Introduction and Objective: β cell identity and insulin secretion depend on intact cyclic adenosine monophosphate (cAMP) signaling, and its disruption contributes to β cell failure in type 2 diabetes (T2D), yet the upstream regulators remain incompletely defined. Here, we identify phosphodiesterase-4B (PDE4B) as a key negative regulator of β cell cAMP that contributes to β cell dysfunction in human diabetes.Methods: scRNA-seq of human islet grafts in mice fed with a high fat diet (HFD) and HPAP datasets were analyzed. β cell function, identity and cAMP levels were assessed by insulin secretion assays, cAMP measurements, immunolabeling, and qPCR in sorted human β cells and EndoC-βH1 cells with PDE4B overexpression (OE) or knockdown (KD).Results:In vivo, HFD increased human plasma insulin in mice with human islet grafts compared to regular diet fed mice, and scRNA-seq analysis showed a unique reduction of PDE4B in engrafted human β cells, compared with other PDE family members. In contrast, PDE4B was significantly elevated in T2D β cells in HPAP datasets and inversely correlated with INS. Immunolabeling confirmed increased PDE4B in β cells of T2D donors, with minimal expression in non-diabetic donors. PDE4B OE suppressed glucose and exendin-4 (E) increases in cAMP in EndoC-βH1 cells, impaired glucose-stimulated and E-mediated potentiation of insulin secretion, and reduced expression of INS, MAFA, and PDX1 in ENTPD3-sorted human β cells. Importantly, glucolipotoxicity (GLT) induced PDE4B expression in human β cells, whereas PDE4B KD restored glucose-stimulated insulin secretion and β cell identity, and reduced β cell stress markers (TXNIP and CASP3) in both GLT-treated and T2D β cell pseudoislets.Conclusion: These studies highlight PDE4B as a T2D-associated suppressor of cAMP levels and signaling that promotes β cell dysfunction and identity loss. Targeting PDE4B restores β cell function under metabolic stress and in T2D, identifying PDE4B as a promising therapeutic target for preserving human β-cell identity and function.
G. Lu: None. R.B. Kang: None. M. Varela: None. J. Aldaco: None. J. Lee: None. L. Kebrom: None. E. Oh: None. D. Thurmond: None. A. Garcia-Ocana: Advisory Panel; Current; Paulex Bio.
NIH-NIDDK (R01 DK139631)
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