In patients with Type I diabetes and healthy volunteers, ingestion of modest amounts of caffeine augments the usual symptomatic and counter-regulatory responses to hypoglycaemia. The aim of the present study was to determine whether these are lost with sustained caffeine use, i.e. does tolerance develop? Eleven healthy caffeine consumers underwent two identical hyperinsulinaemic glucose clamp procedures. For 7 days prior to each clamp, subjects consumed a caffeine-free diet supplemented with 200mg of caffeine capsules twice daily (caffeine-replete) or placebo (caffeine-withdrawn). During each clamp, blood glucose was held for 80min at 4.5mmol/l and then 2.5mmol/l. At 85min, subjects were given a 200mg caffeine capsule. Measurements were taken of symptoms, plasma catecholamine, middle cerebral artery blood velocity (VMCA) and cognition. Following the acute caffeine challenge and during hypoglycaemia, VMCA fell only in the caffeine-withdrawn condition [-5.1 (-7.3, -3.0)cm/s compared with -1.9 (-4.0, +0.2) cm/s in caffeine-replete condition; P<0.04; values are differences (95% confidence intervals)]. Plasma catecholamine levels and global cognitive performance were unaffected by caffeine status, whereas tests of executive intellectual function were better preserved during hypoglycaemia in the caffeine-replete condition (P<0.05). The influence of caffeine on hypoglycaemic symptomatic awareness depended upon the duration of the hypoglycaemic stimulus. At onset, symptoms were more intense in caffeine-withdrawn state (P<0.01); however, with increasing duration of hypoglycaemia, symptom intensity was greater in caffeine-replete condition (P<0.05). Thus previous caffeine consumption influences the physiological and symptomatic responses to acute hypoglycaemia, but complete tolerance does not develop with sustained use.

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