What are the causes of hypoglycemia?

Causes of Hypoglycemia

Hypoglycemia is primarily caused by medications (insulin, sulfonylureas, and meglitinides), with additional contributions from endocrine disorders, critical illness, kidney disease, and social/nutritional factors. 1, 2

Medication-Related Causes

Insulin therapy is the most common cause of hypoglycemia, particularly with intensive regimens including multiple daily injections, insulin pumps, or automated insulin delivery systems. 1, 2 Rates of hypoglycemia are highest with intensive insulin therapy, followed by basal insulin alone, then sulfonylureas or meglitinides. 1 Combining insulin with sulfonylureas further amplifies hypoglycemia risk. 1

Sulfonylureas and meglitinides cause hypoglycemia by stimulating insulin release from the pancreas, independent of glucose levels. 1, 2 First-generation sulfonylureas carry particularly high risk for prolonged hypoglycemia. 3 Clinically significant hypoglycemia is rare with other diabetes medication classes including GLP-1 receptor agonists, SGLT2 inhibitors, metformin, TZDs, and DPP-4 inhibitors. 1

Clinical and Biological Risk Factors

Major Risk Factors

• Recent severe hypoglycemia (within past 3-6 months) is the strongest predictor of future hypoglycemic events. 1, 2
• Impaired hypoglycemia awareness (reduced ability to perceive warning symptoms) creates a vicious cycle where patients cannot detect and treat falling glucose levels. 1, 2, 4
• End-stage kidney disease causes hypoglycemia through decreased renal gluconeogenesis, impaired insulin clearance, poor nutritional status, and accumulation of uremic toxins. 1, 2, 3
• Cognitive impairment or dementia prevents recognition of and appropriate response to hypoglycemic symptoms. 1, 2
• Intensive insulin therapy with tight glycemic targets (A1C <7%) increases hypoglycemia rates. 1

Other Important Risk Factors

• Advanced age (≥75 years) is associated with reduced counterregulatory hormone responses and highest hypoglycemia risk in type 2 diabetes. 1, 2
• Female sex carries increased risk. 1, 2
• High glycemic variability predisposes to hypoglycemia. 1, 2
• Chronic kidney disease (eGFR <60 mL/min/1.73 m²) reduces renal glucose production and insulin clearance. 1, 2, 3
• Cardiovascular disease, neuropathy, and retinopathy are associated with increased hypoglycemia risk. 1, 2
• Major depressive disorder and severe mental illness contribute to hypoglycemia risk. 1, 2
• Polypharmacy increases risk through drug interactions and medication errors. 1

Endocrine Disorders

Adrenal insufficiency with cortisol deficiency impairs counterregulatory responses to hypoglycemia. 3, 5 Hypopituitarism can cause hypoglycemia through multiple hormone deficiencies. 5

Insulinoma causes hypoglycemia through autonomous insulin secretion; paradoxically, glucagon administration may stimulate exaggerated insulin release from the tumor, worsening hypoglycemia. 6, 5

Glucagon deficiency can contribute to hypoglycemia, particularly in combination with other risk factors. 5

Critical Illness and Hospital-Related Causes

• Interruptions in nutritional intake including NPO status and delayed meals are major contributors to hospital hypoglycemia. 2, 3
• Sepsis causes dysregulated glucose metabolism. 2, 3
• Critical illness alters metabolism and insulin sensitivity. 2, 3
• Acute kidney injury is an important risk factor for in-hospital hypoglycemia. 3
• Low albumin levels affect drug binding and pharmacokinetics. 2, 3
• Changes in medication regimens without appropriate dose adjustments. 2

Social, Cultural, and Economic Risk Factors

• Food insecurity with irregular access to adequate nutrition is a major risk factor. 1, 2
• Low-income status limits resources for proper diabetes management. 1, 2
• Housing insecurity affects medication adherence and meal timing. 1, 2
• Fasting for religious or cultural reasons creates prolonged periods without food intake. 1, 2
• Underinsurance limits access to newer, safer medications and monitoring technologies. 1
• Low health literacy impairs understanding of hypoglycemia prevention and treatment. 1
• Alcohol or substance use disorder is particularly dangerous as alcohol inhibits gluconeogenesis. 1, 2

Rare Causes

Genetic causes include monogenic congenital hyperinsulinism with mutations in glucokinase-activating genes or insulin receptors, and inborn errors of metabolism affecting glycogen synthesis, fatty acid oxidation, or gluconeogenesis. 5

Paraneoplastic hypoglycemia (NICTH) results from Big-IGF2 secretion by large tumors, with characteristically low insulin, C-peptide, and IGF-1 levels. 5

Autoimmune hypoglycemia involves antibodies against insulin (Hirata syndrome, especially with Graves' disease) or against insulin receptors. 5

Post-bariatric surgery hypoglycemia and nesidioblastosis can cause severe postprandial hypoglycemia. 1, 5

Mechanism of Hypoglycemia in Diabetes

The fundamental mechanism is failure of insulin levels to decrease appropriately combined with defective counterregulatory hormone responses (particularly glucagon and epinephrine) as glucose falls. 7, 4 In insulin-deficient diabetes, exogenous insulin levels cannot be regulated by pancreatic feedback, and the combination of deficient glucagon and attenuated epinephrine responses creates defective glucose counterregulation. 4

Hypoglycemia-associated autonomic failure creates a vicious cycle where recent hypoglycemia shifts glycemic thresholds for sympathoadrenal responses to lower glucose concentrations, leading to recurrent hypoglycemia and progressive impairment of glucose counterregulation. 4

Critical Clinical Pitfalls

• Failing to adjust insulin or sulfonylurea doses when kidney function declines is a common and preventable cause of severe hypoglycemia. 3
• Continuing intensive insulin regimens when nutrition is interrupted in hospitalized patients. 3
• Inadequate assessment of hypoglycemia risk at every clinical encounter for patients on high-risk medications. 2
• Lack of self-monitoring of blood glucose is an independent risk factor for severe hypoglycemia requiring medical assistance. 8
• Insufficient patient education about hypoglycemia recognition and treatment, particularly in those with prior episodes. 8