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

Causes of Hypoglycemia

Hypoglycemia in both diabetic and non-diabetic patients results from distinct mechanisms: in diabetes, it is primarily medication-induced (insulin, sulfonylureas, meglitinides) combined with defective counterregulation, while in non-diabetic patients, it signals critical illness, organ failure, or nutritional compromise. 1, 2, 3

Medication-Related Causes (Diabetic Patients)

Insulin therapy is the most common cause of hypoglycemia, with risk highest in intensive regimens using multiple daily injections, continuous subcutaneous infusion, or automated insulin delivery systems. 1, 3, 4

• Sulfonylureas and meglitinides stimulate endogenous insulin release and cause hypoglycemia, particularly first-generation sulfonylureas which have prolonged action. 1, 3, 5
• Combining insulin with sulfonylureas further amplifies hypoglycemia risk. 1
• Medication errors between insulin products have been reported—always verify the insulin label before each injection. 4

Key Mechanism in Diabetes

The fundamental problem is failure of insulin levels to decrease as glucose falls, combined with deficient glucagon and epinephrine counterregulatory responses. 6 In insulin-deficient diabetes, exogenous insulin has no pancreatic regulation, creating absolute or relative insulin excess. 7, 6

Critical Illness and Organ Dysfunction (Non-Diabetic Patients)

Spontaneous hypoglycemia in hospitalized non-diabetic patients indicates severe underlying disease, particularly sepsis, renal failure, liver disease, and malignancy. 1, 2

Renal Insufficiency

• Renal failure causes hypoglycemia through multiple mechanisms: decreased renal gluconeogenesis (which normally accounts for 20-40% of glucose production), impaired insulin clearance, lack of gluconeogenic substrates with poor intake, and blunted counterregulatory hormone responses. 1, 2, 5
• End-stage kidney disease is a major risk factor, with hypoglycemia risk increasing 10-fold in patients with acute kidney injury. 1, 3, 8

Sepsis and Critical Illness

• Sepsis causes dysregulated glucose metabolism and is a predictive marker of hypoglycemia in hospitalized patients. 2, 3
• Sequential Organ Failure Assessment (SOFA) score elevation increases hypoglycemia risk by 52%. 8

Other Organ Dysfunction

• Low albumin levels predict hypoglycemia through altered drug binding and pharmacokinetics. 1, 2, 3
• Liver disease impairs gluconeogenesis and glycogen storage. 2
• Malignancy can cause hypoglycemia through non-islet cell tumors secreting Big-IGF2 (NICTH syndrome). 2, 9

Nutritional and Metabolic Causes

Interruptions in nutritional intake during hospitalization—NPO status, delayed meals, emesis, or unexpected cessation of enteral/parenteral nutrition—precipitate hypoglycemia, especially when glucose-lowering medications continue unchanged. 1, 2, 3

• Malnutrition is particularly common in elderly hospitalized patients and increases hypoglycemia risk. 1, 2
• Sudden reduction of corticosteroid dose removes cortisol's counterregulatory effect, triggering hypoglycemia. 2

Endocrine Disorders

• Adrenal insufficiency with cortisol deficiency impairs counterregulatory responses. 5, 9
• Hypopituitarism affects multiple counterregulatory hormones. 9

Patient-Specific Risk Factors

Major Risk Factors (High Risk Category)

• Recent level 2 (<54 mg/dL) or level 3 (severe) hypoglycemia within past 3-6 months is the strongest predictor of future episodes. 1, 3, 5
• Impaired hypoglycemia awareness—reduced ability to perceive warning symptoms—creates a vicious cycle where antecedent hypoglycemia shifts glycemic thresholds lower, leading to recurrent episodes. 1, 3, 6
• Intensive insulin therapy (multiple daily injections, pumps, automated delivery). 1, 3
• End-stage kidney disease. 1, 3
• Cognitive impairment or dementia limits ability to recognize or respond to symptoms. 1, 3, 5

Other Clinical Risk Factors

• Age ≥75 years with reduced counterregulatory hormone responses and higher comorbidity burden. 1, 3
• Female sex. 1, 3
• High glycemic variability. 1, 3, 5
• Chronic kidney disease (eGFR <60 mL/min/1.73 m²). 1, 3
• Cardiovascular disease. 1, 3, 5
• Diabetic neuropathy and retinopathy. 1, 3, 5
• Major depressive disorder. 1, 3
• Polypharmacy. 1

Social, Cultural, and Economic Risk Factors

• Food insecurity with irregular access to adequate nutrition. 1, 2, 3
• Low-income status and housing insecurity affecting medication adherence and meal timing. 1, 3
• Fasting for religious or cultural reasons during prolonged periods without food. 1, 2, 3
• Alcohol or substance use disorder—alcohol inhibits gluconeogenesis. 1, 2, 3
• Low health literacy. 1
• Underinsurance. 1

Rare Causes (Non-Diabetic)

• Insulinoma with autonomous insulin secretion. 9
• Autoimmune hypoglycemia: antibodies against insulin (Hirata syndrome, especially with Graves' disease) or insulin receptor antibodies. 9
• Genetic causes: glucokinase-activating mutations, insulin receptor mutations (postprandial hypoglycemia with hyperinsulinism), inborn errors of metabolism affecting glycogen synthesis, fatty acid oxidation, or gluconeogenesis. 9
• Post-bariatric or gastric surgery. 9
• Surreptitious insulin or sulfonylurea use. 9

Hospital-Specific Precipitants

• Changes in insulin regimen (strength, manufacturer, type, injection site) affect glycemic control. 4
• Repeated injections into areas of lipodystrophy or localized cutaneous amyloidosis cause hyperglycemia, then sudden change to unaffected injection sites triggers hypoglycemia. 4
• Failure to adjust insulin to nutritional intake and changes in hospital routine. 1
• Changes in medication regimens or drug interactions. 3, 4

Critical Clinical Pitfalls

• Elderly patients fail to perceive neuroglycopenic and autonomic hypoglycemic symptoms despite comparable cognitive impairment, delaying recognition and treatment. 1
• Any person with diabetes on anti-diabetic medication who behaves oddly in any way is hypoglycemic until proven otherwise. 7
• Mortality is higher among patients with spontaneous hypoglycemia, which may be a marker of disease severity rather than a direct cause of death. 1
• Failing to adjust insulin doses in patients with declining kidney function is a common error. 5
• Beta-blockers and other sympathetic nervous system blockers mask hypoglycemic symptoms. 4