What is C-peptide, and what is its primary structural role in proinsulin?

C-peptide, also known as the connecting peptide, is a short polypeptide composed of 31 amino acids. Its main function in the proinsulin molecule is to link insulin's A-chain and B-chain together.

How can measuring C-peptide levels in blood serum be clinically useful?

Measuring C-peptide levels in blood serum can help distinguish between different medical conditions that present with similar symptoms, particularly in the context of diabetes or hypoglycemia.

Describe the initial stages of insulin synthesis within the pancreatic beta cells.

Initially, preproinsulin is translocated into the endoplasmic reticulum of pancreatic beta cells. This molecule contains an A-chain, a C-peptide, a B-chain, and a signal sequence. A signal peptidase then cleaves the signal sequence from the N-terminus, resulting in proinsulin.

What happens to proinsulin after it is packaged into vesicles?

After proinsulin is packaged into vesicles within the Golgi apparatus, specifically in structures called beta-granules, the C-peptide is removed. This process leaves the A-chain and B-chain, which are then bound together by disulfide bonds to form the mature insulin molecule.

What is the affinity of C-peptide for the insulin receptor?

C-peptide has virtually no affinity for the insulin receptor, meaning it does not directly bind to it to trigger insulin's primary signaling pathways.

What cellular activities does C-peptide promote, and what is the current understanding of their physiological significance?

C-peptide is known to promote the activity of at least two enzymes: the sodium-potassium pump and nitric oxide synthase. These effects occur downstream of C-peptide binding to a membrane structure, presumed to be a G protein-coupled receptor. However, the overall physiological significance of these C-peptide-induced effects remains unresolved.

When was proinsulin C-peptide first identified, and what discovery was it linked to?

Proinsulin C-peptide was first described in 1967, in connection with the discovery of the insulin biosynthesis pathway.

What key developments regarding C-peptide occurred in 1971?

In 1971, researchers achieved the isolation of bovine C-peptide, determined its amino acid sequence, and prepared human C-peptide.

What crucial role does C-peptide play in the endoplasmic reticulum during insulin synthesis?

C-peptide acts as a linker between the A- and B-chains of insulin, which is essential for the efficient assembly, proper folding, and processing of the insulin molecule within the endoplasmic reticulum.

What is the relationship between C-peptide and insulin secretion in terms of quantity?

Equimolar amounts of C-peptide and insulin are stored together in the secretory granules of pancreatic beta cells and are eventually released into the portal circulation in equal quantities.

What was the initial primary interest in C-peptide within the medical field?

Initially, the primary interest in C-peptide was solely as a marker to measure insulin secretion. This measurement proved valuable in advancing the understanding of the pathophysiology of both type 1 and type 2 diabetes.

When was the C-peptide test first documented for clinical use?

The first documented use of the C-peptide test in a clinical setting was in 1972.

What significant finding about C-peptide emerged in the early 21st century?

In the first decade of the 21st century, research revealed that C-peptide is not just a byproduct but a bioactive peptide in its own right, possessing effects on microvascular blood flow and tissue health.

On which cell types has C-peptide been observed to bind, and at what concentrations?

C-peptide has been observed to bind to the surface of various cell types, including neuronal, endothelial, fibroblast, and renal tubular cells, typically at nanomolar concentrations.

What type of receptor is C-peptide believed to interact with on cell surfaces?

C-peptide is believed to bind to a receptor on cell surfaces that is likely a G protein-coupled receptor.

What intracellular signaling pathways are activated by C-peptide binding to cells?

Upon binding to its receptor, C-peptide activates calcium-dependent intracellular signaling pathways, such as MAPK, PLCγ, and PKC.

What specific enzyme activities are upregulated by C-peptide signaling, and why is this significant?

C-peptide signaling leads to the upregulation of transcription factors, endothelial nitric oxide synthase (eNOS), and the sodium-potassium ATPase (Na+K+ATPase). Reduced activities of eNOS and Na+K+ATPase are associated with long-term complications in type 1 diabetes, such as neuropathy.

What improvements in nerve function were observed in animal models of type 1 diabetes treated with C-peptide?

In animal models of type 1 diabetes, administration of C-peptide resulted in significant improvements in nerve function. This included increased nerve conduction velocity, enhanced nerve Na+,K+ ATPase activity, and a notable amelioration of nerve structural damage.

