Recent in vitro studies suggest that lactate, rather than glucose, may be the preferred fuel for neuronal metabolism. The authors examined the effect of lactate on global brain glucose uptake in euglycemic human subjects using 18 fluoro-deoxyglucose (FDG) positron emission tomography (PET). Eight healthy men, aged 40 to 54 years, underwent a 60-minute FDG-PET scan on two occasions in random order. On one occasion, 6.72% sodium lactate was infused at a rate of 50 micro mol. kg-1. min-1 for 20 minutes and then reduced to 30 micro mol. kg-1. min-1; 1.4% sodium bicarbonate was infused as a control on the other occasion. Plasma glucose levels were not different between the two groups (5.3 +/- 0.23 and 5.3 +/- 0.24 mmol/L, P = 0.55). Plasma lactate was significantly elevated by lactate infusion (4.08 +/- 0.35 vs. 0.63 +/- 0.22 mmol/L, P < 0.0005. The whole-brain rate of glucose uptake was significantly reduced by approximately 17% during lactate infusion (0.195 +/- 0.022 vs. 0.234 +/- 0.020 micro mol. g-1. min-1, P = 0.001). The authors conclude that, in vivo in humans, circulating lactate is used by the brain at euglycemia, with sparing of glucose.

The effect of basal insulin on global and regional brain glucose uptake and metabolism in humans was studied using 18-fluorodeoxyglucose and positron emission tomography (FDG-PET). Eight healthy male volunteers aged 49.3 +/- 5.1 years were studied twice in random order. On each occasion, they received an infusion of 0.1 mg. kg(-1). min(-1) somatostatin to suppress endogenous insulin production. In one study 0.3 mU. kg(-1). min(-1) insulin was infused to replace basal circulating insulin levels, and in the other study a saline infusion was used as control. We sought stimulatory effects of basal insulin on brain glucose metabolism particularly in regions with deficiencies in the blood-brain barrier and high density of insulin receptors. Insulin levels were 27.07 +/- 1.3 mU/l with insulin replacement and 3.51 +/- 0.4 mU/l without (P = 0.001). Mean global rate of brain glucose utilization was 0.215 +/- 0.030 mmol. kg(-1). min(-1) without insulin and 0.245 +/- 0.021 mmol. kg(-1). min(-1) with insulin (P = 0.008, an average difference of 15.3 +/- 12.5%). Regional analysis using statistical parametric mapping showed that the effect of basal insulin was significantly less in the cerebellum (Z = 5.53, corrected P = 0.031). We conclude that basal insulin has a role in regulating global brain glucose uptake in humans, mostly marked in cortical areas.

The rising prevalence of obesity and type 2 diabetes is a global challenge. A possible mechanism linking insulin resistance and weight gain would be attenuation of insulin-evoked responses in brain areas relevant to eating in systemic insulin resistance. We measured brain glucose metabolism, using [(18)F]fluorodeoxyglucose positron emission tomography, in seven insulin-sensitive (homeostasis model assessment of insulin resistance [HOMA-IR] = 1.3) and seven insulin-resistant (HOMA-IR = 6.3) men, during suppression of endogenous insulin by somatostatin, with and without an insulin infusion that elevated insulin to 24.6 +/- 5.2 and 23.2 +/- 5.8 mU/l (P = 0.76), concentrations similar to fasting levels of the resistant subjects and approximately threefold above those of the insulin-sensitive subjects. Insulin-evoked change in global cerebral metabolic rate for glucose was reduced in insulin resistance (+7 vs. +17.4%, P = 0.033). Insulin was associated with increased metabolism in ventral striatum and prefrontal cortex and with decreased metabolism in right amygdala/hippocampus and cerebellar vermis (P < 0.001), relative to global brain. Insulin's effect was less in ventral striatum and prefrontal cortex in the insulin-resistant subjects (mean +/- SD for right ventral striatum 3.2 +/- 3.9 vs. 7.7 +/- 1.7, P = 0.017). We conclude that brain insulin resistance exists in peripheral insulin resistance, especially in regions subserving appetite and reward. Diminishing the link be-tween control of food intake and energy balance may contribute to development of obesity in insulin resistance.

