Islet Cell Research:
Proinsulin is the dominant form of insulin in the early secretory pathway after rapid removal of the signal peptide from preproinsulin. The cellular proinsulin is an important product of beta-cells because its folding produces insulin (a key hormone in the control of glucose homeostasis), which accounts for 12-14% of the dry weight of rodent islet or beta-cells (Dixit et al: Nature, 1962,195, 388-389, Hellman and Lernmark: Diabetologia, 1969, 5, 22-24), whereas the more than 20,000 other protein products and other non-protein cellular components just constitute 86-88% of the total islet or beta cell dry weight. Proinsulin folding bears the greatest burden in the folding of proteins in beta-cells. Thus, accurate understanding of how this important protein product folds and matures in cloned pancreatic beta-cells and islets of normal and diabetic mice models is crucial in the study of mechanisms underlying beta-cell failure in diabetes.
Recent findings in Dr. Wang's research have shown that aggregation-prone proinsulin is inherent with a low relative folding rate and thus maintains a homeostatic balance of natively and non-natively folded states (i.e., proinsulin homeostasis) in beta-cells as a result of the integration of maturation and disposal processes. Proinsulin homeostasis is highly susceptible to the influence of genetic disorders such as mutations in the insulin gene, and to various diabetes-associated risk factors (Wang et al: PLoS ONE, 2011, 6(4), e19446).
In cloned beta-cell lines and primate/mouse models, Dr. Wang and his research team are currently studying:
(1) Whether proinsulin homeostasis disorders link to diabetes development,
(2) The mechanisms for maintenance and perturbation of proinsulin homeostasis in beta-cells,
(3) The therapeutic efficacy on diabetes of partially/adequately restoring disturbed proinsulin homeostasis in beta-cells.
For more information about the Islet Cell research, click here.
Islet Cell Transplant: