Human fatty pancreas in vitro model reveals specific effects on beta-cell function and incretin responsiveness in T2D

Introduction and Objective: Pancreatic adipose tissue (PAT) accumulation is linked to reduced insulin secretion in individuals at high risk for type 2 diabetes (T2D). However, the mechanisms by which PAT influences islet function remain unclear, partly due the lack of functional in vitro models of human pancreatic adipocytes. We developed a human PAT organoid model that mimics the in vivo phenotype and display donor-related metabolic memory. Our aim is to investigate the functional characteristics of PAT in T2D and its interactions with pancreatic islets.

Methods: Primary pancreatic adipocytes and stromal vascular fraction (SVF) cells were isolated from peripancreatic fat biopsies of non-diabetic (ND; n=11) and T2D patients (n=8). SVF were used to generate PAT organoids, which were subsequently co-cultured with ND human islets for 72 hours in a fatty pancreas in vitro system. Outcomes included glucose-stimulated insulin secretion (GSIS) and response to incretins (Exendin-4, GIP, Tirzepatide) for human islets, as well as adipogenesis (RT-qPCR) and lipolysis (measured by free fatty acid [FFA] release in response to isoproterenol [1µM] and insulin [100 nM, 10 nM]) for PAT organoids.

Results: T2D-derived PAT organoids displayed impaired adipogenesis compared to ND-derived organoids, as shown by significantly lower PPARG (0.31±0.07 in ND vs 0.22±0.04 in T2D) and ADIPOQ (0.97±0.20 in ND vs 0.59±0.16 in T2D) mRNA expression. Additionally, T2D-derived organoids exhibited increased isoproterenol-induced lipolysis and were insulin resistant compared to ND-derived organoids (insulin inhibition of isoproterenol-stimulated lipolysis: 64% in ND vs 29% in T2D). In co-culture experiments, the effects of PAT organoids on beta-cell function varied based on the donor’s metabolic background. ND-derived PAT organoids enhanced insulin secretion in response to GIP and Tirzepatide but not Exendin-4. However, T2D-derived PAT organoids impaired GSIS and selectively augmented Tirzepatide-induced insulin secretion, without significantly affecting responses to Exendin-4 or GIP. Notably, these selective effects were most probably FFA-independent, as secretome analysis revealed no significant differences in FFA release between mono-culture (islets or PAT organoids cultured separately) and co-culture conditions. Insulin sensitivity of ND-derived PAT organoids remained unaffected with the co-culture with human islets. In contrast, T2D-derived PAT organoids exhibited further impairment, as evidenced by a reduction in insulin-mediated inhibition of isoproterenol-induced lipolysis, decreasing from 29% in mono-culture to 15% in co-culture.

Conclusion PAT has divergent effects on beta-cell function, exacerbating dysfunction in T2D while enhancing or protecting function in ND individuals. Our co-culture model provides a valuable platform for investigating the role of pancreatic adipocytes-islet interactions in T2D pathophysiology.

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Artikel online veröffentlicht:
28. Mai 2025