Immunometabolic reprogramming and β-cell dedifferentiation: Integrated mechanisms driving type 2 diabetes progression

Area of Science:

• Endocrinology
• Immunometabolism
• Cell Biology

Background:

• Type 2 diabetes is increasingly viewed as a result of metabolic overload and chronic inflammation.
• Pancreatic beta-cells undergo progressive identity alterations due to glucotoxicity, lipotoxicity, oxidative stress, and inflammation.

Purpose of the Study:

• To synthesize evidence on how metabolic and immune pathways influence beta-cell fate.
• To describe interorgan communication's role in beta-cell disturbances.
• To present a conceptual framework, the beta-cell identity clock, for dynamic beta-cell transitions.

Main Methods:

• Review of current scientific literature.
• Analysis of findings from single-cell transcriptomics, human islet studies, and metabolic profiling.
• Synthesis of evidence on molecular regulators of beta-cell fate.

Main Results:

• Metabolic and immune factors converge on key molecular regulators of beta-cell identity.
• Interorgan communication exacerbates beta-cell dedifferentiation and functional decline.
• Beta-cell dedifferentiation is a dynamic, potentially reversible process influenced by immunometabolic stress.

Conclusions:

• Emerging therapies include anti-inflammatory agents, metabolic modulators, epigenetic regulators, and regenerative approaches.
• Therapeutic strategies aim to preserve or restore beta-cell identity under metabolic stress.
• The beta-cell identity clock framework captures the dynamic nature of beta-cell transitions in diabetes.