Gestational diabetes mellitus (GDM) is a serious perinatal condition affecting up to 14% of pregnancies globally, and can result in negative outcomes for the pregnancy as well as future maternal and offspring health PMID: 34883186. Pancreatic β-cell dysfunction is a major driver of GDM pathogenesis, and individuals with GDM exhibit an increased polygenic risk score for type 2 diabetes (T2D) PMID: 32843565. Autophagy, the evolutionarily conserved process for recycling cytoplasmic components, is a critical system for maintaining β-cell homeostasis PMID: 34016598. T2D, similar to GDM in terms of insulin resistance and β-cell dysfunction, is characterized by a reduction in islet autophagy. Our preliminary data show that compared to nondiabetic male human islets (n=3), T2D islets (n=3) exhibit reduced protein expression of the autophagy initiation kinase ULK1 (P=0.07) and the autophagosome protein LC3B (P=0.04), alongside reduced autophagic signaling as evidenced by lower phosphorylation of Atg14(Ser29) (P=0.06). Due to the metabolic and cellular similarities between T2D and GDM, we hypothesized that reduced autophagy is an important contributor to β-cell dysfunction in GDM, and that β-cell autophagy alterations are also involved in the normal adaptation to pregnancy. Previous work has shown that in mice, multiparity induces gestational glucose intolerance, akin to GDM in humans PMID: 22127227. We collected pancreata from age-matched nonfasted (n=4) multiparous (parity 4) and primiparous C57BL/6J dams on gestational day (gd) 17.5 to evaluate differences in islet autophagic signaling in normoglycemic vs glucose intolerant pregnancies. In the islets of multiparous dams, we identified a marked accumulation of large LC3B-positive puncta (P0.9). On 1st and 2nd parity, however, preliminary evidence indicates that gd18.5 βULK1KO dams (n=4) may exhibit improved gestational glucose tolerance compared to control (n=2), with an average 35% reduction in IPGTT serum glucose area under the curve (AUC). As this potential improvement in glucose tolerance with reduced ULK1-mediated β-cell autophagy conflicts with our expectations of autophagy disruption leading to gestational dysglycemia, ongoing experiments will be done to further establish the role of islet autophagy, with tissue analysis and additional dams taken through multiple pregnancies to determine if effects of reduced autophagy are parity-dependent. This work was supported by the National Institutes of Health funding grants T32DK083250 to VLP and R01DK136237 to EUA, with additional funding to TKH from UMN RAISE. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Pszczolkowski et al. (Fri,) studied this question.