The conventional risk factors for iatrogenic hypoglycemia (3) are based on the premise that insulin excess is the sole determinant of risk. Absolute or relative insulin excess occurs when: 1) Insulin, or insulin secretagogue or sensitizer, doses are excessive, ill-timed or of, the wrong type. 2) Exogenous glucose delivery is decreased as following missed meals or snacks and during the overnight fast. 3) Endogenous glucose production is decreased as following alcohol ingestion. 4) Glucose utilization is increased as during exercise. 5) Sensitivity to insulin is increased as during treatment with an insulin sensitizer, late after exercise, in the middle of the night or following weight loss, increased fitness or improved glycemic control. 6) Insulin clearance is decreased as in renal failure. However, these risk factors explain only a minority of episodes of severe hypoglycemia, at least in T1DM (13).

Iatrogenic hypoglycemia is more appropriately viewed as the result of the interplay of insulin excess and compromised glucose counterregulation, discussed earlier, in T1DM and in advanced T2DM (3,8,9). Risk factors related to compromised glucose counterregulation include: 1) Insulin deficiency. 2) A history of severe hypoglycemia, hypoglycemia unawareness, or both. 3) Aggressive glycemic therapy per se as evidenced by lower hemoglobin A1C levels, glycemic goals, or both. These are clinical surrogates of compromised defenses against developing hypoglycemia. Insulin deficiency indicates that insulin levels will not decrease and predicts accurately that glucagon levels will not increase as glucose levels fall. A history of severe hypoglycemia indicates, and that of hypoglycemia unawareness or even aggressive therapy per se implies, recent antecedent hypoglycemia that compromises autonomic (including epinephrine) and neurogenic symptom responses to falling glucose levels as discussed earlier.