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

Aims/hypothesis: Fat deposition in the pancreas is implicated in beta cell dysfunction and the progress of type 2 diabetes. However, there is limited evidence to confirm the correlation and explore how pancreatic fat links with beta cell dysfunction in human type 2 diabetes. This study aimed to examine the spatial relationship between pancreatic fat and islets in human pancreases.

Methods: Histological analysis of pancreatic specimens from 50 organ donors (15 with type 2 diabetes, 35 without) assessed pancreatic fat content variation among individuals with diabetes and its correlation with estimated beta cell mass and cell distribution within islets. Bioinformatic analysis of single-cell RNA-seq of 11 type 2 diabetic donors (from the Human Pancreatic Analysis Project database) explored the impact of high pancreatic fat content on beta cell gene expression and cell fate. Validation of bioinformatic results was performed with the above diabetic pancreases.

Results: Pancreatic fat content was higher in individuals with type 2 diabetes (10.24% [3.29-13.89%] vs 0.74% [0.34-5.11%], p<0.001), negatively correlated with estimated beta cell mass (r=-0.675, p=0.006) and positively with alpha-to-beta cell ratio (r=0.608, p=0.016). Enrichment analysis indicated that in diabetic donors with higher pancreatic fat content, the expression of ALDH1A3, beta cell dedifferentiation marker, in both alpha and beta cells was significantly increased, and in beta cells, the expression of NPY decreased. Pseudotime analysis revealed beta cell dedifferentiation and transdifferentiation towards alpha cells in diabetic donors with higher pancreatic fat content, with decreased expression of genes related to beta cell maturation and function, including INSM1, MafA and NPY. Concurrently, pathways related to inflammation and immune response were activated. Histologically, pancreatic fat content correlated positively with the percentage of beta cells positive for aldehyde dehydrogenase 1 family member A3 (ALDH1A3) within the islets (r=0.594, p=0.020) and the ALDH1A3 positivity rate in beta cells (r=0.615, p=0.015). And the number of T cells adjacent to adipocytes was related to the distribution pattern of adipocytes and the dedifferentiation phenotype in islets.

Conclusions/interpretation: Higher pancreatic fat content was accompanied by increased beta cell dedifferentiation in the individuals with diabetes. Clusters of adipocytes significantly contribute to higher pancreatic fat content and immune cell recruitment. Overall, the interactions among adipocytes, immune cells and beta cells in the pancreas microenvironment might contribute to beta cell failure and dedifferentiation in type 2 diabetes.