What are the causes of hypoglycemia in diabetic and non-diabetic patients?

Causes of Hypoglycemia

Hypoglycemia in both diabetic and non-diabetic patients stems from medication-induced insulin excess, impaired glucose counterregulation, critical illness, endocrine disorders, and nutritional factors, with insulin therapy being the single most common cause in diabetic patients. 1, 2

Medication-Related Causes (Most Common in Diabetes)

Insulin Therapy

• Insulin is the most frequent cause of hypoglycemia, particularly with intensive regimens including multiple daily injections, continuous subcutaneous insulin infusion, or automated insulin delivery systems 1, 3, 2
• Exogenous insulin lacks pancreatic regulation and cannot decrease appropriately as glucose falls, creating absolute insulin excess 4, 5
• Basal insulin therapy carries lower but still significant risk compared to intensive regimens 1

Insulin Secretagogues

• Sulfonylureas and meglitinides stimulate endogenous insulin release and cause prolonged hypoglycemia, especially first-generation sulfonylureas 1, 3, 2
• Combining insulin with sulfonylureas further amplifies hypoglycemia risk 1
• Other diabetes medication classes rarely cause clinically significant hypoglycemia 1

Disease-Related Causes

Kidney Disease (Critical Risk Factor)

• End-stage kidney disease and chronic kidney disease (eGFR <60 mL/min/1.73 m²) dramatically increase hypoglycemia risk through multiple mechanisms 1, 3, 2
• Decreased renal gluconeogenesis eliminates 20-40% of normal glucose production, which can increase two- to threefold during fasting 1, 6
• Impaired insulin clearance and degradation prolong insulin action, as kidneys metabolize a large proportion of exogenous insulin 1, 6
• Accumulation of uremic toxins affects glucose metabolism 3
• Acute kidney injury represents an important risk factor for in-hospital hypoglycemia 3

Endocrine Disorders

• Adrenal insufficiency with cortisol deficiency impairs counterregulatory hormone responses 3, 7
• Hypopituitarism disrupts multiple hormonal axes affecting glucose regulation 7
• Glucagon deficiency eliminates a primary counterregulatory mechanism 7

Rare Non-Diabetic Causes

• Insulinoma causes endogenous hyperinsulinism 7
• Non-islet cell tumor hypoglycemia (NICTH) from Big-IGF2 secretion by large tumors, characterized by low insulin, C-peptide, and IGF-1 levels 7
• Autoimmune hypoglycemia from antibodies against insulin (Hirata syndrome, especially with Graves' disease) or insulin receptors 7
• Genetic causes including monogenic congenital hyperinsulinism with glucokinase-activating gene mutations or insulin receptor mutations 7
• Inborn errors of metabolism: glycogen storage disorders (types 0, I, III), fatty acid oxidation defects, gluconeogenesis disorders, inherited fructose intolerance 7
• Post-bariatric or gastric surgery hypoglycemia 7

Impaired Glucose Counterregulation (Fundamental Mechanism)

Defective Hormonal Responses

• Failure of insulin to decrease and failure of glucagon/epinephrine to increase appropriately as glucose falls creates the pathophysiologic basis for severe hypoglycemia 4, 5
• Deficient glucagon response combined with attenuated epinephrine secretion causes defective glucose counterregulation in advanced diabetes 4, 5
• Hypoglycemia-associated autonomic failure: recent antecedent hypoglycemia shifts glycemic thresholds lower, creating a vicious cycle of recurrent hypoglycemia 5

Impaired Hypoglycemia Awareness

• Reduced ability to perceive warning symptoms (neuroglycopenic and autonomic) is a major risk factor for severe hypoglycemia 1, 3, 2
• Long diabetes duration, diabetic neuropathy, and intensified glycemic control reduce symptom recognition 8, 5
• Transfer from animal-source to human insulin may alter early warning symptoms 8
• Elderly patients particularly fail to perceive hypoglycemic symptoms despite comparable reaction time prolongation 1, 6

