Evaluation of hypoglycemic counterregulation using a modification of the Andres glucose clamp

The glucose clamp, developed by Andres for the quantification of insulin action and secretion, was modified to study counterregulatory mechanisms against hypoglycemia, thereby overcoming the technical difficulties in producing a standardized, reproducible hypoglycemic stimulus. Normal subjects are exquisitely sensitive to small decrements in glucose; levels within the normal range cause suppression of endogenous insulin (approximately 4.0 mM) and activation of glucagon and epinephrine (approximately 3.5 mM) secretion. The glucose threshold for hormone release is modified by multiple factors, including age, gender, and the level of insulin per se. If glucose continues to fall toward 3.0 mM, the hormonal response is intensified and symptoms appear. The window between the appearance of symptoms triggering carbohydrate ingestion and the earliest signs of neuroglycopenia are surprisingly narrow. Subtle neuroelectrophysiological changes in cortical and brain stem function are evident at 2.9 mM. Insulin-dependent diabetes mellitus (IDDM) patients must rely heavily on their ability to secrete epinephrine to overcome a defective glucagon response. Unfortunately, this defense mechanism may diminish as disease duration increases, and may become further impaired by iatrogenic hypoglycemia accompanying insulin treatment. Commonly, the glucose level triggering adrenergic responses is shifted downward during intensive insulin therapy of IDDM. This may help explain why such patients release epinephrine and experience symptoms of hypoglycemia at a lower glucose level.