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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 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 to -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 - 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 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 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 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, 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--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 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 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

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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 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 , 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 . 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 . 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. 17 the outcome measure in clinical trials diabetic taking insulin unnecessarily .15 The inaccuracy of clinical diagnosis and investigating methods to preserve -cell mellitus is characterized the usefulness of C-peptide in the classi - β function .1, 14 by -cell destruction, which leads to very fication of diabetes mellitus are illustrat - β Additionally, the use of C-peptide and low or undetectable levels of C-peptide. In ed in a study by Wright-Pascoe et al. 18 on insulin measurements together provides contrast, type 2 diabetes mellitus is asso - a small series of diabetic patients treated valuable information for the evaluation ciated with insulin resistance and typical - with insulin. Patients were classified on of hypoglycemia and the diagnosis of ly initially has normal or elevated levels the basis of the criteria of the National insulinoma, and will be examined later of C-peptide, which can decrease over Diabetes Data Group and the World in this article. the course of the disease. 16 Health Organization (WHO) that relies on C-peptide levels are typically measured glucose levels and patient history. This in serum or plasma and can also be study found that using fasting C-peptide

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Some studies have shown that C-peptide replacement with or without insulin ameliorates some complications experienced by diabetic patients.

measurements, only 5 of 13 patients type 1 diabetes mellitus had to be on The optimum cutoffs identified in this (38 percent) initially classified as having insulin for at least 3 years after diagnosis study were 1.5 ng/ml (0.5 nmol/l) for type 1 diabetes mellitus actually had the and patients with type 2 diabetes melli - random C-peptide, 1.27 ng/ml (0.42 disease. 18 In a similar study also using tus had to have been managed without nmol/l) for fasting C-peptide, and 1.81 C-peptide measurements, 31 percent of insulin for 3 or more years after initial ng/ml (0.6 nmol/l) for glucagon-stimu- type 2 diabetics (diagnosed by American diagnosis. In this study, 1093 patients lated C-peptide. 21 Diabetic Association [ADA] and WHO and 1449 samples were analyzed. Using Consistent with the Berger et al. study, criteria) were determined to be misclas- receiver operating characteristics (ROC) Bakhtadze et al. 22 , in another diabetes sified as type 1 diabetics. 19 Shiraj et al. 20 curve analysis, all three methods were classification study, found that patients found that 84 percent of type 1 diabet - able to distinguish between type 1 and diagnosed with type 1 diabetes mellitus ics, 7 percent of type 2 diabetics, and 4 type 2 diabetics ( Figure 3) .21 Random C- had significantly lower (p <0. 0001) percent of healthy controls had basal C- peptide also correlated well with both median fasting plasma C-peptide than peptide levels below a cutoff of 0.6 fasting and glucagon-stimulated C-pep - patients with type 2 diabetes mellitus or ng/ml (0.2 nmol/l), indicating that tide, with r values of 0.78 and 0.77, diabetes mellitus that was unclassified. C-peptide can discriminate between these respectively. These data show that a The median values were 0.73 ng/ml populations. random C-peptide was slightly, but not (0.24 nmol/l) for type 1 diabetes mellitus, Similar percentages were obtained for significantly, better than fasting and 2.24 ng/ml (0.74 nmol/l) for type 2 glucagon-stimulated C-peptide below a glucagon stimulated C-peptide for the dia betes mellitus, and 1.45 ng/ml (0.48 cutoff of 0.32 nmol/l: 86 percent of type classification of diabetes mellitus. nmol/l) for unclassified diabetes mellitus. 1 diabetics, 8 percent of type 2 diabet - ics, and 0 percent of healthy controls 3 had levels below the cutoff. 20 Other clinical studies have also shown C-peptide protocol ROC curve (AUC) Confidence interval (9 5%) that C-peptide measurements can be used Random 0.98 0.97 to 0.99 to aid in the classification of diabetes Fasting 0.91 0.89 to 0.93 mellitus. 21–23 Berger et al. 21 compared classification of diabetes by random, Glucagon-stimulated 0.92 0.87 to 0.96 fasting, and glucagon-stimulated C-pep - tide measurement with classification by 3 Receiver operating characteristics (ROC) curve analysis results of random, fasting, and a prior diagnosis of type 1 or type 2 dia - glucagon-stimulated C-peptide test s 21 betes mellitus made without C-peptide AUC, area under the curve measurements. Patients diagnosed with

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Type 1 diabetes patients who are able to maintain C-peptide levels have fewer complications and better glycemic control.

