OVERVIEW

What is autoimmune hypoglycemia?

Autoimmune hypoglycemia was first reported by Japanese scholars and is a rare disease. It is one of the important causes of hypoglycemia. Its typical manifestation is recurrent fasting or postprandial hypoglycemia, and blood tests reveal inappropriately elevated insulin levels.

What are the types of autoimmune hypoglycemia?

Autoimmune hypoglycemia is divided into two types:

• The first is autoimmune hypoglycemia caused by insulin antibodies, also known as insulin autoimmune syndrome.

This occurs when the body produces insulin autoantibodies, which can bind excessively to endogenous insulin, interfering with its normal function.

For example, after eating, blood sugar rises, prompting the body to secrete large amounts of insulin. However, insulin autoantibodies quickly bind to this insulin, preventing it from lowering blood sugar. As a result, blood sugar remains significantly elevated, further stimulating the body to secrete even more insulin, leading to a large amount of insulin bound to antibodies in the blood.

Later, as postprandial blood sugar levels gradually decrease, insulin secretion drops significantly. At this point, the insulin-insulin autoantibody complexes begin to dissociate, releasing large amounts of insulin, which then starts to lower blood sugar. However, since blood sugar is already low at this stage, the untimely release of insulin causes hypoglycemia.

• The second type is autoimmune hypoglycemia caused by insulin receptor antibodies, also known as type B insulin resistance syndrome.

This occurs when the body produces insulin receptor antibodies, which can have varying effects when binding to insulin. When antibody levels are low, they exhibit a stimulatory effect, significantly enhancing insulin's blood sugar-lowering action and causing hypoglycemia. When antibody levels are high, they exhibit an inhibitory effect, greatly weakening insulin's ability to lower blood sugar, leading to hyperglycemia.

Is autoimmune hypoglycemia common?

Autoimmune hypoglycemia is uncommon and is considered a rare disease.

SYMPTOMS

What are the common manifestations of autoimmune hypoglycemia?

Patients with autoimmune hypoglycemia often seek medical attention due to recurrent episodes of low blood sugar.

During an episode, blood sugar levels typically drop below 2.8 mmol/L. Initially, symptoms may include headache, anxiety, and hunger. As blood sugar continues to decline, symptoms progress to sweating, tremors, palpitations, fatigue, and pale skin. If blood sugar drops further, it can lead to hypoglycemic shock or coma.

Hypoglycemia can occur during fasting or after meals. Some patients experience irregular timing of hypoglycemic episodes, particularly those with a long disease course or older age, and may present with asymptomatic hypoglycemia, where coma is the first noticeable symptom.

What serious consequences can autoimmune hypoglycemia cause?

If severe hypoglycemia is not promptly detected or treated, it can lead to brain damage in mild cases or even death in severe cases.

CAUSES

What are the causes of autoimmune hypoglycemia?

The onset of autoimmune hypoglycemia is related to genetics, autoimmune defects, drug use, and other factors.

Among drug-induced autoimmune hypoglycemia, methimazole is the most common, while hydralazine, penicillin G, glutathione, lipoic acid, captopril, propylthiouracil, pyrithioxine, carbimazole, and others have also been reported.

These drugs can alter the structure of insulin in the body, triggering an autoimmune response that produces insulin autoantibodies and induces autoimmune hypoglycemia.

Who is more likely to develop autoimmune hypoglycemia?

• Autoimmune hypoglycemia caused by insulin antibodies (insulin autoimmune syndrome) is relatively more common in Japan. Most patients are over 40 years old, with the peak incidence occurring between 60 and 69 years, and no gender difference. The total number of cases in China is relatively low.

Individuals with autoimmune diseases (such as Graves' disease, systemic lupus erythematosus, acanthosis nigricans, autoimmune hepatitis, autoimmune thyroiditis, etc.) have a higher incidence. Those taking certain medications (e.g., methimazole) also face an increased risk.

• Autoimmune hypoglycemia caused by insulin receptor antibodies (type B insulin resistance syndrome) is more common in middle-aged Black women of African or Caribbean descent. Individuals with autoimmune diseases (e.g., systemic lupus erythematosus) or malignancies (e.g., multiple myeloma, Hodgkin's disease) have a higher likelihood of developing it. Anti-HIV therapy and interferon-α treatment for hepatitis C can also trigger this condition.

Is autoimmune hypoglycemia contagious?

No, it is not contagious.

Is autoimmune hypoglycemia hereditary?

It has a certain degree of heritability. Autoimmune hypoglycemia may be associated with human leukocyte antigens and can be passed on to offspring, but they may not necessarily develop the condition.

DIAGNOSIS

How is autoimmune hypoglycemia diagnosed?

The presence of typical hypoglycemic symptoms, including headache, anxiety, hunger, sweating, tremors, palpitations, fatigue, pale skin, shock, or coma; blood glucose levels < 2.8 mmol/L during episodes; detection of highly active insulin autoantibodies or insulin receptor antibodies in the blood; elevated insulin levels in the blood; and exclusion of insulinoma or other causes of hypoglycemia can confirm the diagnosis.

