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Fat, Muscle, and More: How Inter-Organ Crosstalk Fuels Type 2 Diabetes Mellitus

Type 2 Diabetes Mellitus (T2DM) isn't just high blood sugar—it’s a systemic failure of communication between key organs!

Here’s how multi-organ crosstalk goes awry, and the mediators behind the dysfunction:


🔑 Key Players & Mediators:


➡️ Adipose Tissue (Fat):

  • Releases non-esterified fatty acids (NEFA), leading to lipid accumulation in the liver, muscle, and pancreas.

  • Produces pro-inflammatory cytokines (e.g., TNF, IL-6), which promote insulin resistance.

  • Dysfunctional fat releases lipokines like ceramides and diacylglycerols that disrupt insulin signaling.


➡️ Skeletal Muscle:

  • Impaired glucose uptake due to elevated branched-chain amino acids (BCAA) and metabolic stress.

  • Excess lipid metabolites activate novel protein kinase C (nPKC), inhibiting insulin pathways.

  • Reduced mitochondrial function limits glucose and lipid metabolism.


➡️ Liver:

  • Overproduces glucose while accumulating fat, driven by signals from adipose tissue and circulating lipids.

  • Releases ceramide-loaded exosomes and inflammatory markers that exacerbate insulin resistance.


➡️ Gut Microbiota:

  • Imbalanced microbiota reduces short-chain fatty acids (SCFA), which normally enhance insulin sensitivity.

  • Releases harmful metabolites that drive inflammation and dysregulated glucose metabolism.


➡️ Brain:

  • Hypothalamic inflammation affects appetite control and insulin regulation.


🔬 Why This Matters:These mediators—lipids, cytokines, metabolites, and exosomes—turn organs into "dysfunction amplifiers," creating a vicious cycle that drives T2DM progression.


Xourafa, G., Korbmacher, M., & Roden, M. (2024). Inter-organ crosstalk during development and progression of type 2 diabetes mellitus. Nature Reviews Endocrinology, 20(1), 27-49. https://doi.org/10.1038/s41574-023-00898-1




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