Hyperinsulinism due to INSR deficiency

Hyperinsulinism due to INSR deficiency is an extremely rare genetic condition caused by mutations in the INSR gene, which encodes the insulin receptor. This disorder is characterized by a paradoxical combination of insulin resistance and hyperinsulinism. Because the insulin receptor does not function properly, the body's cells cannot respond adequately to insulin, leading to compensatory overproduction of insulin by the pancreatic beta cells. Despite elevated insulin levels, patients may experience both hyperglycemia (due to insulin resistance) and episodes of hypoglycemia, which can occur when the markedly elevated insulin levels intermittently overcome the receptor defect or act through alternative pathways. The condition primarily affects the endocrine and metabolic systems. Clinical features can include fasting or postprandial hypoglycemia, failure to thrive, and signs of insulin resistance such as acanthosis nigricans (darkened, thickened skin patches, particularly in skin folds). Affected individuals may also demonstrate features overlapping with other insulin receptor-related disorders such as Donohue syndrome (leprechaunism) or Rabson-Mendenhall syndrome, depending on the severity of the receptor defect. Growth abnormalities and metabolic disturbances are common. Management of this condition is challenging and largely supportive. Treatment strategies focus on managing blood glucose levels and may include dietary modifications, glucose monitoring, and pharmacological interventions to address both hypoglycemia and hyperglycemia. In some cases, agents such as recombinant IGF-1 (mecasermin) have been used to help bypass the defective insulin signaling pathway. Given the rarity of this condition, management is typically guided by specialized metabolic and endocrine centers with experience in congenital hyperinsulinism and severe insulin resistance syndromes.

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