Doctoral thesis (Dissertations and theses)
CONNECTING THE DOTS IN TYPE-2 DIABETES: EARLY LIFE ADVERSITY, STRESS AND THE IMMUNE SYSTEM
SEAL, Snehaa
2023
 

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Keywords :
Type-2 diabetes; Stress; Early life adversity; glucose; cortisol; corticosterone
Abstract :
[en] Psychological stress prompts metabolic reactions aimed at increasing glucose supply to the brain, to initiate fight/flight responses in healthy individuals. The quality of the first 1000 days of life is a critical window which impacts lifelong metabolic trajectories and stress reactions. Exposure to stress during this critical window appears to have an exaggerated long-term effect on glucose availability during stress, leading to an increased risk of cardiometabolic disorders. Early life adversity also appears to have an effect on baseline glucose levels in both pre-clinical models of maternal deprivation and perinatal infection, and in human participants that have experienced early life adversity (institutionalisation-adoption). In this thesis, we initially critically examined the dogma that the stress induced glucose rise was mediated by glucocorticoids. However, the kinetics of stress-induced glucose release in healthy individuals, peaking 15-28 minutes before cortisol suggests that it is a glucocorticoid-independent process. This was confirmed by the absence of glucocorticoid induced glucose rise after intravenous administration of escalating doses of cortisol in a healthy human cohort. Instead we suggest that this mechanism is most likely orchestrated by a direct innervation in the liver. Results from our initial study indicate that the metabolic status and early life stress are intimately intertwined, and in order to fully understand either profiles, the other should be thoroughly studied. Type-2 diabetes (T2D) is a complex disorder characterized by insulin resistance, hyperglycaemia, dysregulations in metabolism and is now even considered to have an immune component, with functional impairments in many immune cell types. Through epidemiological data, it is clear that, although the genetic component appears to be weak, the ‘pathogenic component’ may be transmitted in a pedigree due a common shared environment. This vertical transfer of risk factors through generations may suggest that T2D in itself can also act as a type of early life adversity/stress that further triggers a vicious cycle. In thesis, we predominantly focus on T2D as a source of early life adversity (nutritional stress) and investigate its effects on stress response and the immune system. Although often accompanied by comorbid obesity, the immune status in Type-2 diabetes independent of obesity is still a knowledge gap. Using Goto-Kakizaki rats as a non-obese Type-2 diabetes model, we demonstrated that these rats have a limited pro-inflammatory baseline immune profile outside the pancreas. To finally examine when these changes arise in the disease cycle, we conducted a longitudinal study in these rats encompassing the transition period from prediabetes to a fully diabetic phase. Additionally we also studied how the diabetic phenotype impacted lymphocyte redistribution when subjected to a metabolic challenge and restraint stress. Our study will help understand the immune component of the diabetic aetiology independent of obesity, genetic variations, diet and other confounding parameters. Additionally, our studies pave the way for strategizing effective immunotherapeutic approaches and proposes the nervous system as an effective target in stress biology to neutralise the ELA induced stress-glucose changes.
Disciplines :
Endocrinology, metabolism & nutrition
Immunology & infectious disease
Author, co-author :
SEAL, Snehaa ;  University of Luxembourg ; Unilu - University of Luxembourg [LU] > The Faculty of Science, Technology and Medicine
Language :
English
Title :
CONNECTING THE DOTS IN TYPE-2 DIABETES: EARLY LIFE ADVERSITY, STRESS AND THE IMMUNE SYSTEM
Defense date :
02 May 2023
Number of pages :
187
Institution :
Unilu - University of Luxembourg [The Faculty of Science, Technology and Medicine], Esch-sur-Alzette, Luxembourg
Degree :
DOCTEUR DE L’UNIVERSITÉ DU LUXEMBOURG EN BIOLOGIE
Promotor :
Turner, Jonathan;  Luxembourg Institute of Health > Department of Infection and Immunity > Group Leader & Deputy Head (Funding and Finance), Doctoral Thesis Supervisor
President :
HEUSCHLING, Paul ;  University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Life Sciences and Medicine (DLSM)
Jury member :
Duman, Elif;  Boğaziçi University > Assistant Professor
Ruiz-Castell, Maria;  Luxembourg Institute of Health > Public Health Research
Meyre, David;  McMaster University > Associate Professor ; UL - Université de Lorraine [FR] > UMRS INSERM 1256, Nutrition-Génétique et Exposition aux Risques Environnementaux > Deputy Director
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since 12 December 2023

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