In this study, they also tested for the C-peptide and subclassification Consistent with these results, fasting presence of islet cell antibodies and of type 1 diabetes C-peptide levels at onset for fulminant HLA-DRQB1 genotypes, both of which type 1 diabetics were also lower than are associated with type 1 diabetes. fasting C-peptide levels for type 1 dia - Type 1 diabetic patients were 3.6 times C-peptide levels may also be able to sub - betes mellitus. ROC curve analysis found more likely to have islet cell antibodies classify type 1 diabetes. C-peptide levels an area under the curve ( AUC) for inte - (autoantibodies) than were type 2 were found by Tanaka et al. 23 to distin - grated C-peptide of 0.974 a nd fasting diabetics. Moreover, patients with islet guish a subtype of type 1 diabetes mel- C-peptide of 0.973 for distinguishing cell antibodies had markedly lower mean li tus called fulminant type 1 diabetes between these two types of diabetes fasting plasma C-peptide levels than mellitus. This condition is characterized mellitus. The optimum cutoff for integrat- those without islet cell antibodies by an abrupt onset of symptoms, marked ed C-peptide was less than or equal to (0.73 ng/ml [0.24 nmol/l] vs. 2.1 ng/ml hyperglycemia, severe diabetic ketoacidot - 1.63 ng/ml (0.540 nmol/l) and for fasting [0.69 nmol/l], p <0.0001). The patients ic coma, normal or near normal HbA1c C-peptide was less than or equal to with HLA-DRQB1 genotypes, which are levels, absence of autoantibodies, and 0.1 ng/ml (0.033 nmol/l). 23 associated with a risk for type 1 diabetes involvement of the exocrine pancreas Several studies present consistent evi - mellitus and negative islet cell anti- with elevated levels of serum pancreatic dence that supports the use of C-peptide bodies, also had lower median levels of enzymes. They recruited 125 patients who as an aid in the classification of diabetes C-peptide than those without the risk- met the criteria for type 1 diabetes melli - mellitus and suggests that it might be a associated genotypes (1.54 ng/ml [0.51 tus as defined by the ADA. A subset of useful tool in the management of this nmol/l] vs. 2.24 ng/ml [0.74 nmol/l]). these patients (n = 25) who were nega - disease. The authors propose that low C-peptide tive for autoantibodies against pancreat - levels and the presence of a HLA-DRQ1 ic and had HbA1c levels of less C-peptide used as indicator genotype may be used to differentiate than 8.3 percent were diagnosed as hav - of glycemic control and idiopathic type 1 diabetes mellitus (neg - ing fulminant type 1 diabetes mellitus. ative for autoantibodies) from type 2 The remaining patients were labeled as declining -cell function diabetes mellitus, which would not have type 1 diabetes mellitus. They found that β the HLA-DRQ1 genotype and would have the integrated C-peptide levels (∑C-pep - The Diabetes Control and Complications normal or high levels of C-peptide. 22 tide taken at 0, 30, 60, 90, and 120 min - Trial (DCCT) found that C-peptide levels Clearly, although there is some overlap, utes during an oral glucose tolerance correlate with overall glycemic control. C-peptide levels can be used to discrimi- test) were lower in patients with fulmi - They analyzed patients on the basis of a nate between type 1 and type 2 diabetes nant type 1 diabetes mellitus at onset mixed meal-stimulated C-peptide levels. mellitus. and at 1 and 2 years after onset than in Patients with stimulated C-peptide patients with type 1 diabetes mellitus. greater than 0.6 ng/ml (0.2 nmol/l) had