How does C-peptide administration impact renal function and structure in diabetic animal models?

In animal models with type 1 diabetes and C-peptide deficiency, C-peptide administration improved renal function and structure. Specifically, it decreased urinary albumin excretion and prevented or reduced diabetes-induced glomerular changes, such as mesangial matrix expansion.

What other potential beneficial effects of C-peptide have been reported?

Beyond its effects on nerve and kidney function, C-peptide has also been reported to possess anti-inflammatory properties and to aid in the repair of smooth muscle cells.

What relationship has been suggested between C-peptide levels and cardiovascular disease risk?

An epidemiological study suggests a U-shaped relationship between C-peptide levels and the risk of cardiovascular disease, indicating that both very low and potentially very high levels might be associated with increased risk.

How is C-peptide testing used to differentiate between types of diabetes?

C-peptide testing is used to help distinguish between type 1 diabetes, type 2 diabetes, and maturity-onset diabetes of the young (MODY). It indicates the body's own insulin production capacity.

Why is C-peptide measurement often preferred over direct insulin level measurement for assessing endogenous insulin production?

C-peptide measurement is often preferred because it accurately reflects a person's own insulin secretion even if they are receiving insulin injections. Additionally, while the liver metabolizes a significant amount of insulin, it does not metabolize C-peptide, making C-peptide levels a potentially more reliable indicator of insulin secretion into the portal vein compared to insulin itself.

What is the clinical significance of very low C-peptide levels?

Very low C-peptide levels strongly confirm type 1 diabetes and indicate insulin dependence. This condition is often associated with high glucose variability, hyperglycemia, and an increased risk of diabetes-related complications.

In which specific type of diabetes might C-peptide testing alone be insufficient for diagnosis?

C-peptide testing may be less sufficient for diagnosing Latent Autoimmune Diabetes in Adults (LADA), a subtype of type 1 diabetes. This is because LADA patients may have C-peptide levels that overlap with those seen in type 2 diabetes, necessitating additional beta-cell antibody testing for a more accurate diagnosis.

How can C-peptide testing assist in the differential diagnosis of hypoglycemia?

C-peptide testing can help determine the cause of hypoglycemia (low blood glucose). Levels will be low if the hypoglycemia is due to an overdose of exogenous insulin, but they will not be suppressed if the low blood glucose is caused by an insulinoma or the use of sulfonylurea medications.

How does C-peptide testing help identify factitious hypoglycemia?

Factitious hypoglycemia can occur from the surreptitious self-administration of insulin. Measuring C-peptide levels helps differentiate this condition from other causes, as C-peptide levels would be suppressed in cases of surreptitious insulin use, unlike in conditions like insulinoma.

What is the role of C-peptide testing in diagnosing gastrinomas associated with MEN 1?

In cases of suspected gastrinomas linked to Multiple Endocrine Neoplasia type 1 (MEN 1), elevated C-peptide levels, alongside the presence of a gastrinoma, can suggest that neoplasms may also be present in other endocrine organs like the pancreas, parathyroids, or pituitary gland.

How might C-peptide levels be relevant for women diagnosed with Polycystic Ovarian Syndrome (PCOS)?

C-peptide levels are sometimes checked in women with PCOS to help assess the degree of insulin resistance they are experiencing, as insulin resistance is a common feature of this condition.

What is the clinical benefit of detecting residual C-peptide in long-standing type 1 diabetes?

The detection of residual C-peptide in patients with long-standing type 1 diabetes is clinically significant as it is associated with a lower risk of developing microvascular complications and a reduced incidence of severe hypoglycemia.

What therapeutic application for C-peptide has been investigated?

The therapeutic use of C-peptide has been explored in small clinical trials, primarily focusing on its potential benefits in managing diabetic kidney disease.

Which pharmaceutical companies were involved in developing C-peptide as a therapeutic agent?

Companies such as Creative Peptides, Eli Lilly, and Cebix were involved in drug development programs for C-peptide products.

What was the outcome of Cebix's clinical trial for its C-peptide drug, and what happened to the company?

Cebix completed a Phase IIb trial for its C-peptide product in December 2014, which showed no difference between the C-peptide treatment and a placebo. Consequently, the company terminated its development program and subsequently went out of business.

What is the chemical formula for C-peptide?

The chemical formula for C-peptide is C129H211N35O48.

What is the molar mass of C-peptide?

