Innate inflammation in type 1 diabetes

Abstract

Type 1 diabetes mellitus (T1D) is an autoimmune disease often diagnosed in childhood that results in pancreatic β-cell destruction and life-long insulin dependence. T1D susceptibility involves a complex interplay of genetic and environmental factors and has historically been attributed to adaptive immunity, though there is now increasing evidence for a role of innate inflammation. Here, we review studies that define a heightened age-dependent innate inflammatory state in T1D families that is paralleled with high fidelity by the T1D-susceptible BioBreeding rat. Innate inflammation may be driven by changes in interactions between the host and environment, such as through an altered microbiome, intestinal hyper-permeability, or viral exposures. Special focus is placed on the temporal measurement of plasma induced transcriptional signatures of recent onset T1D patients and their siblings as well as in the Biobreeding rat as it defines the natural history of innate inflammation. These sensitive and comprehensive analyses have also revealed that those who successfully managed T1D risk develop an age-dependent immunoregulatory state, providing a possible mechanism for the juvenile nature of T1D. Therapeutic targeting of innate inflammation has been proven effective in preventing and delaying T1D in rat models. Clinical trials of agents that suppress innate inflammation have had more modest success, but efficacy is improved by the addition of combinatorial approaches that target other aspects of T1D pathogenesis. An understanding of innate inflammation and mechanisms by which this susceptibility is both potentiated and mitigated offers important insight into T1D progression and avenues for therapeutic intervention.

Integrated multi-omics of the human gut microbiome in a case study of familial type 1 diabetes

“…The unused single-end reads were combined with the unmapped reads and cd-hit-dup from the CD-HIT software suite 63 was used to remove duplicate reads. Velvet was then run over a range of k-mer sizes (27,31,35,39,43,47,51,55,59,63) with the IDBA-UD contigs as long read input (velveth parameters: -long contig.fa, velvetg parameter: -conserveLong yes). Afterwards, all newly assembled contig sequences from the different k-mer runs and the original IDBA-UD contigs were concatenated and clustered using cd-hit from the CD-HIT software suite (parameter: -c 0.99) to remove redundancy.…”

“…Little is known about changes in the function of the gastrointestinal tract with respect to T1DM traits, such as the proposed heightened innate inflammatory state 27 . Among the ten human proteins with the greatest changes in abundance in the faeces of individuals with T1DM (Supplementary Table 5), we identified two with higher abundance in the individuals with T1DM, namely lactotransferrin (LTF) and the lactotransferrin receptor intelectin (ITLN1), which maintain an important functional position at the crossroads of iron uptake, innate immunity and insulin function [40][41][42][43] , and whose antimicrobial activity may influence the gastrointestinal microbiota 44 (Supplementary Section 18 and Supplementary Fig.…”

“…24), especially in individuals with a low genetic risk 25 , suggests that environmental factors may trigger the autoimmune destruction of insulin-producing beta cells in the endocrine pancreas that causes T1DM. Gastrointestinal agents have been implicated in this process due to the immune-modulatory role of the gastrointestinal tract 26,27 and the potential involvement of the pancreatic ducts in the inflammation that culminates in beta-cell destruction 28 . Case-control studies of the microbial community structure during [29][30][31][32] , immediately after 33,34 and before 31,35 seroconversion, have tried but failed to identify generalizable disease-causing or biomarker organism signatures.…”

Effect of resistance exercise training on expression of Hsp70 and inflammatory cytokines in skeletal muscle and adipose tissue of STZ-induced diabetic rats

“…Type 1 diabetes is an inflammatory autoimmune disease, resulting in a lack of insulin (Cabrera et al 2016;Price and Tarbell 2015). It has been proposed that impairment of some tissues such as skeletal muscles and adipose tissue accrued following type 1 diabetes is associated with incorrect protein folding (Takada et al 2007;Ono et al 2015).…”

Chitinase 3 Like-1: An Emerging Molecule Involved in Diabetes and Diabetic Complications

“…Subclinical systemic inflammation and changes of a wide variety of inflammatory markers together with the alterations of the metabolic syndrome, including IR, have been found in DM [79,80]. Rathcke and Vestergaard [81] first reported that CHI3L1 levels increased significantly in T2DM patients.…”