What are the causes of hypoglycemia?

Causes of Hypoglycemia

Hypoglycemia is primarily caused by medications (insulin, sulfonylureas, meglitinides), endocrine disorders (adrenal insufficiency), critical illness, kidney disease, and nutritional factors, with medication-related causes being the most common in clinical practice. 1, 2

Medication-Related Causes

Insulin therapy is the leading cause of hypoglycemia, particularly with intensive regimens involving multiple daily injections, continuous subcutaneous insulin infusion, or automated insulin delivery systems. 1, 2 The risk is highest with intensive insulin therapy, followed by basal insulin regimens. 1

Sulfonylureas and meglitinides stimulate pancreatic insulin release and carry significant hypoglycemia risk, especially first-generation sulfonylureas which can cause prolonged episodes. 1, 3 Combining insulin with sulfonylureas further amplifies this risk. 1

Other medications that can precipitate hypoglycemia in non-diabetic individuals include quinine, quinolones, pentamidine, and certain antibiotics. 4

Clinical and Biological Risk Factors

Major Risk Factors

• Recent severe hypoglycemia (within the past 3-6 months) is the strongest predictor of future hypoglycemic events. 1, 2
• Impaired hypoglycemia awareness—the reduced ability to perceive warning symptoms—creates a dangerous cycle where patients cannot detect falling glucose levels. 1, 2, 5
• End-stage kidney disease dramatically increases risk through multiple mechanisms: decreased renal gluconeogenesis, impaired insulin clearance, poor nutritional status, and accumulation of uremic toxins affecting glucose metabolism. 1, 2, 3
• Cognitive impairment or dementia prevents patients from recognizing or appropriately responding to hypoglycemic symptoms. 1, 2
• Intensive insulin therapy creates the highest risk category among all treatment modalities. 1

Other Clinical Risk Factors

• Advanced age (≥75 years) is associated with reduced counterregulatory hormone responses, making elderly patients particularly vulnerable. 1, 2, 3
• Female sex carries increased risk compared to males. 1, 2
• High glycemic variability predisposes to unpredictable glucose fluctuations. 1, 2
• Chronic kidney disease (eGFR <60 mL/min/1.73 m² or albuminuria) reduces renal glucose production capacity. 1, 2
• Cardiovascular disease, neuropathy, and retinopathy are all independent risk factors. 1, 2
• Major depressive disorder and severe mental illness increase hypoglycemia risk. 1, 2

Endocrine Disorders

Adrenal insufficiency with cortisol deficiency critically impairs counterregulatory responses to falling glucose levels, as cortisol is essential for maintaining blood glucose during stress. 3, 4, 6

Hypopituitarism can cause hypoglycemia through multiple hormone deficiencies affecting glucose homeostasis. 6

Social, Cultural, and Economic Risk Factors

• Food insecurity creates irregular access to adequate nutrition, leading to unpredictable glucose patterns. 1, 2
• Low-income status limits resources for proper diabetes management, medication adherence, and consistent meal timing. 1, 2
• Housing insecurity disrupts stable living conditions necessary for medication adherence and regular meals. 1, 2
• Fasting for religious or cultural reasons creates prolonged periods without food intake while medications continue to act. 1, 2, 3
• Alcohol or substance use disorder is particularly dangerous because alcohol directly inhibits hepatic gluconeogenesis. 1, 2
• Low health literacy impairs patients' ability to understand and manage their condition. 1

Hospital-Specific Risk Factors

• Interruptions in nutritional intake including NPO status and delayed meals are common precipitants in hospitalized patients. 2, 3
• Changes in medication regimens with new drugs or altered dosing without corresponding nutritional adjustments. 2
• Critical illness causes altered metabolism and dysregulated glucose homeostasis. 2, 3
• Sepsis produces severely dysregulated glucose metabolism. 2, 3
• Low albumin levels alter drug binding and pharmacokinetics, potentially increasing free drug concentrations. 2, 3
• Acute kidney injury is an important and often overlooked risk factor for in-hospital hypoglycemia. 3

Rare Causes

Insulinoma is the most common hormone-secreting islet cell tumor, though rare overall, characterized by hypoglycemia with inappropriately elevated insulin and C-peptide levels. 6, 7

Genetic causes include monogenic congenital hyperinsulinism (glucokinase-activating gene mutations, insulin receptor mutations), inborn errors of metabolism (glycogen storage disorders types 0, I, III), fatty acid oxidation disorders, and gluconeogenesis defects. 6

Non-islet cell tumor hypoglycemia (NICTH) results from Big-IGF2 secretion by large tumors, presenting with low insulin, C-peptide, and IGF-1 levels. 6

Autoimmune causes involve antibodies against insulin (Hirata syndrome, especially with Graves' disease) or against the insulin receptor. 6

Post-bariatric surgery hypoglycemia occurs due to altered gastric anatomy and exaggerated insulin responses. 1, 6

Critical Pitfalls to Avoid

Failing to adjust insulin doses in patients with declining kidney function is a common and dangerous error, as renal clearance of insulin decreases progressively. 3

Continuing unchanged insulin regimens when nutrition is interrupted in hospitalized patients leads to predictable hypoglycemia. 3

Misdiagnosing hypoglycemia as hyperglycemia can be fatal—any person with diabetes on anti-diabetic medication who behaves oddly should be assumed hypoglycemic until proven otherwise. 8, 9

Underestimating risk in elderly patients who often have blunted symptoms and may not manifest typical warning signs. 4