The molar mass of C-peptide is approximately 3020.29 grams per mole.

What standard conditions are assumed for the properties listed in the C-peptide infobox?

Unless otherwise specified, the properties listed in the C-peptide infobox are given for materials in their standard state, which is defined as 25 degrees Celsius (77 degrees Fahrenheit) and 100 kilopascals.

What is the CAS Registry Number associated with C-peptide?

The CAS Registry Number for C-peptide is 59112-80-0.

What is the significance of the 'connecting peptide' name for C-peptide?

The name 'connecting peptide' highlights C-peptide's structural role within proinsulin, where it physically links the A-chain and B-chain of the insulin molecule before being cleaved.

What is the role of the signal sequence in the insulin synthesis pathway?

The signal sequence is part of the preproinsulin molecule and directs the translocation of preproinsulin into the endoplasmic reticulum of beta cells. It is cleaved off by a signal peptidase early in the process, leaving proinsulin.

What are disulfide bonds and why are they important for insulin?

Disulfide bonds are chemical bonds formed between sulfur atoms, typically in cysteine amino acid residues. In insulin, these bonds link the A-chain and B-chain together, stabilizing the mature, functional structure of the hormone.

What is the typical concentration range at which C-peptide exhibits cellular effects?

C-peptide exhibits its cellular effects, such as promoting enzyme activity, at nanomolar concentrations.

What is the significance of C-peptide being released into the portal circulation?

C-peptide is released into the portal circulation along with insulin. Because it is not metabolized by the liver like insulin, its concentration in the portal circulation can serve as a more stable indicator of the amount of insulin secreted by the pancreas.

What is the chemical structure identifier for C-peptide known as InChI?

The InChI identifier for C-peptide is InChI=1S/C112H179N35O46/c1-51(2)32-66(144-104(184)63(21-29-92(170)171)137-85(161)46-127-99(179)59(16-23-72(114)148)134-87(163)49-131-111(191)95(55(9)10)146-106(186)62(18-25-74(116)150)135-86(162)47-129-103(183)70(36-94(174)175)145-105(185)64(22-30-93(172)173)136-84(160)45-124-98(178)58(113)15-27-90(166)167)102(182)126-41-80(156)119-38-77(153)122-50-89(165)147-31-13-14-71(147)110(190)130-44-81(157)132-56(11)96(176)123-39-78(154)121-43-83(159)140-68(34-53(5)6)108(188)141-60(17-24-73(115)149)100(180)128-48-88(164)139-67(33-52(3)4)107(187)133-57(12)97(177)143-69(35-54(7)8)109(189)142-61(20-28-91(168)169)101(181)125-40-79(155)118-37-76(152)120-42-82(158)138-65(112(192)193)19-26-75(117)151/h51-71,95H,13-50,113H2,1-12H3,(H2,114,148)(H2,115,149)(H2,116,150)(H2,117,151)(H,118,155)(H,119,156)(H,120,152)(H,121,154)(H,122,153)(H,123,176)(H,124,178)(H,125,181)(H,126,182)(H,127,179)(H,128,180)(H,129,183)(H,130,190)(H,131,191)(H,132,157)(H,133,187)(H,134,163)(H,135,162)(H,136,160)(H,137,161)(H,138,158)(H,139,164)(H,140,159)(H,141,188)(H,142,189)(H,143,177)(H,144,184)(H,145,185)(H,146,186)(H,166,167)(H,168,169)(H,170,171)(H,172,173)(H,174,175)(H,192,193)/t56-,57-,58-,59-,60-,61-,62-,63-,64-,65-,66-,67-,68-,69-,70-,71-,95-/m0/s1.

What is the SMILES string representation for C-peptide?

The SMILES string for C-peptide is CC(C)CC(C(=O)NC(C)C(=O)NC(CC(C)C)C(=O)NC(CCC(=O)O)C(=O)NCC(=O)NCC(=O)NCC(=O)NC(CCC(=O)N)C(=O)O)NC(=O)CNC(=O)C(CCC(=O)N)NC(=O)C(CC(C)C)NC(=O)CNC(=O)CNC(=O)C(C)NC(=O)CNC(=O)C1CCCN1C(=O)CNC(=O)CNC(=O)CNC(=O)C(CC(C)C)NC(=O)C(CCC(=O)O)NC(=O)CNC(=O)C(CCC(=O)N)NC(=O)CNC(=O)C(C(C)C)NC(=O)C(CCC(=O)N)NC(=O)CNC(=O)C(CC(=O)O)NC(=O)C(CCC(=O)O)NC(=O)CNC(=O)C(CCC(=O)O)N.

