RESEARCH
New Insulin for Diabetes Treatments
Although currently available insulin analogues reduce blood glucose levels, this blood glucose lowering action is not regulated in a glucose dependent fashion. The major consequence of excess insulin administration is hypoglycemia, which can lead to acute complications such as loss of consciousness, coma, and even death. On the other hand, insufficient insulin administration leads to chronic hyperglycemia and complications such as blindness, kidney failure, and heart disease. There remains a need to modulate the kinetics of injected insulin therapy to more closely match the dynamics of fluctuating blood glucose levels. We are interested in developing glucose-responsive or “smart” insulin with its biological activity regulated by circulating glucose levels. Ideally, smart insulin would be administered once daily and, by responding to the circulating local glucose levels, would maintain normal glucose levels throughout the day. Furthermore, we are developing ultrafast-acting insulin with fast-on, fast-off properties for uses in artificial pancreas. Last but not least, in order to mimic the effects of insulin secretion, we are developing hepato-selective insulin to restore the physiological gradient of insulin in vivo.
Although currently available insulin analogues reduce blood glucose levels, this blood glucose lowering action is not regulated in a glucose dependent fashion. The major consequence of excess insulin administration is hypoglycemia, which can lead to acute complications such as loss of consciousness, coma, and even death. On the other hand, insufficient insulin administration leads to chronic hyperglycemia and complications such as blindness, kidney failure, and heart disease. There remains a need to modulate the kinetics of injected insulin therapy to more closely match the dynamics of fluctuating blood glucose levels. We are interested in developing glucose-responsive or “smart” insulin with its biological activity regulated by circulating glucose levels. Ideally, smart insulin would be administered once daily and, by responding to the circulating local glucose levels, would maintain normal glucose levels throughout the day. Furthermore, we are developing ultrafast-acting insulin with fast-on, fast-off properties for uses in artificial pancreas. Last but not least, in order to mimic the effects of insulin secretion, we are developing hepato-selective insulin to restore the physiological gradient of insulin in vivo.
Studies of Insulin Receptor Isoforms and Hybrid Receptors
Insulin and insulin receptor (IR) are involved in metabolism, proliferation and differentiation. In mammals, two isoforms (IR-A and IR-B) exist due to differences in alternative splicing. Although it was suggested in the literature that IR-A activation is “mitogenic” and IR-B activation is “metabolic”, in-depth investigations about the biological roles of the IR isoforms are challenging due to the lack of tools to study the individual effects. Our lab is developing isoform-selective insulin analogs by combining a structure guided and a high throughput screening approach. These isoform selective analogs will be developed to research probes to dissect the roles of each IR isoform. Furthermore, we are interested hybrid receptors formed by IR and IGF-1R. We are developing chemical biological tools to study the cell signaling of these hybrid receptors.
Insulin and insulin receptor (IR) are involved in metabolism, proliferation and differentiation. In mammals, two isoforms (IR-A and IR-B) exist due to differences in alternative splicing. Although it was suggested in the literature that IR-A activation is “mitogenic” and IR-B activation is “metabolic”, in-depth investigations about the biological roles of the IR isoforms are challenging due to the lack of tools to study the individual effects. Our lab is developing isoform-selective insulin analogs by combining a structure guided and a high throughput screening approach. These isoform selective analogs will be developed to research probes to dissect the roles of each IR isoform. Furthermore, we are interested hybrid receptors formed by IR and IGF-1R. We are developing chemical biological tools to study the cell signaling of these hybrid receptors.
Methodology Development for Creating New Peptides and Proteins
We are also developing new methods, both chemical and enzymatic, to generate peptides and proteins that are difficult to synthesize. First, we are involved in developing methods for peptide macrocyclizations, which are known to improve properties for peptide therapeutics. Furthermore, we are interested in methods to generate new insulin analogs and modified insulin derivatives. Last but not east, we are interested in using biopolymers to improve the formulation of peptides and proteins.
We are also developing new methods, both chemical and enzymatic, to generate peptides and proteins that are difficult to synthesize. First, we are involved in developing methods for peptide macrocyclizations, which are known to improve properties for peptide therapeutics. Furthermore, we are interested in methods to generate new insulin analogs and modified insulin derivatives. Last but not east, we are interested in using biopolymers to improve the formulation of peptides and proteins.