C-peptide
C-peptide is released in equal amounts to insulin and shows how much insulin the pancreas makes. A US survey laboratory observed fasting values of 0.66 to 2.63 ng/mL in 23 adults without diabetes. In insulin-treated diabetes, one review reads a fasting value below 0.24 as absolute insulin deficiency. Random and stimulated tests use different cut points.
- Status
- Ordered by a clinician and also sold direct to consumers by some US laboratories. FDA classifies test systems for the C-peptides of proinsulin as class I devices exempt from premarket notification [1]. Medicare ties coverage of insulin pumps to a fasting C-peptide criterion or a positive beta cell autoantibody test [2].
- Measures
- The concentration of C-peptide in blood drawn after an overnight fast. C-peptide is the fragment split off when the pancreas turns proinsulin into insulin, and it is produced in equal amounts to insulin [3][4].
- Also called
- C-peptide, C peptide, fasting C-peptide, serum C-peptide, C-peptide level, connecting peptide, proinsulin C-peptide, insulin C-peptide
- Tested for
- telling type 1 from type 2 diabetes, how much insulin the body still makes, latent autoimmune diabetes, monogenic diabetes, insulin resistance, deciding on insulin treatment, insulin pump coverage, unexplained low blood sugar
Strong several reviews agree · Moderate one review or consistent trials · Limited one or a few small studies · Untested no study in people, listed with what it rests on
Linked in research2
- LimitedLimited evidence: two analyses of one US survey linked the highest quarter of fasting C-peptide to about 70% to 80% more deaths in adults without diabetes.
- LimitedLimited evidence: in one type 1 diabetes trial cohort, higher stimulated C-peptide went with less retinopathy and hypoglycemia, and fasting C-peptide showed weaker links.
Reported risks0
No risks sourced yet.
Reference ranges
Each range is the one its source published, in ng/mL. Also reported in nmol/L. Where sources differ, each is shown.
US national survey laboratory procedure manual, 2003 to 2004
Adults without diabetes, on a sample taken after an overnight fast · [3]
| Range | What the source calls it |
|---|---|
| below 0.66 ng/mL | No name given |
| 0.66 to 2.63 ng/mL | "reference range" |
| above 2.63 ng/mL | No name given |
The lowest and highest fasting values observed in 23 non-obese adults without diabetes aged 20 to 38, not a percentile interval, measured by radioimmunoassay at the laboratory that ran the test for the US National Health and Nutrition Examination Survey. Printed as 0.22 to 0.87 pmol/mL, with a mean of 0.56, and converted here with the manual's own equivalence of 1.0 ng/mL to 0.331 pmol/mL. The manual states that results are affected by body mass, age and state of nutrition, and that a result outside the range is not necessarily of clinical significance. It also prints ranges at 30 minutes, 1 hour and 2 hours after a 360 calorie liquid meal. Those are stimulated values, a different quantity, and are not placed here [3].
Jones and Hattersley, review of C-peptide in diabetes care, 2013
People with diabetes treated with insulin, on a fasting sample · [4], [5]
| Range | What the source calls it |
|---|---|
| below 0.24 ng/mL | "absolute insulin deficiency" A doctor, immediately |
| 0.24 to 0.74 ng/mL | "likely Type 1 diabetes" |
| 0.75 or above ng/mL | No name given |
Suggested thresholds from a review by two UK diabetes researchers, not from a guideline body. Printed as below 0.08 nmol/L and below 0.25 nmol/L, and converted here with the review's own equivalence of 1 nmol/L to 3 ng/mL. The review's full labels are "Absolute insulin deficiency/absolute insulin requirement" and "Likely Type 1 diabetes/inability to achieve glycaemic control with non-insulin therapies". The fasting values were calculated from mixed-meal thresholds of 0.2 and 0.6 nmol/L in 120 people with insulin-treated diabetes. The authors call them approximate and state that values close to a threshold are to be treated with great caution. The same table reads a fasting value above 0.08 nmol/L as suggesting type 2 or monogenic diabetes in a person with presumed type 1 diabetes 3 to 5 years or more after diagnosis, and a value above 0.4 nmol/L as a prompt to consider those types in young-onset diabetes at diagnosis. The review states that low blood glucose suppresses C-peptide and that an obese, insulin-resistant person can have a normal or high value even with autoimmune diabetes [4]. A second review lists below 0.075 nmol/L as the fasting cut-off [5].
