Type 2 diabetes: A complex metabolic disorder

Type 2 diabetes (T2D) is a multi-tissue metabolic disorder that results when pancreatic islets fail to compensate for insulin resistance in peripheral tissues. Recent genomics research examining the chromatin architecture and gene expression programs of human islets have implicated several different genetic, environmental, and cellular mechanisms that may be contributing to islet failure and ultimately T2D pathogenesis.

An overview of potential cellular changes contributing to T2D

In recent years, several studies have used single cell RNA-seq to profile and define the gene expression programs of the different cell types (alpha, beta, delta, gamma/PP, and epsilon) that comprise islets check out my other post about scRNA-seq. In addition, by comparing gene expression profiles between these cell types in individuals with and without T2D, these studies have highlighted specific alterations in islet cell type transcriptomes that may be underlying T2D pathogenesis (see Figure 3A below).

However, there’s more! Reserachers have also suggested that changes in actual cell proportions (Figure 3B) may be contributing to the onset of T2D. In patients with T2D, it is common to observe a decline in the total beta cell mass. Overall, this decrease in beta cell number means the patient with T2D is unable to produce sufficient insulin to maintain normal blood glucose levels. However, what causes this reduction in beta cell number is still somewhat unclear. In addition to beta cell death (Figure 3B), researchers are also suggesting that the decreases in diabetic beta cell mass may be caused by reversion to endocrine progenitor (hormone-negative) cells (Figure 3C), a phenomena frequently referred to as de-differentiation. Another possibile explanation is that diabetic beta cells undergoing stress may convert to another islet cell type in a process called trans-differentiation (Figure 3D). Nonetheless, it still remains unclear what exactly causes these changes in islet cellular biology and ultimately islet dysfunction.

If you’re interested in learning more about islet failure and its importance in T2D onset please check out this review paper:

Trends in Genetics, 2017. Genomics of Islet (Dys)function and Type 2 Diabetes