## 4 Exosomal Pentad  
Diabetes mellitus (DM) is one of the most extensively researched diseases in endocrinology. Over time, various pathophysiological models have been proposed to explain its underlying mechanisms in a more structured and comprehensive manner. In 1988, DeFronzo introduced the triumvirate model, identifying dysfunctions in pancreatic beta cells, the liver, and skeletal muscle as key contributors to non-insulin-dependent diabetes mellitus (NIDDM) [87]. This model was later expanded into the _disharmonious quartet_ with the inclusion of adipose tissue. In 2009, further additions, including the small intestine (_quintessential quintet_), pancreatic alphaiit is not necessary cells (_setaceous sextet_), kidneys (_septicidal septet_) and, finally, central nervous system (CNS), culminated in the _ominous octet_, which remains a widely accepted framework for explaining type 2 diabetes mellitus (T2 DM) pathophysiology [88; 89]. Given the established inter-organ interactions in T2 DM, we propose a novel perspective in which five of these key tissues--liver, skeletal muscle, pancreatic beta cells, adipose tissue, and small intestine--form a metabolic axis driven by exosome-mediated communication.  
Exosomes have emerged as crucial mediators of intercellular signaling, influencing metabolic homeostasis through the transfer of bioactive molecules, including microRNAs (miRNAs), proteins, and lipids. Pancreatic beta cells secrete exosomes enriched with miRNAs such as miR-146a and miR-29a [60], which regulate insulin sensitivity and immune responses in target tissues. Similarly, liver-derived exosomes contribute to adipose tissue remodeling by modulating lipogenesis and inflammatory pathways [15; 55]. Exosomes from adipose tissue, carrying miRNAs like miR-802-5p, influence insulin signaling in the liver and heart, impacting systemic metabolism [46; 47]. Skeletal muscle-derived exosomes, particularly those released during exercise, promote angiogenesis and tissue repair [61; 63], while intestinal exosomes play a key role in glucose homeostasis and immune regulation [72; 81; 86].  
This proposed model aligns with the ominous octet, which underscores the interconnected dysfunction of multiple metabolic organs in diabetes. However, we introduce an expanded framework, emphasizing exosomes as central mediators of inter-organ crosstalk. By recognizing their role in metabolic regulation and their potential as therapeutic targets, we propose the term \"_exosomal pentad_\", acknowledging that additional tissues may be integrated into this dynamic system (Figure 2).  
The importance of comparing this model with the ominous octet of TD2M lies in the historical addition of the kidney to form the \"septicidal septet\". This inclusion was based on evidence highlighting the critical role of SGLT2 transporter inhibition with gliflozins, which have become cornerstone medications in T2D treatment [90]. In this context, the introduction of a model such as the exosomal pentad could facilitate the study of inter  
Figure 2: Exosomes are key messengers of the most critical metabolic tissues, with crucial biological effects. It is proposed that these five tissues are interconnected through the secretion of exosomes and their molecular cargo, a concept we have termed the “exosomal pentad”, analogous to the ominous octet in type 2 diabetes mellitus. Exosomes carry bioactive molecules like miRNAs, proteins, and lipids that influence inflammation, insulin sensitivity, cell proliferation, and apoptosis.  
organ communication, providing a mechanistic basis for pharmacological therapies under investigation or already approved that are derived from exosomes. Furthermore, as previously mentioned, this model may evolve in the future by incorporating additional tissues, potentially leading to novel therapeutic strategies. In the following section, we will present examples of exosome-derived therapies reported in the scientific literature.