A single mechanism for the stimulation of insulin release and 86Rb+ efflux from rat islets by cationic amino acids

Abstract

The mechanisms by which cationic amino acids influence pancreatic B-cell function have been studied by monitoring simultaneously (86)Rb(+) efflux and insulin release from perifused rat islets. The effects of two reference amino acids arginine and lysine were compared with those of closely related substances to define the structural requirements for recognition of these molecules as secretagogues. Arginine accelerated (86)Rb(+) efflux and increased insulin release in the absence or in the presence of 7mm-glucose. Its effects on efflux did not require the presence of extracellular Ca(2+) or Na(+), but its insulinotropic effects were suppressed in a Ca(2+)-free medium and inhibited in an Na(+)-free medium. Among arginine derivatives, only 2-amino-3-guanidinopropionic acid mimicked its effects on (86)Rb(+) efflux and insulin release; citrulline, guanidinoacetic acid, 3-guanidinopropionic acid and guanidine were inactive. Norvaline and valine also increased (86)Rb(+) efflux, but their effect required the presence of extracellular Na(+); they did not stimulate insulin release. Lysine as well as the shorter-chain cationic amino acids ornithine and 2,4-diaminobutyric acid accelerated (86)Rb(+) efflux in a Ca(2+)- and Na(+)-independent manner. Their stimulation of insulin release was suppressed by Ca(2+) omission, but only partially inhibited in an Na(+)-free medium. The uncharged glutamine and norleucine increased the rate of (86)Rb(+) efflux in the presence of glucose, only if extracellular Na(+) was present. Norleucine slightly increased release in a Ca(2+)- and Na(+)-dependent manner. The effects of lysine on efflux and release were not mimicked by other related substances such as 1,5-diaminopentane and 6-aminohexanoic acid. The results suggest that the depolarizing effect of cationic amino acids is due to accumulation of these positively charged molecules in B-cells. This causes acceleration of the efflux of K(+) ((86)Rb(+)) and activation of the influx of Ca(2+) (which triggers insulin release). The prerequisite for the stimulation of B-cells by this mechanism appears to be the presence of a positive charge on the side chain of the amino acid, rather than a specific group.

Effects of Glucose and Amino Acids on Free ADP in βHC9 Insulin-Secreting Cells

“…Through an unknown mechanism, antecedent hyperglycemia decreases the secretory response of B-cells to glutamine plus leucine (17). Glucose-induced insulin release is amplified by arginine or lysine alone (18)(19)(20). Thereby, on a molar basis, arginine is about equipotent with a physiological mixture of amino acids (18).…”

<b>Pancreatic islets isolated from β₂ adrenergic receptor knockout mice show reduced insulin secretion in response to nutrients</b> - doi: 10.4025/actascibiolsci.v35i3.15842

“…The insulin secretion induced by the hyperpolarizing agent KCl was also reduced to 43% of that detected in the isolated pancreatic islets of the wild-type (Figure 3). Furthermore, the total insulin content was reduced in pancreatic islets β 2 KO mice as compared to the control group (WT = 125.2 ± 5.6 vs β 2 KO = 102.8 ± 8.5 ng islets β 2 KO mice showed lower body weight, as reported by Chruscinski et al (1999). Those animals are leaner when compared to the control group, and that result was evidenced by the reduced weight of the periepididymal fat pad.…”

“…Another interesting observation was the reduced effect of glucose plus arginine and leucine on insulin secretion. Despite the fact that the mechanism of L-arginine-induced insulin secretion is not fully clarified, many authors suggest that the potentiation of glucose-induced insulin secretion by L-arginine is mediated by β-cell membrane depolarization due to the electrogenic influx of the cationic amino acid into the β-cell as described by Charles et al (1982), Henquin and Meissner (1981), Blachier et al (1989), Hermans et al (1987), andSmith et al (1997). Thus, amino acid depolarizes the plasma membrane, whose effect is enhanced by glucose as shown by Hermans et al (1987), and stimulates Ca 2+ influx by activation of voltage-sensitive Ca 2+ channels according to Hermans et al (1987), Smith et al (1997), andWeinhaus et al (1997).…”

“…Several matings were carried out to obtain knockout mice for the β 2 -AR -/-(β 2 KO) (CHRUSCINSKI et al, 1999;MEDEIROS et al, 2008). Four-month-old mice were used.…”

Overexpression of dominant negative mutant hepatocyte nuclear factor (HNF)-1α inhibits arginine-induced insulin secretion in MIN6 cells

“…Nitric oxide, which is generated from arginine, was proposed as a mediator of insulin secretion [16] but this is controversial [13,17]. A more favoured hypothesis is that the uptake of cationic amino acids directly depolarizes the beta-cell membrane and triggers insulin secretion [13,18]. Recently, the high capacity, low affinity cationic amino acid transporter, CAT2 was suggested to mediate the potentiation of insulin secretion [13].…”