What is the MeSH (Medical Subject Headings) identifier for C-peptide?

C-peptide is listed under the MeSH identifier 'C-Peptide'.

What is the PubChem Compound ID for C-peptide?

The PubChem Compound ID for C-peptide is 16132309.

What is the UNII (Unique Ingredient Identifier) for C-peptide?

The UNII for C-peptide is O2J76Y002M.

What is the CompTox Chemicals Dashboard identifier for C-peptide?

The CompTox Chemicals Dashboard identifier for C-peptide is DTXSID401059551.

What are the primary functions of C-peptide in the context of diabetes management?

In the context of diabetes, C-peptide serves two main roles: structurally, it links the A and B chains of insulin in proinsulin, and clinically, its measurement is used to assess the body's endogenous insulin production, helping to differentiate diabetes types and diagnose hypoglycemia.

What is the relationship between C-peptide and insulin levels in the portal circulation?

C-peptide and insulin are secreted in equimolar amounts into the portal circulation. However, unlike insulin, C-peptide is not significantly metabolized by the liver, making its circulating level a more direct reflection of pancreatic insulin secretion.

What are the potential therapeutic implications of C-peptide's effects on eNOS and Na+K+ATPase?

Since reduced activities of eNOS and Na+K+ATPase are implicated in long-term complications of type 1 diabetes, such as neuropathy, C-peptide's ability to upregulate these enzymes suggests a potential therapeutic role in mitigating these complications.

C-peptide Wiki: C-Peptide: The Body's Insulin Signal

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Introduction to C-Peptide

The Connecting Peptide

C-peptide, or connecting peptide, is a short polypeptide consisting of 31 amino acids. It plays a vital role in the synthesis of insulin, acting as a linker that connects the A-chain and B-chain within the proinsulin molecule. This structural role is essential for the proper folding, assembly, and processing of insulin in the endoplasmic reticulum.

Biomarker Significance

In clinical practice, particularly in endocrinology, C-peptide levels in blood serum are measured. This measurement serves as a valuable indicator of the body's endogenous insulin production. It helps clinicians differentiate between various types of diabetes and diagnose conditions causing hypoglycemia, offering insights into pancreatic beta-cell function.

Beyond Insulin Production

While primarily known for its role in insulin synthesis, emerging research suggests C-peptide possesses its own biological activity. It has been observed to influence microvascular blood flow and tissue health, potentially activating cellular signaling pathways like the sodium-potassium pump and nitric oxide synthase. The full physiological significance of these effects is an active area of investigation.

Historical Context

Discovery and Early Research

The concept of proinsulin C-peptide was first elucidated in 1967, coinciding with advancements in understanding the insulin biosynthesis pathway. Significant milestones followed in 1971 with the isolation and sequencing of bovine C-peptide and the preparation of human C-peptide. Its role as a linker facilitating insulin maturation was recognized early on.

1967: First description of proinsulin C-peptide in relation to insulin biosynthesis.
1971: Isolation and sequencing of bovine C-peptide; preparation of human C-peptide.
1972: First documented clinical use of the C-peptide test for diagnostic purposes.
Early 21st Century: Recognition of C-peptide's potential bioactive functions beyond its role as an insulin marker.

Evolving Clinical Utility

Initially valued solely as a marker for insulin secretion, the C-peptide test became instrumental in understanding the pathophysiology of diabetes mellitus. Its ability to reflect endogenous insulin production, even in patients receiving exogenous insulin therapy, cemented its place in clinical diagnostics.

Functional Roles

Cellular Mechanisms

C-peptide interacts with cell surfaces, including neuronal, endothelial, and renal cells, potentially via a G-protein-coupled receptor. This interaction is associated with the activation of intracellular signaling pathways, such as those involving MAPK, PLCγ, and PKC. These pathways can modulate gene expression and influence the activity of key enzymes like endothelial nitric oxide synthase (eNOS) and the sodium-potassium pump (Na+/K+-ATPase).