Differential changes in brain glucose metabolism during hypoglycaemia accompany loss of hypoglycaemia awareness in men with type 1 diabetes mellitus. An Abstract Aims/hypothesis: Hypoglycaemia unawareness in type 1 diabetes increases the risk of severe hypoglycaemia and impairs quality of life for people with diabetes. To explore the central mechanisms of hypoglycaemia awareness, we used [ 11 C]-3-O-methyl-D-glucose (CMG) positron emission tomography (PET) to measure changes in global and regional brain glucose metabolism between euglycaemia and hypoglycaemia in aware and unaware diabetic subjects. Materials and methods: Twelve men with type 1 diabetes, of whom six were characterised as aware and six as unaware of hypoglycaemia, underwent two CMG-PET brain scans while plasma glucose was controlled by insulin and glucose infusion either at euglycaemia (5 mmol/l) or at hypoglycaemia (2.6 mmol/l) in random order. Results: With hypoglycaemia, symptoms and sweating occurred only in the aware group. Brain glucose content fell in both groups (p=0.0002; aware, 1.18± 0.45 to 0.02±0.2 mmol/l; unaware, 1.07±0.46 to 0.19±0.23 mmol/l), with a relative increase in tracer uptake in prefrontal cortical regions, including the anterior cingulate. No detectable differences were found between groups in global brain glucose transport parameters (K 1 , k 2 ). The cerebral metabolic rate for glucose (CMRglc) showed a relative rise in the aware subjects (11.839±2.432 to 13.958± 2.372) and a fall in the unaware subjects (from 12.457± 1.938 to 10.16±0.801 μmol 100 g −1 min −1 , p=0.043). Conclusions/interpretation: Hypoglycaemia is associated with reduced brain glucose content in aware and unaware subjects, with a relative preservation of metabolism in areas associated with sympathetic activation. The relative rise in global glucose metabolic rate seen in aware subjects during hypoglycaemia contrasted with the relative fall in the unaware subjects and suggests that cortical neuronal activation is a necessary correlate of the state of hypoglycaemia awareness.

Aims/hypothesis. Our hypothesis is that reducing release of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) with modafinil will enhance symptomatic and hormonal responses to hypoglycaemia. Methods. Nine healthy men received, in random order, two 100-mg doses of modafinil or placebo, followed by an insulin clamp in which plasma glucose was either reduced stepwise to 2.4 mmol/l or was sustained at euglycaemia (four studies). Catecholamines, symptom scores and cognitive function were measured. Results. Modafinil had no effect on the measured parameters during euglycaemia. During hypoglycaemia, autonomic symptom scores were significantly higher with modafinil (increase at lowest plasma glucose concentration 271.3±118.9 vs 211.2±80.4/40 min, p=0.019), and the heart rate response was increased (12,928±184 vs 6773±148 bpm/140 min, p=0.016). Deterioration in performance of two cognitive tasks was reduced: Stroop colour-word test (613±204 vs 2375±161/65 min, p=0.009) and accuracy of a simple reaction task (11.3±1.8 vs 9.4±3.7, p=0.039). Conclusions/interpretation. We conclude that modafinil improves adrenergic sensitivity and some aspects of cognitive function at hypoglycaemia, possibly by reducing neuronal central GABA concentrations.

Single doses of pharmacological agents which alter membrane KATP channel activity do not affect the counterregulatory response to hypoglycaemia but may modify cognitive function during cerebral glucopenia. The unexpected effects of glibenclamide on cortical function suggest a novel action of sulphonylureas that warrants further investigation.

Aims/hypothesis. The role of glucose sensing cells in the human hepatic portal system in the initiation of the neuroendocrine responses to acute hypoglycaemia is not known. We investigated the effect of raising blood glucose concentrations in the hepatic-portal vein on neurohumoral responses during induction of systemic hypoglycaemia in nine healthy male volunteers. Methods. Each subject received an insulin infusion (3 mU·kg -1 ·min -1 ) on two occasions, in random order. Variable rate glucose infusion was used to maintain plasma glucose at 5 mmol/l for 60 min, then 3.2 mmol/l for 60 min. At 20 min prior to hypoglycaemia, subjects drank 20 g of glucose in water or water sweetened with saccharin. In five of the volunteers, the oral glucose was labelled with U-13C6 glucose, which showed peak systemic glucose absorption between 90 and 110 min. Five volunteers also repeated the study with a euglycaemic clamp.Results. Oral glucose was associated with a reduction in the early adrenaline response to hypoglycaemia, the area under the curve from 90 to 110 min falling from 24.02±20.84 (means ± SD) to 15. vere hypoglycaemia during the pharmacological treatment of diabetes mellitus. The inability to generate or detect the warning symptoms of early hypoglycaemia puts diabetic patients at high risk of episodes of severe hypoglycaemia [1] and often the fear of hypoglycaemia limits the optimisation of glycaemic control [2]. Associated with loss of subjective awareness of hypoglycaemia is a lowering of the glucose concentration required to initiate the counterregulatory response to hypoglycaemia, as well as a reduction in the magnitude and intensity of the counterregulatory response at any given blood glucose concentration [3,4,5]. The speculation that these defects are principally the result of defective glucose sensing gains support from data showing similar changes in the neuroendocrine rePerception of a minor decrease in plasma glucose concentration and initiation of a counterregulatory response are essential factors in the defence against se-

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