What are the causes of hyperinsulinism?

Causes of Hyperinsulinism

Hyperinsulinism results from either compensatory insulin hypersecretion in response to insulin resistance, reduced hepatic insulin clearance, or primary β-cell dysfunction, with causes ranging from genetic defects and obesity to endocrine disorders, medications, and developmental syndromes. 1

Primary Pathophysiological Mechanisms

The development of hyperinsulinism occurs through two distinct pathways that are critical to understand:

• Compensatory hyperinsulinemia develops when pancreatic β-cells increase insulin secretion to overcome peripheral insulin resistance and maintain normal blood glucose levels 1
• Primary hyperinsulinemia may itself be the initial pathological event, driven by either intrinsic β-cell hypersecretion or reduced hepatic insulin clearance, which subsequently promotes insulin resistance 1
• The relative contribution of β-cell hypersecretion versus impaired hepatic clearance remains debated, though both mechanisms can coexist 1

Genetic and Congenital Causes

Congenital Hyperinsulinism in Infants and Children

• Recessive inactivating mutations in ABCC8 and KCNJ11 (encoding ATP-sensitive K+ channel subunits) are the most common genetic cause of congenital hyperinsulinism, accounting for approximately 50% of cases 2
• Dominant activating mutations in GLUD1 (encoding glutamate dehydrogenase) cause hyperinsulinism-hyperammonemia syndrome 2
• Activating mutations in GCK (encoding glucokinase) lead to dysregulated insulin secretion by lowering the glucose threshold for insulin release 2
• Recessive mutations in HADH (encoding 3-hydroxyacyl-CoA dehydrogenase) cause another form of congenital hyperinsulinism 2
• Dominant mutations in HNF4A and SLC16A1 have been recently identified as causes of hyperinsulinemic hypoglycemia 2

Genetic Defects in Insulin Action (Adults)

• Insulin receptor mutations cause a spectrum ranging from hyperinsulinemia with modest hyperglycemia to severe diabetes, often accompanied by acanthosis nigricans, virilization in women, and enlarged cystic ovaries (formerly termed type A insulin resistance) 3, 1
• Leprechaunism and Rabson-Mendenhall syndrome are severe pediatric syndromes with insulin receptor gene mutations causing extreme insulin resistance; leprechaunism has characteristic facial features and is usually fatal in infancy, while Rabson-Mendenhall involves dental/nail abnormalities and pineal gland hyperplasia 3, 1

Obesity and Metabolic Factors

• Obesity is the most significant acquired cause of insulin resistance with consequent compensatory hyperinsulinemia, characterized by adipocyte hypertrophy, oxidative stress, inflammation, and ectopic fat accumulation in liver and muscle 1
• Abdominal/visceral fat distribution particularly promotes insulin resistance and hyperinsulinemia even in individuals not meeting traditional obesity criteria 1

Endocrine Disorders (Hormone Excess States)

Several counter-regulatory hormones antagonize insulin action, requiring compensatory hyperinsulinemia:

• Acromegaly (excess growth hormone) causes insulin resistance requiring increased insulin secretion 3, 1
• Cushing's syndrome (excess cortisol) antagonizes insulin action systemically 3, 1
• Glucagonoma (excess glucagon) directly opposes insulin effects 3, 1
• Pheochromocytoma (excess catecholamines) impairs insulin action 3, 1
• Somatostatinoma and aldosteronoma can cause hyperinsulinemia through hypokalemia-mediated effects 3

These hormone excess states generally cause hyperinsulinemia in individuals with preexisting defects in insulin secretion, and the condition typically resolves after successful tumor removal 3

Developmental and Overgrowth Syndromes

• Beckwith-Wiedemann syndrome (BWS) is the most common developmental syndrome associated with hyperinsulinism, affecting approximately 50% of children with BWS; hypoglycemia is usually transient and resolves within days but rarely may require pancreatectomy 4
• Soto's syndrome may overlap with BWS and present with hyperinsulinism 4
• Costello, Timothy, and Kabuki syndromes can present with hyperinsulinemic hypoglycemia, though the genetic mechanisms remain unclear 4
• Congenital disorders of glycosylation (CDG), particularly CDG-Ib, are associated with hyperinsulinism due to deficient N-glycosylation of proteins 4

Transient Neonatal Hyperinsulinism

• Perinatal asphyxia can cause transient hyperinsulinism in newborns 5
• Small-for-gestational-age birthweight is associated with transient neonatal hyperinsulinism 5
• Maternal diabetes can lead to transient hyperinsulinism in infants 5
• Intrauterine growth retardation and prematurity may result in prolonged neonatal hypoglycemia due to hyperinsulinism 6

Pancreatic Lesions

• Islet cell adenoma or carcinoma (insulinoma) causes autonomous insulin secretion independent of glucose levels 7
• Extrapancreatic malignancy can be associated with hyperinsulinism 7
• Focal hyperinsulinism represents localized adenomatous hyperplasia that is sporadic in inheritance and potentially curable with limited pancreatectomy 2
• Diffuse islet cell hyperplasia/nesidioblastosis involves diffuse β-cell dysfunction and may require near-total pancreatectomy 2

Autoimmune Causes

• Anti-insulin receptor antibodies can paradoxically act as insulin agonists after binding to the receptor, causing hypoglycemia and hyperinsulinemia; these are occasionally found in systemic lupus erythematosus and other autoimmune diseases (formerly termed type B insulin resistance) 3

Population-Specific Considerations

• Black African populations demonstrate characteristically higher insulin secretion and lower insulin clearance compared to White Europeans, independent of adiposity differences, presenting with hyperinsulinemia even at normal glucose tolerance 3, 1
• This phenotype is observed in both indigenous and diasporic Black African adults and children, suggesting it is a highly conserved trait that may contribute to increased risk of type 2 diabetes 3, 1

Drug-Induced Hyperinsulinism

• Sulfonylureas and other insulin secretagogues directly stimulate β-cell insulin secretion 6
• Various medications can impair insulin action, requiring compensatory hyperinsulinemia, though specific agents are not detailed in the provided guidelines 3

Critical Clinical Pitfalls

• Hyperinsulinism is the most common cause of hypoglycemia in early infancy and requires prompt, aggressive treatment to prevent permanent brain damage 5, 8
• Genetic testing has rapid turnaround and combined with advanced imaging can identify surgically-curable focal lesions, but these resources are only available in certain developed centers 8
• Diazoxide remains the only FDA-approved medication for hyperinsulinism management but is unavailable in many under-developed regions despite WHO designation as an "essential medicine" 7, 8
• Mimickers of hyperinsulinism include neonatal panhypopituitarism, drug-induced hypoglycemia, and insulin-receptor stimulating antibodies, requiring careful diagnostic evaluation 6