Effect of caffeine on recognition of and physiological responses to hypoglycaemia in insulin-dependent diabetes

Background For the patient with diabetes, hypoglycaemia unawareness-ie, the warning signs of falling blood glucose are missing-is potentially dangerous. One study has suggested that, in healthy volunteers, caffeine might be a helpful treatment. Our study looked at two effects of caffeine ingestion (250 mg) on the brain-namely, a decrease in cerebral blood flow and an increase in brain glucose use-to see if the recognition of and physiological responses to hypoglycaemia were altered in patients with insulin-dependent diabetes mellitus (IDDM). Methods 12 patients were studied twice. A hyperinsulinaemic glucose clamp was used to maintain plasma glucose at 5 mmol/L for 90 min, followed by 60 min at 3.8 mmol/L, and then 2.8 mmol/L for a further hour. After 30 min at 5 mmol/L, patients consumed, in a double-blind, crossover design, 250 mg caffeine or matched placebo. We recorded middle cerebral artery velocity (V-MCA), counterregulatory hormone levels, and cognitive function, and patients recorded hypoglycaemia symptoms on a visual analogue scale. Results Caffeine caused an immediate and sustained fall in V-MCA of 10 cm/s, from 60 to 50 cm/s (95% Cl -5 to -15 cm/s; p<0.001). At a blood glucose of 3.8 mmol/L, plasma adrenaline levels were twice as high after caffeine than after placebo (difference 524 pmol/L). When glucose was lowered to 2.8 mmol/L, caffeine ingestion was associated with: greater awareness of hypoglycaemia in 9 patients, significantly more intense autonomic and neuroglycopenic symptoms, and higher levels of adrenaline, cortisol, and growth hormone. Cognitive function (latency of P-300 evoked potentials) deteriorated to the same extent in both studies at this glucose level. Interpretation The sustained fall in V-MCA and augmented sympathoadrenal and symptomatic responses during moderate hypoglycaemia suggest caffeine as a potentially useful treatment for diabetic patients who have difficulty recognising the onset of hypoglycaemia.