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Autoimmune Hypoglycemia - Types, Causes, Symptoms, Diagnosis, and Treatment

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Autoimmune hypoglycemia is a rare genetic condition causing low blood sugar. Read the article to know more about the condition.

Written by

Dr. Vennela. T

Medically reviewed by

Dr. Raveendran S R

Published At July 24, 2023
Reviewed AtJuly 31, 2023


Autoimmune hypoglycemia is a rare disorder resulting in low blood sugar. This happens because the body starts producing a certain kind of protein known as antibodies that target insulin. The hormone insulin, which is present in all living things, regulates blood sugar levels. Insulin assists in storing sugar for later use when blood sugar levels get uncontrollably high. Antibodies attack insulin in people with autoimmune insulin syndrome, which makes it work harder than it should and lowers blood sugar levels. The autoimmune insulin syndrome typically manifests in adulthood. This disorder is also known as autoimmune insulin syndrome.

What Are the Types of Autoimmune Hypoglycemia?

When misdiagnosed, autoimmune forms of hypoglycemia, a rare cause of low blood sugar in Caucasians, can subject patients to a prolonged sequence of fruitless, sometimes hazardous, and expensive testing. Atherosclerotic hypoglycemia comes in two different forms:

  • Insulin Autoimmune Syndrome (IAS) is defined by pancreatic islets' pathological abnormalities, high insulin autoantibody (IAA) titers, and hyperinsulinemic hypoglycemia without prior exposure to exogenous insulin. ‘Hirata's disease’ is another name for this ailment.

  • Type B Insulin Resistance Syndrome (TBIRS) is a rare autoimmune condition induced by the presence of insulin receptor autoantibodies that results in a wide range of problems in glucose homeostasis, from hypoglycemia to severely insulin-resistant hyperglycemia (IRAbs).

What Are the Causes of Autoimmune Hypoglycemia?

The causes of autoimmune hypoglycemia are:

  • Insulin Autoimmune Syndrome - It is unclear what causes IAS. The disulfide link in the insulin molecule interacts with medications in the sulfhydryl group, such as Methimazole, Carbimazole, Captopril, Isoniazid, Hydralazine, Imipenem, and Lipoic acid. Insulin autoantibodies that arise a few weeks after ingesting a medication are indications of drug-induced auto-immunization. The link between IAS and a specific HLA class indicates that IAS has a substantial genetic susceptibility.

  • Type B Insulin Resistance Syndrome - Polyclonal autoantibodies against the insulin receptor, typically immunoglobulins of the IgG class, are the primary cause of TBIRS.

What Are the Symptoms of Autoimmune Hypoglycemia?

The symptoms of autoimmune hypoglycemia are

  1. Insulin Autoimmune Syndrome:

    • Autoimmune Antibody Positivity - An antibody that is present in the bloodstream that is directed against an organism's cells or tissues.

    • Systemic Lupus Erythematosus - A multisystemic, relapsing, chronic, inflammatory, and frequently febrile condition of connective tissue, mainly affecting the skin, joints, kidneys, and serosal membranes.

    • Acanthosis Nigricans - A dermatosis that often affects the neck and intertriginous surfaces and is characterized by thicker, hyperpigmented plaques.

    • Arthralgia or Arthritis - Inflammation of joints.

    • Autoimmunity - The manifestation of an immune response directed against an organism's cells or tissues.

    • Fasting Hypoglycemia - Low blood sugar in fasting.

    • Weight loss.

  2. Type B insulin resistance syndrome (TBIRS) - The following are typical signs of type B insulin resistance:

    • Diabetes develops suddenly and is difficult to control, even with very high insulin dosages.

    • Skin darkening, particularly on the face, under the arms, and in the groin area.

    • Loss of weight despite an increase in hunger.

    • High testosterone levels, irregular or no periods, and increased hair growth are possible in women. In the early stages of the disease, type B Insulin resistance patients may experience low blood sugar levels, but this is uncommon. Low blood sugar levels typically happen after type B Insulin resistance improves.

How Does Autoimmune Hypoglycemia Occur?

