Date of Award

2026

Embargo Period

3-31-2026

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Molecular and Cellular Biology and Pathobiology

College

College of Graduate Studies

First Advisor

Joshua Lipschutz

Abstract

Diabetes Mellitus (DM) affects 13.9% of men and 14.3% of women worldwide, a total of approximately 828 million people. Patients with diabetes are at risk of several complications including diabetic nephropathy (DN) and metabolic-associated steatohepatitis (MASH). These diseases eventually lead to end stage kidney disease (ESKD) and liver failure requiring dialysis and organ transplantation. In addition, diabetes exacerbates disease severity of autosomal dominant polycystic kidney disease (ADPKD), the most common potentially lethal genetic disease to affect humans with a prevalence of 1 in 500-1000. Therefore, a therapeutic approach that can attenuate organ damage and restore function in patients with DM, could greatly benefit the global population. We have shown previously that administration of a long acting β2-adrenergic receptor agonist rescued kidney damage following acute kidney injury. It has also been published that knock out of β2-adrenergic receptors in a high fat diet mouse model exacerbated liver steatosis. Therefore, we tested the therapeutic effect of formoterol, a long acting β2-adrenergic receptor agonist, in mouse models of diabetes with respect to DN and MASH in addition to a mouse model of ADPKD. Following formoterol treatment, there was a marked recovery from and reversal of diabetic nephropathy in high fat diet mice, a type 2 diabetes (T2D) model, compared with those treated with vehicle alone at the ultrastructural, histological, and functional levels. Similar results were seen after formoterol treatment in a streptozotocin induced type 1 diabetes mouse model. A retrospective analysis of Veterans with stage 4 chronic kidney disease (CKD) taking formoterol showed a 33.2% reduced incidence of ESKD compared to Veterans with stage 4 CKD without β2-adrenergic receptor agonist exposure. Formoterol treatment in a high fat diet T2D model attenuated steatosis and rescued metabolic derangements. Human HepaRG cells exposed to free fatty acids and formoterol attenuated lipid accumulation and increased ATP-linked basal and maximal respiration. Finally, a retrospective analysis of 59,644 patients with MASH showed that patients taking Long-acting β2-adrenergic receptor agonists had fewer complications of advanced liver disease and 35% reduced incidence of all-cause mortality. Therapeutic benefit was not observed in polycystic kidney disease.

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