The ability to maintain adequate nutrient intake is critical for survival. Complex interrelated neuronal circuits have developed in the mammalian brain to regulate many aspects of feeding behaviour, from food-seeking to meal termination. The hypothalamus and brainstem are thought to be the principal homeostatic brain areas responsible for regulating body weight. However, in the current 'obesogenic' human environment food intake is largely determined by non-homeostatic factors including cognition, emotion and reward, which are primarily processed in corticolimbic and higher cortical brain regions. Although the pleasure of eating is modulated by satiety and food deprivation increases the reward value of food, there is currently no adequate neurobiological account of this interaction between homeostatic and higher centres in the regulation of food intake in humans. Here we show, using functional magnetic resonance imaging, that peptide YY3-36 (PYY), a physiological gut-derived satiety signal, modulates neural activity within both corticolimbic and higher-cortical areas as well as homeostatic brain regions. Under conditions of high plasma PYY concentrations, mimicking the fed state, changes in neural activity within the caudolateral orbital frontal cortex predict feeding behaviour independently of meal-related sensory experiences. In contrast, in conditions of low levels of PYY, hypothalamic activation predicts food intake. Thus, the presence of a postprandial satiety factor switches food intake regulation from a homeostatic to a hedonic, corticolimbic area. Our studies give insights into the neural networks in humans that respond to a specific satiety signal to regulate food intake. An increased understanding of how such homeostatic and higher brain functions are integrated may pave the way for the development of new treatment strategies for obesity.

The authors' aim was to examine the regional anatomy of brain activation by cognitive tasks commonly used in hypoglycemia research and to assess the effect of acute hypoglycemia on these in healthy volunteers. Eight right-handed volunteers performed a set of cognitive tasks-finger tapping (FT), simple reaction time (SRT), and four-choice reaction time (4CRT)-twice during blood oxygen level-dependent (BOLD) functional magnetic resonance imaging of the brain on two occasions. In study 1 (n ‫؍‬ 6), plasma glucose was maintained at euglycemia (5 mmol/l) throughout. In study 2 (n ‫؍‬ 6), plasma glucose was reduced to 2.5 mmol/l for the second set. Performance of the tasks resulted in specific group brain activation maps. During hypoglycemia, FT slowed (P ‫؍‬ 0.026), with decreased BOLD activation in right premotor cortex and supplementary motor area and left hippocampus and with increased BOLD activation in left cerebellum and right frontal pole. Although there was no significant change in SRT, BOLD activation was reduced in right cerebellum and visual cortex. The 4CRT deteriorated (P ‫؍‬ 0.020), with reduction in BOLD activation in motor and visual systems but increased BOLD signal in a large area of the left parietal association cortex, a region involved in planning. Hypoglycemia impairs simple brain functions and is associated with task-specific localized reductions in brain activation. For a task with greater cognitive load, the increased BOLD signal in planning areas is compatible with recruitment of brain regions in an attempt to limit dysfunction. Further investigation of these mechanisms may help devise rational treatment strategies to limit cortical dysfunction during acute iatrogenic hypoglycemia. Diabetes 50:1618 -1626, 2001

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.

This study investigates and compares human insulin (recombinant DNA) and purified porcine insulin (PPI) in healthy volunteers and in type II diabetic patients, in terms of whether both these insulins were capable of influencing in a different manner pancreatic glucagon, C-peptide, and free fatty acids (FFA) concentrations. The findings reveal that the beta-cell of human pancreas apparently recognizes human insulin more readily than PPI, as assessed by the inhibition of C-peptide, and a similar conclusion follows for the alpha-cell; this conclusion is underscored by the inhibited glucagon values. The delayed increments of glucagon under human insulin following arginine stimulation may be the result of a more rapid insulin absorption from subcutaneous tissue and a greater biologic action of this insulin in comparison with the PPI. Finally, human insulin has additional properties as demonstrated by its stronger antilipolytic effects.

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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