Effects on metabolic rate and fuel selection of a selective beta-3 agonist (ICI D7114) in healthy lean men.

METHOD: ICI D7114 is a selective beta-3 agonist which in some animals increases metabolic rate, promotes weight loss and improves glucose tolerance. To investigate its potential usefulness in humans, 16 healthy young men (mean age 28.9 +/- 8.0 years; body mass index 22.5 +/- 1.6 kg/m2) were given ICI D7114 (150 mg/day, 2.08 +/- 0.24 mg/kg body weight) or placebo for 14 days in a double-blind randomised parallel group trial. Energy expenditure (EE) and substrate oxidation were assessed by continuous whole-body indirect calorimetry on Day 0 (before dosing), on day 1 (acute effect) and on Day 14 (chronic effect). RESULTS: Analysis of covariance indicated no significant effects on EE 4 h post-dose (Day 1, +2.4%, NS; Day 14, +1.0%, NS). There was no chronic effect on either the lowest 1 h of sleeping EE (+2.2%, NS) or 24 h EE (+0.7%, NS). There was a marginally significant chronic stimulation of basal metabolic rate (+3.6%, P = 0.042). ICI D7114 had no significant influence on protein, fat or carbohydrate oxidation. Tolerability and safety data showed that there were no increases in resting heart rate or blood pressure; no change in plasma potassium or reports of tremor; no haematological or biochemical abnormalities and no adverse events. CONCLUSION: We conclude that over 14 days ICI D7114 at a dose level of 150 mg/day has no biologically significant effect on EE in healthy, lean men.

Lactate alters plasma membrane potential, increases the concentration of cytosolic Ca2+ and stimulates the secretion of insulin by the hamster beta-cell line HIT-T15.

We have studied the effect of lactate on a number of intracellular events which may be important in controlling the secretion of insulin by the hamster beta-cell line HIT-T15. Using the fluorescent dye Oxonol V, as well as intracellular recording techniques to measure changes in membrane potential, we found that lactate, glucose, K+ and tolbutamide caused depolarization of HIT cells, while valinomycin resulted in hyperpolarization. Consistent with these findings was the observation that 10 mM lactate caused an increase of 69.0 +/- 18.4% (S.E.M., n = 6) in the level of free cytosolic Ca2+ within HIT cells (assessed by fluorescence of quin 2). This was probably due to influx of Ca2+ through voltage-sensitive calcium channels, since it was dependent upon the concentration of extracellular Ca2+ and inhibited by verapamil. Lactate also caused cytosolic acidification in HIT cells and increased the secretion of insulin. These findings are consistent with the view that the electrogenic efflux of lactate could be a determinant in the activation of HIT cells by lactate and possibly by glucose.

Inositol uptake and metabolism in molluscan neuronal tissue.

The uptake of myo-[3H]inositol into neurones from Lymnaea stagnalis has been demonstrated to be a sodium-dependent process, saturable with a Km of approximately 50 microM and shown to be linear with time for at least 120 min. The rate of transport of myo-inositol into the cell appears to influence directly its incorporation into neuronal lipids. Using anion-exchange high-performance liquid chromatography, we have demonstrated a high rate of breakdown of phosphatidylinositol 4,5-bisphosphate in Lymnaea nerve under basal conditions. Stimulation with carbamylcholine enhanced production of inositol 1-phosphate, inositol bisphosphate, inositol 1,4,5-trisphosphate, and inositol 1,3,4-trisphosphate. Formation of inositol tetrakisphosphate was not detected. Electrical stimulation also caused an increased formation of inositol phosphates. These results provide evidence for an active myo-inositol transport system in molluscan neurones and suggest that the hydrolysis of inositol lipids may play a role as an intracellular signalling system in this tissue.

Organization of rhythmic buccal motor output of Lymnaea stagnalis in the absence of food.

The pond snail Lymnaea stagnalis exhibits spontaneous rasping movements in the absence of food which are thought to be involved in food searching activity. Rasping activity is patterned into bouts, separated by periods of quiescence. Recordings from buccal feeding motoneurons in the isolated CNS reveal similar bouts of rhythmic motor output, though the modal cycle period is significantly longer than that shown by intact snails. Log survivorship curves of interval data from both intact animals and isolated CNS indicate that the pattern of motor output is controlled by at least two processes, one generating intervals between rasps within a bout, and the other generating intervals between bouts of rasping. When compared to well-fed individuals, 2-day-starved snails show significant enhancement of the probability function for generation of intervals between rasps within a bout; the function underlying between-bout intervals is not significantly affected.

Food arousal in the pond snail, Lymnaea stagnalis.

Factors affecting food arousal were examined in a behavioral study of the freshwater, browsing pulmonate, Lymnaea stagnalis. Presentation of a food stimulus (sucrose) leads to a progressive decrease in interbite interval over the first four subsequent bites. This is thought to represent an increase in food-induced arousal. The latency to first bite is correlated with total number of bites in the first 5 min following application of food. Latency to bite is significantly reduced for up to 15 min following a brief food stimulus. Previous levels of food consumption do not significantly affect latency to bite (i.e., food responsiveness). However, hunger does lead to an increase in spontaneous biting activity in the absence of food (i.e., food search activity). Latency to bite is negatively correlated with a more general measure of behavioral arousal, the Behavioral State Score. These results are discussed in relation to previous work on other gastropod species. It is concluded that mechanisms of food arousal are adapted to the animal's habitat and life-style.