Beta cell changes in Type 2 Diabetes

Type 2 Diabetes affects 415 million people world-wide and is characterised by chronic high blood sugar (hyperglycaemia) and insulin resistance, progressing to insufficient insulin production. This occurs due to failure of the insulin producing beta cells in the pancreas. Over time, chronic hyperglycaemia can ultimately lead to the loss of beta cells, leaving patients insulin dependent. Until recently the loss of beta cells was thought to be due to increased rates of cell death (apoptosis). However, it has been recently been proposed that death of the insulin producing beta cells is not the whole story. Instead, it is thought that the beta cells are losing their function because they are reverting to earlier cell types or even changing into different cell types that secrete different hormones other than insulin. This is referred to as a change in beta cell differentiation status.

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 reverting to earlier cell types. It appears that these cells are moving back down the cell development pathway towards a more stem cell like state. Some studies have also shown that the cells are changing into another pancreatic cell type called the alpha cell, which produces a hormone called glucagon. 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.

However, the studies in mice and rats have yet to be reproduced in humans. This is important because there are significant differences between mouse and human

pancreatic physiology. It is therefore vital that these findings are now re-investigated using human model systems. This project is using a newly developed human beta cell that can be cultured in vitro to see whether or not the same changes can be seen in human cells. The cells will be exposed to the same sorts of physiological changes that are seen in patients with Type 2 diabetes to see if there are any effects on the differentiation status of the cells at the genetic level. Alongside this, pancreatic tissue from patients with the disease will also be tested to see if there are any changes to the beta cells and if there is any evidence for a shift towards an earlier, more stem cell like state, or a shift towards different hormone producing cells.