Hyperinsulinemic Euglycemia – Definition & Causes

What is Hyperinsulinemic Euglycemia?

Hyperinsulinemic euglycemia (HE) is a metabolic condition characterized by elevated levels of insulin in the blood (hyperinsulinemia) while blood glucose remains within the normal range (euglycemia; from Greek “eu” = normal, “glykos” = sugar). Although this may initially appear harmless, it can indicate serious metabolic disorders or dangerous drug side effects.

The condition is particularly well-known in the context of hyperinsulinemic euglycemic diabetic ketoacidosis (HE-DKA), a rare but serious adverse effect of SGLT2 inhibitors (gliflozins). In this scenario, blood glucose may remain near-normal despite a life-threatening acidification of the blood (ketoacidosis), making prompt diagnosis especially challenging.

Causes

Hyperinsulinemic euglycemia can arise from several different causes:

• SGLT2 Inhibitors (Gliflozins): Medications such as empagliflozin, dapagliflozin, and canagliflozin can trigger euglycemic ketoacidosis, in which insulin is elevated while blood glucose appears normal.
• Insulinoma: A benign tumor of the pancreas that autonomously secretes insulin, leading to chronically elevated insulin levels with normal or low blood glucose.
• Insulin Resistance and Metabolic Syndrome: The pancreas compensates for reduced insulin sensitivity by producing more insulin, maintaining normal blood glucose – a hallmark of early-stage type 2 diabetes risk.
• Exogenous Insulin Administration: Excessive insulin dosing in diabetic patients can transiently cause hyperinsulinemia before blood glucose drops.
• Nesidioblastosis: A rare condition involving excessive insulin secretion from pancreatic beta cells.

Symptoms

The symptoms of hyperinsulinemic euglycemia vary depending on the underlying cause and severity. Because blood glucose remains normal initially, classic hypoglycemic symptoms are often absent or delayed:

• Fatigue and general malaise
• Nausea and vomiting
• Abdominal pain
• Rapid or deep breathing (Kussmaul respiration in the case of ketoacidosis)
• Confusion or altered consciousness (in severe cases)
• Weight gain (in chronic hyperinsulinemia due to insulin resistance)

In the case of euglycemic ketoacidosis, symptoms can be particularly deceptive since the absence of markedly elevated blood glucose removes a key warning signal.

Diagnosis

Diagnosing hyperinsulinemic euglycemia requires targeted laboratory investigations, as normal blood glucose values do not provide a direct indication:

• Serum Insulin Levels: Detection of elevated fasting insulin concentrations (fasting levels above 25 mIU/L are considered indicative)
• C-Peptide Measurement: Differentiates between endogenous (body-produced) and exogenous (externally administered) insulin
• Blood Gas Analysis: Identifies metabolic acidosis when euglycemic ketoacidosis is suspected
• Blood or Urine Ketone Bodies: Elevated ketone levels confirm ketoacidosis
• Imaging: Ultrasound or MRI of the pancreas when an insulinoma is suspected
• 72-Hour Fasting Test: The standard diagnostic test for insulinoma, conducted under close medical supervision

Treatment

Treatment is directed at the underlying cause:

For Euglycemic Ketoacidosis (HE-DKA)

• Immediate hospital admission and intensive medical monitoring
• Discontinuation of the SGLT2 inhibitor
• Intravenous glucose and fluid administration to correct ketoacidosis
• Insulin therapy as directed by a physician to suppress ketone body production

For Insulinoma

• Surgical resection of the tumor as the preferred treatment approach
• Medical management with diazoxide to inhibit insulin secretion as a bridge to surgery

For Insulin Resistance / Metabolic Syndrome

• Lifestyle modifications: a balanced diet, regular physical activity, and weight reduction
• Pharmacological therapy with metformin or other insulin-sensitizing agents

Clinical Relevance and Risks

Hyperinsulinemic euglycemia holds particular clinical significance because normal blood glucose can mask a serious underlying metabolic crisis. In the context of SGLT2 inhibitor-associated euglycemic ketoacidosis, risk is especially elevated in patients who:

• Undergo caloric restriction or prolonged fasting
• Are scheduled for or recovering from surgery
• Consume excessive amounts of alcohol
• Follow low-carbohydrate or ketogenic diets
• Have type 1 diabetes and use SGLT2 inhibitors off-label

Patients taking SGLT2 inhibitors should inform their treating physician and discontinue the medication in advance of planned surgical procedures, in accordance with current clinical guidelines.

References

1. Handelsman Y. et al. - American Association of Clinical Endocrinologists and American College of Endocrinology Position Statement on the Association of SGLT-2 Inhibitors and Diabetic Ketoacidosis. Endocrine Practice, 2016.
2. Danne T. et al. - International Consensus on Risk Management of Diabetic Ketoacidosis in Patients With Type 1 Diabetes Treated With Sodium-Glucose Cotransporter (SGLT) Inhibitors. Diabetes Care, 2019.
3. Cryer P.E., Axelrod L., Grossman A.B. et al. - Evaluation and Management of Adult Hypoglycemic Disorders. Journal of Clinical Endocrinology & Metabolism, 2009.