Cpeptide & Diabetes - DDA 2015

ALAA WAFA. MDAssociate Professor of Internal Medicine

PGDIP DM Cardiff University UKDiabetes and Endocrine unit

Mansoura university 2015

C – Peptide & Diabetes

AgendaBackground

Natural history

Biological role of C peptide

Function of C peptide

Clinical usesConclusion

Background

The connecting peptide, or C-peptide, is a short 31-amino-acid protein

that connects insulin's A-chain to its B-chain in the

proinsulin molecule.

Peptide" is derived from the Greek

word "peptein" (to digest). Another

term derived from "peptein" is

"peptic ulcer" (stomach ulcer).

Background

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

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

Background

It is released in a 1:1 ratio with insulin as this is secreted.

C-peptide has a half-life of about 30 minutes

Is cleared by the kidneys; 5–10% is excreted in the urine

Measured in either serum, plasma or urine.

Background

C-peptide is more reliable than insulin as a measure of endogenous insulin secretion, and (not being present in injectable insulin preparations) can also be measured in insulin-treated patients.

Background

During the past decade, C-peptide has been found to be a bioactive peptide , with effects on microvascular blood flow and tissue health.

C-peptide was considered to be biologically inert, but might have a biological role, and has been considered as a possible therapeutic role.

Synthesis and secretion

Insulin exocytosis

ATP

Glut2Potassium Channel

Calcium Channel

Glucose

K+

TCA

Amplifying

Pyruvate

EpacTriggering

GsαGsα

ATPcAMP

Ca2+

Ca2+

Synthesis and secretion

Hinke SA et al. J Physiol 2004;558:369–380; Henquin JC. Diabetes 2000;49:1751–1760; Henquin JC. Diabetes 2004;53:S48–S58; Drucker D. Cell Metab 2006;3:153–165

C-peptide metaboli

sm• C-peptide is removed from the peripheral circulation at a constant rate.

• It is metabolized in the proximal renal tubules

• 5–10% is excreted unchanged in the urine

Measuring C-peptide

plasma or serum, fasting or following stimulation.

Stimulated C-peptide secretion can be assessed in response to a standard mixed meal tolerance test

(MMTT) or following glucagon injection.

Fasting C-peptide correlates well with stimulated C-peptide, and is more routinely used in clinical care .

A spot urine sample measuring urinary C-peptide creatinine ratio (UCPCR) may provide a useful non-

invasive alternative, a particular advantage for children

Natural history of C-peptide secretion in type

1 diabetes

• Most patients with type 1 diabetes become severely insulin deficient within 5 years of diagnosis due to T cell mediated autoimmune destruction of pancreatic beta cells.

• C-peptide levels are lower in children compared with adults, and the speed of C-peptide decline is more rapid (particularly in children aged <5 years).


1 diabetes

Increasing use of sensitive C-peptide assays have demonstrated that type 1 diabetes patients may continue to secrete C-peptide at low levels, often for decades after diagnosis and these beta cells may continue to be functionally reactive to stimulation with a mixed meal load


1 diabetes

• Persistence of C-peptide is advantageous for the patient.

• The Diabetes Control and Complications Trial (DCCT) demonstrated that 90 minute stimulated C-peptide ≥0.2 nmol/l (200 pmol/l) was associated with improved clinical outcomes (less retinopathy, neuropathy and severe hypoglycemia).


1 diabetes

• The honeymoon period (also known as partial remission), the time following diagnosis when some beta cell recovery occurs, can be followed by measuring C-peptide, usually during a MMTT, in type 1 diabetes trials to monitor interventions aimed at preserving beta cell function.

Biological role

It binds to a membrane structure, probably a G-protein coupled membrane receptor, eliciting a rise in intracellular Ca2+ concentration and subsequent activation of at least two enzyme systems, Na+,K+ ATPase and endothelial nitric oxide synthase (eNOS).

C-peptide administration leads to Increased blood flow in skeletal muscle and skin, Diminished glomerular hyperfiltration, Reduced urinary albumin excretion Improved nerve function

in patients with type 1 diabetes who lack C-peptide, but not in healthy subjects.

