Proinsulin

When your body needs insulin, it does not produce the finished hormone directly. Instead, your pancreatic beta cells build a larger starter molecule called proinsulin (intact proinsulin), which then gets cut into two pieces: mature insulin and a byproduct called C-peptide. Under normal conditions, this cutting process is thorough. Very little proinsulin escapes into the bloodstream intact. When your proinsulin level is elevated, it signals that your beta cells are struggling to keep up, either because they are under stress, working too fast, or failing to process insulin properly.

This test is most commonly used to evaluate unexplained low blood sugar episodes, particularly when doctors suspect an insulin-producing tumor called an insulinoma. But proinsulin can also tell you something important from a preventive standpoint: whether your beta cells are showing early signs of dysfunction, even before your fasting glucose or HbA1c looks abnormal. A rising proinsulin level can be one of the earliest metabolic warning signs that your insulin production machinery is under strain.

What Proinsulin Tells You About Beta Cell Health

Your beta cells are small factories. They manufacture proinsulin, fold it into the correct three-dimensional shape, and then snip it apart inside tiny storage compartments called secretory granules. The snipping is done by specialized molecular scissors known as prohormone convertases. When everything works well, insulin and C-peptide are released into the bloodstream in equal amounts, and almost no intact proinsulin leaks out.

When beta cells are stressed or overworked, the granules do not have enough time to finish processing. The result is that partially cut or fully intact proinsulin gets released alongside insulin. This is why a disproportionately high ratio of proinsulin to insulin is considered a hallmark of beta cell dysfunction in type 2 diabetes. It reflects the release of incompletely processed proinsulin rather than a change in how much total insulin your body makes.

In type 1 diabetes, a different problem can arise. Beta cells may accumulate misfolded proinsulin inside the folding compartment of the cell (the endoplasmic reticulum), triggering internal stress signals that can accelerate beta cell death. More than 20 known mutations in the insulin gene cause a condition called MIDY (Mutant INS-gene-induced Diabetes of Youth), in which proinsulin cannot fold correctly, leading to cellular stress and eventual beta cell failure.

When This Test Matters Most

The clearest clinical use of proinsulin testing is in the evaluation of unexplained hypoglycemia. If you experience episodes of low blood sugar without an obvious cause, measuring proinsulin alongside insulin and C-peptide helps determine whether the hypoglycemia is coming from your own body's overproduction or from an external source like injected insulin.

For insulinoma evaluation, proinsulin has strong diagnostic accuracy. In one study, a specific threshold measured at the end of a supervised fast correctly identified every insulinoma case while producing zero false positives. A lower, more commonly cited threshold had a 59% false positive rate. This means the cutpoint your clinician uses matters significantly for interpretation.

Proinsulin also helps distinguish between different causes of hypoglycemia. If someone is injecting insulin secretly or accidentally, their proinsulin and C-peptide levels will be suppressed because the external insulin shuts down the beta cells' own production. In contrast, hypoglycemia caused by certain medications like sulfonylureas will show elevated proinsulin, insulin, and C-peptide together, mimicking an insulinoma. In that case, a urine or blood test for the medication itself resolves the question.

What this means for you: if you have unexplained episodes of shakiness, confusion, or sweating that resolve with eating, and your glucose has been documented as low during these episodes, proinsulin testing as part of a supervised fasting evaluation can help pinpoint whether the cause is an internal overproduction problem or something else entirely.

Special Considerations

In children with persistent low blood sugar, proinsulin measurement is recommended when hyperinsulinism is suspected, especially when standard insulin assays may not be sensitive enough to detect mildly elevated levels. Elevated proinsulin provides supportive evidence for a diagnosis of hyperinsulinemic hypoglycemia in pediatric cases.

Some rare insulinomas predominantly secrete proinsulin rather than mature insulin. Newer insulin assays are designed to measure only mature insulin and do not cross-react with proinsulin. This means that if your doctor relies solely on an insulin measurement using one of these specific assays, a proinsulin-secreting tumor could be missed. Measuring proinsulin directly closes that diagnostic gap.

Certain lab factors can occasionally affect proinsulin results, so interpreting borderline values should always account for the specific assay your lab uses. Reference ranges vary between laboratories, and your lab report will indicate whether your result falls outside expected bounds.

What Moves This Biomarker

Because proinsulin reflects the internal processing efficiency of your beta cells, interventions that reduce beta cell stress or improve insulin sensitivity can influence your level. The key principle is straightforward: anything that lowers the demand on your beta cells gives them more time to properly process proinsulin into mature insulin.

Insulin-sensitizing medications: Pioglitazone, a medication in the thiazolidinedione class, has been shown to reduce elevated proinsulin levels. By improving how well your tissues respond to insulin, it reduces the workload on beta cells, allowing more complete processing. This effect has been observed in people with type 2 diabetes and insulin resistance. If your proinsulin is elevated in the context of metabolic dysfunction, this is a medication class worth discussing with your clinician.

Reducing insulin resistance through lifestyle: While the provided research focuses on the mechanistic link between insulin resistance and beta cell strain, the logic is direct. Excess demand on beta cells, driven by insulin resistance, shortens the time granules have to fully process proinsulin. Strategies that improve insulin sensitivity, such as reducing excess body fat, regular physical activity, and dietary changes that lower postmeal glucose spikes, would be expected to ease this burden.

Questions This Biomarker Can Answer

• Are my insulin-producing cells processing insulin efficiently, or are they under strain?
• Is my unexplained low blood sugar coming from my body overproducing insulin internally?
• Could I have an insulin-producing tumor that a standard insulin test might miss?
• Is the cause of my hypoglycemia an internal problem or an external medication effect?