C-Peptide: What Type of Type 1 Diabetes Do You Have?

What C-peptide is and why it is the right measure

Before insulin is released from the beta-cell, it must be cleaved from C-peptide. For every molecule of insulin released, one molecule of C-peptide is released alongside it.

Once separated, insulin and C-peptide both enter the portal vein. Around half of the insulin is used immediately by the liver to store glucose. C-peptide, however, escapes the liver almost entirely and enters the general circulation, where it is eventually broken down or excreted by the kidneys.

This makes C-peptide a better measure of how much insulin the beta-cells are producing than insulin itself, because injected or infused insulin does not carry C-peptide. C-peptide in the blood comes only from the pancreas.

Simply put: C-peptide tells a person with type 1 diabetes how much help, if any, they are getting from their own pancreas.

How to test for C-peptide

Several C-peptide tests are available (7):

• Glucagon Stimulated Test (GST) — an injection of 1 mg glucagon is given, and C-peptide is measured at two, four, and six minutes. The peak value is recorded.
• Mixed Meal Tolerance Test (MMTT) — a liquid mixed meal (carbohydrate, fat, and protein) is consumed without a bolus. C-peptide is measured over two hours. The peak value is recorded.
• Urinary C-peptide to creatinine ratio (UCPCR) — a single urine sample. Research confirms this is accurate (8), though less commonly used than blood-based methods.
• Fasting C-peptide (FC) — C-peptide measured after an overnight fast.
• Random C-peptide (RC) — a single blood test taken at any time.

The GST and MMTT are most commonly used in research settings but are rarely available outside clinical trials. Research shows that random C-peptide correlates very closely with MMTT results, with a correlation coefficient of 0.91 (9), and it requires no preparation, making it the most practical option in most settings.

For the best result from a random C-peptide test, eat a mixed meal in the two hours before and use only around half the usual bolus insulin. This allows glucose to rise enough to stimulate the beta-cells, so any residual function will be captured.

What the result means: HIGH, INTERMEDIATE, and LOW

C-peptide cut-offs differ slightly between studies but can be broadly categorised as (3):

For context, people without type 1 diabetes typically have levels of 1–3 nmol/L (1,000–3,000 pmol/L) after eating (10). Even someone in the HIGH category in type 1 diabetes has only around 10% of fully functioning beta-cell capacity.

Does it matter when the test is done, and how old you were at diagnosis?

Yes, significantly.

Data from 610 people with type 1 diabetes aged 13–39 years from the DCCT found that 1–5 years after diagnosis, up to 48% still have HIGH function. By 5–15 years after diagnosis, only 8% retain HIGH function. For those diagnosed between 13 and 18 years of age, none were classified as HIGH at the 5–15 year mark (11).

These findings were replicated in a study from Massachusetts General Hospital of 1,273 patients with type 1 diabetes aged 8–90 years (12). Each participant had a fasting C-peptide measured at one point in their diabetes journey.

Graph A above shows that C-peptide declines progressively the longer a person has been living with type 1 diabetes.

Graph B shows significantly lower C-peptide for people diagnosed under the age of 20 years, at both diabetes duration timepoints (12).

What this means practically: if type 1 diabetes was diagnosed fewer than five years ago, the result is likely to change further over time and a repeat test later may be worthwhile. If diagnosis was under the age of 20, INTERMEDIATE or LOW function is more probable, though not certain. If at least five years have passed since diagnosis, the result is likely to be fairly stable.

What the research shows about health outcomes

The landmark DCCT trial, published in 1987, looked at 610 participants with C-peptide results. Those with HIGH function had lower HbA1cs, lower fasting glucose levels, and lower total daily insulin doses compared to the LOW group at seven years of follow-up (11).

A more recent DCCT report confirmed the benefit persists over decades. The HIGH group had lower HbA1cs, lower insulin doses, and a lower risk of eye disease 35 years later compared to the LOW group. This report also identified a linear relationship between C-peptide level and improved clinical outcomes (13).

Most recently, the HIGH and INTERMEDIATE groups had significantly fewer episodes of severe hypoglycaemia compared to the LOW group (3). Taken together, the higher the C-peptide, the lower the risk of future diabetes-related complications (13).

Time in range

A team in Newcastle (England) followed 66 people with type 1 diabetes in free-living conditions after categorising them by C-peptide (5). After accounting for key variables, the HIGH group had 76% time in range overnight versus 58% for the LOW group. After meals, the HIGH group achieved 68% time in range versus 51% for the LOW group.

Exercise and time in range

The same research group categorised 30 adults with type 1 diabetes by residual beta-cell function and had them complete 45 minutes of incline treadmill walking at a pace causing heavy breathing (6). In the 12 hours after exercise, the HIGH group had 73% time in range compared to 44% and 41% for the INTERMEDIATE and LOW groups respectively. The HIGH group also had lower glucose variability, less time above 13.9 mmol/L (250 mg/dL), and a trend towards less time below 3.9 mmol/L (70 mg/dL). The LOW and INTERMEDIATE groups experienced worsening time in range after exercise, while the HIGH group improved by 12.1% (6).

How higher C-peptide helps — the mechanisms

Several mechanisms are likely to be at play:

• Portal insulin delivery. Insulin secreted by the beta-cell goes directly into the portal vein, where much of the glucose from a meal can be stored in the liver as glycogen. This reduces post-meal rises in a way that subcutaneous insulin cannot fully replicate.
• Glucagon suppression. In type 1 diabetes, glucagon is not reliably suppressed when glucose rises — an abnormality that does not occur in people without diabetes. Residual beta-cell function may dampen this inappropriate glucagon release (14). Glucagon causes the liver to release stored glucose, so unhelpful glucagon secretion can cause glucose to spiral upward.
• Cardiovascular protection through exercise. A study using exercise as a stimulus found that cardioprotective haematopoietic and endothelial progenitor cells increased in the HIGH group after exercise, to the same level as non-diabetic controls. The LOW group showed no increase (16). Residual beta-cell function may therefore also amplify the protective cardiovascular effects of exercise.

The mechanisms are likely multifactorial and research is ongoing. The overall picture is that residual beta-cell function helps in several ways, though the full picture is not yet clear.

C-peptide as a tool of empathy

Knowing C-peptide level can help everyone in the diabetes conversation — the person with type 1 diabetes, their family, and their clinical team — understand why management can be such a challenge for some people, despite their best efforts.

Comparing outcomes between someone with HIGH residual function and someone with LOW function is not a meaningful comparison. The physiological starting points are genuinely different. C-peptide puts a number on that difference.

Quick recap

• C-peptide reveals how much residual help the pancreas is providing
• It can be measured two hours after a mixed meal using a random blood test
• Results can be categorised as HIGH (>200 pmol/L), INTERMEDIATE (30–200 pmol/L), or LOW (<30 pmol/L)
• If tested within five years of diagnosis, the result may fall further over time
• People diagnosed under age 20 are more likely to fall in the INTERMEDIATE or LOW group
• Higher C-peptide is associated with better time in range, fewer severe hypos, and lower complication risk

References

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12. Kuhtreiber WM, et al. Low levels of C-peptide have clinical significance for established Type 1 diabetes. Diabet Med. 2015;32(10):1346.
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14. Guo K, et al. The Role of Glucagon in Glycemic Variability in Type 1 Diabetes. Diabetes Metab Syndr Obes. 2021;14:4865–4873.
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17. Mathieu C, et al. Efficacy and Safety of Liraglutide Added to Insulin Treatment in Type 1 Diabetes: The ADJUNCT ONE Trial. Diabetes Care. 2016;39(10):1702–1710.