Adult Hypoglycaemia Interpreter: Insulin, C-Peptide and Proinsulin
Adult Hypoglycaemia Interpreter: Insulin, C-Peptide and Proinsulin
Work out why an adult without diabetes had a low glucose. Enter the insulin, C-peptide, proinsulin and β-hydroxybutyrate taken during the hypoglycaemia, with the sulfonylurea screen and insulin antibodies, and the page matches them to the Endocrine Society’s 2009 table: exogenous insulin, insulinoma or other endogenous hyperinsulinism, a sulfonylurea, insulin autoimmune hypoglycaemia, IGF-2 from a tumour, or a cause not driven by insulin at all.
Why was the glucose low?
Insulin, C-peptide, proinsulin, β-hydroxybutyrate, drug screen → causeA 52-year-old woman has confusion before breakfast. During a supervised fast at 14 hours: glucose 2.4 mmol/L with symptoms relieved by glucose; insulin 9 µU/mL, C-peptide 0.5 nmol/L, proinsulin 22 pmol/L, β-hydroxybutyrate 0.4 mmol/L; sulfonylurea screen negative.
Thresholds during hypoglycaemia (Endocrine Society 2009, recommendation 2.1)
insulin ≥ 3 µU/mL (18 pmol/L), C-peptide ≥ 0.6 ng/mL (0.2 nmol/L), proinsulin ≥ 5 pmol/L → endogenous hyperinsulinism
β-hydroxybutyrate ≤ 2.7 mmol/L and a glucose rise ≥ 25 mg/dL (1.4 mmol/L) after IV glucagon → mediated by insulin (or IGF)
- Whipple’s triad
- symptoms or signs of hypoglycaemia, a low plasma glucose, and their relief when glucose is raised
- C-peptide
- secreted with insulin in equal molar amounts; absent from pharmaceutical insulin
Worked example
A 52-year-old woman has confusion before breakfast. During a supervised fast at 14 hours: glucose 2.4 mmol/L with symptoms relieved by glucose; insulin 9 µU/mL, C-peptide 0.5 nmol/L, proinsulin 22 pmol/L, β-hydroxybutyrate 0.4 mmol/L; sulfonylurea screen negative.
Whipple's triad documented; glucose 2.4 is below 3.0 at the time of sampling
Insulin 9 (3 or more), C-peptide 0.5 (0.2 or more), proinsulin 22 (5 or more): endogenous insulin not suppressed
β-hydroxybutyrate 0.4 (2.7 or less): insulin is acting
Drug screen negative → row 3: endogenous hyperinsulinism; fasting onset favours insulinoma
Table 3 of the Endocrine Society guideline, reconstructed
| Insulin (µU/mL) | C-peptide (nmol/L) | Proinsulin (pmol/L) | β-OHB (mmol/L) | Glucagon rise (mg/dL) | Oral agent | Insulin antibody | Interpretation |
|---|---|---|---|---|---|---|---|
| < 3 | < 0.2 | < 5 | > 2.7 | < 25 | No | No | Normal (no symptoms) |
| ≫ 3 | < 0.2 | < 5 | ≤ 2.7 | > 25 | No | Neg (Pos) | Exogenous insulin |
| ≥ 3 | ≥ 0.2 | ≥ 5 | ≤ 2.7 | > 25 | No | Neg | Insulinoma, NIPHS, PGBH |
| ≥ 3 | ≥ 0.2 | ≥ 5 | ≤ 2.7 | > 25 | Yes | Neg | Oral hypoglycaemic agent |
| ≫ 3 | ≫ 0.2 * | ≫ 5 * | ≤ 2.7 | > 25 | No | Pos | Insulin autoimmune |
| < 3 | < 0.2 | < 5 | ≤ 2.7 | > 25 | No | Neg | IGF † |
| < 3 | < 0.2 | < 5 | > 2.7 | < 25 | No | Neg | Not insulin (or IGF)-mediated |
Why the sample has to be taken during the low
Hypoglycaemia in someone who does not have diabetes is uncommon, and most of the effort in investigating it is spent proving it happened. The Endocrine Society’s 2009 guideline (Cryer et al.) begins there: evaluate only when Whipple’s triad is documented — symptoms, a low glucose measured properly, and relief when the glucose is raised. A meter reading is not enough, and a low fasting glucose with no symptoms can be normal.
The whole diagnosis then rests on one blood sample drawn while the glucose is below 3.0 mmol/L (55 mg/dL). At that glucose a healthy pancreas has switched insulin off, so any insulin that is still there is inappropriate. The guideline’s thresholds — insulin 3 µU/mL, C-peptide 0.2 nmol/L, proinsulin 5 pmol/L and β-hydroxybutyrate 2.7 mmol/L — mean nothing on a sample taken at a normal glucose, or after glucose has been given. If no spontaneous episode can be caught, the guideline recreates the setting with a supervised fast of up to 72 hours, or a mixed meal when symptoms come after eating.
The logic of the table is simple. C-peptide is cut from proinsulin and secreted with insulin molecule for molecule, and it is not in any pharmaceutical insulin; so insulin without C-peptide is injected insulin, and insulin with C-peptide is the patient’s own. A sulfonylurea makes the patient’s own pancreas secrete, so it looks exactly like an insulinoma until the drug screen comes back. Low ketones prove that something insulin-like is acting; when insulin itself is suppressed, that something is IGF-2 from a tumour — or an insulin analogue that the immunoassay does not recognise, which is why the laboratory should be asked before a tumour is sought. The insulin unit converter and the C-peptide unit converter convert units; the C-peptide to insulin molar ratio calculator shows the molar ratio. This interpreter supports, and does not replace, specialist assessment.
Frequently asked questions
What insulin level is inappropriate during hypoglycaemia?
3 µU/mL (18 pmol/L) or more while the plasma glucose is below 55 mg/dL (3.0 mmol/L), with C-peptide 0.6 ng/mL (0.2 nmol/L) or more and proinsulin 5 pmol/L or more, documents endogenous hyperinsulinism in the Endocrine Society 2009 guideline.
How do you tell injected insulin from an insulinoma?
By C-peptide. An insulinoma secretes insulin and C-peptide together; injected insulin contains no C-peptide and suppresses the patient’s own, so insulin is high while C-peptide is below 0.2 nmol/L.
Why does the sample have to be taken during the hypoglycaemia?
Because the thresholds only apply when the glucose is low. At a normal glucose, insulin and C-peptide are expected to be present, so a normal result proves nothing. The guideline measures glucose, insulin, C-peptide, proinsulin and β-hydroxybutyrate, and screens for oral agents, during a spontaneous episode or a supervised fast.
Can a normal insulin level rule out factitious insulin use?
Not always. Insulin immunoassays differ in how well they detect insulin analogues, so an injected analogue can give a low measured insulin with a suppressed C-peptide and low ketones — the pattern the guideline attributes to IGF. Ask the laboratory about its assay.
Related calculators
References
- Cryer PE, Axelrod L, Grossman AB, et al. Evaluation and management of adult hypoglycemic disorders: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2009;94(3):709–728. Recommendations 1.1 and 2.1; Table 3.
Medical Disclaimer: The tools and content provided here are for educational and reference purposes only. They are not intended to substitute for professional medical advice, diagnosis, or treatment. Clinical decisions should always be based on the comprehensive assessment of a qualified healthcare professional.