What causes hypoglycemia (low blood sugar) in a non-diabetic patient?

Causes of Hypoglycemia in Non-Diabetic Patients

In non-diabetic patients, hypoglycemia most commonly results from critical illness (sepsis, renal failure, liver disease, malignancy), altered nutritional states (starvation, malnutrition), medications (particularly those affecting insulin or glucose metabolism), endocrine disorders (adrenal insufficiency), and alcohol use. 1

Critical Illness and Organ Dysfunction

Sepsis, renal failure, liver disease, and malignancy are major causes of spontaneous hypoglycemia in hospitalized non-diabetic patients. 1

• Renal insufficiency causes hypoglycemia through multiple mechanisms: decreased renal gluconeogenesis (which normally accounts for 20-40% of overall glucose production), lack of gluconeogenic substrates with decreased food intake, and impairment of counterregulatory hormonal responses 1
• Sepsis causes dysregulated glucose metabolism and is a predictive marker of hypoglycemia in hospitalized patients 1
• Low albumin levels predict hypoglycemia risk, likely through altered drug binding and pharmacokinetics 1
• Heart failure is associated with hypoglycemia in hospitalized patients 1
• Malignancy can cause hypoglycemia through various mechanisms including non-islet cell tumors 1

Nutritional and Metabolic Causes

Altered nutritional states are critical causes of hypoglycemia because they deplete hepatic glycogen stores necessary for glucose production. 2

• Starvation or prolonged fasting depletes hepatic glycogen, making patients unable to mount an effective counterregulatory response 2
• Malnutrition is more common in elderly hospitalized patients and increases hypoglycemia risk 1
• Interruptions in usual nutritional intake during hospitalization (NPO status, delayed meals, emesis) precipitate hypoglycemia 1
• Unexpected interruption of enteral feedings or parenteral nutrition can trigger hypoglycemia, especially if glucose infusions are reduced 1

Medication-Related Causes

While insulin and sulfonylureas are the primary culprits in diabetic patients, non-diabetic patients can develop medication-induced hypoglycemia from various drugs:

• Alcohol (ethanol) is one of the most common causes of hypoglycemia in non-diabetics, typically developing 6-24 hours after moderate or heavy intake in someone with insufficient food intake for 1-2 days, as alcohol inhibits gluconeogenesis 3, 4, 5
• Sudden reduction of corticosteroid dose can precipitate hypoglycemia by removing the counterregulatory effect of cortisol 1
• Quinine and other medications can cause hyperinsulinemia and refractory hypoglycemia 5

Endocrine Disorders

Adrenal insufficiency with cortisol deficiency impairs counterregulatory responses to hypoglycemia and is a recognized cause in non-diabetic patients 6, 2

Tumor-Related Causes

• Insulinomas (insulin-producing pancreatic tumors) cause hypoglycemia through excessive insulin secretion 7, 4
• Non-islet cell tumors can produce insulin-like substances causing hypoglycemia 7, 4

Important Clinical Pitfalls

A critical distinction exists between spontaneous and iatrogenic hypoglycemia: Recent studies show that mortality is higher only among patients with spontaneous hypoglycemia (from underlying severe illness) rather than treatment-induced hypoglycemia, suggesting that spontaneous hypoglycemia may be a marker of disease severity rather than a direct cause of death 1

In elderly patients, the risk is compounded by:

• Higher rates of comorbidities (renal failure, malnutrition, malignancies, dementia, frailty) 1
• Failure of regulatory mechanisms, especially reduced release of glucagon and epinephrine in response to hypoglycemia 1
• Inability to perceive neuroglycopenic and autonomic hypoglycemic symptoms, delaying recognition and treatment 1

Social and Economic Risk Factors

• Food insecurity with irregular access to adequate nutrition 3, 6
• Fasting for religious or cultural reasons during prolonged periods without food 3, 6
• Alcohol or substance use disorder where alcohol inhibits gluconeogenesis 3

The key to diagnosis is recognizing Whipple's triad: (1) low plasma glucose concentration, (2) neurogenic and neuroglycopenic symptoms, and (3) resolution of symptoms with normalization of glucose 8