A Holistic View of the Goto-Kakizaki Rat Immune System: Decreased Circulating Immune Markers in Non- Obese Type 2 Diabetes

Type-2 diabetes is a complex disorder that is now considered to have an immune component, with functional impairments in many immune cell types. Type-2 diabetes is often accompanied by comorbid obesity, which is associated with low grade inflammation. However,the immune status in Type-2 diabetes independent of obesity remains unclear. Goto-Kakizaki rats are a non-obese Type-2 diabetes model. The limited evidence available suggests that Goto-Kakizaki rats have a pro-inflammatory immune profile in pancreatic islets. Here we present a detailed overview of the adult Goto-Kakizaki rat immune system. Three converging lines of evidence: fewer pro-inflammatory cells, lower levels of circulating pro-inflammatory cytokines, and a clear downregulation of pro-inflammatory signalling in liver, muscle and adipose tissues indicate a limited pro-inflammatory baseline immune profile outside the pancreas. As Type-2 diabetes is frequently associated with obesity and adipocyte-released inflammatory mediators, the pro-inflammatory milieu seems not due to Type-2 diabetes per se; although this overall reduction of immune markers suggests marked immune dysfunction in Goto-Kakizaki rats. Copyright © 2022 Seal, Henry, Pajot, Holuka, Bailbé, Movassat, Darnaudéry and Turner.Diabète maternel et vulnérabilité neuropsychiatrique chez la descendance : rôle de la méthylation de l'AD

CONNECTING THE DOTS IN TYPE-2 DIABETES: EARLY LIFE ADVERSITY, STRESS AND THE IMMUNE SYSTEM

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

The COVID-19 Pandemic: Does Our Early Life Environment, Life Trajectory and Socioeconomic Status Determine Disease Susceptibility and Severity?

A poor socioeconomic environment and social adversity are fundamental determinants of human life span, well-being and health. Previous influenza pandemics showed that socioeconomic factors may determine both disease detection rates and overall outcomes, and preliminary data from the ongoing coronavirus disease (COVID-19) pandemic suggests that this is still true. Over the past years it has become clear that early-life adversity (ELA) plays a critical role biasing the immune system towards a pro-inflammatory and senescent phenotype many years later. Cytotoxic T-lymphocytes (CTL) appear to be particularly sensitive to the early life social environment. As we understand more about the immune response to SARS-CoV-2 it appears that a functional CTL (CD8+) response is required to clear the infection and COVID-19 severity is increased as the CD8+ response becomes somehow diminished or exhausted. This raises the hypothesis that the ELA-induced pro-inflammatory and senescent phenotype may play a role in determining the clinical course of COVID-19, and the convergence of ELA-induced senescence and COVID-19 induced exhaustion represents the worst-case scenario with the least effective T-cell response. If the correct data is collected, it may be possible to separate the early life elements that have made people particularly vulnerable to COVID-19 many years later. This will, naturally, then help us identify those that are most at risk from developing the severest forms of COVID-19. In order to do this, we need to recognize socioeconomic and early-life factors as genuine medically and clinically relevant data that urgently need to be collected. Finally, many biological samples have been collected in the ongoing studies. The mechanisms linking the early life environment with a defined later-life phenotype are starting to be elucidated, and perhaps hold the key to understanding inequalities and differences in the severity of COVID-19