What tests are needed to diagnose autoimmune hypoglycemia?

• Blood glucose: To confirm the occurrence of hypoglycemia.

• Insulin autoantibodies and insulin receptor antibodies: A positive antibody test is a key diagnostic criterion.

• Blood insulin levels and C-peptide levels: Inappropriately elevated insulin levels are a critical diagnostic indicator. Patients often have insulin levels > 100 mU/L. When insulin levels exceed 1,000 mU/L, autoimmune hypoglycemia caused by insulin autoantibodies should be highly suspected. In such cases, C-peptide levels are also elevated but significantly lower than insulin levels, known as the "dissociation phenomenon" (in healthy individuals, insulin and C-peptide levels are proportional).

• Autoantibodies: To assess the presence of other concurrent autoimmune diseases.

Which diseases can autoimmune hypoglycemia be confused with, and how to differentiate them?

• Insulinoma: Both conditions can cause hypoglycemia and significantly elevated insulin levels. However, hypoglycemia in insulinoma typically occurs during fasting, serum insulin levels rarely exceed 10 times the normal range, and pancreatic thin-slice CT may reveal a mass.

• Impaired glucose tolerance (prediabetes): Autoimmune hypoglycemia can also present with hyperglycemia and glycosuria. Prediabetic patients exhibit delayed insulin release, resembling the delayed reactive hypoglycemia of autoimmune hypoglycemia, leading to confusion. However, prediabetic patients have normal baseline insulin levels, proportional C-peptide and insulin levels, negative insulin autoantibodies and insulin receptor antibodies, often a family history of diabetes, and are frequently overweight or obese, distinguishing them from autoimmune hypoglycemia.

• Insulin antibodies: Patients who have received exogenous insulin therapy may develop insulin antibodies, which can also cause hypoglycemia, requiring differentiation from autoimmune hypoglycemia. However, insulin antibodies induced by exogenous insulin are typically lower in concentration, mainly causing recurrent nocturnal and early morning hypoglycemia with normal or elevated postprandial blood glucose.

TREATMENT

Which department should I visit for autoimmune hypoglycemia?

Endocrinology, General Internal Medicine.

Can autoimmune hypoglycemia resolve on its own?

Autoimmune hypoglycemia caused by insulin autoantibodies, also known as insulin autoimmune syndrome, resolves spontaneously in 80% of patients within 1–3 months.

However, autoimmune hypoglycemia caused by insulin receptor antibodies (Type B insulin resistance syndrome) does not resolve on its own. It is often difficult to treat and has a high mortality rate. The transition from hyperglycemia to hypoglycemia indicates a poor prognosis.

How is autoimmune hypoglycemia treated?

1. Correcting hypoglycemia:

• During an episode of autoimmune hypoglycemia, prompt correction of low blood sugar is necessary. This may involve intravenous glucose infusion or intramuscular glucagon injection. Severe or recurrent hypoglycemic coma may require glucocorticoids, immunosuppressants, or plasmapheresis.

2. Treatment for insulin autoimmune syndrome (autoimmune hypoglycemia caused by insulin autoantibodies):

• Small, frequent meals with low sugar, high protein, and high fiber are recommended.
• If triggered by medications (e.g., methimazole or thiol-containing drugs), discontinuation of the drug usually leads to gradual reduction and eventual disappearance of hypoglycemic episodes within months. Reuse of the drug can trigger recurrence, so it must be avoided.
• Alpha-glucosidase inhibitors (e.g., acarbose) can slow glucose absorption, reducing insulin secretion and alleviating postprandial hypoglycemia.
• For rare cases with prolonged symptoms, low-dose glucocorticoids (30 mg/day) may help accelerate recovery.

3. Treatment for Type B insulin resistance syndrome (autoimmune hypoglycemia caused by insulin receptor antibodies):

• Treatment is more challenging, with a high mortality rate. For details, refer to "Type B Insulin Resistance Syndrome."

Does autoimmune hypoglycemia require hospitalization?

Episodes of autoimmune hypoglycemia are often severe, requiring hospitalization for observation and treatment.

Can autoimmune hypoglycemia be cured?

Autoimmune hypoglycemia caused by insulin autoantibodies resolves spontaneously in 80% of patients within 1–3 months. However, cases caused by insulin receptor antibodies cannot be cured and have a poor prognosis.

DIET & LIFESTYLE

What should patients with autoimmune hypoglycemia pay attention to in their diet?

The diet should emphasize small, frequent meals that are low in sugar, high in protein, and high in fiber. This helps slow the rate and extent of postprandial insulin rise, reducing the occurrence of hypoglycemia.

PREVENTION

Can autoimmune hypoglycemia be prevented?

There are currently no effective preventive measures.

How to prevent recurrence of autoimmune hypoglycemia?

For those with identified triggers, such as a clear history of drug-induced episodes, reusing the same medication may trigger the condition again. Therefore, such medications must be avoided.