SENSOR(S) OF MEMBRANE LIPID FLUIDITY IN HEALTH AND DIABETES
- Reference number
- ID16-0049
- Start and end dates
- 170101-220630
- Amount granted
- 2 500 000 SEK
- Administrative organization
- Göteborg University
- Research area
- Life Sciences
Summary
Studying the C. elegans homologs of the anti-diabetic adiponectin receptors (ADIPOR1/2) has led us to formulate a radically new hypothesis: The Membrane Theory of Diabetes. We hypothesize that excess saturated fatty acids (obtained through a diet rich in saturated fats or through conversion of sugars into fats via lipogenesis) leads to rigid cellular membranes that in turn impair insulin signalling, glucose uptake and blood circulation, thus creating a vicious cycle that contributes to the development of overt diabetes. AIM: We aim to thoroughly test this hypothesis and extend our exciting discovery of ADIPOR function in C. elegans to the context of pathophysiology of type 2 diabetes in mammalian systems such that the therapeutic potential of the ADIPOR pathway may be realized. The experimental plan includes: 1) Mammalian cell line models to test the membrane fluidity hypothesis and define the mechanisms of action of the ADIPORs; 2) Mouse models to test the membrane fluidity hypothesis in vivo; 3) Work on C. elegans to define the ADIPOR pathway and function in glucose tolerance; and 4) Screen for compounds that modulate membrane fluidity. Expected results are the determination of the role of membrane fluidity in diabetes, elucidation of molecular mechanisms that regulate membrane fluidity, and the identification of compounds that influence membrane fluidity. This is a wonderful PhD project based on great preliminary results and a path to many exciting experiments.
Popular science description
It is well known that diabetes is associated with high blood glucose and that this is bad for the affected patients. But why is it bad to have slightly elevated blood glucose. Yes: it leads to kidney failure, loss of sensation in extremities, damaged to the retina in the eyes and cardiovascular disease... But that doesn't explain why the high glucose causes these problems. We have studied a very small nematode worm, C. elegans, and found that when these worms lack a specific protein (PAQR-2) they become very sensitive to glucose and die when exposed to the same amounts of glucose that leads to diabetes complications in patients. When we studied that protein, we then discovered that its function is to make sure that the membranes that surround the cells are soft and dynamic. We further found that glucose causes the membranes to become rigid in our mutant worms lacking PAQR-2. So now we think we have a possible new explanation for diabetes: high sugars cause bad cellular membranes. Bad cellular membranes could lead to poor insulin secretion and signalingand even hurt glucose clearance from blood! The reason for this is that the membranes of the cells is exatly where the receptors for insulin and the proteins that can transport glucose out of the blood are located. Now, we propose to test our new "membrane theory of diabetes" using cell lines, mouse models and doing more research with the small nematode worm that has been so useful so far.