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significantly lower HbA1c levels and monitoring -cell function has been used (0.8 nmol/l) had a 72 percent positive β were treated with less insulin, indicating to detect transplant failure. Transplant predictive value for patients without better overall glycemic control, as com - failure is typically monitored with meas - autoantibodies. 26 pared with those with levels less than urements of insulin, glucose, and C-pep - 0.6 ng/ml (0.2 nmol/l) (Figure 4). The tide, and in some protocols, graft failure DCCT found that there was less retinopa - has been defined by a specific level of Hypoglycemia thy and nephropathy with preserved C-peptide. 24, 25 -cell function .1 Thus, in addition to good Hypoglycemia is a symptom associated β glycemic control, the preservation of C-peptide levels can be with a wide range of conditions, and a -cell function is now a therapeutic goal careful history in addition to the appro - β for type 1 diabetes mellitus, and moni - predictive of autoantibodies priate laboratory tests are necessary for toring -cell function in these patients its evaluation (Figure 5). The population β via C-peptide levels is a rational approach Törn et al. 26 have found that C-peptide most at risk for hypoglycemia is diabet - because insulin measurements would levels can predict the presence of auto- ics, particularly type 1 diabetics. It has be complicated by the presence of antibodies (defined as the presence of at been estimated that 10 to 30 percent of exogenous insulin. least one of the following: islet cell anti - these patients have one episode of hypo - While type 1 diabetes mellitus is asso- bodies, GADA, or phosphatase glycemia requiring third-party assistance ciated with markedly decreased -cell antibodies). They determined that a ran - per treatment year. 27 In these patients, β function, following -cell function in dom C-peptide value of below 0.91 ng/ml the cause of hypoglycemia is usually due β type 2 diabetics may also be important (0.3 nmol/l) had a 94 percent positive to insulin overdose, and C-peptide levels since it can decline over the course of predictive value for patients with auto- would be low in comparison to insulin the disease. Kim et al. 16 found that type antibodies and a value above 2.42 ng/ml levels. Thus, C-peptide measurements 2 diabetic patients positive for decarboxylase antibodies (GADA) 4 experienced a decline in C-peptide val - ues over 2 years, indicating a decrease in Characteristic C-peptide ≥ 0.6–1.51 ng/ml C-peptide < 0.6 ng/ml p value -cell function. Fasting C-peptide levels ≥ 0.2–0.5 nmol/l < 0.2 nmol/l β decreased from 1.24 ng/ml (0.41 nmol/l) n 138 274 to 0.95 ng/ml (0.31 nmol/l) and stimulat - Age (years) 28.2 ± 6.7 26.1 ± 7.4 <0.007 ed C-peptide from 1.99 ng/ml (0.66 nmol/l) to 1.61 ng/ml (0.53 nmol/l). In HbA1c 8.3 ± 1.6 9.2 ± 1.6 <0.001 patients without GADA, there was no Insulin (U/kg/day) 0.49 ± 0.20 0.69 ± 0.24 <0.001 decrease in C-peptide, indicating no decrease in -cell function. 16 This sug - β 4 A comparison of type 1 diabetics on the basis of levels of stimulated C-peptide gests that a GADA screen in combination in the Diabetes Control and Complications Trial (DCCT) intensive treatment group 1 with C-peptide measurements can be used to identify a subset of type 2 patients whose disease is progressing 5 and who may need to be treated more Type Examples aggressively. Organ related Insulinoma, nesidioblastosis, multiple endocrine neoplasia, Lower C-peptide levels in type 2 diabetics noninsulinoma pancreatogenic hypoglycemia, severe liver disease, are also associated with insulin treat - end-stage kidney disease, dialysis, congestive heart failure, ment. Siraj et al. found lower basal and acute respiratory failure glucagon-stimulated C-peptide levels in Endocrine disorders Generalized hypopituitarism and hypothalamic deficiency, adrenal type 2 diabetic patients treated with failure, hypothyroidism, after removal of pheochromocytoma insulin than in type 2 diabetics not treat - Inborn errors of Glycogen storage disease, hereditary fructose intolerance, ed with insulin. 20 These data suggest that metabolism galactosemia, carnitine deficiency, disorders of gluconeogenesis, C-peptide levels might be able to identify disorders of mitochondrial -oxidation type 2 diabetic patients that would be β managed better with insulin. Nonislet tumor Insulin-like growth factor-secreting tumor (mesenchymal tumors, hemangiopericytomas), lymphoma, myeloma, leukemias C-peptide and Miscellaneous Sepsis, starvation, total parenteral nutrition, severe excessive exercise transplant failure -induced and Insulin, sulfonylurea, repaglinide, salicylates, paracetamol, dietary quinine, beta-blockers, alcohol, mushrooms, unripe ackee fruit

