Hypoglycemia Pathophysiology

Clinical Manifestations

The symptoms caused by hypoglycemia can be divided into the following categories: (1) neurogenic (autonomic) symptoms attributable to the sympathoadrenal and parasympathetic discharge triggered by a falling plasma glucose level and (2) neuroglycopenic symptoms attributable to cerebral dysfunction caused by glucose deprivation. Neurogenic manifestations include tachycardia, palpitations, anxiety, tremor, sweating, and hunger.

The magnitude of the sympathoadrenal and parasympathetic response to decrements in plasma glucose is inversely related to the glucose nadir, so the lower the plasma glucose concentration, the more intense the neurogenic symptoms. However, the neuroendocrine response is not altered by the rate of plasma glucose decline. Awareness of hypoglycemia is largely due to recognition of neurogenic symptoms.

Neuroglycopenic manifestations range from subtle mental impairment to coma and death. Symptoms may include lethargy, drowsiness, faintness, confusion, blurred vision, difficulty speaking, abnormal behavior, incoordination and seizures. Both hypothermia during hypoglycemia and posthypoglycemic fever have been described.

During a fall in plasma glucose level, normal individuals develop symptoms at a plasma glucose concentration of 50 to 55 mg/dl (2.8 to 3 mmol/L), below the thresholds for suppression of insulin secretion and activation of counterregulatory hormone secretion. The threshold for cerebral dysfunction that becomes evident as impaired cognition is 45 to 50 mg/dl (2.5 to 2.8 mmol/L). Thus the normal sequence of responses to a fall in plasma glucose level is (1) decreased insulin secretion, (2) increased counterregulatory hormone secretion, (3) symptoms, and (4) impaired cognition.

These glycemic thresholds are not fixed but may be altered by antecedent plasma glucose levels. Even a single episode of hypoglycemia shifts the glycemic thresholds for counterregulatory hormone secretion and hypoglycemic symptoms to a lower value.

This phenomenon accounts for the occurrence of hypoglycemia with only minor symptoms in some patients with fasting hypoglycemia. Although cognitive dysfunction generally correlates with the degree of hypoglycemia, some patients tolerate low plasma glucose concentrations relatively well. The mechanism by which hypoglycemia alters glycemic thresholds appears to involve increased transport of glucose across the blood-brain barrier.

Hypoglycemic symptoms typically clear rapidly after the plasma glucose concentration is restored to normal. More gradual clearing of neuroglycopenic symptoms over hours, or even days, sometimes follows profound hypoglycemia. Prolonged, severe hypoglycemia can cause permanent cerebral damage.

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