Defining Alpha-Cell PC1/3 Expression Regulation for Type 2 Diabetes

Fellow: Marlena Holter

Mentor: Bethany Cummings

Co-Mentor: John Schimenti, Charles Danko

Department of Biomedical Sciences
Sponsor: NIH-National Institute of Diabetes and Digestive and Kidney Diseases
Grant Number: 5F30DK126538-02
Title: Defining Alpha-Cell PC1/3 Expression Regulation for Type 2 Diabetes
Project Amount: $42,516
Project Period: March 2021 to March 2022

DESCRIPTION (provided by applicant): 

Glucagon-like peptide-1 (GLP-1) enhances islet function by potentiating glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells; however, the mechanisms by which GLP-1 potentiates GSIS remain incompletely defined. In the classic model, GLP-1 secreted by the intestinal L cells in response to the ingestion of nutrients stimulates the β-cell GLP-1 receptor (GLP-1R) to enhance GSIS. This model is currently in question, as the short half-life of GLP-1 and its rapid degradation present limitations as to how GLP-1 can mediate effects in distant targets, such as pancreatic β-cells. In explanation of such limitations, there is an emerging hypothesis suggesting that GLP-1 locally produced by α-cells acts in a paracrine manner on neighboring β-cells to stimulate GSIS, which ultimately promotes lowering of glycemia. Proglucagon is expressed in the gut and α-cells and is cleaved to form GLP-1 or the counter-regulatory hormone, glucagon, depending on the prohormone convertase (PC) type present. It was previously thought that the tissue-specific processing of proglucagon was due to the differential expression of PC1/3 and PC2, but several studies in rodent models and humans have shown that α- cells can produce active GLP-1 and express PC1/3. However, the mechanisms by which α-cell PC1/3 expression is regulated are unknown. Identifying a mechanism to increase α-cell PC1/3 expression to increase GLP-1 production at the expense of glucagon will provide a powerful therapeutic modality for the regulation of blood glucose concentrations in patients with T2DM. We have shown that increased β-cell GLP-1R signaling increases α-cell PC1/3 and GLP-1 expression. My preliminary data suggest that insulin may serve as potential intermediate by which β-cell GLP-1R signaling alters α-cell proglucagon processing. Specifically, I hypothesize that β-cell GLP-1R signaling increases α-cell PC1/3 expression through both α-cell insulin receptor (IR) dependent and independent pathways. In Aim 1, I will assess the role of α-cell IR signaling to determine whether insulin is necessary to alter the secretory phenotype of α-cells by measuring glucose regulation, GSIS, and PC1/3 expression in α-cell-specific Irα-cell +/+ and Irα-cell -/- mice with and without stimulation by exogenous GLP-1. In Aim 2, I will determine the pathways through which β-cell GLP-1R signaling increases α-cell PC1/3 expression by single-cell RNA-sequencing of islets from inducible β-cell-specific Glp-1rβ-cell+/+ and Glp-1r-cell-/- mice, as well as human islets with β-cell-specific GLP-1R knockout. Together, these studies will define a link between the pathways regulating α-cell PC1/3 expression and GLP-1 production; thus, enabling targeting of the α-cell secretory phenotype for the treatment of T2DM.