From the Guidelines
Elevated proinsulin levels should be interpreted as a potential indicator of beta cell dysfunction, insulin resistance, or insulinoma, particularly when considered in the context of insulin and C-peptide measurements, as recommended by recent guidelines 1. When evaluating proinsulin levels, it is essential to consider the clinical context, including fasting status, as levels can increase after meals.
- Normal proinsulin levels are typically less than 20 pmol/L in fasting individuals, with elevated levels suggesting beta cell dysfunction.
- An increased proinsulin-to-insulin ratio (normally <20%) is particularly significant, as it indicates inefficient processing of proinsulin to insulin, which occurs in conditions like type 2 diabetes, insulin resistance, and insulinomas.
- Elevated proinsulin with normal or high insulin levels suggests insulin resistance or early beta cell dysfunction, while high proinsulin with low insulin may indicate more advanced beta cell failure.
- In cases of suspected insulinoma, a proinsulin level >22 pmol/L during hypoglycemia is highly suggestive of this tumor, as it indicates the presence of an islet cell tumor 1. Proinsulin measurement is most valuable when interpreted alongside glucose, insulin, and C-peptide levels, providing a comprehensive picture of insulin production and processing capacity rather than as an isolated value.
- The diagnosis of an islet cell tumor is based on the persistence of inappropriately increased plasma insulin concentrations in the face of a low glucose concentration, and an increase in the ratio of fasting proinsulin to insulin in an individual with hypoglycemia strongly suggests the presence of an islet cell tumor 1.
- However, routine testing for insulin or proinsulin is not recommended for most people with diabetes or risk for diabetes or cardiovascular disease, as these assays are useful primarily for research purposes 1.
From the Research
Interpretation of Elevated Proinsulin Levels
Elevated proinsulin levels have been associated with various conditions, including:
Association with Insulin Resistance and Beta-Cell Dysfunction
Studies have shown that elevated proinsulin levels are closely related to insulin resistance, as assessed by iv glucose tolerance test and HOMA analysis 2. Additionally, proinsulin levels have been found to be associated with defects in insulin secretion rather than a reduction in beta-cell area 3.
Diagnostic and Therapeutic Implications
Elevated intact proinsulin levels (> 10 pmol/L) may indicate insulin resistance, while elevation of total proinsulin (>45 pmol/L) may help identify high cardiovascular risk patients 2. Effective treatment of insulin resistance, such as with thiazolidindiones, can lead to a decrease in elevated proinsulin levels and cardiovascular risk profile 2.
Limitations of Proinsulin to Insulin Ratio
The fasting proinsulin to insulin ratio has been suggested as a marker of beta-cell health, but its utility is limited due to the different half-lives of proinsulin and insulin, and the lack of hepatic extraction of proinsulin prior to reaching the systemic circulation 6. This ratio may not be a useful marker of beta-cell function, especially in nondiabetic individuals 6.
Clinical Evaluation and Laboratory Assessment
A new specific ELISA for intact proinsulin has been developed and evaluated, showing excellent agreement with a commercial chemiluminescence test 5. This assay can be used to establish and identify optimal anti-diabetic treatment, as well as to monitor potential protective treatment effects on beta-islet cell dysfunction 5.