C-Peptide: Roles in Diabetes, Insulinoma, and Hypoglycemia

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C-Peptide: Roles in Diabetes, Insulinoma, and Hypoglycemia Diagnostic Trends C-peptide: Roles in diabetes, insulinoma, and hypoglycemia C-peptide measurements are proving to be a useful aid in the diagnosis of diabetes mellitus, hypoglycemia, and insulinoma. This article provides a concise review of C-peptide production and physiology, explores its application in diabetes testing, and reviews its well-established role in hypoglycemia and insulinoma. A comparison of C-peptide assays on the Siemens Immunoassay systems is also provided. By Tricia A. Bal, MD Perspectives · Winte r/Spring 2009 · www.siemens.com/diagnostics 19 Diagnostic Trends C-peptide was initially thought to be just 1 the peptide has also been shown to a by-product of insulin production and activate Na +-K +-ATPase, but not as S S biologically inert; however, research S S strongly as the full peptide or the penta- 3 findings indicate that it does have impor - SS peptide sequence (Figure 2). C-peptide’s tant biological activity, especially in rela - Proinsulin beneficial affects on the microvascular tion to diabetes mellitus. complications of diabetes mellitus are Studies have linked low levels of C-pep - thought to be mediated through endo- tide to diabetes mellitus complications, thelial nitric oxide synthase. 2 In addition and evidence suggests that maintaining Carboxypeptidases to receptor-mediated effects, C-peptide and Proconvertases higher levels of C-peptide is especially has been shown to produce non-recep - beneficial for type 1 diabetics. 1 C-peptide tor-mediated effects. 4 measurements have also been used to classify diabetes mellitus and as a marker S S S S Clinical research studies: of pancreatic -cell function. Insulin β S S C-peptide replacement in Free C-peptide diabetes mellitus C-peptide production In addition to the biological activity C-peptide is produced by a series of shown in the laboratory studies, clinical enzymatic cleavages of the precursor 1 Proinsulin is the precursor of insulin studies have found that replacement of molecules preproinsulin and proinsulin. and C-peptide C-peptide in type 1 diabetic patients Preproinsulin, a precursor of proinsulin, improves many of the complications is produced in the endoplasmic reticulum associated with this disease. Complica - of pancreatic -cells in response to tions frequently associated with diabetes β elevated blood glucose levels in healthy include retinopathy, nephropathy (charac - individuals; it is then cleaved by microso- Mechanisms of action terized by glomerular hyperfiltration and mal enzymes into proinsulin. 2 and biological activity albuminuria), neuropathy, and cardiac Proinsulin is the precursor of insulin and disease. Johansson et al. 5–7 have per - C-peptide. It consists of the -chain and formed multiple studies evaluating the α -chain of insulin linked together by C- While the physiological functions of effects of the short-term replacement of β peptide (Figure 1). C-peptide is composed insulin are well established and under - C-peptide in type 1 diabetic patients. They of 31 amino acids (Figure 2) and facili - stood, the functions of C-peptide are still investigated renal function and whole tates the correct folding of proinsulin being established and investigated. C- body glucose uptake in type 1 diabetic to allow the cysteine disulfide bridges peptide has been shown to bind to spe - patients and found that low-dose C-pep - between the -chain and the -chain of cific cell surface receptors in cultured tide infusion as compared with sodium α β insulin to form. Enzymatic cleavage of cells derived from human renal tubules, chloride infusion significantly increased proinsulin by proconvertases and carb- mesangium, skin fibroblasts, and saphe - whole body glucose utilization by 25 oxypeptidases produces insulin and C- nous vein endothelium. 2 Data suggest percent and decreased glomerular hyper - peptide, which are released in equimolar that it acts through G-protein-coupled filtration by 6 percent. 5 In a follow-up amounts from -cells into the portal cir - receptors to activate calcium-dependent study, they found that administration of β culation (Figure 1). C-peptide is cleared signaling pathways via the C-terminal C-peptide for one month in type 1 dia - by the kidney and has a half-life of about pentapeptide portion of the molecule. 3 betics decreased HbA1c by 9 to 16 per - 20 to 30 minutes compared to insulin C-peptide activation of calcium signaling cent vs. controls, which suggested that which is cleared through the liver and is thought to increase the activity of C-peptide improved glycemic control in has a half-life of about 3 to 5 minutes. 2 Na +-K +-ATPase, which has been found these patients. 6 They also observed The longer half-life, renal clearance, and to be reduced in patients with the 40 percent and 55 percent decreases in equimolar release of C-peptide make it advanced microvascular complications albuminuria at 2 and 4 weeks, respec - an attractive proxy for estimating insulin of diabetes mellitus (nephropathy and tively, indicating that C-peptide amelio - secretion and -cell function. retinopathy). 