Type 2 diabetes mellitus (T2DM) is a very complex disease with major pathological derangements, including insulin resistance and pancreatic β cell dysfunction (Kulkarni, Muralidharan, May et al., 2022). Many pathways, including MAPK, Wnt, PI3K/Akt, and NF-kB, have been reported to show direct or indirect influences on β cell proliferation, apoptosis, or insulin secretion in response to different stimuli (Garcia-Aguilar and Guillen, 2022). For these reasons, the exploration of novel and specific mechanisms for the regulation of β cell function has been helpful in the development of new therapeutic targets to protect β cell function and slow down the process of T2DM.

A previous study has identified the transcription factor Forkhead box O-1 (Foxo1) as a potential regulator of β cell function (Marchelek-Mysliwiec, Nalewajska, Turon-Skrzypinska et al., 2022). In our own work on the mechanism in palmitate-induced β cell apoptosis, we found that Polypeptide N-Acetylgalactosaminyl transferase 14 (Glant14) was a target gene of Foxo1 (Lin, Yin, Zhang et al., 2012). GALNT14, the newest member of the GalNAc-transferase (GalNAc-T) family, adds a GalNAc moiety to Ser and Thr residues of proteins to initiate mucin-type O-glycosylation, an important post-translational modifications (PTMs) (van Tol, Wessels and Lefeber, 2019). Currently, direct glycosylation by GALNT14 has been identified for only a few substrates, such as DR5, a death receptor that promotes apoptosis (by Apo2L/TRAIL) upon glycosylation at highly conserved O-glycosylation sites (Wagner, 2007). Another identified substrate is PHB2, which is O-glycosylated at Ser161 and enhances cell growth and migration via the insulin-like growth factor (IGF) signaling pathway (Chu, Fan, Lai and Yeh, 2022). A third identified substrate is transmembrane mucin 13 (MUC13), whose aberrant glycosylation is related to ovarian carcinogenesis (Wang, Yu, Zhao et al., 2013).

One reason for the limited evaluation of GALNT14 has been the difficulty associated with high-throughput screening of its substrates, as well as its strict tissue-specific distribution. The Galnt14 gene is expressed at high levels only in the kidney (https://www.proteinatlas.org/) and in several cancer cells, including epithelial ovarian cancer cells, hepatocellular carcinoma cells, and Dakiki cells, in which its biofunction is limited to tumor tissue invasiveness, cell migration, and multidrug resistance (Lin, 2020). Among the GalNAc-T family members, only GALNT2 has been associated with the development of T2DM through its mediation of insulin sensitivity by regulation of insulin signaling via the IRS-1/AKT and PEPCK pathways in human liver (HepG2) cells (Antonucci, Marucci, Trischitta and Di Paola, 2022). However, our chance discovery of high and specific expression of Galnt14 in islet β cells prompted further investigation of a role for the Galnt14 gene in T2DM.

In the present study, we examined the biological function of GALNT14 by db/db mice, high fat diet (HFD)-fed mice, GK rats and knockout in rat insulinoma INS-1 cells models, followed by proteomics analysis. The findings provide the first verification of the distribution of GALNT14 in pancreatic islets, while also providing insight into the significance of GALNT14 in the regulation of β cell morphology, viability, and insulin secretion.