Role of the incretin hormone GIP
Role of the incretin hormone GIP in the development of diabetic vascular complications - good or bad?
The incretin hormones GIP (glucose-dependent insulinotropic polypeptide) and GLP-1 (glucagon-like peptide-1) are released from the intestine after food ingestion to stimulate insulin secretion in a glucose-dependent manner. Both GIP and GLP-1 are rapidly degraded by the enzyme dipeptidyl peptidase IV (DPP IV), inhibition of which is a novel approach to enhance incretin levels in the treatment of type 2 diabetes. Apart from their insulinotropic activity, GIP and GLP-1. I have been ascribed a plethora of actions in other tissues, including the cardiovascular system. Growing evidence suggests a cardioprotective role of GLP-1-signaling, but not much is known about GIP-signalng in this context.
In these studies we explore the role of GIP, its receptor GIPR and their genetic variation, as well as their downstream target, the cytokine osteopontin (OPN) in the development of vascular complications of diabetes.
Specifically, we aim to:
Investigate whether genetic deletion of GIPR prtects the retina and kidney from early changes induced by diabetes.
Study whether GIP/GIPRsignaling is involved in the regulation of blood pressure.
Study the impact of common variants in the genes encoding for GIP, the GIP degrading enzymes dipeptidyl peptidases (DPPs), and OPN on diabetic complications.
Explore the underlying factors and molecular mechanisms involved in the regulation of GIPR and OPN expression in the vasculature.
This project includes in vitro and in vivo experiments, using human (large number of non-diabetic and diabetic individuals, vesll biopsies) and animal (GIPR KO, Ins2Akita and STZ-induced diabetic mice) materials and well-equipped facilities for molecular biology (high-throughput genotyping platform, Mass Array-Sequenom, Taqman), biochemistry (multiplex), histology (confocal imaging, EM) and functional blood pressure microvascular function, GFR) studies.
The described project has great potential to generate novel information on molecular genetic mechanisms contributing to diabetic microvascular complications.