Identification of genipin as a potential treatment for type 2 diabetes

Type 2 diabetes (T2D) is a chronic metabolic disease characterized by hyperglycemia, insulin resistance, and the dysfunction of β-cells. While there are several therapies for T2D, there is no effective treatment that can reverse the functional decline of pancreatic β cells in T2D patients. Glucagon-like peptide-1 (GLP-1) is a peptide hormone secreted by human intestinal L cells, which can stimulate the proliferation and differentiation of β cells and promote glucose-stimulated insulin secretion (GSIS), thereby playing a critical role in maintaining glycemic homeostasis. Recently, GLP-1-based medications have been developed for treating T2D. However, most of the GLP-1-based drugs are expensive and have significant adverse effects. Therefore, development of safer and more convenient agents that can mimic the physiologically fed state to promote endogenous GLP-1 secretory function of intestinal L-cells to improve glucose homeostasis holds great potential for the prevention and treatment of T2D. This project aimed to examine whether natural compound genipin promotes intestinal GLP-1 secretion and exerts anti-diabetic effects. I found that genipin rapidly increased GLP-1 secretion from intestinal L-cells, with 10 and 100 μM concentration inducing significant incretin hormone release. L-cells exposed to genipin displayed a rapid increase in intracellular [Ca²⁺]i and the activity of phospholipase C (PLC). Inhibition of PLC ablated genipin-stimulated Ca²⁺] increase and GLP-1 secretion, suggesting that genipin-induced GLP-1 release from the cells depends on the PLC/Ca²⁺ pathway. In vivo, genipin reduced the non-fasting and fasting blood glucose levels, improved insulin resistance, and protected again high fat diet-induced liver damage. All together, these data indicate that genipin is a naturally occurring anti-diabetic agent, which could be a pharmaceutical lead for developing anti-diabetic drugs.

Name thesis:degree_name

M.S.

Level thesis:degree_level

masters

Discipline thesis:degree_discipline

Molecular and Cellular Science

Department dc:contributor.department

Human Nutrition, Foods, and Exercise

Grantor dc:publisher

Virginia Tech

Year dc:date.issued

2022

Author dc:creator

• Wu, Yajun

Chair dc:contributor.committeechair

• Liu, Dongmin

Committee members dc:contributor.committeemember

• Gilbert, Elizabeth R.
• Schmelz, Eva

• Genipin
• GLP-1
• L cells
• blood glucose
• liver
• mice

Statement dc:rights

• In Copyright

Licence dc:rights.uri

• http://rightsstatements.org/vocab/InC/1.0/

Language dc:language.iso

en

Handle dc:identifier.uri

http://hdl.handle.net/10919/108188

OAI identifier oai:identifier

oai:vtechworks.lib.vt.edu:10919/108188