In humans increase in intrapancreatic adipose tissue predicts beta-cell dedifferentiation score before diabetes onset: A pilot study

Background: The role of intrapancreatic fat (WAT) in the development of T2D remains debated. In T2D, β-cell dedifferentiation is one of the mechanisms responsible for β-cell failure but its role in prediabetes is unknown. We aimed to investigate the relation between WAT and β-cell dedifferentiation prior to diabetes onset. Methods: We evaluated pancreatic samples from patients without history of diabetes, who had previously undergone an oral glucose tolerance test and hyperglycemic clamp. Subjects were divided into 3 glucose tolerance groups: normal (NGT), altered (IGT) or newly diagnosed diabetes (nDM). Dedifferentiation and WAT% were morphologically assessed. Results: WAT was higher in nDM patients compared to NGT and IGT (WAT nDM 43.79 ± 20.83 %, IGT 10.67 ± 8.5 %, NGT 4.43 ± 4.37 %). We observed a progressive increase in dedifferentiation score, in parallel with worsening glucose tolerance (from NGT to IGT to nDM; 4.8 ± 3.8; 32.37 ± 7.4; 40.38 ± 19 respectively). A strong linear regression established that WAT could statistically significantly predict dedifferentiated β-cells (R = 0.86, p = 0.005), and that the predicted increase in dedifferentiated β-cells was 1.25 points for every extra one-point change in WAT. Interestingly, the WAT and dedifferentiation score variable pair were significantly related to 1-hour post-load glycemia. Conclusions: The accumulation of WAT might be responsible for dedifferentiation, making it a potential new target to curb diabetes onset.