Effect of antecedent hypoglycemia on cognitive function and on glycemic thresholds for counterregulatory hormone secretion in healthy humans

OBJECTIVE - To determine whether reduced hormonal, symtomatic, and/or cognitive responses to hypoglycemia are caused by an increase in the plasma glucose concentration required to stimulate these counterregulatory parameters after antecedent hypoglycemia. RESEARCH DESIGN AND METHODS - We studied nine healthy volunteers during stepped hypoglycemia clamps (plasma glucose targets from 80 to 50 mg/dl in 10 mg/dl steps) on two separate days. The study was preceded either by a 2-h period of hypoglycemia (plasma glucose 58 ± 2 mg/dl) or a 2-h period of euglycemia (plasma glucose 94 ± 2 mg/dl) for 90 min. RESULTS - The plasma glucose that triggered secretion of plasma norepinephrine (NE) was lower after antecedent hypoglycemia (control = 74 ± 2 and experimental = 67 ± 2 mg/dl, respectively, P < 0.005). In contrast, a relatively higher plasma glucose stimulated secretion of other counterregulatory hormones after antecedent hypoglycemia: growth hormone (GH) (65 ± 2 to 72 ± 2 mg/dl, P < 0.01); glucagon (63 ± 2 to 70 ± 2 mg/dl, P < 0.01); and epinephrine (EPI) (68 ± 2 to 76 ± 2 mg/dl, P < 0.01) when comparing control days with experimental days. Hypoglycemic symptoms were first observed at a plasma glucose plateau of 59 ± 2 mg/dl. Motor function reflected by Digit Symbol Substitution deteriorated equally whether there had been antecedent hypoglycemia or euglycemia. Logical (immediate) memory deteriorated in the control study at a plasma glucose of 54 ± 2 mg/dl but remained unchanged at equivalent hypoglycemia in the experimental study (P < 0.03). CONCLUSIONS - Our conclusions are as follows: 1) symptoms of moderate hypoglycemia occur at plasma glucose levels averaging ~5-15 mg/dl lower than the plasma glucose concentrations required to trigger counterregulatory hormone release; 2) after acute antecedent hypoglycemia, glucagon, EPI, and GH secretion occur at higher plasma glucose concentrations and NE is released at lower plasma glucose concentrations; and 3) there may be CNS adaptation to prior hypoglycemia reflected in preservation of logical memory function at plasma glucose levels of ~50 mg/dl. These findings suggest that thresholds for hormone secretion and for changes in cognitive function can be altered very acutely by foregoing hypoglycemia in healthy humans.