Jason Collier, Ph.D.
Project 4: Dynamic Regulation of β-cell Function and Mass by SGK1
The pancreatic islets of Langerhans contribute to metabolic homeostasis via synthesis and secretion of polypeptide hormones that control the storage and utilization of protein, carbohydrate and lipid molecules. One of the predominant cell types in the pancreatic islet is the β-cell, which produces and secretes insulin in response to glucose and other stimuli. The endocrine disease Diabetes Mellitus results from an insufficient amount of insulin to efficiently regulate blood glucose levels. This decrease in circulating insulin results from a diminution in the number of total β-cells as well as losses in cellular function. Decreases in functional β-cell mass occur in both autoimmune (Type 1) and obesity-related (Type 2) forms of the disease.
My current interests revolve around understanding how inflammatory stimuli lead to a decrement in β-mass and how to prevent these losses in islet β-cell mass and function. We use a variety of interdisciplinary approaches to address key questions in islet biology with the ultimate goal of providing information that leads to novel therapeutic strategies to prevent and/or treat diabetes.
Project Focus: Glucocorticoid-regulated Genes that Control Proliferation, Viability and Insulin Secretion
The glucocorticoid receptor (GR) is a ligand activated transcription factor that coordinately regulates changes in cellular gene expression. These changes in gene expression produce powerful anti-inflammatory effects; however, chronic activation of the GR has many side effects, including insulin resistance, muscle wasting, suppression of immune system function, and impairment of glucose-stimulated insulin secretion. Notably, the side effects of chronic glucocorticoid therapy share many similarities with the metabolic syndrome. Thus, a comprehensive understanding of GR function in metabolically relevant tissues is important for understanding how to control inflammation and prevent metabolic disease.
Acutely, the glucocorticoid hormones protect islet β-cells from damage induced by pro-inflammatory cytokines. However, these hormones impair glucose-stimulated insulin secretion (GSIS) and induce muscle insulin resistance, thereby limiting their utility as a potential therapeutic treatment. We hypothesize that the discovery of glucocorticoid-regulated genes that control cellular viability but do not impair function is one way to potentially prevent losses in β-cell mass and thus provide enough insulin to maintain glucose homeostasis. An additional approach is the synthesis of novel GR agonist compounds that provide anti-inflammatory effects without the loss in insulin secretion.
A microarray analysis of glucocorticoid-regulated genes in rat insulinoma cell lines has been performed and several differentially regulated genes are being tested for their efficacy against cytokine-induced β-cell damage. In addition, we are currently examining two discrete chemical classes of GR ligands using the β-cell as a model system to measure alterations in metabolic function.
All current ongoing projects employ chemical biology approaches coupled to in vitro and in vivo biochemical, physiological, and imaging techniques to address glucocorticoid receptor activity in islet beta-cells.