Clinical and Biological Risk Factors

Major Risk Factors (Strongest Predictors)

• Recent severe hypoglycemia within past 3-6 months is the strongest predictor of future events 1, 3, 2
• Intensive insulin therapy (multiple daily injections, pumps, automated delivery) 1, 3
• Impaired hypoglycemia awareness 1, 3, 2
• End-stage kidney disease 1, 3, 2
• Cognitive impairment or dementia limiting ability to recognize or respond to symptoms 1, 3, 2

Other Significant Risk Factors

• Age ≥75 years with reduced counterregulatory hormone responses 1, 3, 2
• Female sex 1, 2
• High glycemic variability 1, 3, 2
• Cardiovascular disease 1, 3, 2
• Diabetic neuropathy and retinopathy 1, 3, 2
• Major depressive disorder and severe mental illness 1, 2
• Polypharmacy 1

Hospital-Specific Causes

Nutritional Interruptions

• NPO status, delayed meals, and changes in usual nutritional intake precipitate hypoglycemia when hypoglycemic agents continue unchanged 1, 3, 2
• Failure to adjust insulin to nutritional intake is a common preventable cause 1

Critical Illness

• Sepsis causes dysregulated glucose metabolism 1, 3, 2
• Critical illness with altered metabolism increases hypoglycemia risk, with severe hypoglycemia (glucose ≤40 mg/dL) occurring in 5-18.7% of ICU patients with intensive glycemic control 1
• Low albumin levels affect drug binding and pharmacokinetics 1, 3, 2

Spontaneous vs. Iatrogenic Hypoglycemia

• Spontaneous hypoglycemia in hospitalized patients (not from insulin therapy) indicates severe underlying illness and carries higher mortality than iatrogenic hypoglycemia 1

Social, Cultural, and Economic Causes

Major Social Risk Factors

• Food insecurity with irregular access to adequate nutrition 1, 3, 2
• Low-income status limiting resources for proper diabetes management 1, 2
• Housing insecurity affecting medication adherence and meal timing 1, 2

Behavioral and Cultural Factors

• Fasting for religious or cultural reasons creates prolonged periods without food 1, 3, 2
• Alcohol consumption inhibits gluconeogenesis and is a significant risk factor 2, 8
• Substance use disorder 1, 2
• Low health literacy 1

Precipitating Factors and Triggers

Medication-Related Triggers

• Missing or delaying meals while on insulin or secretagogues 8
• Taking excessive insulin doses 8
• Drug interactions: oral antidiabetic agents, salicylates (aspirin), sulfa antibiotics, certain antidepressants, kidney and blood pressure medications all lower glucose or affect insulin response 8
• Oral contraceptives, corticosteroids, and thyroid replacement increase insulin requirements; abrupt discontinuation can cause relative insulin excess 8

Activity and Metabolic Triggers

• Exercising or working more than usual lowers insulin requirements during and after activity 8
• Exercise involving the injection site area accelerates insulin absorption 8
• Infection or illness with diarrhea or vomiting alters insulin needs 8

Dialysis-Specific Mechanisms

• Increased erythrocyte glucose uptake during hemodialysis creates additional glucose depletion 6
• Glucose-free or low-glucose dialysate significantly increases hypoglycemia risk 6
• Insulin requirements typically decrease 40-50% when transitioning to dialysis 6

Critical Clinical Pitfalls to Avoid

• Failing to adjust insulin doses in patients with declining kidney function leads to severe hypoglycemia 3, 6
• Continuing the same insulin regimen when nutrition is interrupted in hospitalized patients 3
• Not recognizing that any diabetic patient on anti-diabetic medication who behaves oddly is hypoglycemic until proven otherwise 4
• Overlooking that hypoglycemia symptoms are subjective, vary between individuals and episodes, and may be absent in those with impaired awareness 4, 5
• Missing that elderly hospitalized patients have higher rates of comorbidities (renal failure, malnutrition, malignancies, dementia, frailty) that compound hypoglycemia risk 1