What are the causes of hypoglycemia (low blood glucose) in diabetic and non-diabetic patients?

Causes of Hypoglycemia

Medication-Related Causes (Most Common in Diabetic Patients)

Insulin therapy is the most common cause of hypoglycemia, particularly with intensive regimens using multiple daily injections or insulin pumps, followed by sulfonylureas and meglitinides which stimulate insulin release in a glucose-independent manner. 1, 2, 3

High-Risk Medications

• Insulin therapy: Highest risk with intensive regimens (multiple daily injections, continuous subcutaneous insulin infusion, or automated insulin delivery systems), followed by basal insulin therapy 1, 2
• Sulfonylureas: Stimulate insulin release regardless of glucose levels; first-generation agents carry higher risk of prolonged hypoglycemia 2, 4, 5
• Meglitinides: Similar mechanism to sulfonylureas with shorter duration of action 1, 2
• Combination therapy: Insulin plus sulfonylureas further increases hypoglycemia risk 1

Medications Rarely Causing Hypoglycemia

• Other diabetes medication classes (metformin, GLP-1 agonists, SGLT2 inhibitors, DPP-4 inhibitors, thiazolidinediones) rarely cause clinically significant hypoglycemia 1

Clinical and Biological Risk Factors

Major Risk Factors (Strongest Predictors)

• Recent severe hypoglycemia (within past 3-6 months): The strongest predictor of future hypoglycemic events 1, 2, 4
• Impaired hypoglycemia awareness: Reduced ability to perceive warning symptoms of falling glucose 1, 2, 4, 5
• End-stage kidney disease: Decreased renal gluconeogenesis (normally 20-40% of glucose production) and impaired insulin clearance 1, 2, 6
• Cognitive impairment or dementia: Inability to recognize or appropriately respond to hypoglycemic symptoms 1, 2, 4
• Intensive insulin therapy: As detailed above 1, 2

Other Important Clinical Risk Factors

• Advanced age (≥75 years): Reduced counterregulatory hormone responses, though younger patients with type 1 diabetes also face very high risk 1, 2, 4
• Female sex 1, 2
• High glycemic variability: Both low and high A1C associated with hypoglycemia in J-shaped relationship 1, 2, 4
• Chronic kidney disease (eGFR <60 mL/min/1.73 m² or albuminuria): Reduces renal glucose production 1, 2, 4
• Cardiovascular disease 1, 2, 4
• Diabetic complications: Neuropathy and retinopathy 1, 2, 4
• Major depressive disorder 1, 2
• Polypharmacy 1

Social, Cultural, and Economic Risk Factors

Major Social Risk Factors

• Food insecurity: Irregular access to adequate nutrition 1, 2, 6
• Low-income status: Limited resources for proper diabetes management and associated factors like living in socioeconomically deprived areas 1, 2
• Housing insecurity: Unstable living conditions affecting medication adherence and meal timing 1, 2
• Fasting for religious or cultural reasons: Prolonged periods without food 1, 2, 6

Other Social Risk Factors

• Underinsurance 1
• Low health literacy 1
• Alcohol or substance use disorder: Alcohol inhibits gluconeogenesis 1, 2, 6

Causes in Non-Diabetic Patients

Critical Illness and Organ Dysfunction

• Sepsis: Dysregulated glucose metabolism; predictive marker of hypoglycemia in hospitalized patients 2, 6
• Renal failure: Decreased renal gluconeogenesis and impaired insulin clearance 6
• Liver disease: Impaired hepatic glucose production 6
• Malignancy: Various mechanisms including non-islet cell tumors producing Big-IGF2 (NICTH syndrome) 6, 7
• Heart failure: Associated with hypoglycemia in hospitalized patients 6
• Low albumin levels: Altered drug binding and pharmacokinetics 2, 6

Endocrine Disorders

• Adrenal insufficiency: Cortisol deficiency impairs counterregulatory responses; patients may lack adequate hepatic glycogen 4, 8, 7
• Hypopituitarism: Multiple hormone deficiencies affecting glucose regulation 7
• Insulinoma: Autonomous insulin secretion causing hypoglycemia; glucagon administration contraindicated as it may stimulate exaggerated insulin release 8, 7
• Glucagonoma: Paradoxically can cause secondary hypoglycemia when treated with glucagon 8

Nutritional and Metabolic Causes

• Malnutrition: More common in elderly hospitalized patients 6
• Starvation states: Inadequate hepatic glycogen stores render glucagon ineffective 8
• Chronic hypoglycemia: Depleted glycogen stores 8
• Inborn errors of metabolism: Including glycogen storage disorders (types 0, I, III), fatty acid oxidation defects, gluconeogenesis disorders, and inherited fructose intolerance 7

Rare Causes

• Genetic causes: Mutations in glucokinase-activating gene, insulin receptors, or SLC16A1 gene (exercise-induced hyperinsulinism) 7
• Autoimmune causes: Antibodies against insulin (Hirata syndrome, especially with Graves' disease) or insulin receptor 7
• Paraneoplastic syndromes: Non-islet cell tumor hypoglycemia (NICTH) with Big-IGF2 secretion 7
• Post-bariatric or gastric surgery: Altered glucose metabolism 7

Hospital-Specific Risk Factors

Nutritional Interruptions

• NPO status: Nothing by mouth orders 2, 4, 6
• Delayed meals: Timing mismatch with insulin administration 2, 4, 6
• Emesis: Unexpected loss of nutritional intake 6
• Interruption of enteral or parenteral nutrition: Especially if glucose infusions reduced without adjusting insulin 6

Acute Medical Conditions

• Critical illness: Altered metabolism and increased insulin resistance 2, 4, 6
• Sepsis: As detailed above 2, 6
• Acute kidney injury: Important risk factor for in-hospital hypoglycemia 4

Medication Changes

• Sudden reduction of corticosteroid dose: Removes counterregulatory effect of cortisol 6
• Changes in medication regimens: New drugs or altered dosing 2

Critical Pitfalls to Avoid

• Failing to adjust insulin doses in declining kidney function: Renal insufficiency requires dose reduction due to decreased insulin clearance 4, 6
• Continuing same insulin regimen when nutrition interrupted: Hospitalized patients require immediate insulin adjustment when NPO or meals delayed 4, 6
• Overlooking impaired hypoglycemia awareness: This major risk factor requires aggressive prevention strategies and possibly less stringent glycemic targets 1, 2, 5
• Ignoring that prior hypoglycemia predicts future events: History of severe hypoglycemia in past 3-6 months is the strongest predictor and mandates treatment plan revision 1, 2
• Underestimating risk in elderly patients: Age ≥75 years with comorbidities, polypharmacy, and reduced counterregulatory responses creates compounded risk 1, 2, 6
• Missing starvation or adrenal insufficiency: These patients lack adequate hepatic glycogen, making glucagon ineffective; they require glucose administration instead 8
• Administering glucagon to patients with insulinoma or pheochromocytoma: Absolutely contraindicated due to risk of exaggerated insulin release or catecholamine crisis respectively 8