Author ORCID Identifier

Date Available


Year of Publication


Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation




Microbiology, Immunology, and Molecular Genetics

First Advisor

Barbara S. Nikolajczyk

Second Advisor

Subbarao Bondada


Chronic, low-grade systemic inflammation rises in obesity and promotes type 2 diabetes (T2D). Circulating immune cells are key indicators of obesity and T2D pathogenesis. T cells outnumber monocytes, in blood, suggesting that T cells might fuel peripheral inflammation in obesity/T2D. Our lab’s work supports this idea by identification of a Th17 cytokine profile in T2D from T-cell stimulated peripheral blood mononuclear cells. Work described herein further supported this work by demonstrating that T cells dominate peripheral inflammation over monocytes across the spectrum of obesity and glycemic control. Our lab has also recently shown that inflammation changes during prediabetes (preT2D), identified bioinformatically by a Th1/Th2 cytokine profile that shared similarities with T cells from people with normal glucose tolerance (NGT), suggesting a potential compensatory mechanism to shift inflammation away from T2D pathogenesis. T cells from preT2D donors also had higher oxidative phosphorylation (OXPHOS) activity, thus supporting the relationship between T-cell metabolism and function, leading to our hypothesis that enhanced mitochondrial function in CD4+ T cells promotes peripheral inflammation in preT2D.

We first tested mitochondrial function parameters, which were indistinguishable amongst NGT, preT2D, and T2D donors. Thus, high T-cell OXPHOS in preT2D was not due to changes in mitochondrial function. We next tested the possibility that differential mitochondrial fuel metabolism promotes high T-cell OXPHOS in preT2D and the differences between preT2D and T2D-associated cytokine profiles. Of the fuel sources tested, we saw a profound reduction in OXPHOS activity in both preT2D and T2D cells by glutaminolysis restriction via glutaminase-1 (GLS-1) inhibition, of which also reduced Th1/Th17 cytokines from T-effector cells. While GLS-1 inhibition reduced mTORC1 activity, reductions in Th1/Th17 cytokines were not dependent on mTORC1. Therefore, GLS-1 activity supports high OXPHOS and T2D-associated inflammation independent of the positive feedback loop between glutamine and mTORC1. Alternatively, GLS-1 function could be downstream of mTORC1. These results provide a novel mechanism that links metabolic reprogramming in preT2D T cells to T2D pathogenesis. We hypothesize that changes in metabolism occur in T cells prior to onset of T2D-associated inflammation, of which we think happens later in T2D development through glutaminolysis reliance. Data from this work could have promising clinical implications in potential efforts to repurpose the glycemic control drug peroxisome proliferator-activated receptor-gamma agonists for T2D-associated inflammation as they have been shown to inhibit GLS-1 activity and Th17 function.

Digital Object Identifier (DOI)

Funding Information

Funds awarded to the author:

1. 2019-2021: University of Kentucky Department of Pharmacology and Nutritional Sciences, T32 Training Program T32 DK007778

2. 2021-2023: University of Kentucky Center for Clinical and Translational Science, TL1 Predoctoral Training Program TL1TR001997

Funds awarded to the research team:

1. NIDDK, R01DK108056 (Barbara Nikolajczyk and Philip A. Kern)

2. Shared Resource Facility of the University of Kentucky Markey Cancer Center (P30 CA177558) (Barbara Nikolajczyk)

3. Barnstable Brown Diabetes and Obesity Research Center (Barbara Nikolajczyk and Philip A. Kern)

4. Center for Clinical and Translational Research (UL1TR000117) (Barbara Nikolajczyk)

5. NIH National Center for Advancing Translational Sciences UL1TR001998 (Philip A. Kern)