The effect of a falling plasma glucose concentration, from one hyperglycemic to another lower, yet still hyperglycemic, level, on the release of counterregulatory hormones was examined in nine diabetic subjects. The fasting plasma glucose concentration (201 ± 22 mg/dl) was lowered at the rate of 2.3 ± 0.3 mg/min with an exogenous insulin infusion and maintained between 100 and 110 mg/dl for an additional 60 min employing the glucose clamp technique. During the phase of rapidly falling glucose concentration, or shortly thereafter while the plasma glucose was being maintained at or above 100 mg/dl, eight of nine diabetics released growth hormone, five of nine released cortisol, six of nine released epinephrine, and five of nine released norepinephrine. No subject demonstrated any increase in plasma glucagon. One subject experienced a frank hypoglycemic reaction when her plasma glucose concentration had decreased to 149 mg/dl. In contrast, control subjects did not demonstrate the release of any counterregulatory hormones despite a similar rate of decline in plasma glucose concentration. These results indicate that diabetic subjects with fasting hyperglycemia have an upward resetting of the glucostat at which counterregulatory hormones are released and provide direct support for the clinical observation of hypoglycemic reactions in some diabetics with “normal” or high plasma glucose concentrations.

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