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Effect of Caffeine on the Recognition of and Responses to Hypoglycemia in Humans

David Kerr, MD; Robert S. Sherwin, MD; Frank Pavalkis, PA-C; Pierre B. Fayad, MD; Lori Sikorski, RN; Frances Rife, RN; William V. Tamborlane, MD; and Matthew J. During, MD
[+] Article, Author, and Disclosure Information

From Yale University School of Medicine, New Haven, Connecticut. Requests for Reprints: David Kerr, MD, Royal Bournemouth Hospital, Castle Lane East, Bournemouth, Dorset, England BH7 7DW. Acknowledgments: The authors thank Aida Grossman and Andrea Belous for help with measurements of hormone levels, Val Pascale for his help with randomization and for supplying the drinks, and Dr. Lawrence M. Brass for his comments. Grant Support: By grants DK 20495, RR 00125, RR 06022, and NS 28227 from the National Institutes of Health and in part by gifts to the Yale Stroke Program.

Copyright 2004 by the American College of Physicians

Ann Intern Med. 1993;119(8):799-804. doi:10.7326/0003-4819-119-8-199310150-00005
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Objective: To determine whether two effects of acute caffeine ingestiondecrease in cerebral blood flow and increase in brain glucose usealter 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 (VMCA), 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.


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Figure 1.
Mean ( SE) plasma glucose and caffeine levels during both studies.

After 30 minutes, a drink containing caffeine-free diet cola with or without caffeine (400 mg) was given. At baseline in the caffeine study and throughout the placebo study, plasma caffeine levels were below the limit of detection of the assay.

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Figure 2.
Levels (mean SE) of epinephrine, norepinephrine, cortisol, and growth hormone.PPPPP

When plasma glucose was lowered to 3.8 mmol/L, epinephrine ( < 0.001), norepinephrine ( < 0.002), cortisol ( < 0.008), and growth hormone ( < 0.05) responses were greater after ingestion of caffeine compared with placebo. At a plasma glucose level of 2.8 mmol/L, epinephrine, norepinephrine, and cortisol (all < 0.05) levels were higher in the caffeine study. Glucagon levels were almost identical throughout each study (see text).

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Figure 3.
Middle cerebral artery velocity and P300 latency.PP

The mean values ( SE) are shown at baseline (5 mmol/L), at the end of euglycemia, and when plasma glucose was lowered to 3.8 and to 2.8 mmol/L. Data shown are the average values for the final 20 minutes of each period. *** < 0.001 and * < 0.05 caffeine compared with placebo. Black bars depict caffeine; white bars, placebo.

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