New Gene To Be Potentially Targeted In Diabetes Mellitus

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New Gene To Be Potentially Targeted In Diabetes Mellitus
ScienceDaily
Jan. 31, 2009

Cell biology Professor Romeo Ricci and his team have discovered a new signal transduction pathway that might play an important role in the promotion of type 2 diabetes mellitus.

The pancreatic beta cell is the subject of Dr. Ricci’s latest paper published in Cell. Dr. Ricci’s team discovered a gene that may play an important role in pancreatic beta cell function, maintenance of which is pivotal to prevent overt diabetes mellitus. The gene encodes for the kinase p38delta, which appears to negatively control the secretion of insulin from the beta cells constituting the major part of the islets of Langerhans in the pancreas. p38delta inhibits another kinase, namely Protein Kinase D (PKD), which normally ensures that vesicles filled with insulin are efficiently transported to the cell surface for the release of this hormone after fusion with the plasma membrane. p38delta directly phosphorylates PKD, which suppresses the activity of the latter kinase.

Experiments with mice lacking the p38delta gene revealed quite astonishing results. Compared to wild type mice, knockout mice revealed a markedly improved glucose tolerance. When they were injected with glucose, the level of glucose in the blood was not increasing as high and was more efficiently removed from the blood compared to wild type mice. Looking at the graphs showing raises of blood glucose levels after injections, Dr. Ricci explains that, "Knockout mice lacking p38delta release more insulin because secretion of this hormone is not inhibited."

Cellular stress followed by cellular collapse
After a meal, the beta cell secretes insulin to regulate the blood glucose uptake in peripheral organs. In obese patients, the beta cells produce more insulin and the overall cellular mass is enhanced through cell growth and proliferation. However, these circumstances entail an unusual stress to those cells that culminates in cell failure/death and consequently in a reduction in insulin production and release. At this stage, the affected patient develops diabetes and a regular insulin supply will be mandatory.

Dr. Ricci’s team was also able to show that cellular stress strongly activated p38delta and that this molecular event contributed to beta cell failure. In their experiments, the researchers subjected beta cells to oxidative stress. Wild type mice became immediately diabetic, while p38delta-deficient mice were protected. The latter animals had a normal level of insulin and the insulin content in the islet cells was unchanged.

Today’s diet habits and evolution
Dr. Ricci explains that "Obviously, p38delta has the task to negatively regulate PKD." He indicates that this feature is evolutionary pre-determined and indeed makes perfect sense from a physiological point of view. However, our actual dietary habits and our lifestyle are known to cause unusual stresses to beta cells that might lead to a strong activation of p38delta and thus inhibition of insulin secretion.

Ricci stresses that, "For therapeutic purposes, it is interesting that a kinase of the p38 type is involved in the development of diabetes." Kinases of this kind could be targeted relatively easily. If p38delta is inhibited, insulin levels in the blood raise and consequently the glucose levels should decrease.

However, only suppressants that act quite specifically, known as inhibitors, come into consideration. Following the lock and key principle, they should fit exactly into the active site of p38delta.

Search for an inhibitor
No specific inhibitor against p38delta currently exists. Therefore, Dr. Ricci’s team is collaborating with the pharmaceutical industry that is able to develop such inhibitors in an efficient way. Around 700 kinases are known; corresponding inhibitors for many of them are available on the market and are currently tested. However, the design of a suitable inhibitor against p38delta would require the analysis of its exact structure. Mammalian cells have four very similar kinases of the p38 family. Therefore, it will be quite a challenge to design a highly specific inhibitor.

Once available, the use of such small compound for treatment of diabetes still needs to be thoroughly investigated. The majority of kinase inhibitors actually bring along several side-effects. Among others, they frequently are immunosuppressive. Dr. Ricci stresses that, "A corresponding drug would need to be tested very thoroughly."

Researchers from Oxford and Geneva also took part in this research work in addition to those from ETH Zurich at the Institute of Cell Biology. The study was funded by the SNF (Swiss National Science Foundation), the Roche Research Foundation and the Bonizzi-Theler Foundation and by Boehringer Ingelheim Inc..

Journal reference:

1. Sumara et al. Regulation of PKD by the MAPK p38d in Insulin Secretion and Glucose Homeostasis. Cell, DOI: 10.1016/j.cell.2008.11.018

Adapted from materials provided by ETH Zurich.