Berger and colleagues, Swedish diabetes population study, 2000
Adults with diabetes being classified as type 1 or type 2, on a fasting sample · [6], [4]
| Range | What the source calls it |
|---|---|
| below 1.27 ng/mL | No name given |
| 1.27 or above ng/mL | No name given |
The fasting cut-off the study selected from its curve analysis to separate type 1 from type 2 diabetes, in 1,093 patients whose diabetes type was already well defined. It is printed as 0.42 nmol/L and converted here by dividing by 0.331. The study found a random sample, with a cut-off of 0.50 nmol/L, more powerful than a fasting one [6]. A later review reports that fasting values below the cut-off had an 81.0% predictive value for type 1 diabetes, and values above it a 91.3% predictive value for type 2 [4]. The cut-off is 0.52 ng/mL higher than the review threshold in the block above, so a fasting result between 0.75 and 1.26 ng/mL falls on different sides in the two sources.
How it compares with the reference method
Mixed results2
Telling type 1 from type 2 diabetes
Mixed results: fasting C-peptide separated diabetes types better than age or body mass index, yet many adults with autoimmune diabetes had normal or high levels at diagnosis.
The numbers and sources
- Compared with
- Clinical diabetes type and islet autoantibody status
- Effect
- In 1,093 Swedish patients with well-defined diabetes type, fasting, random and glucagon-stimulated C-peptide all had high discriminative power, with cut-offs of 0.42, 0.50 and 0.60 nmol/L, and the random sample had the greatest discriminating power [6]. In 1,180 adults with newly diagnosed diabetes, mean fasting C-peptide was 0.73 nmol/L in people with islet autoantibodies and 1.42 nmol/L in people without. The area under the curve for separating the two was 0.78 for C-peptide, 0.68 for age and 0.66 for body mass index, and the authors report that most adults with autoimmune diabetes had normal or high C-peptide at presentation [11]. A review tabulates fasting cut-offs from 0.08 to 0.6 nmol/L across earlier studies, with predictive values for type 1 diabetes or islet autoantibodies from 30% to 98% [4]. A consensus report from the American Diabetes Association and the European Association for the Study of Diabetes states that a C-peptide test is only indicated in people receiving insulin, and places it beyond 3 years after diagnosis when the type is uncertain [12].
- Population
- 1,093 patients with diabetes in Skaraborg, Sweden [6]. 1,180 adults with newly diagnosed diabetes in Kronoberg, Sweden [11].
- Sources
- [6], [11], [4], [12]
- Caveats
- The two cohorts are Swedish, and the consensus report notes that its own flow chart rests on data from White European populations. The review states that a higher result early after diagnosis may reflect insulin still being made in the first phase of type 1 diabetes, so it is to be read with caution [4][12].
Fasting against random and stimulated samples
Limited evidence: random and stimulated C-peptide are separate measurements with their own cut points, and one study of 41 people found random samples tracked a meal test closely.
The numbers and sources
- Compared with
- C-peptide 90 minutes into a mixed-meal tolerance test
- Effect
- A fasting sample is one of three kinds. A random sample is taken without regard to meals, and a stimulated sample is taken after glucagon or a standard liquid meal. In 41 people with insulin-treated diabetes, random C-peptide correlated with the 90-minute meal test value (r = 0.91), and a random cut-off of 200 pmol/L had 100% sensitivity and 93% specificity for severe insulin deficiency on the meal test [13]. A review reports correlations of 0.84 to 0.99 between fasting and stimulated values in insulin-treated patients, and gives stimulated thresholds of 0.2 and 0.6 nmol/L where it gives fasting thresholds of 0.08 and 0.25 [4]. The American and European consensus report uses a random sample within 5 hours of eating, with glucose measured at the same time. It reads a value above 600 pmol/L as strongly suggestive of type 2 diabetes, 200 to 600 pmol/L as usually consistent with type 1 or monogenic diabetes, and below 80 pmol/L as very low, and asks for a repeat when a result under 600 pmol/L may have been taken fasting [12]. An international panel on latent autoimmune diabetes in adults sorts random C-peptide into below 0.3 nmol/L, 0.3 to 0.7 nmol/L, which it calls a gray area, and above 0.7 nmol/L [14]. None of these random or stimulated cut points is placed against this page's fasting ranges.
- Population
- 41 people with insulin-treated diabetes, median age 72 [13].
- Sources
- [13], [4], [12], [14]
- Caveats
- The direct comparison is one study of 41 older adults, and it compared random with stimulated samples, not fasting ones. A laboratory report does not always record whether a sample was fasting [13].
Did not match the reference method2
Variation between laboratories and assays
One study of 15 laboratories using 9 assay methods found C-peptide results did not always agree, most of all at higher concentrations.
