Gene Expression Analysis of the Pre-Diabetic Pancreas to Identify Pathogenic Mechanisms and Biomarkers of Type 1 Diabetes

Abstract

Type 1 Diabetes (T1D) occurs as a result of the autoimmune destruction of pancreatic β-cells by self-reactive T cells. The etiology of this disease is complex and difficult to study due to a lack of disease-relevant tissues from pre-diabetic individuals. In this study, we performed gene expression analysis on human pancreas tissues obtained from the Network of Pancreatic Organ Donors with Diabetes (nPOD), and showed that 155 genes were differentially expressed by ≥2-fold in the pancreata of autoantibody-positive (AA+) at-risk individuals compared to healthy controls. Only 48 of these genes remained changed by ≥2-fold in the pancreata of established T1D patients. Pathway analysis of these genes showed a significant association with various immune pathways. We were able to validate the differential expression of eight disease-relevant genes by QPCR analysis: A significant upregulation of CADM2, and downregulation of TRPM5, CRH, PDK4, ANGPL4, CLEC4D, RSG16, and FCGR2B was confirmed in the pancreata of AA+ individuals versus controls. Studies have already implicated FCGR2B in the pathogenesis of disease in non-obese diabetic (NOD) mice. Here we showed that CADM2, TRPM5, PDK4, and ANGPL4 were similarly changed in the pancreata of pre-diabetic 12-week-old NOD mice compared to NOD.B10 controls, suggesting a possible role for these genes in the pathogenesis of both T1D and NOD disease. The loss of the leukocyte-specific gene, FCGR2B, in the pancreata of AA+ individuals, is particularly interesting, as it may serve as a potential whole blood biomarker of disease progression. To test this, we quantified FCGR2B expression in peripheral blood samples of T1D patients, and AA+ and AA- first-degree relatives of T1D patients enrolled in the TrialNet Pathway to Prevention study. We showed that FCGR2B was significantly reduced in the peripheral blood of AA+ individuals compared to AA- controls. Together, these findings demonstrate that gene expression analysis of pancreatic tissue and peripheral blood samples can be used to identify disease-relevant genes and pathways and potential biomarkers of disease progression in T1D.

A discovery-based proteomics approach identifies protein disulfide isomerase (PDIA1) as a biomarker of β cell stress in type 1 diabetes

“…This biphasic pattern is reminiscent of metabolic data from natural history cohorts of autoantibody-positive individuals who progress to T1D, where there are compensatory changes in the architecture of insulin secretion that largely maintain glycemia until ∼12 months prior to disease onset, followed by marked loss of insulin secretion and rapidly worsening glycemic control until diabetes diagnosis (1). Our findings are also consistent with cross-sectional studies that have analyzed gene and protein expression patterns in pancreatic sections from human donors with diabetes (49–52) and in previous studies in mouse models of diabetes, where a prominent role for ER and mitochondrial dysfunction has been identified during disease progression (6,10,53,54). Notably, we found these pathways are activated early in the disease process, and there is continued overlap between several of these key activated stress pathways in the NOD mouse model and in the acute, inducible model of T1D at the time of diabetes onset.…”

Highly perturbed genes and hub genes associated with type 2 diabetes in different tissues of adult humans: A bioinformatics analytic workflow

“…Also, hyperglycemia-induced global downregulation of gene expression in adipose and skeletal muscle tissues have been documented previously (54). A similar pattern has been observed in T1D (55) as well as other endocrine disorders such as polycystic ovary syndrome (56). In contrast, highly perturbed genes and hub genes associated with T2D, which might together constitute the candidate gene set critical for pathogenicity of T2D, were found to contain both up-and down-regulated genes.…”

Retinal transcriptome and cellular landscape in relation to the progression of diabetic retinopathy

“…For example, interferon gamma, a signature proinflammatory cytokine, escalates FCGR2B mRNA and cell surface expression by lipopolysaccharide-stimulated B cells while reduces it on monocytes, a process keeping immune response away from antibody production to pathogen clearance. 39 Increase levels of FCGR2B has been observed in the pancreata of autoantibody-positive at-risk individuals with type 1 diabetes versus controls, 40 and in the retina of a rat model with type 1 diabetes induced by streptocotocin. 31 Similar to CCND1, FCGR2B is also one of severity-associated genes with strong interaction with other genes.…”