Thesis Defence: Immunometabolic Differences Between South Asians and White Individuals With Type 2 Diabetes: A Cross-sectional Study

Sriyashika Nekkanti, supervised by Dr. Hashim Islam, will defend their thesis titled “Immunometabolic Differences Between South Asians and White Individuals With Type 2 Diabetes: A Cross-sectional Study” in partial fulfillment of the requirements for the degree of Master of Science in Health & Exercise Sciences.

An abstract for Sriyashika Nekkanti’s thesis is included below.

Defences are open to all members of the campus community as well as the general public. Registration is not required for in-person defences.

Abstract

Mitochondria are vital for immune cell function; Persistent immune cell activation, referred to as chronic inflammation, is observed in individuals with type 2 diabetes (T2D). South Asians are at disproportionately greater risk for T2D and exhibit elevated inflammatory profiles compared to White individuals, yet the mechanisms underlying this disparity remain incompletely understood. Evidence from rodent models suggests that mitochondrial dysfunction in immune cells may drive inflammation; however, differences in mitochondrial function in immune cells between South Asians and White individuals with T2D had not previously been characterized.

In this study, we directly compared mitochondrial profiles in monocytes, a key innate immune cell population, isolated from South Asian and White individuals with T2D, matched forage. Using high-resolution respirometry and flow cytometry, we measured mitochondrial energy production and major monocyte subsets, respectively. To link mitochondrial profiles to immune function, we assessed cytokine production in whole blood stimulated with two mechanistically distinct immune-activating stimuli, LPS and Poly(I:C), which mimic bacterial and viral inflammatory environments, respectively.

Contrary to our initial hypothesis, monocytes from South Asians with T2D and metabolic characteristics similar to their White counterparts exhibited higher mitochondrial respiration across multiple states, along with a significantly reduced spare respiratory capacity, suggesting that these cells are operating near their bioenergetic ceiling. While LPS-stimulated TNFαproduction in whole blood was similar between groups, Poly(I:C)-stimulated TNFα production was significantly lower in South Asians with T2D. South Asians with T2D also showed a lower proportion of classical monocytes, a higher proportion of non-classical monocytes, and reducedTLR4 expression on intermediate monocytes, with no differences in conventional blood inflammatory markers. Additionally, the diabetes distress scale highlighted that South Asians experience more burden and distress related to their T2D than White individuals. These findings demonstrate that South Asians with T2D exhibit a distinct pattern of monocyte immunometabolic dysregulation characterized by elevated bioenergetics and pathway-selective innate immune impairment. This work provides novel insights into ethnic disparities in inflammatory risk and identifies monocyte bioenergetics as an avenue for further investigation.