Effect of caffeine on the recognition of and responses to hypoglycemia in humans

OBJECTIVE: To determine whether two effects of acute caffeine ingestion--decrease in cerebral blood flow and increase in brain glucose use--alter the recognition of and physiologic responses to hypoglycemia. DESIGN: On two occasions, a hyperinsulinemic glucose clamp technique (2 mU/kg body weight per minute) was used to maintain plasma glucose at 5 mmol/L for 90 minutes, followed by 60 minutes at 3.8 mmol/L, and then 2.8 mmol/L. After 30 minutes at 5 mmol/L, participants consumed, using a randomized, double-blind design, caffeine-free cola with or without caffeine (400 mg) added. SETTING: Yale Clinical Research Center. PARTICIPANTS: Eight healthy, nonobese volunteers (5 men; age range, 20 to 33 years). MEASUREMENTS: Middle cerebral artery velocity (V MCA), counter-regulatory hormone levels, hypoglycemic symptoms, and cognitive function (P300 evoked potentials). RESULTS: Caffeine caused an immediate and sustained 23% decrease in VMCA from 64 to 49 cm/s (point estimate of difference, +15 cm/s 95% CI, 10 to 21 cm/s], P < 0.001). At a glucose level of 3.8 mmol/L, only the participants given caffeine had warning symptoms and "felt hypoglycemic." Moreover, the level of epinephrine was 118% (CI of point difference, 76% to 158%] CI, P < 0.001]) higher after caffeine consumption compared with placebo. Similarly, levels of norepinephrine (41% CI, 26% to 60%], P < 0.002), cortisol (65% CI, 26% to 78%], P < 0.008), and growth hormone (60% CI, 16% to 143%], P < 0.05) were higher after caffeine consumption compared with placebo. At 2.8 mmol/L, epinephrine (40% point estimate of the percentage difference], P < 0.05), norepinephrine (27%, P < 0.05), and cortisol (24%, P < 0.05) levels were higher, participants were more aware (P < 0.02) of hypoglycemia, and P300 latency was prolonged in the group that consumed caffeine (7.2%, P < 0.05). CONCLUSIONS: Acute ingestion of caffeine is associated with sympathoadrenal activation and awareness of hypoglycemia at a glucose level not usually considered hypoglycemic. Our data suggest that individuals who ingest moderate amounts of caffeine may develop hypoglycemic symptoms if plasma glucose levels fall into the "low-normal" range, as might occur in the late postprandial period after ingestion of a large carbohydrate load.