β cell responses to inflammation

Abstract

BackgroundThe extended and clinically silent progression of Type 1 diabetes (T1D) creates a challenge for clinical interventions and for understanding the mechanisms that underlie its pathogenesis. Over the course of the development of Type 1 diabetes, studies in animal models and of human tissues have identified adaptive changes in β cells that may affect their immunogenicity and susceptibility to killing. Loss of β cells has traditionally been identified by impairment in function but environmental factors may affect these measurements.Scope of ReviewIn this review we will highlight features of β cell responses to cell death, particularly in the setting of inflammation, and focus on methods of detecting β cell death in vivo.Major conclusionsWe developed an assay to measure β cell death in vivo by detecting cell free DNA with epigenetic modifications of the INS gene that are found in β cells. This assay has robust technical performance and identifies killing in individuals at very high risk for disease, but its ability to identify β cell killing in at-risk relatives is limited by the short half-life of the cell free DNA and the need for repeated sampling over an extended course. We present results from the Diabetes Prevention Trial-1 using this assay. In addition, recent studies have identified cellular adaptations in some β cells that may avoid killing but impair metabolic function. Cells with these characteristics may aggravate the autoimmune response but also may represent a potentially recoverable source of functional β cells.

Gene expression signatures of target tissues in type 1 diabetes, lupus erythematosus, multiple sclerosis, and rheumatoid arthritis

“…For instance, while in the  cell preparation the number of transcripts per million (TPM) for CD45 in the patient group was 16.4 (mean), the TPM values for the following  cell markers were as follows: INS (Insulin), 125.359; Sodium/potassium-transporting ATPase gamma chain (FXYD2a), 65; GCK (Glucokinase), 20; Homeobox protein Nkx-2.2 (NKX2-2), 28; Synaptotagmin 4 (SYT4), 36; Neurogenic Differenciation 1 (NEUROD1), 27; Homeobox protein Nkx-6.1 (NKX6-1), 27; and MAF BZIP Transcription Factor B (MAFB), 23, indicating that the observed responses are driven, at least in part, by the constitutive cells of the target tissues. Of note, proinflammatory cytokines decrease the expression of several of the  cell markers (3,20,32) described above.…”

Pro-resolving lipid mediators: regulators of inflammation, metabolism and kidney function

“…A growing consensus suggests that inflammation is an important driver of type 1 diabetes mellitus and type 2 diabetes mellitus (T2DM) and associated vascular complications 5 . Inflammation in pancreatic islet β-cells results in cell depletion and loss of function 6 , 7 . Findings from experimental models and observational studies in humans demonstrate a key role for macrophages in islet β-cell inflammation in obesity and T2DM, driven largely by synergistic responses to IFNγ, TNF and IL-1β 8 .…”

Significant impact of body mass index on the relationship between increased white blood cell count and new-onset diabetes

“…The results of previous studies have been inconsistent with regards to whether increased WBC count contributes to DM prediction models independently of obesity 4 , 5 or whether elevated WBC count only reflects an increase in adipose tissue mass 6 . Increased BMI has been shown to be an essential contributor to DM through insulin resistance and islet β-cell failure 2 , 3 , 18 , 19 . Kashima et al reported that increased WBC count was predictive of type 2 DM, and that the combination of increased WBC count and BMI augmented the risk of DM, regardless of whether BMI was high or low 4 .…”

“…Chronic inflammation has been demonstrated to play a key role in the pathogenesis of type 2 diabetes mellitus (DM) 1 . Inflammation itself has been shown to cause insulin resistance 2 and promote β-cell death 3 . Previous studies have suggested an association between white blood cell (WBC) count, a non-specific parameter of inflammation, and incident DM 4 , 5 .…”