The role of insulin is to lower blood glucose levels by stimulating glucose uptake into muscle and adipose tissue. Resistance to insulin, a phenomenon directly involved in the pathogenesis of type 2 diabetes, remains to be understood. Basic research has yet to fully discover how insulin action is elicited. Research in the laboratory of Paul R. Langlais, Ph.D., focuses on the identification and characterization of proteins involved in insulin signal transduction and also tests whether the dysfunction of these proteins is involved in the pathogenesis of insulin resistance and type 2 diabetes.
Dr. Langlais specializes in the use of mass spectrometry to perform proteomics, a technique that allows for large-scale quantitative analysis of protein abundances between different treatments. This approach led him to make the discovery that CLIP-associating protein 2 (CLASP2) is responsive to insulin stimulation, and his now-published findings support the involvement of CLASP2 in insulin-stimulated glucose uptake. Current research is aimed at discovering the role of CLASP2 in insulin action, in addition to identifying new proteins previously unknown to function in this system.
Dr. Langlais leads the Mayo Clinic Proteomics Laboratory, a collaborative environment for investigators at Mayo Clinic's campus in Arizona and their colleagues to perform proteomic studies in their respective projects.
CLASP2 colocalization with glucose transporter 4 (GLUT4). Insulin spurs the movement of vesicles storing GLUT4 to the plasma membrane of the cell, resulting in an influx of glucose into target tissues such as muscle and fat. Dr. Langlais and colleagues have observed that CLASP2 colocalizes with GLUT4, allowing for the first proposed mechanism of GLUT4 landing zone assignment.
Since CLASP2 is responsible for anchoring the cell's microtubules (a key part of the cytoskeleton) to the cortical membrane, CLASP2 may be the missing link for guiding the microtubule track to deliver GLUT4 to downstream partners at specific insulin-related hotspots on the plasma membrane. Additionally, CLASP2 colocalization with GLUT4 at the cell cortex provides compelling evidence for the direct involvement of the microtubule network in GLUT4 plasma membrane fusion within muscle and fat cell systems.
These hypotheses are truly novel, as the question of how microtubules are guided to deliver the GLUT4 storage vesicles is a completely untouched field.
- Hybrid mass spectrometry. Using the Mayo Clinic Proteomics Laboratory's newest hybrid mass spectrometer, Dr. Langlais has been able to delve deeper into the proteome than ever before, allowing for access into new areas of GLUT4 trafficking and cytoskeletal dynamics in insulin action that were previously unattainable.
- Identification of novel proteins and protein functions. The study of how microtubules are targeted to the very specific areas on the plasma membrane that are responsible for the acceptance of GLUT4-containing vesicles is a completely new field. This opens up the possibility of identifying a whole new collection of proteins with novel, previously unidentified functions in insulin action. The detailed scrutiny of CLASP2 action in GLUT4 trafficking and the ensuing discoveries and new directions that could stem from this proposal could lead to an understanding of the critical interphase of actin reorganization, microtubule dynamics, GLUT4 trafficking and the plasma membrane.
Significance to patient care
Dr. Langlais' research is designed with the intention of improving understanding of the steps of insulin-regulated GLUT4 trafficking that involve the cytoskeleton. With this knowledge, studies can be performed in vivo to test for insulin resistance at these new steps in order to provide novel targets for rational treatments of insulin resistance, which underlies obesity, type 2 diabetes and cardiovascular disease.