The numbers and sources
- Compared with
- A mass spectrometry reference method
- Effect
- Forty serum samples were sent to 15 laboratories using 9 routine methods. Within-run variation ranged from under 2% to over 10%, and between-run variation from under 2% to over 18%. Results from different methods and laboratories did not always agree, especially at higher concentrations. After results were normalized to the reference method with serum calibrators, the differences among laboratories were no longer statistically significant [15]. The survey laboratory's manual states that its standards vary by lot because no universal reference material was available [3].
- Population
- 40 serum samples analyzed in 15 laboratories [15].
- Sources
- [15], [3]
- Caveats
- The study dates from 2008 and the manual from 2003 to 2004, so they describe assays as they then were. The ranges on this page come from different assays and are not adjusted to one another [15][3].
Kidney function and blood glucose at the time of the draw
Limited evidence: a review states that impaired kidney function raises C-peptide and low blood glucose lowers it, and Medicare doubles its fasting threshold in kidney disease.
The numbers and sources
- Compared with
- C-peptide with normal kidney function and no low blood glucose at the draw
- Effect
- A review states that about half of the C-peptide produced is removed by the kidneys, so blood levels can be falsely elevated in kidney impairment, and that low blood glucose suppresses insulin and C-peptide [4]. Medicare defines insulinopenia as a fasting C-peptide at or below 110% of the lower limit of normal of the laboratory's method, or at or below 200% of that limit when creatinine clearance is 50 mL/min or less, and counts a fasting value only when fasting glucose drawn at the same time is 225 mg/dL or below [2]. The American and European consensus report asks for a repeat test when the result is under 600 pmol/L and glucose at the same time is below 72 mg/dL, and against testing within 2 weeks of a hyperglycemic emergency [12].
- Population
- No study population. These are statements from a review, a coverage rule and a consensus report [4][2][12].
- Sources
- [4], [2], [12]
- Caveats
- None of the three sources gives the size of the shift. The Medicare criterion is set against each laboratory's own lower limit, so it has no single number and is not placed as a range on this page [2].
What studies tie it to
Linked in research2
Death in adults without diabetes
Limited evidence: two analyses of one US survey linked the highest quarter of fasting C-peptide to about 70% to 80% more deaths in adults without diabetes.
The numbers and sources
- Effect
- In 5,153 adults aged 40 to 74 without diabetes, the highest quarter of fasting C-peptide, 0.984 nmol/L (about 2.97 ng/mL) or above, had an adjusted hazard ratio of 1.72 (95% CI 1.34 to 2.21) for death from any cause and 1.60 (1.07 to 2.39) for cardiovascular death against the lowest quarter, 0.418 nmol/L (about 1.26 ng/mL) or below. C-peptide predicted these deaths better than fasting glucose, insulin or indices built from them [7]. In 5,902 adults aged 40 and older from the same survey, the highest quarter had a hazard ratio of 1.80 (1.33 to 2.43) for death from any cause and 3.20 (2.07 to 4.93) for cardiovascular death against the lowest [8].
- Population
- 5,153 adults without diabetes in the third US National Health and Nutrition Examination Survey of 1988 to 1994, followed for a median of 14.4 years with 513 deaths [7]. 5,902 adults with no history of diabetes in the same survey, mean C-peptide 0.78 nmol/L [8].
- Sources
- [7], [8]
- Caveats
- Observational, and both analyses draw on the same survey, so they are not independent. The authors read a high C-peptide in a person without diabetes as a sign of insulin resistance. Neither source tested whether lowering it changes the risk of death [7][8].
Eye disease and low blood sugar in type 1 diabetes
Limited evidence: in one type 1 diabetes trial cohort, higher stimulated C-peptide went with less retinopathy and hypoglycemia, and fasting C-peptide showed weaker links.
The numbers and sources
- Effect
- In the intensive treatment group of the Diabetes Control and Complications Trial, a 50% higher stimulated C-peptide at entry, such as 0.15 against 0.10 nmol/L, went with a 25% lower risk of sustained retinopathy, an 8.2% lower risk of hypoglycemia, a lower insulin dose and an HbA1c 0.07 percentage points lower. Outcomes changed in a nearly linear way as C-peptide fell to unmeasurable levels, with no threshold. Fasting C-peptide had weaker associations with outcomes than stimulated C-peptide [9].
- Population
- Participants in the Diabetes Control and Complications Trial with up to 5 years of type 1 diabetes at entry, followed for 7 years [9].
- Sources
- [9]
- Caveats
- The main findings are for C-peptide measured after a stimulus, a different quantity from the fasting value on this page. They are unadjusted, come from one trial cohort, and concern people with type 1 diabetes only. The abstract gives no participant count [9].