2 The middle segment of rated the diabetic nephropathy. 6 β 2 EAE DL QVGQV E LGGGPG AGSL QPL A L E GSLQ 1 31 2 Sequence for human C-peptide. The pentapeptide sequence is highlighted in blu e 3 20 Perspectives · Winte r/Spring 2009 · www.siemens.com/diagnostics Diagnostic Trends In another follow-up study of type 1 study by Ekberg et al. 8 This study found ics increased to the levels observed in diabetics, they compared the effects of that in type 1 diabetic patients, admin- the healthy controls. These findings sug - subcutaneous injections of insulin and istration of C-peptide for three months gest that C-peptide exerts a beneficial C-peptide or insulin and placebo for three improved sensory nerve conduction and effect on myocardial function. 9 months. During C-peptide treatment, vibration perception. 8 C-peptide clearly has several important albuminuria decreased, signs of autonom - Diabetics are also at high risk for heart biological actions and more research is ic neuropathy decreased as evidenced disease and often have diastolic dysfunc - needed to fully delineate its functions by increased respiratory heart rate vari - tion and myocardial perfusion abnormal - and to characterize the effects and the ability, and sensory perception improved ities. The effect of C-peptide replacement role of long-term replacement therapy as evidenced by improved thermal on myocardial function was evaluated in for diabetes mellitus. thresholds. These changes were statis- a study by Hansen et al. 9 This was a ran - tically significant as compared with the domized double-blind crossover study Rationale for C-peptide insulin plus placebo treatment period. 7 that compared the effect of C-peptide These studies consistently show that infusion with saline infusion on myo car - measurement C-peptide replacement with or without dial function in type 1 diabetic patients. insulin ameliorates several of the comon They used healthy volunteers as controls. Since C-peptide and insulin are released complications experienced by diabetic Com pared to age-matched controls, in equimolar amounts from the -cells β patients. diabetic patients had reduced diastolic of the pancreas, the measurement of Also supporting the role of C-peptide velocities and myocardial blood volume C-peptide has been used as a marker of replacement for the amelioration of dia - at baseline. During administration of C- -cell function and an index of insulin β betic neuropathy are the results of a ran - peptide, however, the diastolic velocities secretion. Direct measurements of endo- domized double-blind placebo controlled and myocardial blood flow of the diabet - genous insulin by immunoassay are Perspectives · Winte r/Spring 2009 · www.siemens.com/diagnostics 21 Diagnostic Trends problematic in patients undergoing C-peptide and the classification measured in urine. Urine measurements insulin therapy because assays can cross- of diabetes mellitus generally require a 24-hour collection react with the insulin analogs that the and are not as convenient as serum or patient is taking. Moreover, these assays plasma measurements. The testing pro - are affected by the presence of anti- The diagnosis of diabetes mellitus is tocols used for serum or plasma C-pep - insulin antibodies. 10, 11 One study found based on the finding of glucose levels tide measurements include fasting, that 36 percent of patients on human measured on two separate occasions random, and stimulated protocols. In insulin developed autoantibodies after 12 exceeding the designated cutoff. Typi- the stimulation protocols, the stimulant months of treatment. 12 Thus, C-peptide cally, patient history, age of onset, and mimics the rise in glucose induced by measurements represent a better alter - physical characteristics like body mass meals and gives an estimate of the -cell β native index of insulin secretion and index (BMI) are used to determine what function. C-peptide can be stimulated by residual -cell function. In addition, the type of diabetes a patient has; however, a glucose load, mixed meal, or glucagon. β extensive and variable hepatic extraction relying on these characteristics for accu - In type 1 diabetics, little or no increase of insulin also makes it difficult to accu - rate classification can be misleading. would be expected above baseline in a rately estimate insulin secretion from Type 1 accounts for 5 to 10 percent, and C-peptide stimulation test, but type 2 peripheral insulin concentrations. 13 Moni - type 2 accounts for 90 to 95 percent of diabetics would be expected to show an toring residual -cell function through all diabetes. increase in levels over baseline. Agree - β the measurement of C-peptide is a strat - Misclassification of patients can lead to ment between C-peptide immunoassay egy endorsed by the American Diabetes a delay in appropriate treatment and methods is poor, so measurements for Association (ADA), and it recommends unnecessary patient morbidity: a type 1 comparison should be done with a single the use of C-peptide measurements as diabetic not receiving insulin or a type 2 method at a single institution.
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