  7.3
Plasma glucose (mM) 8.7  ?nbsp; 1.0 7.6  ?nbsp; 2.9   30.0 ?nbsp;  6.2||  26.6 ?nbsp;  4.1||
MNCV (m/s)dagger 38.2  ?nbsp; 0.9 36.2  ?nbsp; 3.3   33.4 ?nbsp;  1.3||   37.1 ?nbsp;  0.8?/sup>
Sorbitolddagger
Retina 86  ?nbsp; 19 139  ?nbsp; 62  756   ?nbsp;284||  913   ?nbsp;243||
Sciatic nerve 125  ?nbsp; 18 163  ?nbsp; 56 1556   ?nbsp;338|| 1587   ?nbsp;306||
Na+,K+-ATPase?/sup>
Sciatic nerve 23.7  ?nbsp; 5.7 --   13.7 ?nbsp;  2.7||   20.8 ?nbsp;  4.8?/sup>

* Mean ?nbsp;SD.
dagger Caudal MNCV was measured as meters per second as described in (6).
ddagger Sorbitol levels (nmol/g wet weight) were determined as their butylboronate derivatives by gas chromatography mass spectrometry (22).
?/sup> Na+,K+-ATPase (nanomoles of ADP per milligram of protein per minute) was measured as described in (6).
| Significantly different from controls (12): P < 0.005. 
?/sup> Significantly different from untreated diabetics: P < 0.005.

Ido Y, et al. Science. 1997 Jul 25;277(5325):563-6



Linear representation of human proinsulin indicating amino acid sequence of C-peptide and showing position of COOH-terminal pentapeptide, which mimics action of C-peptide in assays of binding and Na+-K+-ATPase activity.
Wahren J, et al. Am J Physiol Endocrinol Metab. 2000 May;278(5):E759-68


Stimulation of Na+-K+-ATPase activity (means ?nbsp;SE) in renal tubular segments from rats by homologous C-peptide in different concentrations. Wahren J, et al. Am J Physiol Endocrinol Metab. 2000 May;278(5):E759-68
Amino acid sequences for different mammalian C-peptides

Human EAEDLQVGQVELGGGPGAGSLQPLALEGSLQ
Monkey EAEDPQVGQVELGGGPGAGSLQPLALEGSLQ
Bovine EVEGPQVGALELAGGPGAGG_____LEGPPQ
Mouse-1 EVEDPQVEQLELGGSPG__DLQTLALEVARQ
Rat-1 EVEDPQVPQLELGGGPEAGDLQTLALEVARQ
Pig EAENPQAGAVELGGGLGG__LQALALEGPPQ
Sheep EVEGPQVGALELAGGPG_____AGGLEGPPQ
Horse EAEDPQVGEVELGGGPGLGGLQPLALAGPQQ

Lines indicate gap positions.

Binding of rhodamine-labeled C-Peptide (Human)   to  human rental tubular cells

Binding of rhodamine-labeled human C-peptide to human renal tubular cells as evaluated by fluorescence correlation spectroscopy (FCS) in concentration range of 0-5 nM. Association rate constant (Kass) for C-peptide binding was 3.3 ?nbsp;109 M-1. Values are means ?nbsp;SE shown as %. Wahren J, et al. Am J Physiol Endocrinol Metab. 2000 May;278(5):E759-68

C-peptide binding curve. Binding of Rh-labeled C-peptide to cell membranes of renal tubular cells. Fractional saturation of the membrane-bound Rh-CP (y) as a function of the ligand concentration (L) in the binding medium. Each data point represents the mean of at least six measurements. The binding curve was simulated with Kass = 3.3 ?nbsp;109 M-1 and n = 1. Scatchard plot is shown as Inset. Rigler R, et al. Proc Natl Acad Sci U S A. 1999 Nov 9;96(23):13318-23.

C-peptide binding and displacement to the membranes of cultured renal tubular cells. Fluorescence intensity fluctuations (A) and autocorrelation function (B) for Rh-CP (5 nM) free in solution, tau  = 0.15 ms. Fluorescence intensity fluctuations (D) and autocorrelation function (E) for Rh-CP bound to membranes on the cell surface. Diffusion times (tau ) and corresponding fractions (y): tau 1 = 80 ms, y1 = 0.75; tau 2 = 1 ms, y2 = 0.15; tau 3 = 0.15 ms, y3 = 0.1. Autocorrelation functions of displacement of membrane bound Rh-CP by postincubation of a thousandfold molar excess of nonlabeled C-peptide (F) and nonlabeled C-terminal pentapeptide (C). The observed and calculated data points are completely overlapping (B, C, E, and F). Rigler R, et al. Proc Natl Acad Sci U S A. 1999 Nov 9;96(23):13318-23.