Mixed results1
Nerve function in a trial that gave C-peptide in type 1 diabetes
One trial found 52 weeks of long-acting C-peptide in type 1 diabetes did not improve nerve conduction against placebo, while vibration sense improved 25%.
The numbers and sources
- Effect
- Patients received weekly pegylated C-peptide at 0.8 mg or 2.4 mg, or placebo. Plasma C-peptide rose to 1.8 to 2.2 nmol/L on the low dose and 5.6 to 6.8 nmol/L on the high dose. After 52 weeks, sural nerve conduction velocity had risen by 1.0 m/s on C-peptide and 1.2 m/s on placebo. Vibration perception threshold improved by 25% on C-peptide and was unchanged on placebo (P below 0.001), and the clinical neuropathy score did not change [10].
- Population
- 250 people with type 1 diabetes and mild to moderate peripheral neuropathy, 144 on C-peptide and 106 on placebo [10].
- Sources
- [10]
- Caveats
- One trial, in which the main nerve conduction measure did not differ from placebo. It tested giving C-peptide to people who make little of their own, and says nothing about a person's own C-peptide level [10].
Sources
- US Food and Drug Administration. 21 CFR 862.1135, C-peptides of proinsulin test system. Electronic Code of Federal Regulations. https://www.ecfr.gov/current/title-21/section-862.1135
- Centers for Medicare and Medicaid Services. National Coverage Determination 280.14, Infusion Pumps. Medicare Coverage Database. https://www.cms.gov/medicare-coverage-database/view/ncd.aspx?NCDId=223
- Centers for Disease Control and Prevention, National Center for Health Statistics. National Health and Nutrition Examination Survey 2003-2004 Laboratory Procedure Manual: C-Peptide, serum, radioimmunoassay. Performed by the Department of Child Health, University of Missouri-Columbia. https://wwwn.cdc.gov/nchs/data/nhanes/public/2003/labmethods/l10am_c_met_cpeptide.pdf
- Jones AG, Hattersley AT. The clinical utility of C-peptide measurement in the care of patients with diabetes. Diabetic Medicine. 2013. https://doi.org/10.1111/dme.12159
- Leighton E, Sainsbury CA, Jones GC. A Practical Review of C-Peptide Testing in Diabetes. Diabetes Therapy. 2017. https://doi.org/10.1007/s13300-017-0265-4
- Berger B, Stenström G, Sundkvist G. Random C-peptide in the classification of diabetes. Scandinavian Journal of Clinical and Laboratory Investigation. 2000. https://doi.org/10.1080/00365510050216411
- Patel N, Taveira TH, Choudhary G, Whitlatch H, Wu WC. Fasting Serum C-Peptide Levels Predict Cardiovascular and Overall Death in Nondiabetic Adults. Journal of the American Heart Association. 2012. https://doi.org/10.1161/JAHA.112.003152
- Min JY, Min KB. Serum C-peptide levels and risk of death among adults without diabetes mellitus. Canadian Medical Association Journal. 2013. https://doi.org/10.1503/cmaj.121950
- Lachin JM, McGee P, Palmer JP, DCCT/EDIC Research Group. Impact of C-Peptide Preservation on Metabolic and Clinical Outcomes in the Diabetes Control and Complications Trial. Diabetes. 2014. https://doi.org/10.2337/db13-0881
- Wahren J, Foyt H, Daniels M, Arezzo JC. Long-Acting C-Peptide and Neuropathy in Type 1 Diabetes: A 12-Month Clinical Trial. Diabetes Care. 2016. https://doi.org/10.2337/dc15-2068
- Thunander M, Törn C, Petersson C, et al. Levels of C-peptide, body mass index and age, and their usefulness in classification of diabetes in relation to autoimmunity, in adults with newly diagnosed diabetes in Kronoberg, Sweden. European Journal of Endocrinology. 2012. https://doi.org/10.1530/EJE-11-0797
- Holt RIG, DeVries JH, Hess-Fischl A, et al. The management of type 1 diabetes in adults. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia. 2021. https://doi.org/10.1007/s00125-021-05568-3
- Hope SV, Knight BA, Shields BM, et al. Random non-fasting C-peptide: bringing robust assessment of endogenous insulin secretion to the clinic. Diabetic Medicine. 2016. https://doi.org/10.1111/dme.13142
- Buzzetti R, Tuomi T, Mauricio D, et al. Management of Latent Autoimmune Diabetes in Adults: A Consensus Statement From an International Expert Panel. Diabetes. 2020. https://doi.org/10.2337/dbi20-0017
- Little RR, Rohlfing CL, Tennill AL, et al. Standardization of C-Peptide Measurements. Clinical Chemistry. 2008. https://doi.org/10.1373/clinchem.2007.101287