Severe Insulin Resistance: Diagnosis and Management

Insulin resistance is an endocrine disorder associated with various diseases, including diabetes, metabolic syndrome, cardiovascular diseases, and cancer. However, severe insulin resistance differs significantly from common insulin resistance regarding the causes and treatment approaches. Severe insulin resistance is a group of rare disorders characterized by hyperglycemia and hyperinsulinemia, with or without hypoglycemia, along with various metabolic abnormalities and diverse clinical manifestations. Owing to their rarity and complexity, these conditions can be easily misdiagnosed as common diabetes and are often overlooked. Severe insulin resistance is typically reported in individual case studies, lacking comprehensive summaries. This article provides a detailed overview of the different types of severe insulin resistance based on the specific sites of insulin signaling defects. It includes pre-receptor signaling defects, such as insulin autoimmune syndrome, which results from insulin autoantibodies; receptor-level insulin resistance syndromes, including type A and type B insulin resistance syndromes; and post-receptor signaling defects, such as lipodystrophy syndrome. We describe the causes, clinical symptoms, diagnosis, and treatment of extreme insulin resistance and differentiate between these diseases. In this review, we aim to assist physicians in identifying the causes of severe insulin resistance early and in providing individualized treatment for patients, ultimately improving clinical outcomes.