Targeting Inflammation in Type 2 Diabetes: The Emerging Role of Decorin

Type 2 diabetes (T2D) is a metabolic disease characterized by insulin resistance and progressive deterioration of pancreatic insulin-producing β-cell function, leading to chronic hyperglycemia. Although initially considered a “disease of the pancreas,” latest views acknowledge that optimal glycemic regulation involves complex and mutual communication between different organs and tissues including the pancreas, liver, intestine, brain, muscle and adipose tissue. Skeletal muscle has long been recognized as a metabolic organ [1], producing myokines such as irisin and interleukin-6 (IL6) with key role in modulating insulin sensitivity and metabolic health [2]. In a recent issue of Acta Physiologica, Langlois et al. [3] provides novel insight to the role of another myokine, decorin, a promising protective factor involved in preserving the pancreatic β-cell function and insulin secretion under inflammatory conditions.

Myokines are proteins that are produced and released from skeletal muscle cells and act as hormones on other organs, including the pancreas, liver, brain, and adipose tissue [1]. Decorin, a small leucine-rich proteoglycan [4], has been established as a myokine [5] (Figure 1), promoting muscle hypertrophy through inhibition of myostatin (MSTN, or growth and differentiation factor 8). MSTN is a member of the transforming growth factor-β (TGF-β) superfamily, having a crucial role in the negative regulation of muscle growth by suppressing both myoblast proliferation and myofibre hypertrophy. Higher levels of MSTN were detected in T2D but also in non-obese insulin-resistant patients. Also, MSTN was shown to inhibit glucose transporter 4 (GLUT4) and thus decrease muscle glucose uptake. Decorin, which binds and contributes to the stabilization of collagen fibers in the extracellular matrix (ECM) was shown to be produced by muscle activity and to sequester MSTN in the ECM, thus blocking its inhibitory effect on myoblast proliferation [6] and potentially having also an indirect role in glucose regulation. But, can decorin act long-range as well?

Langlois et al. provided significant experimental insights into this muscle-pancreatic islet crosstalk by showing that decorin could also have a direct role on pancreatic islet cells. Applied in vitro, decorin protected the isolated β-cells and pancreatic islets from inflammatory stress. Recent studies showed that chronic low-grade inflammation leads to insulin signaling disruption, thus exacerbating β-cell stress leading to functional dysfunction and eventual cell loss [7, 8]. Moreover, elevated levels of pro-inflammatory cytokines such as tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), and interferon γ (IFN-γ) were previously shown to hinder glucose homeostasis and increase metabolic stress. Exposure to TNF-α typically impairs glucose-stimulated insulin secretion (GSIS), disrupts cytoskeletal integrity, and activates NF-κB signaling, finally leading to β-cell dysfunction [9]. Decorin treatment effectively counteracted these effects by preserving GSIS and restoring insulin granule docking, as well as preventing NF-κB activation, thus reducing inflammation-induced β-cell damage. Moreover, decorin increased the focal adhesion length and restored the adhesion number decreased by TNF-α treatment, further supporting its role in sustaining insulin secretion under inflammatory conditions (Figure 1).

In human pancreatic islets from T2D donors, decorin improved insulin content and secretion, suggesting its relevance in restoring β-cell function. Transcriptomic analysis indicated that decorin reversed T2D-associated gene expression alterations, restoring pathways essential for β-cell metabolism, survival, and insulin processing. These findings suggest that decorin may counteract diabetes-associated islet dysfunction and promote β-cell resilience under chronic inflammatory stress. Together, these results highlight its potential as a therapeutic target in both cellular and physiological models of diabetes.

Interestingly, the identification of decorin as a myokine that directly improves β-cell survival and function under inflammatory stress is reinforcing the concept that muscle-derived factors can have endocrine functions extending beyond muscle metabolism. Although decorin demonstrates a protective role, future studies should explore its potential synergies with other anti-inflammatory agents or metabolic modulators to enhance β-cell resilience. Given that inflammation-driven β-cell failure is a hallmark of diabetes progression, targeting decorin could be a novel strategy to enhance endogenous insulin secretion, to protect β-cells, and to delay the disease progression. However, one should also consider that decorin binds to multiple targets, including TGFβ1, and directly antagonizes several members of the receptor tyrosine kinase family, like the epidermal growth factor receptor, insulin-like growth factor 1 receptor, and the hepatocyte growth factor receptor (Met). Its pleiotropic function includes cell cycle regulation, autophagy, angiogenesis, inflammation, wound healing, fibrosis, and inhibiting tumor metastasis [10]. Further studies will be crucial in determining its translational potential in metabolic disease interventions.

In conclusion, the study by Langlois et al. provides a significant advance, adding to the growing body of research on interorgan crosstalk and improving the understanding of how muscle-derived factors influence pancreatic function. Decorin represents a promising therapeutic target for diabetes management, particularly in protecting β-cells from inflammatory damage.

Shayla Sharmine: writing – original draft, visualization. Luiza Ghila: conceptualization, writing – review and editing, supervision, funding acquisition.

The authors declare no conflicts of interest.