Immune cell-adipose tissue crosstalk in metabolic diseases with a focus on type 1 diabetes

Abstract

Adipose tissue, once regarded merely as an energy reservoir, has emerged as a critical regulator of both metabolic and immune processes. This paradigm shift has profound implications for understanding and managing type 1 diabetes, a condition typically associated with lean individuals. The growing global prevalence of obesity has introduced an underexplored dimension to type 1 diabetes pathophysiology, a phenomenon that has significant consequences for disease development, progression and management. The coexistence of obesity and type 1 diabetes presents unique challenges, including exacerbation of insulin resistance and an elevated risk of complications such as CVD. Obesity-induced chronic low-grade inflammation, or 'meta-inflammation', creates a proinflammatory environment within adipose tissue. This disrupts systemic immune regulation, promotes insulin resistance and may even potentiate autoimmunity directed to pancreatic beta cells. Addressing these interactions will allow us to reframe research priorities and the management of type 1 diabetes in individuals who also live with obesity. In this review, we explore how adipose tissue maladaptation in obesity influences the pathophysiology of type 1 diabetes. We discuss existing literature and gaps in knowledge, and emphasise the importance of addressing these gaps. We also highlight the potential of emerging technologies and precision medicine to tackle the dual challenge of obesity and type 1 diabetes. Advances such as continuous glucose monitoring and automated insulin delivery systems and insights from genomics and metabolomics are revolutionising diabetes care. These tools can enhance glucose management and provide opportunities to mitigate weight-related complications and personalise treatment strategies.

Keywords: Adipose tissue; Epidemiology; Immune cells; Obesity; Review; Translational; Type 1 diabetes.

Fig. 1

Obesity-driven adipocyte–immune cell miscommunication triggers inflammation, causing impaired insulin sensitivity and beta cell dysfunction. Obesity causes a shift in the populations of immune cells in adipose tissue, switching the usual quiescent state to a proinflammatory state with a predominance of ‘M1-like’ proinflammatory macrophages. The close interplay between adipocytes and immune cells, specifically proinflammatory macrophages, induces secretion of proinflammatory cytokines/chemokines and adipokines in a paracrine and/or endocrine fashion, resulting in a systemic proinflammatory state called meta-inflammation. This meta-inflammation interferes with insulin signalling, leading to insulin resistance in insulin target tissues, for example muscle. Within pancreatic islets, it promotes the infiltration of activated immune cells, resulting in islet inflammation, beta cell dysfunction, endoplasmic reticulum (ER) stress and impaired insulin secretion. CLS, crown-like structures; GLUT4, solute carrier family 2 (facilitated glucose transporter) member 4; IL-1R, IL-1 receptor type 1; IL-6R, IL-6 receptor; IR, insulin receptor; PP, pancreatic polypeptide; TLR, Toll-like receptor; TNFR, TNF receptor. Created in BioRender. Bahman, F. (2025) https://BioRender.com/nnc91vq. This figure is available as part of a downloadable slideset

Fig. 2

Mechanistic links between obesity and autoimmunity. In obesity, adipose tissue inflammation (meta-inflammation) disrupts immune regulation through several mechanisms: persistent mammalian target of rapamycin (mTOR) activation in T cells reduces regulatory T cell (Treg) differentiation; elevated leptin levels impair Treg function and enhance pro-inflammatory Th1 and Th17 cell activity; increased expression of MHC class II in adipocytes promotes CD4+ T cell activation and IFN-γ secretion, further exhausting Tregs; and diminished PPAR-γ activity compromises Treg proliferation. Collectively, these alterations promote autoimmune responses leading to pancreatic beta cell loss characteristic of type 1 diabetes. Healthy adipose tissue supports FOXP3 expression, promoting the development and maintenance of anti-inflammatory Tregs. Created in BioRender. Bahman, F. (2025) https://BioRender.com/imbg578. This figure is available as part of a downloadable slideset

Fig. 3

Obesity and management challenges in type 1 diabetes. The cyclical relationship between increased body fat, insulin resistance, higher insulin doses and weight gain highlights how excess adiposity contributes to a cascade of physiological and behavioural factors that complicate type 1 diabetes management. Created in BioRender. Alzaid, F. (2025) https://BioRender.com/3hiviw3. This figure is available as part of a downloadable slideset