Prolonged stimulation of insulin secretion by depolarization and Ca²⁺ influx regularly leads to a reversible state of decreased secretory responsiveness to nutrient and nonnutrient stimuli. This state is termed “desensitization.” The onset of desensitization may occur within 1 h of exposure to depolarizing stimuli. Desensitization by exposure to sulfonylureas, imidazolines, or quinine produces a marked cross-desensitization against other ATP-sensitive K⁺ channel (K_ATP channel)-blocking secretagogues. However, desensitized β-cells do not necessarily show changes in K_ATP channel activity or Ca²⁺ handling. Care has to be taken to distinguish desensitization-induced changes in signaling from effects due to the persisting presence of secretagogues. The desensitization by depolarizing secretagogues is mostly accompanied by a reduced content of immunoreactive insulin and a marked reduction of secretory granules in the β-cells. In vitro recovery from a desensitization by the imidazoline efaroxan was nearly complete after 4 h. At this time point the depletion of the granule content was partially reversed. Apparently, recovery from desensitization affects the whole lifespan of a granule from biogenesis to exocytosis. There is, however, no direct relation between the β-cell granule content and the secretory responsiveness. Even though a prolonged exposure of isolated islets to depolarizing secretagogues is often associated with the occurrence of ultrastructural damage to β-cells, we could not find a cogent link between depolarization and Ca²⁺ influx and apoptotic or necrotic β-cell death.

The pancreatic beta-cell transduces the availability of nutrients into the secretion of insulin. While this process is extensively modified by hormones and neurotransmitters, it is the availability of nutrients, above all glucose, which sets the process of insulin synthesis and secretion in motion. The central role of the mitochondria in this process was identified decades ago, but how changes in mitochondrial activity are coupled to the exocytosis of insulin granules is still incompletely understood. The identification of ATP-sensitive K⁺-channels provided the link between the level of adenine nucleotides and the electrical activity of the beta cell, but the depolarization-induced Ca²⁺-influx into the beta cells, although necessary for stimulated secretion, is not sufficient to generate the secretion pattern as produced by glucose and other nutrient secretagogues. The metabolic amplification of insulin secretion is thus the sequence of events that enables the secretory response to a nutrient secretagogue to exceed the secretory response to a purely depolarizing stimulus and is thus of prime importance. Since the cataplerotic export of mitochondrial metabolites is involved in this signaling, an orienting overview on the topic of nutrient secretagogues beyond glucose is included. Their judicious use may help to define better the nature of the signals and their mechanism of action.

The question whether K⁺ depolarization is an appropriate experimental substitute for the physiological nutrient-induced depolarization of the β-cell plasma membrane was investigated using primary mouse β-cells and islets. At basal glucose 40 mM K⁺ induced a massive monophasic response, whereas 15 mM K⁺ had only a minimal insulinotropic effect, even though the increase in the cytosolic Ca²⁺ concentration ([Ca²⁺]_i) was not inferior to that by 20 mM glucose. In voltage-clamp experiments, Ca²⁺ influx appeared as nifedipine-inhibitable inward action currents in the presence of sulfonylurea plus TEA to block compensatory outward K⁺ currents. Under these conditions, 15 mM K⁺ induced prolonged action currents and 40 mM K⁺ transformed the action current pattern into a continuous inward current. Correspondingly, 15 mM K⁺ led to an oscillatory increase and 40 mM K⁺ to a plateau of [Ca²⁺]_i superimposed on the [Ca²⁺]_i elevated by sulfonylurea plus TEA. Raising K⁺ to 15 or 40 mM in the presence of sulfonylurea (±TEA) led to a fast further increase of insulin secretion. This was reduced to basal levels by nifedipine or CoCl₂. The effects of 15 mM K⁺ on depolarization, action currents, and insulin secretion were mimicked by adding 35 mM Cs⁺ and those of 40 mM K⁺ by adding 35 mM Rb⁺, in parallel with their ability to substitute for K⁺ as permeant cation. In conclusion, the alkali metals K⁺, Rb⁺, or Cs⁺ concentration-dependently transform the pattern of Ca²⁺ influx into the β-cell and may thus generate stimuli of supraphysiological strength for insulin secretion.