Impact of Western Diet-Induced Gestational Diabetes Mellitus: Role of CD11c+ Macrophages in Offspring Islets from Embryonic Overdevelopment to Adult Dysfunction

Adult pancreatic islets harbor resident macrophages that prominently influence the functional state of islets. Considering the functional heterogeneity of macrophages, could the GDM microenvironment exacerbate macrophage invasion and polarization in embryonic islets, thereby impairing the development and differentiation of β cells? In this study, immunofluorescence, flow cytometry, transmission electron microscopy, qPCR, and Western blot were employed to assess macrophage invasion in offspring-islets, β-cell ultrastructure, and dedifferentiated status; islet function was evaluated through insulin secretion experiments or hyperglycemic clamp. Meanwhile, direct/indirect co-culture of macrophages with primary islet cells was performed to validate the crosstalk between invading macrophages and β cells. We found that hypermetabolic stress and low-grade inflammation observed in GDM patients were recapitulated in GDM rats induced by Western diet (WD) and transmitted to their offspring rats. This resulted in increased invasion of CD11c⁺ macrophages into the embryonic offspring-islets, where they phagocytosed the insulin containing vesicles released by β cells. Moreover, neonatal islets from GDM-offspring rats showed increased insulin secretion in response to both glucose and amino acids, with significant upregulation of dedifferentiation marker Aldh1a3 and disallowed genes Cox5a and Slc16a1 in β cells. Notably, accompanied by severe endoplasmic reticulum stress, the electron density of insulin granules in most GDM β cells significantly dropped to vacuolation, jointly driving the cells towards a near-exhausted state. In vitro, direct contact with CD11c⁺ macrophages readily induced the dedifferentiation and dysfunction of primary β cells. Although islet function in GDM offspring rats gradually normalized during early growth, it declined again after 14 weeks. WD exacerbated the reaccumulation of CD11c⁺ macrophages in adult islets, further impairing the β cells functional state, particularly phase II insulin secretion. Our findings highlight the critical role of WD in driving embryonic reprogramming and adult dysfunction of GDM-offspring islets via CD11c⁺ macrophage.