Project description:Type 1 diabetes (T1D) is a chronic T-cell-mediated autoimmune disease, leading to the destruction of the pancreatic insulin-producing beta cells. Little is known about the involvement of neutrophils that exert multifaceted functions like phagocytosis, degranulation, production of cytokines and the formation of neutrophil extracellular traps (NETosis), in the pathogenesis of T1D. Our aim was to gain insight into the proteome of neutrophils undergoing NETosis from patients with long-standing T1D compared to age- and sex-matched healthy controls under both resting and stimulated conditions (phorbol-myristate acetate, PMA, 100nM; ionomycin, 20µM; 3hours) by LC/MS-MS.
Project description:Objective: Rates of type 2 diabetes (T2D) among adolescents are on the rise. Epigenetic changes could be associated with the
metabolic alterations in adolescents with T2D.
Methods: We performed a cross-sectional integrated analysis of DNA methylation data from peripheral blood mononuclear cells
with serum metabolomic data from First Nation adolescents with T2D and controls participating in the Improving Renal
Complications in Adolescents with type 2 diabetes through REsearch (iCARE) cohort study, to explore the molecular changes in
adolescents with T2D.
Results: Our analysis showed that 43 serum metabolites and 36 differentially methylated regions (DMR) were associated with T2D. Several DMRs were located near the transcriptional start site of genes with established roles in metabolic disease and associated with altered serum metabolites (e.g. glucose, leucine, and gamma-glutamylisoleucine). These included the free fatty acid receptor-1 (FFAR1), upstream transcription factor-2 (USF2), and tumor necrosis factor-related protein-9 (C1QTNF9), among others.
Conclusions: We identified DMRs and metabolites that merit further investigation to determine their significance in controlling
gene expression and metabolism which could define T2D risk in adolescents.
Project description:Glucose-dependent insulinotropic polypeptide (GIP) has been proposed to exert insulin-independent effects on lipid and bone metabolism. We investigated the effect of a 6-day s.c. GIP infusion on circulating lipids, white adipose tissue (WAT), brown adipose tissue (BAT), hepatic fat content, and inflammatory markers in patients with type 1 diabetes. In a randomized, placebo-controlled, double-blind, crossover study, 20 men with type 1 diabetes underwent a 6-day continuous s.c. infusion with GIP (6 pmol/kg/min) and placebo (saline), with an interposed seven-day washout period. Each intervention period involved three study days: Day 0 (baseline measurements, a baseline abdominal adipose tissue biopsy and blood sampling), Day 1 (fasting blood sample after 24 hours infusion), and Day 6 (fasting blood sample, an abdominal adipose tissue biopsy).
Project description:We report for the first time movement of Correia Repeat Enclosed Elements, through inversion of the element at its chromosomal location. Analysis of Ion Torrent generated genome sequence data from Neisseria gonorrhoeae strain NCCP11945 passaged for 8 weeks in the laboratory under standard conditions and stress conditions revealed a total of 37 inversions: 24 were exclusively seen in the stressed sample; 7 in the control sample; and the remaining 3 were seen in both samples. These inversions have the capability to alter gene expression in N. gonorrhoeae through the previously determined activities of the sequence features of these elements. In addition, the locations of predicted non-coding RNAs were investigated to identify potential associations with CREE. Associations varied between strains, as did the number of each element identified. The analysis indicates a role for CREE in disrupting ancestral regulatory networks, including non-coding RNAs. RNA-Seq was used to examine expression changes related to Correia repeats in the strain
Project description:Protein misfolding is a contributor to the development of type 2 diabetes (T2D), but it is unknown whether impaired proteostasis in T2D is generalized or has special features. Here, we report a robust accumulation of misfolded proteins within the mitochondria of human pancreatic islets from patients with T2D and elucidate its impact on β cell viability. Quantitative proteomics studies of protein aggregates surprisingly reveal that islets from donors with T2D have a signature more closely resembling mitochondrial rather than ER protein misfolding. Loss of the matrix protease LONP1, a vital component of the mitochondrial proteostatic machinery whose expression is reduced in β cells of donors with T2D, yields mitochondrial protein misfolding and reduced respiratory function, ultimately leading to β cell apoptosis and hyperglycemia. Intriguingly, LONP1 gain of function ameliorates mitochondrial protein misfolding and restores human β cell survival following glucolipotoxicity via a protease-independent effect requiring LONP1-mtHSP70 chaperone activity. Thus, LONP1 promotes β cell survival and prevents hyperglycemia by facilitating mitochondrial protein folding. These observations open novel insights into the nature of proteotoxicity that promotes β cell loss during the pathogenesis of T2D that could be considered as future therapeutic targets.