Therapeutic Potential

Studies in animal models suggest that C-peptide administration may offer protective effects against diabetes-related complications. Specifically, it has shown promise in improving nerve function and kidney health in models of Type 1 diabetes, potentially by restoring Na+/K+-ATPase activity and mitigating glomerular changes. Research has also indicated potential anti-inflammatory effects and roles in smooth muscle cell repair.

Cardiovascular Link

Epidemiological studies have suggested a complex, potentially U-shaped relationship between C-peptide levels and the risk of cardiovascular disease. This finding highlights the multifaceted biological roles C-peptide may play beyond its established function in glucose metabolism regulation.

Clinical Diagnosis

Differentiating Diabetes Types

Measuring C-peptide is crucial for distinguishing between Type 1 diabetes (autoimmune destruction of beta cells, leading to low C-peptide) and Type 2 diabetes (insulin resistance, often with preserved or even elevated C-peptide initially). It also aids in identifying forms like Maturity-Onset Diabetes of the Young (MODY).

Type 1 Diabetes: Characterized by minimal to absent C-peptide levels, indicating a severe deficiency in insulin production.

Type 2 Diabetes: Often shows normal or high C-peptide levels, reflecting the body's attempt to overcome insulin resistance through increased insulin secretion. However, in later stages, C-peptide may decline.

LADA (Latent Autoimmune Diabetes in Adults): This form can present with intermediate C-peptide levels, sometimes overlapping with Type 2 diabetes, necessitating antibody testing for accurate diagnosis.

Hypoglycemia Investigation

C-peptide testing helps diagnose the cause of hypoglycemia (low blood glucose). In cases of insulinoma (a tumor producing excess insulin) or administration of sulfonylureas (drugs stimulating insulin release), C-peptide levels remain suppressed or inappropriately high relative to insulin levels. Conversely, in factitious hypoglycemia due to surreptitious insulin injection, C-peptide levels would be low.

Other Clinical Applications

C-peptide levels may be monitored in conditions like Polycystic Ovary Syndrome (PCOS) to assess insulin resistance. Additionally, elevated C-peptide levels, in conjunction with gastrinomas, can suggest Multiple Endocrine Neoplasia type 1 (MEN 1), indicating potential tumors in other endocrine organs.

Therapeutic Exploration

Clinical Trials

The potential therapeutic benefits of C-peptide have been explored in clinical trials, particularly for managing diabetic kidney disease. While early research showed promise, some trials, such as a Phase IIb study by Cebix, did not demonstrate a significant difference compared to placebo, leading to the termination of that specific development program.

Drug Development Landscape

Several pharmaceutical companies, including Creative Peptides, Eli Lilly, and Cebix, have investigated C-peptide-based therapies. These efforts aimed to leverage C-peptide's potential effects on microvascular function and tissue repair. However, the path to therapeutic approval has faced challenges, underscoring the complexity of translating preclinical findings into clinical treatments.

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References

C-Peptide - Compound Summary , PubChem.

A full list of references for this article are available at the C-peptide Wikipedia page

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C-Peptide Unveiled

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Introduction to C-Peptide ℹ️

🔗 The Connecting Peptide

🩸 Biomarker Significance

🔬 Beyond Insulin Production

Historical Context ⏳

📜 Discovery and Early Research

📈 Evolving Clinical Utility

Functional Roles ⚙️

🔬 Cellular Mechanisms

🩹 Therapeutic Potential

❤️ Cardiovascular Link

Clinical Diagnosis 🩺

⚖️ Differentiating Diabetes Types

📉 Hypoglycemia Investigation

❓ Other Clinical Applications

Therapeutic Exploration 💊

🔬 Clinical Trials

🧪 Drug Development Landscape

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References

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Disclaimer ⚠️

📜 Important Medical Information

Dive in with Flashcard Learning!

Introduction to C-Peptide

The Connecting Peptide

Biomarker Significance

Beyond Insulin Production

Historical Context

Discovery and Early Research

Evolving Clinical Utility

Functional Roles

Cellular Mechanisms

Therapeutic Potential

Cardiovascular Link

Clinical Diagnosis

Differentiating Diabetes Types

Hypoglycemia Investigation

Other Clinical Applications

Therapeutic Exploration

Clinical Trials

Drug Development Landscape

Teacher's Corner

True or False?

Test Your Knowledge!

Gamer's Corner

Discover other topics to study!

References

Feedback & Support

Disclaimer

Important Medical Information