Nutrient Regulation O F Insulin Secretion

The ATP-sensitive K+ channel (KAT, channel), a particular class of K + channel inhibited by intracellular ATP, was first described in cardiac muscle [ 11 and has subsequently been found in pancreatic B-cells [2], skeletal muscle [3], smooth muscle [4] and central neurons [ 5 ] . There is considerable evidence that this channel plays an essential role in the regulation of insulin secretion from the pancreatic B-cell [6]. Glucose-stimulated insulin release is dependent on both the metabolism of the sugar [7] and B-cell electrical activity [8]. The K, channel plays a central role in stimulus-secretion coupling because it provides the link between metabolic and membrane events. The channel is also, inhibited by the hypoglycaemic sulphonylureas [Y], a class of drugs used in the treatment of non-insulin-dependent diabetes mellitus. This latter observation suggests that non-insulin-dependent diabetes mellitus may be a consequence of defective regulation of the KATp channel. In the absence of glucose, the B-cell is electrically silent. Glucose produces a concentration-dependent depolarization of the B-cell membrane which reaches the threshold for initiation of electrical activity at concentrations beween 5 and 7 mM. This electrical activity consists of slow oscillations of membrane potential (bursts or slow waves) between a depolarized plateau potential on which Ca? +-dependent action potentials are superimposed and a hyperpolarized silent phase. Further increases in glucose concentration augment the frequency of action potentials by increasing the duration of the plateau and decreasing the intervals between them. Finally, at glucose concentrations above 16 mM electrical activity is continuous. Glucose modulation of B-cell electrical activity serves to regulate Ca'+ entry across the plasma membrane and thereby insulin secretion. The resting potential of the unstimulated B-cell is predominantly determined by the K, channel. All primary secretagogues, including glucose and sulphonylureas, depolarize the B-cell, and initiate electrical activity by closing this channel. The properties and regulation of the K,, channel have been previously reviewed [6]. Here we concentrate on three questions which have been the focus of recent studies: (1) Is ATP the main physiological regulator of K, channel activity in the B-cell? ( 2 ) Can the modulation of K, channel activity account for the concentrationdependent effects of glucose on B-cell electrical activity and insulin secretion? ( 3 ) Is the inhibitory action of hormones, such as galanin, on B-cell electrical activity mediated thorough changes in K,,, channel activity?