Diabetes mellitus is caused by the either the inability of the pancreas to produce sufficient quantities of insulin to service the needs of the body (type 1), or the tissue to not sufficiently respond to insulin (type 2).
Insulin is made by specific cells in the pancreas called “beta cells.” These beta cells are isolated from the “exocrine” portion of the pancreas that make all the digestive enzymes that are secreted into the small intestine to digest the complex molecules in our food. These isolated tissues are islands of cells in a sea of exocrine tissue and are literally called “pancreatic islets” or “isles of Langerhans.”
The pancreatic islets contain several different cell types, but the main cells are alpha cells, which make the hormone glucagon and beta cells which make the hormone insulin. Insulin is made in response to increased glucose levels in the blood and glucagon is made in response to low glucose levels in the blood. Type 1 diabetes mellitus often results when the immune system attacks and destroys the beta cells, and this greatly reduces the amount of insulin made in response to high glucose levels. This causes chronically high blood glucose levels, which is the hallmark of diabetes mellitus. The Holy Grail of diabetes research is to regenerate beta cells that were lost in diabetics.
Embryonic stem cells (ESCs) can differentiate into beta cells. When removed from feeder cells, mouse and human ESC cultures form “embryoid bodies” or EBs. EBs are clusters of ESCs that contain cells that have differentiated into a wide variety of cells types. EBs contain beating heart muscle cells, nerve- and gland-like cells, and also, pancreatic beta cells (see S Assady, et al., Diabetes 50 (2001): 1691–1697; and ML Khoo, et al., Biol Reprod 73 (2005): 1147–1156). There are several strategies for increasing the efficiency of beta-cell production from ESC cultures (H Segev, et al., Stem Cells 22 (2004): 265–274; N Lumelsky, et al., Science 292, (2001): 1389–1394; Y Hori, et al., Proc Natl Acad Sci USA 99 (2004): 16105–16110; H Baharvand, et al., Dev Growth Differ 48 (2006): 323–332), but some of these protocols do not work all that well and others do not work when tried by other people (J Rajagopal, et al., Science 299, (2003): 363; M Hansson, et al., Diabetes 53 (2004): 2603–2609). However, the PAX4 gene, if expressed at high levels, can increase the efficiency of beta-cell differentiation of ESCs (CG Liew, et al., PLoS One 12, no. 3 (2008): e1783). Other cells can also differentiate into beta cells that are not embryonic stem cells (K Juhl, et al., Current Opinion in Organ Transplantation 15, no 1 (2010):79-85). There is reason for optimism.
Now a new report has shown that alpha cells in the pancreas, which, remember, do not produce insulin, can convert into insulin-producing beta cells. This is a potential protocol for regenerating beta cells as a cure for type 1 diabetes. These findings come from a study at the University of Geneva, co-funded by the Juvenile Diabetes Research Foundation.
Pedro L Herrera, the lead researcher of this group, showed that beta cells will spontaneously regenerate after near-total beta cell destruction in mice and the majority of the regenerated beta cells are derived from alpha cells that had been reprogrammed, or converted, into beta cells. When they used a unique model of mouse diabetes in which nearly all of the beta cells are rapidly destroyed, if the mice were maintained on insulin therapy, beta cells were slowly and spontaneously restored, eventually eliminating the need for insulin replacement.
Herrera’s results are the first to show that beta cell reprogramming can occur spontaneously, without genetic alterations. Previous efforts to reprogram non-beta cells into beta cells relied on genetic manipulations – processes that cannot be easily translated into therapies.
The critical factor in sparking the alpha-to-beta-cell reprogramming was removing (or ablating) nearly all the original insulin-producing cells in the mice. In mice where the loss of beta cells was more modest, the researchers either found no evidence of beta cell regeneration was observed (when only half the cells were destroyed) or less alpha cell reprogramming (when less than 95% of cells were destroyed) occurred. Herrera said, “The amount of beta-cell destruction thus appears to determine whether regeneration occurs. Moreover, it influences the degree of cell plasticity and regenerative resources of the pancreas in adult organisms.”
In addition to regenerating or replacing insulin producing cells, a cure for type 1 diabetes will also require stopping the autoimmune attack that causes diabetes, and reestablishing excellent glucose control.