VERTICAL SLEEVE GASTRECTOMY IMPROVES GLUCOSE HOMEOSTASIS VIA [beta]- CELL GLUCAGON-LIKE PEPTIDE-1 RECEPTOR SIGNALING BUT PROMOTES COLITIS DEVELOPMENT IN MICE

Bariatric surgery is defined as the surgical manipulation of the gut for the purpose of weight loss. Currently, it is the most effective long-term treatment for obesity and results in multiple cardiometabolic benefits. However, the mechanisms by which these benefits occur remain incompletely defined. In order to identify these mechanisms our lab has developed and validated a murine model of vertical sleeve gastrectomy (VSG), a type of a bariatric surgery. This model recapitulates many of the changes observed in humans after VSG. These include body weight loss, decreases in food intake, decreases in adiposity, improved glucose homeostasis, improved glucose stimulated insulin secretion, increases in post-prandial glucagon-like peptide-1 (GLP-1) secretion, changes in the bile acid pool/profile, and remission of hypertension. Utilizing this model we have investigated the role of β-cell glucagon-like peptide-1 receptor (GLP-1R) signaling in the glucoregulatory benefits of VSG and have also explored the effect of VSG on colitis development. One of the most remarkable changes seen after VSG is high rates of type 2 diabetes (T2DM) remission. This remission occurs hours to days after surgery, prior to significant body weight loss, and the mechanisms by which this occurs remain incompletely defined. The mechanisms that cause remission of T2DM are thought to be multi-factorial. One of these mechanisms is thought to involve increases in endogenous postprandial GLP-1 secretion, which has been shown to occur after multiple types of bariatric surgery. GLP-1R signaling is important for a variety of functions including the potentiation of glucose stimulated insulin secretion (GSIS), enhancement of insulin sensitivity, and decreases in appetite. Given the known role of β-cell GLP-1R signaling in the potentiation of GSIS we investigated its role in the glucoregulatory benefits of VSG utilizing an inducible β-cell GLP-1R mouse model. Utilizing this model, we defined the effect of increased endogenous GLP-1 signaling via β-cell GLP-1R on increases in GSIS, improvements in glucose tolerance, body weight loss in mice after VSG, and the following in pancreatic islets: insulin, glucagon, GLP-1, and prohormone convertase 1/3 (Chapters Two and Three). A growing number of people suffering from irritable bowel disease (IBD) also suffer from obesity and are candidates for bariatric surgery. Bariatric surgery has multiple beneficial effects, however; there is limited and conflicting literature on the effect of bariatric surgery on IBD. In order to investigate this we performed VSG in mice and chemically induced colitis with dextran sodium sulfate (DSS) three weeks after surgery (Chapter Four). The present dissertation describes the contributions of β-cell GLP-1R signaling in the glucoregulatory benefits of VSG surgery; demonstrates β-cell GLP-1R signaling is a novel regulator of α-cell proglucagon processing after VSG; and demonstrates VSG surgery aggravates colitis in mice. The knowledge gained from this research is novel and serves as an anchor for further elucidating the mechanisms by which VSG surgery improves conditions such as T2DM but exacerbates conditions such as IBD.

Name thesis:degree_name

Ph. D., Comparative Biomedical Sciences

Level thesis:degree_level

Doctor of Philosophy

Discipline thesis:degree_discipline

Comparative Biomedical Sciences

Grantor

Cornell University

Year dc:date.issued

2018

Author dc:creator

• Garibay, Darline

Committee members dc:contributor.committeemember

• Roberson, Mark Stephen
• Boisclair, Yves R.
• Thalacker-Mercer, Anna E.

• GLP-1
• glucose regulation
• proglucagon
• TGR5
• VSG
• Biology
• Colitis
• physiology
• Nutrition

Language dc:language.iso

en_US

DOI

https://doi.org/10.7298/X40C4T0H

Dc Identifier Other

ProQuest Submission ID: 10974
ProQuest Publication ID: 10844195

OAI identifier oai:identifier

oai:ecommons.cornell.edu:1813/59524