Research Areas - Signal Transduction

Signal transduction in the pancreatic beta-cell and thereby the insulin secretory process is regulated by a sophisticated interplay between glucose and a plethora of additional factors including other nutrients, neurotransmitters, islet generated factors and systemic growth factors.

Invivo imaging workflow

The coupling of glucose metabolism to electrical activity remains central in all models of beta-cell stimulus-secretion coupling. The resting membrane potential of the beta-cell is set by the ATP-sensitive potassium (KATP) channel. Incubation of the pancreatic beta-cell with stimulatory glucose concentrations leads to the activation of a cascade of reactions which ends in the exocytosis of stored insulin. This complex of processes starts with the uptake of glucose by the beta-cell high-Km/low affinity glucose transporter GLUT2 and proceeds with the conversion of glucose into glucose-6-phosphate by the beta-cell isoform of glucokinase. Metabolism of glucose in glycolysis and the Krebs cycle results in the generation of ATP. Elevation in the ATP/ADP ratio leads to closure of the KATP, which in turn results in depolarization of the plasma membrane.

The subsequent opening of voltage-gated L-type Ca2+ channels leads to an increase in the cytoplasmic free Ca2+ concentration, [Ca2+]i, which promotes insulin secretion. With regard to the actions of the plethora of additional factors like neurotransmitters, islet generated factors and systemic growth factors; they are in most cases mediated by membrane receptors coupled to either G-proteins or tyrosine kinases, many of which subsequently activate the phosphoinositide-derived second messenger cascades. Among other things, the role of signalling through these receptor-operated effector systems is the focus of our work.

Pancreatic beta-cell signal transduction is complex and involves a well-regulated interaction of a number of signals generated by the metabolism of glucose and the activation of a variety of receptor-operated pathways. Our future research will tell to what extent these various signalling pathways are really regulatory pathways under in vivo conditions or rather serve as signalling pathways maintaining normal beta-cell function.