Intrapancreatic adipocytes and beta cell dedifferentiation in human type 2 diabetes.

Summary

In human donor pancreases, higher pancreatic fat—particularly adipocyte clustering—was linked to reduced beta-cell mass, higher alpha:beta ratios, increased ALDH1A3 expression, and transcriptomic signatures of beta-cell dedifferentiation and transdifferentiation toward alpha cells, alongside inflammatory pathway activation.

Key Findings

• Pancreatic fat content was higher in T2D (median ~10%) versus non-diabetic donors (~0.7%) and inversely correlated with estimated beta-cell mass (r = -0.675).
• High pancreatic fat associated with increased ALDH1A3 expression (dedifferentiation marker), reduced NPY, and pseudotime evidence of beta-cell dedifferentiation/transdifferentiation toward alpha cells.
• Adipocyte clusters correlated with T-cell proximity and inflammatory pathway activation, linking adiposity to immune recruitment and islet remodeling.

Clinical Implications

Highlights pancreatic fat as a potential therapeutic target; motivates imaging/biomarker strategies to identify patients with high intrapancreatic adiposity who may benefit from interventions reducing ectopic fat and inflammation.

Limitations

• Cross-sectional donor study limits causal inference; confounding by donor characteristics is possible.
• Single-cell dataset size is modest; functional interventional validation is lacking.

Future Directions

Test whether reducing intrapancreatic adiposity and local inflammation reverses dedifferentiation; develop noninvasive imaging/serologic markers of pancreatic fat clustering and islet immune activation.