© 2007 The Authors. 720 Journal compilation © 2007 Diabetes UK. Diabetic Medicine, 24, 720–727 DIABETICMedicine DOI: 10.1111/j.1464-5491.2007.02131.x Introduction Hypoglycaemia is the major complication of insulin therapy for diabetes. During hypoglycaemia, cerebral metabolic rate falls [1]. This is accompanied by counterregulatory activation of the hypothalamic–pituitary–adrenal axis with activation of the sympathetic nervous system and a decline in cortical performance [2]. The former is associated with a symptom complex that stimulates a protective eating response [3], the latter with problems ranging from slowed reaction times, through confusion to coma. Cerebral blood flow increases when the blood glucose concentrations fall below 2 mmol/l [4], which might be expected to provide some protection, but this is inadequate to protect against brain dysfunction or terminate counterregulatory responses. Caffeine ingestion is associated with augmentation of symptomatic and hormonal responses to acute hypoglycaemia [5,6]. Caffeine enhances cerebral metabolism, while decreasing blood flow [7], the opposite of hypoglycaemia. A fall in cerebral blood flow during hypoglycaemia would exacerbate Correspondence to: Miranda Rosenthal PhD, MRCP, Centre for Diabetes and Endocrinology, Rayne Building, 5 University Street, London WC1 E6JF, UK. E-mail: m.rosenthal@ucl.ac.uk Abstract Aims Caffeine enhances counterregulatory responses to acute hypoglycaemia. Our aim was to explore its effects on cortical function, which are not known at present. Methods Regional brain activation during performance of the four-choice reaction time (4CRT) at different levels of complexity was measured using functional magnetic resonance imaging (fMRI) at euglycaemia (5 mmol/l) and hypoglycaemia (2.6 mmol/l) in the presence and absence of caffeine in six healthy right-handed men. Results During hypoglycaemia, caffeine enhanced adrenaline responses to hypoglycaemia (2.5 ± 0.7 nmol/l to 4.0 ± 1.0 nmol/l, P = 0.01) and restored the brain activation response to the non-cued 4CRT, the linear increases in regional brain activation associated with increased task complexity and the ability to respond to a cue that were lost in hypoglycaemia alone. Conclusions Caffeine can sustain regional brain activation patterns lost in acute hypoglycaemia, with some restoration of cortical function and enhanced adrenaline responsiveness. A methodology has been established that may help in the development of therapies to protect against severe hypoglycaemia in insulin therapy for patients with diabetes and problematic hypoglycaemia. Diabet. Med. 24, 720–727 (2007) Keywords cognitive function, functional magnetic resonance imaging, hypoglycaemia, reaction time, Type 1 diabetes mellitus Abbreviations 4CRT, four-choice reaction time; EC, euglycaemia with caffeine; EP, euglycaemia with placebo tablet administration; fMRI, functional magnetic resonance imaging; HC, hypoglycaemia with caffeine; HP, hypoglycaemia with placebo; MR, magnetic resonance; SMA, supplementary motor area; SSQ ratio, residual sum of squares ratio; TE, echo time; TR, repetition time Blackwell Publishing Ltd Oxford, UK DME Diabetic Medicine 0742-3071 Blackwell Publishing, 2007 24 Original Article Original article Hypoglycaemia and caffeine in HV M. J. Rosenthal et al. Caffeine restores regional brain activation in acute hypoglycaemia in healthy volunteers M. J. Rosenthal*†, D. Smith*, L. Yaguez†, V. Giampietro†, D. Kerr§, E. Bullmore†, M. Brammer†, S. C. R. Williams† and S. A. Amiel* *Centre for Diabetes and Endocrinology, †Diabetes Research Group, King’s College London School of Medicine and ‡Institute of Psychiatry, King’s College, London, and §Department of Diabetes, Royal Bournemouth and Christchurch Hospital, Bournemouth, UK Accepted 21 November 2006