Function: Cellular effects of C-peptide

C-peptide has been shown to bind to the surface of a number of cell types such as neuronal, endothelial, fibroblast and renal tubular, at nanomolar concentrations to a receptor that is likely G-protein-coupled

So it is implicated in the development of long-term complications of type I diabetes such as peripheral and autonomic neuropathy.

Function: Cellular effects of C-peptide

In vivo studies in animal models of type 1 diabetes have established that C-peptide administration results in significant improvements in nerve and kidney function.

Function: C peptide & neuropathy

Recent clinical trial found that ,in early signsof diabetes-induced neuropathy, C peptide treatment in replacement dosage results in improved peripheral nerve function, as evidenced by :

Increased nerve conduction velocity, Increased nerve Na+,K+ ATPase activity, and Significant amelioration of nerve structural changes.

A: Schematic overview of functional and structural effects of C-peptide on diabetic neuropathy.

John Wahren et al. Diabetes 2012;61:761-772

©2012 by American Diabetes Association

Function: C peptide &nephropathy

C-peptide administration in animals that had C-peptide deficiency (type 1 model) with nephropathy

Improves renal function and structure; Decreases urinary albumin excretion andPrevents or decreases diabetes-induced glomerular

changes secondary to mesangial matrix expansion.

A: Schematic overview of C-peptide’s effect on diabetes-induced functional and structural renal abnormalities.



Function:Cellular effects of C-peptide

C-peptide also has been reported to have anti-inflammatory effects as well as aid repair of smooth muscle cells

A: Overview of C-peptide’s cytoprotective, antiapoptotic, and anti-inflammatory effects.



Circulatory effects of C-peptide.



Clinical uses of C-peptide

testing• Patients with diabetes may have their

C-peptide levels measured as a means of distinguishing type 1 diabetes from type 2 diabetes or Maturity onset diabetes of the young (MODY).

Differential diagnosis of hypoglycemia.

Factitious (or factitial) hypoglycemia may occur secondary to the surreptitious use of insulin. Measuring C-peptide levels will help differentiate a healthy patient from a diabetic one


testing

C-peptide may be used for determining the possibility of gastrinomas associated with Multiple Endocrine Neoplasm syndromes (MEN 1).

Since a significant number of gastrinomas are associated with MEN involving other hormone producing organs (pancreas, parathyroids, and pituitary), higher levels of C-peptide together with the presence of a gastrinoma suggest that organs besides the stomach may harbor neoplasms.


testing

C-peptide levels may be checked in women with Polycystic Ovarian Syndrome (PCOS) to help determine degree of insulin resistance.


testing

Therapeutics

• Several physiological effects have been observed in several Phase 1 and exploratory Phase 2 studies in almost 300 type 1 diabetes patients, who lacked endogenous C-peptide.

• Significant Improvement were seen on Type 1 diabetic related complications as peripheral neuropathy, nephropathy and other long-term complications With effective Doses of C-peptide

CONCLUSIONS AND FUTURE OUTLOOK

C-Peptide posses some clinical and therapeutic impact

C-peptide is more reliable than insulin as a measurement of endogenous insulin secretion, can also be measured in insulin-treated patients.

Measurement of C-peptide levels can be used as a means of distinguishing T1DM From T2DM or MODY

C-peptide considered a bioactive endogenous peptide due to :

Specific binding to cell membranes, Articular intracellular signaling pattern Effects involving activation and enhanced

expression of eNOS and Na+,K+-ATPase, Its activation of several important transcription

factors



• Extensive studies in animal models of diabetes and early clinical trials in type 1 diabetic patients demonstrate thatreplacement of C-peptide results in beneficial effects on the diabetes-induced functional and structural abnormalities of peripheral nerves, the kidneys, and the brain


Since no disease-modifying therapy is available for patients with microvascular

complications of type 1 diabetes,

it can be hoped that the ongoing development of a long-acting C-peptide

will facilitate further clinical trials and allow definition of C-peptide’s potential role in the therapy of type 1 diabetes.

Thank you

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Cpeptide & Diabetes - DDA 2015