Secretin is a 27-amino acid long peptide hormone that regulates pancreatic water, bicarbonate, enzymes, and potassium ion secretion. The human secretin receptor (hSR) is a glycoprotein consisting of 440 amino acids, of which there are 5 putative N-linked glycosylation sites at positions Asn72, Asn100, Asn106, Asn128 (N-terminal ectodomain), and Asn291 (second exoloop). Through functional analysis of the hSR-transfected cells cultured in the presence of various glycosylation inhibitors, it was found that tunicamycin and castanospermine were able to significantly reduce the secretin-stimulated cAMP response. On the other hand, the effects of other inhibitors, swainsonine and deoxymannojirimycin, were much lower, suggesting that the high mannose-type carbohydrate side-chain is essential to the expression of a fully functional hSR. The role of individual N-linked glycosylation sites was studied by mutation analysis (Asn to Leu or Ser to Ala) coupled to measurements of cAMP accumulation and extracellular acidification rate. The ED50 values of the wild-type receptor in these two assay systems were 0.25 and 0.11 nM, respectively, and mutation at position 100, 106, or 291 did not affect either the ED50 values or the maximal responses in the two assays. However, the Asn72Leu and Ser74Ala mutations reduced the maximal responses and increased the ED50 values in both assays, suggesting that this site is a true glycosylation signal. This hypothesis was further supported by competitive binding studies, the same mutants were found to be defective in binding with [125I]secretin. To evaluate whether the change in receptor function of the mutants is caused by the change in the process of presenting the receptor to the cell surface, the mutants and the wild-type receptor were tagged with a c-Myc epitope at the C-termini. Using an anti-c-Myc monoclonal antibody and confocal microscopy, all of the mutant receptors were found to be expressed and delivered to the plasma membrane.
Objective: To compare the risks of gastric cancer and other gastric diseases upon exposed to sodium-glucose cotransporter 2 inhibitors (SGLT2I), dipeptidyl peptidase-4 inhibitors (DPP4I) and glucagon-like peptide-1 receptor agonists (GLP1A). Design: This was a retrospective population-based cohort study of prospectively recorded data on type-2 diabetes mellitus (T2DM) patients prescribed either SGLT2I or DPP4I between January 1st 2015 and December 31st 2020 from Hong Kong. The primary outcome was new-onset gastric cancer, peptic ulcer (PU), acute gastritis, non-acute gastritis, and gastroesophageal reflux disease (GERD). Propensity score matching (1:1 ratio) using the nearest neighbour search was performed and multivariable Cox regression was carried out. A three-arm analysis including the GLP1A cohort was subsequently conducted. Results: A total of 62858 T2DM patients (median age: 62.2 years old [SD: 12.8]; 55.93% males; SGLT2I: n=23442; DPP4I: n=39416) were included. After matching, the incidence of gastric cancer was significantly lower in SGLT2I users (Incidence rate, IR: 0.32; 95% confidence interval, CI: 0.23-0.43) than DPP4I users (IR: 1.22; CI: 1.03-1.42). SGLT2I use was associated with lower risks of gastric cancer (HR: 0.30; 95% CI: 0.19-0.48) after adjusting for significant covariates compared to DPP4I use. SGLT2 use was also associated with lower risks of PU, acute gastritis, non-acute gastritis, and GERD (all p<0.05). The three-arm analysis demonstrated higher risks of gastric cancer and GERD in GLP1A than in SGLT2I. Conclusions: SGLT2I was associated with lower risks of new-onset gastric cancer, PU, acute gastritis, non-acute gastritis, and GERD after matching and adjustments compared to DPP4I.
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