Cpeptide & Diabetes - DDA 2015
Transcript of 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).
Natural history of C-peptide secretion in type
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
Natural history of C-peptide secretion in type
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).
Natural history of C-peptide secretion in type
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.
John Wahren et al. Diabetes 2012;61:761-772
©2012 by American Diabetes Association
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.
John Wahren et al. Diabetes 2012;61:761-772
©2012 by American Diabetes Association
Circulatory effects of C-peptide.
John Wahren et al. Diabetes 2012;61:761-772
©2012 by American Diabetes Association
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
Clinical uses of C-peptide
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.
Clinical uses of C-peptide
testing
C-peptide levels may be checked in women with Polycystic Ovarian Syndrome (PCOS) to help determine degree of insulin resistance.
Clinical uses of C-peptide
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
CONCLUSIONS AND FUTURE OUTLOOK
CONCLUSIONS AND FUTURE OUTLOOK
• 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
CONCLUSIONS AND FUTURE OUTLOOK
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