Rebaudioside A directly stimulates insulin secretion

Rebaudioside A directly stimulates insulin secretion

Rebaudioside A directly stimulates insulin secretion from pancreatic beta cells: a glucose-dependent action via inhibition of ATP-sensitive K+-channels

· R. Abudula,11Department of Endocrinology and Metabolism C, Aarhus University Hospital, Aarhus C, Denmark
· V. V. Matchkov,22The Water and Salt Centre, Institute for Physiology and Biophysics, Aarhus University, Aarhus C, Denmark
· P. B. Jeppesen,11Department of Endocrinology and Metabolism C, Aarhus University Hospital, Aarhus C, DenmarkPer Bendix Jeppesen, Associate Prof. PhD, Department of Endocrinology and Metabolism C, Aarhus University Hospital, Tage-Hansens Gade 2, DK-8000 Aarhus C, DenmarkE-mail:per.bendix.jeppesen@ki.au.dk
· H. Nilsson,22The Water and Salt Centre, Institute for Physiology and Biophysics, Aarhus University, Aarhus C, Denmark
· C. Aalkjær22The Water and Salt Centre, Institute for Physiology and Biophysics, Aarhus University, Aarhus C, Denmark and
· K. Hermansen11Department of Endocrinology and Metabolism C, Aarhus University Hospital, Aarhus C, Denmark

· 1Department of Endocrinology and Metabolism C, Aarhus University Hospital, Aarhus C, Denmark2The Water and Salt Centre, Institute for Physiology and Biophysics, Aarhus University, Aarhus C, Denmark

*The study was supported by the Velux Foundation, the Institute of Experimental Clinical Research, Novo Nordisk PhD plus Prize, Toyota-Fonden, the Danish Heart Foundation, the Faculty of Health Sciences Aarhus University, the Danish Research Agency and the Danish Council for Development Research (RUF).

Recently, we showed that rebaudioside A potently stimulates the insulin secretion from isolated mouse islets in a dose-, glucose- and Ca2+-dependent manner. Little is known about the mechanisms underlying the insulinotropic action of rebaudioside A.

The aim of this study was to define the signalling system by which, rebaudioside A acts. Isolated mouse islets were used in the cAMP[125I] scintillation proximity assay to measure total cAMP level, and in a luminometric method to measure intracellular ATP and ADP concentrations.

Conventional and permeabilized whole-cell configuration of the patch-clamp technique was used to verify the effect of rebaudioside A on ATP-sensitive K+-channels from dispersed single β cells from isolated mouse islets.

Insulin was measured by radioimmunoassay from insulinoma MIN6 cells. In the presence of 16.7 mM glucose, the addition of the maximally effective concentration of rebaudioside A (10−9 M) increased the ATP/ADP ratio significantly, while it did not change the intracellular cAMP level. Rebaudioside A (10−9 M) and stevioside (10−6 M) reduced the ATP-sensitive potassium channel (KATP) conductance in a glucose-dependent manner.

Moreover, rebaudioside A stimulated the insulin secretion from MIN6 cells in a dose- and glucose-dependent manner. In conclusion, the insulinotropic effect of rebaudioside A is mediated via inhibition of ATP-sensitive K+-channels and requires the presence of high glucose.

The inhibition of ATP-sensitive K+-channels is probably induced by changes in the ATP/ADP ratio. The results indicate that rebaudioside A may offer a distinct therapeutic advantage over sulphonylureas because of less risk of causing hypoglycaemia.