In severe cases of diabetes that have not Reactive hypoglycemia Post-gastric surgery, alcohol induced been managed successfully with insulin, transplantation may be warranted (pan- 5 Causes of adult hypoglycemia (modified from reference 31) creas or -cell transplant). After trans plan - β tation, monitoring graft function by

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can be used to confirm the diagnosis. In tion as the cause for the hypoglycemia, insulinomas may present as early as 6 the evaluation of a nondiabetic patient whereas low C-peptide levels and high weeks and as late as 70 years. These with hypoglycemia, C-peptide can be a insulin levels point to exogenous insulin tumors are typically solitary adenomas useful aid in narrowing the differential administration as the cause; low glucose and are rarely metastatic. Most are small diagnosis. with low insulin and C-peptide levels with 90 percent less than 2 cm in diame - C-peptide measurements in the evalua - indicate a non-insulin-mediated hypo - ter, but they can be as large as 15 cm. tion of hypoglycemia are performed in glycemia. Sulfonylurea drug use can be Endoscopic ultrasound, transabdominal the context of the 72-hour (prolonged) determined by measurement of the drug ultrasound, and intraoperative ultra - fast, the gold standard procedure. The in plasma or urine. sound are the preferred imaging modali - prolonged fast, generally an inpatient ties, but CT, MRI, and in some cases PET procedure, involves repeated measure - imaging have also been used. These ments of insulin, C-peptide, and glucose Insulinoma tumors are hard to localize because of (every 6 hours) until glucose levels fall their small size and anatomic location to 40 to 45 mg/dL or symptoms of hypo - An insulinoma is a tumor of the -cells and are typically treated by surgical β glycemia develop or until 72 hours have of the pancreas and it is the most com - resection. 32 elapsed. 28–30 Elevated C-peptide and mon cause of hypoglycemia due to Patients present with symptoms of hypo - insulin levels at the end of the fast point endogenous hyperinsulinism. Age of glycemia at irregular intervals and of to an insulinoma or sulfonylurea inges - onset is generally 40 to 60 years, but varying duration. Symptoms include but are not limited to light-headedness, altered mental status, and abnormal 6 behavior. They commonly occur in the Key features ADVIA Centaur ® Assay IMMULITE ® 2000 Assay morning after overnight fast, after skip - Sample size 50 µl 25 µl ping a meal, or after exercise. However, symptoms can occur at other times as Assay format Two-site murine Two-site murine well, and patient presentations are vari - monoclonal sandwich monoclonal sandwich able. Diagnosis of insulinoma typically Time to first result 35 minutes 35 minutes involves the 72-hour fast. Working range 0.5 –30 ng/ml 0.1 –15 ng/ml The C-peptide suppression test can also be used to confirm the diagnosis since Expected range elevated insulin during the test is sug - (95% confidence gestive of insulinoma. 27, 28 This test interval) involves the infusion of insulin and the Serum 0.81 to 3.85 ng/ml 0.9 to 7.1 ng/ml measurement of glucose and C-peptide Urine <156.46 µg/day 3.6 to 253 µg/day during the infusion. The basis of the test is the administration of exogenous Within-run CV 3.7 – 4.7% 1.7 –2.3% insulin to suppress endogenous insulin Total CV 5.1 –9.5% 3.3 – 4.8% and C-peptide production. Lack of sup - pression (percent below baseline) is sug - gestive of endogenous hyperinsulinism 6 Features of C-peptide assays from Siemens Healthcare Diagnostics 27 CV, Coefficient of variation likely due to an insulinoma.

Summary

C-peptide is an important, biologically active molecule. Short-term replacement of C-peptide improves some of the com - plications associated with diabetes melli - tus. In addition, type 1 patients who are able to maintain C-peptide levels have fewer complications and better glycemic control. C-peptide measurements play a key role in the evaluation of hypo - glycemia and insulinoma, are a useful aid in the classification of diabetes mel - litus, and may play a larger role in its management in the future. ADVIA Centaur ® IMMULITE ® 2000 Immunoassay System Immunoassay System

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