The signalling role of action potential depolarization in insulin secretion: metabolism-dependent dissociation between action potential increase and secretion increase by TEA.

The K(+) channel blocker, TEA is known to increase action potential amplitude and insulin secretion of mouse beta-cells when added to a nutrient secretagogue. In the presence of a maximally effective sulfonylurea concentration (2.7 microM glipizide) the nutrient secretagogue alpha-ketoisocaproic acid (KIC, 10mM) strongly increased insulin secretion (about elevenfold). Instead of enhancing the effect of KIC, TEA reduced the KIC-induced secretion by more than 50%. Also, the secretion rate produced by 2.7 microM glipizide alone was significantly reduced by TEA. In contrast, TEA enhanced the insulinotropic effect of glipizide when a basal glucose concentration (5mM) was present. In the presence as well as in the absence of glucose glipizide produced a plateau depolarization with superimposed action potentials. Under both conditions, TEA increased the glipizide-induced action potential amplitude and further elevated the cytosolic free calcium concentration ([Ca(2+)](i)) with an oscillatory characteristic. These effects depended on the activity of L-type Ca(2+) channels, even though the effect of TEA differed from that of 1 microM of the Ca(2+) channel opener, Bay K8644, which primarily increased action potential duration. TEA did not negatively affect parameters of beta-cell energy metabolism (NAD(P)H fluorescence and ATP/ADP ratio), rather, it slightly increased NAD(P)H fluorescence. Apparently, TEA inhibits insulin secretion in the absence of glucose in spite of a persistent ability to block K(+) ion conductance. Thus, the signalling role of action potential depolarization in insulin secretion may require reconsideration and ion conductance-independent actions of K(+) channels may be involved in this paradox effect of TEA.

Reduced conduction reserve of the propagating cardiac impulse in the diabetic rat heart: a model study.

Conduction velocity is dependent on two main factors: intercellular electrical coupling and cellular electrical excitability. There is significant redundancy, 'conduction reserve', in these parameters such that significant reduction in the conduction velocity of the action potential requires either a severe change in one of these parameters or a combined change in both parameters. Studies in diabetic rat hearts have shown a significant reduction in the conduction reserve and it was hypothesized that this is mainly due to the lateralization of the gap junction protein connexin 43 (Cx43). To gain a better understanding of the effect of reduced intercellular coupling, a rat ventricle myocyte model was used to simulate propagation along a strand of cells. Simulations were performed to assess the effect of reduction of intercellular conductance on the conduction velocity. As the conductance of the gap junction decreased a significant reduction in the conduction velocity was observed. The relationship between conduction velocity and intercellular coupling became steeper with decreasing coupling, such that conduction velocity became increasingly sensitive to further uncoupling. This is consistent with experimental results, in which application of the gap junction uncoupler heptanol caused a larger conduction slowing in diabetic hearts than in controls.