Myosteatosis in type 1 diabetes: immunometabolic mechanisms, biomarkers, and therapeutic targets.

Myosteatosis, defined as pathological lipid accumulation within and between skeletal muscle fibers, is increasingly recognized as a determinant of impaired muscle quality, metabolic inflexibility, and adverse clinical outcomes. Although well described in ageing, obesity, and cancer, its relevance to type 1 diabetes (T1D) remains underexplored. T1D is characterized by lifelong insulin deficiency, persistent autoimmune activation, and glycemic variability, conditions that profoundly disrupt cellular energy metabolism and substrate utilization in skeletal muscle, even in the absence of obesity or overt sarcopenia. This review integrates evidence from human imaging, metabolic phenotyping, immunological profiling, and multi-omics analyses to define myosteatosis as an immunometabolic phenotype in T1D. Central to this framework is dysregulation of the AMP-activated protein kinase (AMPK)-peroxisome proliferator-activated receptor (PPAR)-mitochondrial axis, which normally coordinates fatty-acid oxidation, mitochondrial biogenesis, and energy efficiency in skeletal muscle. In T1D, chronic immune activation and metabolic stress suppress AMPK and PPARδ signaling, impair PGC-1α-dependent mitochondrial function, and reduce oxidative capacity, promoting intramyocellular lipid accumulation despite preserved muscle mass. These defects are reinforced by persistent inflammatory signaling (IL-6, TNF-α, IL-1β; NF-κB, JNK, and NLRP3 pathways), accumulation of lipotoxic intermediates (ceramides and diacylglycerols), dysregulated myokine secretion (increased myostatin with reduced IL-15 and irisin), and infiltration of pro-inflammatory macrophages and CD8+ T cells. Mitochondrial stress, reflected by impaired phosphocreatine recovery, altered acylcarnitine profiles, increased oxidative damage, and reduced NAD+-SIRT1/3 activity, further consolidates immunometabolic dysfunction and lipid deposition. Collectively, this review positions myosteatosis as a clinically relevant and potentially modifiable consequence of immune-driven failure of cellular energy utilization in T1D. Because direct mechanistic data from T1D skeletal muscle remain scarce, the framework presented here is deliberately hypothesis-generating: it is assembled substantially by inference from type 2 diabetes (T2D), obesity and ageing models, and we map the resulting evidence gaps explicitly in order to define a research agenda rather than to assert a validated T1D-specific mechanism. Targeting the AMPK-PPAR-mitochondrial axis and its inflammatory and lipotoxic modifiers may enable earlier detection and mechanism-based interventions to preserve muscle metabolic resilience and functional capacity in autoimmune diabetes.