  • Insulin Autoimmune Syndrome - The bloodstream's glucose concentration increases, stimulating insulin release after meals. These insulin molecules are bound by autoantibodies, preventing them from acting as intended. Hyperglycemia encourages more insulin release, resulting in a drop in overall insulin levels. Now that the autoantibodies have separated, hypoglycemia results from an increase in free insulin that is inadequate for a glucose level.

  • Type B Insulin Resistance Syndrome - TBIRS is a rare syndrome characterized by acquired antagonistic autoantibodies to the insulin receptor. The effects of TBIRS are quantitatively most prominent in skeletal muscle, liver, and adipose tissue. The clinical course of the condition, which includes severe hyperglycemia and hypoglycemia, can be explained by the biphasic action of IRAbs. A rapid onset, transient insulin-mimetic activity was observed in 3T3-L1 adipocyte cultures; however, as time passes, this response subsides, and adipocytes develop insulin resistance. In vivo, a similar biphasic reaction was shown in IRAb-injected rats. While the antibodies initially caused hypoglycemia (which occurred within 2 to 4 hours and lasted 8 to 24 hours), long-term administration led to insulin resistance and hyperglycemia. When antibodies were administered in high concentrations, the antagonistic effect (insulin resistance) took control, but in low concentrations, the agonistic impact (insulin-mimetic action) took control.

How Is Autoimmune Hypoglycemia Diagnosed?

Autoimmune hypoglycemia is diagnosed based on the following parameters.

  1. Insulin Autoimmune Syndrome:

    • Multiple episodes of spontaneous hypoglycemia.

    • The development of insulin autoantibodies without a prior history of exogenous insulin treatment.

    • The C-peptide level is noticeably increased.

    • The insulin antibodies are positive.

    • The insulin level is extremely high, typically up to 100 mIU/L.

  2. Type B Insulin Resistance Syndrome: Type B Insulin resistance is suspected even though there is no specific diagnostic test for it if a person has:

  • Extremely high fasting insulin levels.
  • High levels of adiponectin.

  • Low or normal triglyceride levels.

  • Darkening of the skin in a person with a known autoimmune illness.

How Is Autoimmune Hypoglycemia Treated?

The treatment for autoimmune hypoglycemia includes:

  1. Insulin Autoimmune Syndrome:

    • The most well-known remedy is to encourage eating frequently and in small amounts while avoiding simple sweets.

    • Drugs with sulfhydryl groups should be avoided, and steroids can be used in cases of resistance.

    • A glucosidase inhibitor called acarbose is used to treat reactive idiopathic postprandial hyperinsulinemic hypoglycemia episodes because it can slow the absorption of carbohydrates.

    • Plasmapheresis - To treat hypoglycemia symptoms and more quickly reduce IAA titers, plasmapheresis has been routinely employed, either by itself or in combination with corticosteroids in more severe patients. Particularly helpful when glucocorticoids are contraindicated is plasmapheresis alone.

  2. Type B Insulin Resistance Syndrome - Eliminating the antibody that prevents insulin from functioning correctly is the aim of treatment for type B insulin resistance. Treating underlying lupus or lupus-like autoimmune illness is required to achieve this.

    • Diabetes treatment for type B Insulin resistance usually involves Insulin injections. Since most of those with this syndrome do not respond well to Insulin, high insulin dosages are required for treatment. Patients may need to inject 10 to 20 times more frequently than is normal for most diabetics. Other diabetes drugs, including the tablet Metformin, which enhances the body's reaction to Insulin, may also be recommended.

    • In patients with type B Insulin resistance, the following treatment plans address the underlying autoimmune disease:

      • Rituximab - Two intravenous injections spaced by two weeks.

      • Dexamethasone - Until remission, four days of Dexamethasone every four weeks.

      • Cyclophosphamide - Daily pill intake of Cyclophosphamide until in remission.

      • Azathioprine - After remission, one tablet of Azathioprine daily for roughly six months.


In conclusion, diagnosing hypoglycemia in a diabetic patient on insulin requires careful consideration and a step-by-step process; simply adjusting the insulin dose to prevent hypoglycemia may not be sufficient. On the other hand, a proper diagnosis might prevent abdominal examination and unnecessary investigations. Most instances are self-limiting, but a small number of complex cases may necessitate dietary changes, corticosteroids, or steroid-sparing immunosuppressants.

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Dr. Raveendran S R
Dr. Raveendran S R



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