Metabolomics insights into early type 2 diabetes pathogenesis and detection in individuals with normal fasting glucose.

AIMS/HYPOTHESIS: Identifying the metabolite profile of individuals with normal fasting glucose (NFG [<5.55 mmol/l]) who progressed to type 2 diabetes may give novel insights into early type 2 diabetes disease interception and detection. METHODS: We conducted a population-based prospective study among 1150 Framingham Heart Study Offspring cohort participants, age 40-65 years, with NFG. Plasma metabolites were profiled by LC-MS/MS. Penalised regression models were used to select measured metabolites for type 2 diabetes incidence classification (training dataset) and to internally validate the discriminatory capability of selected metabolites beyond conventional type 2 diabetes risk factors (testing dataset). RESULTS: Over a follow-up period of 20 years, 95 individuals with NFG developed type 2 diabetes. Nineteen metabolites were selected repeatedly in the training dataset for type 2 diabetes incidence classification and were found to improve type 2 diabetes risk prediction beyond conventional type 2 diabetes risk factors (AUC was 0.81 for risk factors vs 0.90 for risk factors + metabolites, p = 1.1 × 10-4). Using pathway enrichment analysis, the nitrogen metabolism pathway, which includes three prioritised metabolites (glycine, taurine and phenylalanine), was significantly enriched for association with type 2 diabetes risk at the false discovery rate of 5% (p = 0.047). In adjusted Cox proportional hazard models, the type 2 diabetes risk per 1 SD increase in glycine, taurine and phenylalanine was 0.65 (95% CI 0.54, 0.78), 0.73 (95% CI 0.59, 0.9) and 1.35 (95% CI 1.11, 1.65), respectively. Mendelian randomisation demonstrated a similar relationship for type 2 diabetes risk per 1 SD genetically increased glycine (OR 0.89 [95% CI 0.8, 0.99]) and phenylalanine (OR 1.6 [95% CI 1.08, 2.4]). CONCLUSIONS/INTERPRETATION: In individuals with NFG, information from a discrete set of 19 metabolites improved prediction of type 2 diabetes beyond conventional risk factors. In addition, the nitrogen metabolism pathway and its components emerged as a potential effector of earliest stages of type 2 diabetes pathophysiology.

Genetic regulation of RNA splicing in human pancreatic islets.

BACKGROUND: Non-coding genetic variants that influence gene transcription in pancreatic islets play a major role in the susceptibility to type 2 diabetes (T2D), and likely also contribute to type 1 diabetes (T1D) risk. For many loci, however, the mechanisms through which non-coding variants influence diabetes susceptibility are unknown. RESULTS: We examine splicing QTLs (sQTLs) in pancreatic islets from 399 human donors and observe that common genetic variation has a widespread influence on the splicing of genes with established roles in islet biology and diabetes. In parallel, we profile expression QTLs (eQTLs) and use transcriptome-wide association as well as genetic co-localization studies to assign islet sQTLs or eQTLs to T2D and T1D susceptibility signals, many of which lack candidate effector genes. This analysis reveals biologically plausible mechanisms, including the association of T2D with an sQTL that creates a nonsense isoform in ERO1B, a regulator of ER-stress and proinsulin biosynthesis. The expanded list of T2D risk effector genes reveals overrepresented pathways, including regulators of G-protein-mediated cAMP production. The analysis of sQTLs also reveals candidate effector genes for T1D susceptibility such as DCLRE1B, a senescence regulator, and lncRNA MEG3. CONCLUSIONS: These data expose widespread effects of common genetic variants on RNA splicing in pancreatic islets. The results support a role for splicing variation in diabetes susceptibility, and offer a new set of genetic targets with potential therapeutic benefit.

Specific inulin-type fructan fibers protect against autoimmune diabetes by modulating gut immunity, barrier function, and microbiota homeostasis.

SCOPE: Dietary fibers capable of modifying gut barrier and microbiota homeostasis affect the progression of type 1 diabetes (T1D). Here, we aim to compare modulatory effects of inulin-type fructans (ITFs), natural soluble dietary fibers with different degrees of fermentability from chicory root, on T1D development in nonobese diabetic mice. METHODS AND RESULTS: Female nonobese diabetic mice were weaned to long- and short-chain ITFs [ITF(l) and ITF(s), 5%] supplemented diet up to 24 weeks. T1D incidence, pancreatic-gut immune responses, gut barrier function, and microbiota composition were analyzed. ITF(l) but not ITF(s) supplementation dampened the incidence of T1D. ITF(l) promoted modulatory T-cell responses, as evidenced by increased CD25+ Foxp3+ CD4+ regulatory T cells, decreased IL17A+ CD4+ Th17 cells, and modulated cytokine production profile in the pancreas, spleen, and colon. Furthermore, ITF(l) suppressed NOD like receptor protein 3 caspase-1-p20-IL-1ß inflammasome in the colon. Expression of barrier reinforcing tight junction proteins occludin and claudin-2, antimicrobial peptides ß-defensin-1, and cathelicidin-related antimicrobial peptide as well as short-chain fatty acid production were enhanced by ITF(l). Next-generation sequencing analysis revealed that ITF(l) enhanced Firmicutes/Bacteroidetes ratio to an antidiabetogenic balance and enriched modulatory Ruminococcaceae and Lactobacilli. CONCLUSION: Our data demonstrate that ITF(l) but not ITF(s) delays the development of T1D via modulation of gut-pancreatic immunity, barrier function, and microbiota homeostasis.