During hypoglycemia, cerebral blood flow (CBF) does not increase significantly until peripheral glucose levels are very low (2.0 nmol/l), that is, well below the blood glucose threshold for impairment of cognitive function (3.0 nmol/l). Because increased rates of cerebral blood flow will increase glucose transport, a failure of flow to rise earlier, before brain function is threatened, might be considered maladaptive. To examine the influence of inducing an earlier rise in CBF during hypoglycemia, eight healthy volunteers participated in three studies using a randomized, placebo-controlled design. In all three studies, a hyperinsulinemic (60 mU · m2 · min−1) clamp was used to maintain blood glucose levels at 4.5 nmol/l for 60 min. Thereafter, for EUGACZ, blood glucose was maintained at 4.5 nmol/l from 60 to 170 min and at 90 min from the start of this study, and 1-g acetazolamide i.v. was given to induce an early rise in CBF; for HYPO-ACZ, glucose was lowered over 20 min to 2.8 mmol/l and kept at that level for 90 min, and acetazolamide was given 90 min from the start of this study; and for HYPO-CON, glucose was treated as in HYPO-ACZ, and matching placebo was given in place of acetazolamide. Injection of acetazolamide was associated with a 30% rise in right (95% CI24–34%) and left (20–32%) middle cerebral artery velocity (an index of CBF) during euglycemia without any change in hypoglycemia awareness or counterregulatory hormone levels. When glucose was lowered to 2.8 nmol/l, acetazolamide caused a similar rise in middle cerebral artery velocity in the HYPO-ACZ study. However, all subjects were less “aware” of hypoglycemia, had fewer adrenergic symptoms (sweating, palpitations, tremors; all P < 0.05), and had lower plasma epinephrine levels (1,026 vs. 1,790 pmol/l; –764 [437 to 1,097] pmol/l, point estimate of difference [95% CI]; P < 0.001), compared with the HYPO-CON study, whereas levels of other counterregulatory hormones and norepinephrine were similar. Cognitive function (latency of the P300 evoked response) was unaffected by increasing CBF. In conclusion, enhanced rates of cerebral blood flow at the onset of systemic hypoglycemia are associated with diminished perception of low blood glucose levels and attenuation of the epinephrine counterregulatory response. These findings suggest that augmenting cerebral blood flow leads to an enhanced rate of substrate delivery to the central nervous system.

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