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Gene expression changes contribute to Type 2 diabetes disease pathology

A study, recently published in the Journal of Clinical Investigation, has revealed nearly 400 genes that are expressed differentially in patients with Type 2 diabetes. One of these genes, PAX5, was found to transcriptionally regulate the expression of many of these other genes, and significantly impacts insulin secretion.

Differential expression

Type 2 diabetes is a common chronic disease characterised by a lack of insulin secretion from groups of cells known as pancreatic islets. This in turn impacts the body’s ability to process sugars and leads to symptoms such as dehydration. The disease is relatively well-studied and genome-wide association studies have successfully identified many loci linked with the condition. However, there are a lack of robust, large-cohort studies investigating the differential expression of genes within pancreatic islets.

To address this, researchers from Lund University generated RNA-seq data from over 300 individuals both with and without Type 2 diabetes to assess gene expression within these insulin-secreting cells. They identified 395 genes that were differentially expressed between the cases and controls, 228 of which were upregulated, and 167 which were downregulated. Notably, 301 of the transcriptomic changes identified were novel findings, with the genes having never previously been implicated in Type 2 diabetes. The genes belong to a variety of groups and are involved in a plethora of different functions such as ageing, hormone secretion and inflammatory responses. A further analysis of available data – which describes the impacts of gene knockouts in mice – revealed that many of the identified genes had impacts on the metabolic system.

PAX a punch

One of the novel genes identified in the study was PAX5. This is a transcription factor known to be associated with leukaemia, but has not previously been implicated in the pathology of Type 2 diabetes. The RNA-seq data revealed that PAX5 was expressed highly in pancreatic β cells derived from the patients’ islets but was found in very low levels in the control group. In order to investigate this further, the team opted to stimulate insulin secretion in cultured pancreatic islet cells. They discovered that overexpression of the PAX5 transcription factor impaired the process of insulin secretion via a mitochondrial metabolic pathway. Overexpression of PAX5 also led to increased cell death in pancreatic β cells, a factor that could play a significant role in the depletion of insulin production.

As PAX5 functions as a transcription factor, the team hypothesised that the effects of its overexpression might extend beyond the direct influence of the gene itself. Using data from previous studies, they deduced that nearly 200 of the differentially expressed genes identified in this study had a PAX5 binding motif, meaning their expression is controlled in some way by this gene. Of these genes, many were previously implicated in pancreatic β cell function and other aspects of human metabolism. As a result of these findings, the researchers were able to determine that overexpression of PAX5 is a major driver of Type 2 diabetes. This is not only due to its regulation of other genes, but also its impact on insulin secretion caused by mitochondrial dysfunction and cell death in the pancreatic islets.

Genetic scissors

With the prevalence of Type 2 diabetes increasing globally, it is vital that we understand the mechanisms behind the disease in order to both prevent and treat the illness. A key finding of the present study was that some of the gene expression changes observed within the patient group were also seen in control individuals who, despite not having a diagnosis of Type 2 diabetes, did express HbA1c, a predictor of the disease. This finding implies that many of the expression changes seen in this study contribute to the onset of the condition.

Moving forward, the team hopes to use this information to treat the condition, potentially through gene editing technology. Charlotte Ling, lead author of the study, stated: “Our long-term goal is to regulate the activity of PAX5 using “genetic scissors” and in that way restore PAX5 levels in individuals with type 2 diabetes.”