All ETDs from UAB

Advisory Committee Chair

Anath Shalev

Advisory Committee Members

Maaike Everts

David Pollock

Tim Townes

Martin Young

Document Type

Dissertation

Date of Award

2018

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

The loss of functional beta cell mass represents a major factor in the pathogenesis of type 1 and type 2 diabetes. Inadequate production of insulin, a glucose-lowering hormone, and elevated glucagon production, a gluconeogenic hormone, contribute to impaired glycemic control and hyperglycemia. This promotes a vicious cycle involving glucotoxicity and additional beta cell dysfunction. Currently there are no therapies that halt this process; however, thioredoxin-interacting protein (TXNIP) has recently emerged as a promising therapeutic target. TXNIP was found to be the top glucose-induced gene in a human pancreatic islet microarray, is increased in mouse models of diabetes and diabetic human islets, and overexpression of TXNIP results in beta cell apoptosis. However, TXNIP reduction has shown favorable effects in vivo as genetic TXNIP deletion and pharmacological TXNIP inhibition, via the common anti-hypertensive medication and L-type calcium channel blocker verapamil, prevents and rescues mice from overt diabetes. TXNIP deletion has further shown to increase functional beta cell mass and decrease hepatic glucose production. In adults with diabetes, verapamil improves beta cell function and glycemic control. This suggests that TXNIP inhibition represents a novel mechanism to treat diabetes and underscores the need for developing more specific TXNIP inhibitors. This dissertation details the identification of a novel small molecule TXNIP inhibitor that protects against diabetes. After high-throughput screening of 300,000 small molecules and extensive medicinal chemistry modifications, SRI-37330 was identified as a novel small molecule TXNIP inhibitor. SRI-37330 confers TXNIP inhibition at the level of promoter activity and displays similar dose-dependent reductions in TXNIP mRNA and protein. These reductions can be observed under high glucose conditions and across species, most importantly in human pancreatic islets. RNA sequencing of human islets treated with SRI-37330 has further shown specificity to TXNIP signaling pathways. In vivo, oral administration of SRI-37330 prevents and rescues mice from diabetes. This improvement in glycemic control is associated with reduced serum glucagon levels, via decreased glucagon secretion, and downregulation of hepatic glucose production. Collectively, SRI-37330 may provide a novel and much needed approach to targeting underlying pathways in diabetes involving TXNIP and glucagon to help treat diabetes.

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