From the Guidelines
Low C-peptide levels are primarily caused by conditions that impair insulin production in the pancreas, with the most common cause being type 1 diabetes, as evidenced by the most recent study 1 published in 2025. C-peptide is a byproduct of insulin production, so its levels directly reflect insulin synthesis. The most common cause of low C-peptide is type 1 diabetes, where autoimmune destruction of pancreatic beta cells leads to decreased insulin and C-peptide production. Other significant causes include advanced type 2 diabetes with beta cell burnout, pancreatitis, pancreatic cancer, and cystic fibrosis-related pancreatic insufficiency. Certain medications, such as exogenous insulin therapy, can also suppress endogenous insulin production and consequently lower C-peptide levels. Less common causes include rare genetic disorders affecting insulin synthesis, severe malnutrition, and Addison's disease. It's essential to note that low C-peptide levels should always be interpreted in the context of blood glucose levels and other clinical factors, as recommended by recent guidelines 1 and 1. In cases of unexplained low C-peptide, further investigation of pancreatic function and autoimmune markers may be necessary to determine the underlying cause and guide appropriate treatment, as suggested by recent studies 1 and guidelines 1 and 1. Key points to consider when evaluating low C-peptide levels include:
- Clinical presentation and medical history
- Blood glucose levels and other laboratory results
- Presence of autoimmune markers or other underlying conditions
- Potential impact of medications or other factors on insulin production. Recent studies 1, 1, and 1 provide valuable insights into the diagnosis and management of diabetes, highlighting the importance of considering C-peptide levels in the context of overall clinical presentation and laboratory results.
From the Research
Causes of Low C-Peptide Levels
- Low C-peptide levels can be caused by the decline of pancreatic beta-cell function over time, especially in individuals with type 1 diabetes 2
- The rate of decline in C-peptide levels is significantly related to the age of onset of type 1 diabetes, with earlier onset resulting in a faster decline 2
- C-peptide levels can also be affected by the duration of the disease, with longer duration resulting in lower C-peptide levels 2, 3
- Low C-peptide levels have been associated with poor metabolic control, as measured by HbA1c, and an increased risk of complications such as nephropathy, neuropathy, foot ulcers, and retinopathy 2
- Severe hypoglycaemia is also associated with low C-peptide levels, suggesting that individuals with low C-peptide levels may be at a higher risk of hypoglycaemic episodes 2, 3
Factors Influencing C-Peptide Levels
- Age of onset of type 1 diabetes: earlier onset is associated with a faster decline in C-peptide levels 2
- Duration of disease: longer duration is associated with lower C-peptide levels 2, 3
- Metabolic control: poor metabolic control, as measured by HbA1c, is associated with low C-peptide levels 2
- Presence of complications: low C-peptide levels are associated with an increased risk of complications such as nephropathy, neuropathy, foot ulcers, and retinopathy 2
- Hypoglycaemia: severe hypoglycaemia is associated with low C-peptide levels 2, 3
Measurement of C-Peptide Levels
- C-peptide levels can be measured using various assays, including glucagon stimulation C-peptide testing, which is recommended due to its balance of sensitivity and practicality 4
- Modern assays can detect low levels of C-peptide, which can be used to guide diabetes diagnosis and management 4
- C-peptide levels can be associated with diabetes type and duration of disease, with a level of less than 0.2 nmol/l associated with a diagnosis of type 1 diabetes mellitus (T1DM) 4