👤 Almantas Maleckas

Intestinal dysmotility in type 2 diabetes mellitus (T2DM) may involve impaired cholinergic and incretin-mediated regulation. This study compared cholinergic-induced jejunal contractility and evaluated the effects of Glucagon like peptide-1 (GLP-1) and Gastric inhibitory polypeptide (GIP) in relation to the expression of these peptides, their receptors, and Dipeptidyl peptidase 4 (DPP-4) in jejunal muscle of obese patients with and without T2DM. Jejunal samples were collected from 32 obese patients undergoing bariatric surgery (14 with and 18 without T2DM). Jejunal muscular tissue was examined for expression of GLP-1, GIP, and for expression and localization of DPP-4 and incretin receptors (GLP-1R and GIPR). In addition, DPP-4 enzymatic activity was quantitatively assessed. Contractility of circular and longitudinal muscle strips was assessed GLP-1 receptors were detected in smooth muscle nuclei and enteric ganglia, while GIP receptors localized to both muscle layers. DPP-4 was present in neural and muscular compartments. In T2DM, GIPR and DPP-4 expression and activity were increased, while GIP protein was reduced. GLP-1 protein levels tended to be higher. Longitudinal muscle contractility independent of neural input was reduced in T2DM. GLP-1 selectively inhibited circular muscle contractions in both groups, whereas GIP had no effect. This study demonstrates that reduced cholinergic activity in longitudinal muscle, lower GIP, and increased GLP-1 in T2DM indicate a shifted local incretin environment that may collectively suppress jejunal contractility. Show less

Coding sequence variants comprise a small fraction of the germline genetic variability of the human genome. However, they often cause deleterious change in protein function and are therefore associated with pathogenic phenotypes. To identify novel pancreatic ductal adenocarcinoma (PDAC) risk loci, we carried out a complete scan of all common missense and synonymous SNPs and analysed them in a case-control study comprising four different populations, for a total of 14 538 PDAC cases and 190 657 controls. We observed a statistically significant association between 13q12.2-rs9581957-T and PDAC risk (P = 2.46 × 10-9), that is in linkage disequilibrium (LD) with a deleterious missense variant (rs9579139) of the URAD gene. Recent findings suggest that this gene is active in peroxisomes. Considering that peroxisomes have a key role as molecular scavengers, especially in eliminating reactive oxygen species, a malfunctioning URAD protein might expose the cell to a higher load of potentially DNA damaging molecules and therefore increase PDAC risk. The association was observed in individuals of European and Asian ethnicity. We also observed the association of the missense variant 15q24.1-rs2277598-T, that belongs to BBS4 gene, with increased PDAC risk (P = 1.53 × 10-6). rs2277598 is associated with body mass index and is in LD with diabetes susceptibility loci. In conclusion, we identified two missense variants associated with the risk of developing PDAC independently from the ethnicity highlighting the importance of conducting reanalysis of genome-wide association studies (GWASs) in light of functional data. Show less