Time course of displacement of Rh-CP by nonlabeled C-peptide. After incubation of cells with 5 nM Rh-CP for 60 min, 5 M nonlabeled C-peptide was added, and FCS measurements were carried out at given time intervals. Each data point represents the mean of at least six measurements. Log scale for the binding displacement process is shown as Inset. Rigler R, et al. Proc Natl Acad Sci U S A. 1999 Nov 9;96(23):13318-23.
Table    Binding of C-peptide and insulin to different cell types

Ligand Cells Receptors/m2* Kass, 109 M-1

C-peptide Renal tubular  75 ?nbsp;12 3.3
Fibroblasts  55 ?nbsp;10 2.5
Endothelial  43 ?nbsp; 4 2.0
Insulin Renal tubular 200 ?nbsp;10 1.2

* Calculated from the number of Rh-C-peptide or Rh-insulin binding sites in the volume element with an area of 0.196 m2.
Rigler R, et al. Proc Natl Acad Sci U S A. 1999 Nov 9;96(23):13318-23.

CONTIN distributions of diffusion times P(tau i) of C-peptide binding and displacement to the membranes of cultured renal tubular cells. Rh-CP free in the incubation medium (A), binding of Rh-CP to the cell membranes (B), displacement of membrane-bound Rh-CP by incubation with a thousandfold molar excess of nonlabeled C-peptide (C), and inhibition of membrane binding of Rh-CP after pretreatment of the cells with pertussis toxin (D). Rigler R, et al. Proc Natl Acad Sci U S A. 1999 Nov 9;96(23):13318-23.

FCS experimental setup. Light from an argon ion laser is focused by means of a dichroic mirror and a lens to form a small volume element (0.2 fl). The laser beam is projected from below into a well containing a monolayer of cultured cells and tetramethylrhodamine (Rh)-labeled ligand (see magnified diagram at the top). After excitation of the labeled ligand, emitted light is transmitted via the dichroic mirror, a bandpass filter, and a pinhole to a photodetector. The volume element is positioned onto the cell surface with a microscope for detection of ligand binding. The dimensions of the laser beam focus and the pinhole together define the confocal volume element. The detector signal is fed into a digital signal correlator, which calculates the autocorrelation function of the detected intensity fluctuations. Rigler R, et al. Proc Natl Acad Sci U S A. 1999 Nov 9;96(23):13318-23.

Available data are compatible with the hypothesis that C-peptide binds to cell membrane receptors coupled to a pertussis toxin-sensitive G protein. The G protein activates Ca2+ channels, resulting in an increased intracellular Ca2+ concentration and activation of both endothelial nitric oxide synthase (eNOS) and Ca2+-calmodulin-dependent protein phosphatase 2B (PP2B). PP2B subsequently converts the phosphorylated form of Na+-K+-ATPase into its dephosphorylated, active form.
Wahren J, et al. Am J Physiol Endocrinol Metab. 2000 May;278(5):E759-68


Initial and final left ventricular developed pressure (LVDP) expressed in mmHg in isolated perfused rat hearts before ischemia and after reperfusion. Hearts were perfused in the presence or absence of PMNs. PMNs induced a significant contractile dysfunction, which was attenuated by C-peptide. All values are expressed as means ?nbsp;SE. Numbers of hearts are shown at the bottom of the bars. **P < 0.01, ***P < 0.001 vs. I/R + PMN + vehicle group. 
Young LH, et al. Am J Physiol Heart Circ Physiol. 2000 Oct;279(4):H1453-9

Initial and final maximal rate of development of LVDP (+dP/dtmax) expressed in mmHg/s in isolated perfused rat hearts before ischemia and after reperfusion. Hearts were perfused in the presence or absence of PMNs. PMNs induced a significant contractile dysfunction, which was attenuated by C-peptide. All values are expressed as means ?nbsp;SE. Numbers of hearts are shown at the bottom of the bars. **P < 0.01 vs. I/R + PMN + vehicle group.
Young LH, et al. Am J Physiol Heart Circ Physiol. 2000 Oct;279(4):H1453-9

Histological assessment of extravascular infiltrated PMNs in isolated perfused rat heart samples taken from 3 rats per group and 10 areas per heart. All values are mean numbers of PMNs/mm2 heart area ?nbsp;SE. The number of PMNs infiltrated into postreperfusion cardiac tissue was significantly attenuated by C-peptide. ***P < 0.001 vs. I/R + PMN + vehicle group.
Young LH, et al. Am J Physiol Heart Circ Physiol. 2000 Oct;279(4):H1453-9


Effect of C-peptide on basal release of nitric oxide (NO) from isolated rat aortic segments. C-peptide (70 nmol/kg) was injected intravenously in rats 24 h before isolation of the aorta. All values are means ?nbsp;SE of 12 segments isolated from 4 rats/group. Young LH, et al. Am J Physiol Heart Circ Physiol. 2000 Oct;279(4):H1453-9

Adherence of rat PMNs to rat superior mesenteric artery (SMA) endothelium is expressed as PMNs/mm2. Rat SMAs were isolated from rats given C-peptide or vehicle (0.9% NaCl) and were either nonstimulated or stimulated with thrombin (2 U/ml). PMNs that adhered to endothelium were counted and analyzed. All values are expressed as means ?nbsp;SE. Numbers shown at the bottom of the bars indicate numbers of SMA segments analyzed in each group. KH, Krebs-Henseleit buffer. ***P < 0.001 vs. thrombin group.
Young LH, et al. Am J Physiol Heart Circ Physiol. 2000 Oct;279(4):H1453-9

 

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