Autoimmune Conditions That Cause Hypoglycemia
The primary autoimmune conditions causing hypoglycemia are insulin autoimmune syndrome (Hirata disease) and anti-insulin receptor antibody syndrome, with insulin autoimmune syndrome being the most common autoimmune cause of hypoglycemia. 1, 2
Direct Autoimmune Causes of Hypoglycemia
Insulin Autoimmune Syndrome (Hirata Disease)
- This condition involves autoantibodies against insulin itself, leading to recurrent hypoglycemia predominantly in the postprandial period 3, 2
- The antibodies bind to endogenous insulin after meals, then release it unpredictably, causing delayed hypoglycemic episodes 3
- Often associated with other autoimmune diseases, particularly Graves' disease 2
- Diagnosis requires demonstrating elevated insulin antibodies with high insulin and C-peptide levels during hypoglycemic episodes 3, 2
Anti-Insulin Receptor Antibody Syndrome
- Antibodies against the insulin receptor can mimic insulin action, causing fasting hypoglycemia 1, 2
- This represents a distinct mechanism where receptor antibodies directly stimulate insulin signaling 1
- Blood levels show low insulin and C-peptide during hypoglycemia, distinguishing it from insulin autoimmune syndrome 2
Indirect Autoimmune Associations
Type 1 Diabetes-Related Hypoglycemia
While type 1 diabetes itself causes hyperglycemia, patients with type 1 diabetes are prone to other autoimmune conditions that can complicate glucose management:
- Addison's disease (autoimmune adrenal insufficiency) causes cortisol deficiency, which increases hypoglycemia risk 2
- Autoimmune hypopituitarism leads to cortisol and growth hormone deficiency, predisposing to hypoglycemia 2
- Autoimmune thyroid disease (Hashimoto's thyroiditis with hypothyroidism) may increase symptomatic hypoglycemia risk 4
- Celiac disease can affect glucose absorption patterns 4
These conditions cluster together: patients with type 1 diabetes have increased risk of Hashimoto's thyroiditis, Graves' disease, Addison's disease, celiac disease, vitiligo, autoimmune hepatitis, myasthenia gravis, and pernicious anemia 4
Diagnostic Approach
When evaluating unexplained hypoglycemia, measure insulin, C-peptide, and insulin antibodies during a documented hypoglycemic episode 3, 2:
- Insulin autoimmune syndrome: High insulin, high C-peptide, positive insulin antibodies 3, 2
- Anti-insulin receptor antibodies: Low insulin, low C-peptide, positive insulin receptor antibodies 1, 2
- Cortisol deficiency: Low cortisol with appropriate ACTH response testing 2
Screen for associated autoimmune conditions when autoimmune hypoglycemia is identified, as these disorders commonly coexist 1
Clinical Pitfalls
- Do not confuse insulin autoimmune syndrome with insulinoma—the 75-gram oral glucose tolerance test shows a characteristic pattern in insulin autoimmune syndrome that can prevent unnecessary surgical intervention 3
- Insulin autoimmune syndrome often resolves spontaneously within 2-3 months with dietary management (small frequent meals, low carbohydrate), so avoid aggressive interventions 3
- Consider paraneoplastic causes (Big-IGF2 secretion) in the differential, though these are non-autoimmune 2