Research group leader:
Karolinska University Hospital Solna, L1:03
171 76 Stockholm
Signal transduction in the pancreatic b-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.
The coupling of glucose metabolism to electrical activity remains central in all models of b-cell stimulus-secretion coupling. The resting membrane potential of the b-cell is set by the ATP-sensitive potassium (KATP) channel. Incubation of the pancreatic b-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 b-cell high-Km/low affinity glucose transporter GLUT2 and proceeds with the conversion of glucose into glucose-6-phosphate by the b-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 b-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 b-cell function.
Members of the group