Work using mice and rats has shown that when exposed to the kinds of physiological conditions seen in a person with type 2 diabetes, the insulin producing beta cells are losing their ability to produce insulin because they are either reverting to earlier cell types or changing into other cell types. It appears that these cells are moving back down the cell development pathway towards a more stem cell like state in a process called dedifferentiation. Some studies have also shown that some cells are changing into another pancreatic cell type called the alpha cell, which produces a hormone called glucagon and this process is called trans-differentiation. This has profound implications for the progression of disease in type 2 diabetes because glucagon causes the body to release more sugar, resulting in further increases in blood sugar and worsening prognosis.
We have reproduced these studies in humans because there are significant differences between mouse and human pancreatic physiology. The project makes use of newly developed human beta cell lines that can be cultured in vitro, as well as human pancreatic tissue from donors with both type 1 and type 2 diabetes to investigate the effects of diabetes on human beta cells. We found that a proportion of human beta cells exposed to a diabetic or diabetes like microenvironment stop producing insulin and instead start to produce another hormone called somatostatin which is produced by delta cells in the pancreas. These changes indicate that beta cells are also changing their cell identity (dedifferentiating or trans-differentiating) in both type 1 and type 2 diabetes in humans but not in the same way as has been seen in mice and rats. The project is now focussing on discovering what mechanisms are causing these changes in beta cell identity and how we might intervene in this process in the treatment of both type 1 and type 2 diabetes.
The most recent paper can be seen here.
Figure 1. Hormone staining patterns of donor islets from controls or individuals with T2D. A) Panels 1 to 4 are representative Immunofluorescence images from human donor pancreatic tissue from controls (panels 1 and 2) and from cases of T1D compared to matched controls (panels 3 and 4). The identity of the antibody used to stain is indicated in each panel. B) Panels 5 to 8 are representative Immunofluorescence images from human donor pancreatic tissue from controls (panels 5 and 6) and from cases of T2D compared to matched controls (panels 7 and 8)
Figure 2. The effects of cell stressors to hormone expression in human beta cell line EndoC-βH1. A) Immunofluorescence cytochemistry showing gain of somatostatin expression in cells treated with high glucose. Cells were treated for 24, 36 and 48 hours and showed gains of somatostatin expression at all time points. A) Panels 1 and 2 refer to treatment with 5 mM glucose as a control. Panels 3 and 4 refer to treatment with 25 mM glucose to mimic hyperglycaemia. The identity of the antibody used to stain is indicated in each panel.