IMPORTANCE OF CEREBRAL BLOOD-FLOW TO THE RECOGNITION OF AND PHYSIOLOGICAL-RESPONSES TO HYPOGLYCEMIA

During hypoglycemia, cerebral blood flow (CBF) does not increase signi ficantly until peripheral glucose levels are very low (2.0 mmol/l), th at is, well below the blood glucose threshold for impairment of cognit ive function (3.0 mmol/l). Because increased rates of cerebral blood f low 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 h ypoglycemia, eight healthy volunteers participated in three studies us ing a randomized, placebo-controlled design. In all three studies, a h yperinsulinemic (60 mU.m(2).min(-1)) clamp was used to maintain blood glucose levels at 4.5 mmol/l for 60 min. Thereafter, for EUG-ACZ, bloo d glucose was maintained at 4.5 mmol/l from 60 to 170 min and at 90 mi n 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 2 0 min to 2.8 mmolfl and kept at that level for 90 min, and acetazolami de was given 90 min from the start of this study; and for HYPO-CON, gl ucose was treated as in HYPO-ACZ, and matching placebo was given in pl ace of acetazolamide. Injection of acetazolamide was associated with a 30% rise in right (95% CI 24-34%) and left (20-32%) middle cerebral a rtery velocity (an index of CBF) during euglycemia without any change in hypoglycemia awareness or counterregulatory hormone levels. When gl ucose was lowered to 2.8 mmol/l, acetazolamide caused a similar rise i n middle cerebral artery velocity in the HYPO-ACZ study. However, all subjects were less ''aware'' of hypoglycemia, had fewer adrenergic sym ptoms (sweating, palpitations, tremors; all P < 0.05), and had lower p lasma 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 wi th the HYPO-CON study, whereas levels of other counterregulatory hormo nes 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 hypog lycemia 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 a n enhanced rate of substrate delivery to the central nervous system.