Insulinotropic action of monosaccharide esters: therapeutic perspectives

Abstract

Keywords Monosaccharide esters, insulin release.Several monosaccharide esters were recently introduced as new tools in biomedical research. [1]. These esters seem to be able to cross the plasma membrane without requiring the intervention of a specific carrier system. They then undergo intracellular hydrolysis in esterase-catalysed reactions, so that their glucidic moiety becomes readily available for further metabolism or metabolic action [2,3]. The major aim of this brief review is to draw attention to the possible use of some of these esters as new insulinotropic tools in the treatment of such diseases as Type II (non-insulin-dependent) diabetes mellitus, insulinoma or persistent hyperinsulinaemia in childhood. In the treatment of diabetes, they could be used in combination with other insulinotropic agents such as hypoglycaemic sulphonylureas Experimental findingsEsters of metabolized hexoses, such as a-d-glucose pentaacetate or b-d-glucose pentaacetate, stimulate insulin release from islets incubated either in the absence of any exogenous nutrient or in the presence of such nutrient secretagogues as d-glucose and l-leucine [47] or, as shown in Figure 1, the dimethyl ester of succinic acid (SAD). Unexpectedly, however, some esters of non-metabolized hexoses, such as a-l-glucose pentaacetate and b-l-glucose pentaacetate also show positive insulinotropic action, the most obvious effect being in islets exposed to another nutrient secretagogue, e. g. l-leucine or the dimethyl ester of succinic acid (Fig. 1). Even more surprisingly, monosaccharide esters that inhibit d-glucose metabolism (such as d-mannoheptulose hexaacetate or 2-deoxy-d-glucose tetraacetate) and suppress d-glucose-stimulated insulin release [48, 49], were found to enhance the beta cell secretory response to non-glucidic nutrients, e. g. the dimethyl ester of succinic acid (Fig. 1). When tested in suitably low concentrations, the tetraacetate esters of 2-deoxy-d-glucose even enhance insulin release stimulated by d-glucose [49].Detailed investigations on the metabolic fate of bl-glucose pentaacetate in isolated pancreatic islets and its effects on variables such as protein biosynthesis, cyclic AMP formation, generation of inositol phosphates, intracellular pH, 86 Rb efflux and bioelectrical activity, 45 Ca net uptake and efflux, cytosolic Ca 2+ concentration and insulin release suggest that the esters of non-metabolized monosaccharides with positive insulinotropic action may directly interact with a receptor system, resulting in a decrease in K + conductance, plasma membrane depolarization and induction of electrical activity [50]. This model is thought to have analogies with the recognition of bitter compounds by taste buds [51]. Purified islet beta cells indeed contain the a-gustducin G-protein involved in this recognition process (unpublished observation).The findings mentioned above also raise the idea that some monosaccharide esters, especially those of l-glucose, can be used as insulinotropic tools to stimulate insulin release in Type ...

Pathways in Beta-Cell Stimulus-Secretion Coupling as Targets for Therapeutic Insulin Secretagogues

“…Monosaccharide esters, such as the pentaacetate ester of ␣-D-glucose, enter ␤-cells independently of the glucose transporters and stimulate insulin secretion (33). Because it is unlikely that glucose transport ever becomes ratelimiting in human ␤-cells, the potential interest of these compounds is elsewhere.…”

“…Unexpectedly, in vitro stimulation of insulin secretion is also observed with low concentrations of pentaacetate esters of nonmetabolized hexoses such as L-glucose or 2-deoxyglucose. The effects of these ester compounds are not attributed to an increase in ␤-cell metabolism, which is rather inhibited, but to an interaction with a still unidentified receptor (33). Developments in this area await further studies on the mode of action and potential negative effects of these compounds, as well as demonstration that their insulin-releasing activity is retained in models of type 2 diabetes.…”

Effects of aliphatic dioic acids and glycerol-1,2,3-tris(dodecanedioate) on D-glucose-stimulated insulin release in rat pancreatic islets

“…As far as the triacylglycerol of C12 is concerned, the higher stimulatory effect on insulin release at 1 mM concentration might be ascribed to a bypass phenomenon of dicarboxylic acid-specific receptors with a passive transport by diffusion across the cellular membrane, like that hypothesized for glucose esters (Malaisse, 1999). It is also likely that, once one molecule C12 triacylglycerol enters the b-cells, it must be hydrolysed to one molecule glycerol and three molecules dodecanedioic acid.…”

Differential Acute and Long Term Actions of Succinic Acid Monomethyl Ester Exposure on Insulin‐Secreting BRIN‐BD11 Cells

“…[7] Various esters of a diverse range of nutrients and nutrient metabolites have been demonstrated to exhibit enhanced biological and insulinotropic activity over their parent molecules. [8][9][10][11][12][13][14] *Corresponding author. Tel.…”