Chemical strategies for improving anti-diabetic glucagon therapy

The pancreas functions to carry out one of the most critical functions in the human metabolism, viz. glucose homeostasis. It achieves homeostasis by producing hormones including insulin and glucagon which act on different cell types to affect blood glucose concentrations. Under certain conditions, the concentration of blood glucose falls below normal range. This will lead to several complications including death and must be treated immediately. A clinically approved strategy for the treatment of hypoglycemia is to administer glucagon as a subcutaneous injection. Glucagon acts on hepatocytes and activates the signaling pathways responsible for glycogenolysis and gluconeogenesis increasing the blood glucose concentration, thereby protecting vital organs (brain, heart, kidneys etc.) from hypoglycemic shock. A recent advancement in the treatment of hypoglycemia is the use of artificial pancreas systems for a continuously variable delivery of glucagon. This system ensures that the hormone is delivered to the patient as and when needed in the right quantities, similar to how pancreas delivers the hormones naturally. Many studies have shown that such automated systems better maintain the health of the patient. In this work, two chemical approaches are taken to engineer glucagon to have ideal physicochemical properties such that they can be used in two different artificial pancreas systems. First, the construction and the design principles of a photoactivated trimeric glucagon are discussed in Chapter 2. This material is a pro-glucagon engineered to have two properties: a) low solubility such that it can be injected under the skin as an inert depot, and b) the ability to regenerate native glucagon in response to light. Therefore, the delivery of glucagon can be easily controlled with a light source. Furthermore, it can be translated into an artificial pancreas system when used in combination with a continuous glucose monitor. The inherent property of native glucagon to aggregate and produce toxic fibrils limits its use in pump-based artificial pancreas systems. The second approach (Chapter 3) involves site-specific modification of glucagon to produce enzyme-responsive pro-glucagons. They are observed to remain stable in solution for longer periods and therefore, can be potentially used to develop pump-based bi-hormonal artificial pancreas and more.

Name thesis:degree_name

Ph.D. (Doctor of Philosophy)

Level thesis:degree_level

Doctoral

Discipline thesis:degree_discipline

Pharmaceutical Sciences (UMKC)

Grantor

University of Missouri--Kansas City

Year dc:date.issued

2023

Author dc:creator

• Chintala, Swetha

Advisor dc:contributor.advisor

• Friedman, Simon H. (Simon Hilary), 1966-

Handle dc:identifier.uri

https://hdl.handle.net/10355/95763

OAI identifier oai:identifier

oai:mospace.umsystem.edu:10355/95763