The cytoskeleton and the regulation of gluconeogenesis: a hypothesis

Previous data from our laboratory indicated a role for the cytoskeleton in the hormonal stimulation of gluconeogenesis. To gain further insight into the role of the cytoskeleton in the regulation of gluconeogenesis, we performed further experiments to examine the possibility that the cytoskeleton is involved in the glucagon-mediated changes in calcium distribution. Perfused livers or isolated liver cells were pretreated with either cytochalasin B or colchicine, agents that disrupt microfilaments and microtubules, respectively. Pretreatment with either agent significantly decreased the glucagon-evoked efflux of labeled calcium. Pretreatment with colchicine was more effective in blocking the influx of calcium into the cells than pretreatment with cytochalasin B. These drugs also prevented the characteristic increase in O(2) uptake, which is usually observed after glucagon administration. Thus, an intact cytoskeleton seems to be a prerequisite for the glucagon-evoked changes in calcium distribution to occur. These changes in calcium fluxes were shown previously to be an essential link in the chain of events leading to the metabolic effects of glucagon. Based on these results and on data obtained by others, a hypothesis is presented here. The hypothesis presumes that the cytoskeleton plays a crucial role in the regulation of gluconeogenesis. The hypothesis further assumes that the cytoskeleton influences gluconeogenesis in 3 ways: (1) by influencing the process of calcium signaling; (2) by changing the rate of enzymatic reactions through association and dissociation of enzymes with the cytoskeleton; and (3) by altering the position of intracellular organelles and the movements of molecules. Each of these points is discussed separately. It is known that the intracellular environment exists as a dense mesh in dynamic motion. According to our hypothesis, hormonal stimulation changes this environment by affecting the ionic composition in the cytosol and the structure of the cytoskeleton. Motion and conformational changes by the cytoskeleton play crucial regulatory functions, influencing metabolic processes.