IDMBD: Intelligent Diagnostic Modelling of Bipolar Disorder at its early onset.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by dysregulated glucose metabolism, leading to an increased risk of cardiovascular disease, kidney dysfunction, and other comorbidities []. Lifestyle interventions, particularly aerobic exercise training, have demonstrated benefits for improving glycemic control and reducing the risk of complications associated with T2DM [, , , ] In parallel, conserved inflammatory signalling pathways mediated by pattern recognition receptors (PRRs), including the receptor for advanced glycation end‐products (RAGE) and Toll‐like receptors (TLRs), have emerged as key contributors to T2DM pathophysiology []. RAGE, a multiligand PRR, is implicated in the cellular response to advanced glycation end‐products (AGEs) and other pathogen—and damage‐associated molecular patterns (PAMPs and DAMPs, respectively), perpetuating the inflammatory environment characteristic of T2DM. Similar to RAGE, TLR2 and TLR4 play fundamental roles in the innate immune response due to their overlap in activation by PAMPs and DAMPs, typically elevated in those with metabolic disease and convergence on downstream signalling mechanisms [, , , ]. Of the 10 TLRs in human skeletal muscle, TLR2 and TLR4 are among the most highly expressed [, ] and are also upregulated in those with metabolic dysfunction [, , ]. It is through the inflammatory link, at least in part, that genetic deletion and blockade of RAGE [, ] and TLR [, , , ] signalling improves metabolic function, supporting a mechanistic link between PRR signalling and metabolic regulation. Soluble RAGE (sRAGE), generated through proteolytic cleavage or alternative splicing, has been proposed to act as a decoy receptor that binds circulating ligands and limits RAGE‐mediated signalling. Lower circulating sRAGE concentrations are commonly observed in individuals with obesity and impaired glucose tolerance and are often inversely associated with indices of metabolic dysfunction [, , , , , , ]. However, the functional role of sRAGE in glucose regulation remains incompletely defined. It is not yet clear whether sRAGE primarily reflects improved insulin sensitivity, altered insulin secretion, or broader changes in glycemic control, and disentangling these relationships requires well‐controlled human intervention studies. Extracellular matrix sheddases, including matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinase 10 (ADAM10), along with their endogenous inhibitors (TIMPs), are established regulators of tissue remodelling and receptor ectodomain shedding [, , , , ]. These enzymes can cleave membrane‐bound PRRs, releasing soluble receptor isoforms into circulation. Prior mechanistic work supports a role for ADAM10 and select MMPs in RAGE shedding, with regulation linked to calcium‐dependent signalling pathways and cellular stress responses [, , , ]. Given that AE induces robust calcium flux, redox‐sensitive signalling, and tissue remodelling, it provides a physiologically relevant context to examine regulation of these pathways. However, whether exercise‐induced changes in circulating sRAGE are mediated by alterations in sheddase activity remains a working hypothesis rather than an established mechanism.