Initiation of Insulin Secretion

Initiators of insulin secretion switch on the secretory machinery. Thereafter modulators derived from nutrient metabolism, hormones/peptides and neurotransmitters determine how fast or slow the machine will run. 

It is now well accepted that initiation of insulin release in response to glucose and other nutrients is caused by depolarization of the B-cell as a first step followed by subsequent Ca2+ influx. 

As far as other ions are concerned available evidence suggests that specific permeability to Na+, Cl, Ca2+ or Mg2+ is not involved in the initial depolarization (for a review see Henquin et al., 1992). 

Perforated patch records suggest that about 10-25% of total K+-ATP conductance is activated at rest in mouse B-cells (Ashcroft and Rorsman, 1989) and rather less (about 4%) in rat B-cells (Cohen et al., 1990). Cell-attached patch recordings have established that 50% of the channels are inhibited at 2mM glucose and more than 90% at 5 mM (Misler et al., 1986 Ashcroft et al., 1988 Rorsman and Trube, 1990). For depolarization only the ATP-sensitive K+ channels are responsible. This means that closure occurs when the intracellular ATP and/or the intracellular ATP/ADP ratio (Section 3.3.4) increases in response to increased nutrient (mainly glucose) metabolism (Fig. 17). 

---

The most potent initiator of insulin secretion is glucose. Under physiological conditions its action is modulated by hormones, peptides and neurotransmitters as discussed later. 

As discussed above (see chapter 6, section 4.1), initiation of insulin secretion via depolarization can be modulated by compounds that affect the adenylate cyclase system. It is therefore not surprising that glucagon and db-cAMP potentiate tolbutamide-induced insulin secretion (Ammon, 1975). This also holds for methylxanthines which, at the concentrations used in vitro, inhibit phosphodiesterase and thus cAMP (Lambert et al., 1971 Ammon, 1975). 

Oscillations of [Ca2+][ have been reported following initiation of insulin release by nutrients and sulphonylureas (Heilman etal., 1992). The frequency of these large-amplitude oscillations corresponds to 0.2-0.5 min-1 in mouse B-cells, which is similar to the slow cyclic variations in burst activity recorded with intracellular microelectrodes in intact islets and also the periodicity of insulin release. However, this oscillatory pattern of the electrical and [Ca2+]j responses induced by glucose is not accompanied by, and thus probably not due to, similar oscillations in metabolism (Gilon and Henquin, 1992). However, Longo et al. (1991) reported oscillations with similar periods in insulin secretion, oxygen consumption and [Ca2+]j. Since oscillations appear in vivo as well as in vitro there must be a pacemaker in the islet tissue itself (Goodner et al., 1991). 

Thus, when trying to put the pieces together with regard to glucose as an initiator and modulator of insulin secretion, it appears that formation of ATP switches on the system, but changes in metabolism including the redox state of nicotinamide nucleotides modulate the system in its response to depolarization. 

Regarding stimulation of insulin secretion "in vitro" by amino acids, pieces of rat and rabbit pancreas mere incubated in media consisting of the usual buffer plus o.l, l.o and 10 mg amino acid/ml for 2 and 3 hours, respectively (Pfeiffer et al (1967), Yeboah (1967)). In Fig. 7 are shomn the responses of rabbit and rat pancreas "in vitro" to 1-leucine, the first amino acid shomn to induce insulin secretion "in vivo" in insulinoma patients (Cochrane, et al (1956)). Increases in Iffll concentrations up to 300% of the initial values recorded as 100 mere noted. Higher sensitivity of the rabbit than of the rat 0—... 

Glycolytic oscillations in yeast cells provided one of the first examples of oscillatory behavior in a biochemical system. They continue to serve as a prototype for cellular rhythms. This oscillatory phenomenon, discovered some 40 years ago [36, 37] and still vigorously investigated today [38], was important in several respects First, it illustrated the occurrence of periodic behavior in a key metabolic pathway. Second, because they were soon observed in cell extracts, glycolytic oscillations provided an instance of a biochemical clock amenable to in vitro studies. Initially observed in yeast cells and extracts, glycolytic oscillations were later observed in muscle cells and evidence exists for their occurrence in pancreatic p-cells in which they could underlie the pulsatile secretion of insulin [39]. 

---