The results are published in the scientific journal Cell. Type 2-diabetes is a chronic disease resulting from a reduction in insulin-production from the pancreas or an inability of other tissues in the body to respond adequately to the produced insulin, so called insulin resistance. This leads to increased blood sugar, which in turn leads to a worsening of the insulin resistance, increasing the risk of developing many serious diabetes-associated complications. An international research team, led by Professor Juleen R. Zierath at Karolinska Institutet in Stockholm have identified previously unknown molecular mechanisms by which elevated blood sugar leads to impaired insulin sensitivity in people with diabetes. The research team identified a fat-burning' gene, the products of which are required to maintain the cells insulin sensitivity. They also discovered that this gene is reduced in muscle tissue from people with high blood sugar and type 2-diabetes. In the absence of the enzyme that is made by this gene, muscles have reduced insulin sensitivity, impaired fat burning ability, which leads to an increased risk of developing obesity. The expression of this gene is reduced when blood sugar rises, but activity can be restored if blood sugar is controlled by pharmacological treatment or exercise, says Professor Juleen Zierath. Our results underscore the importance of tight regulation of blood sugar for people with diabetes.

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We were amazed to realize that genes from moss and humans were not only structurally conserved but also shared similar functions, Khandelwal said.

We spent a lot of time trying to find an activity of PS to circumvent cleavage of APP, which has been very difficult, Kopan said. Importantly, the human protein acted in plant cells even if its enzymatic activity was removed by mutation. We stumbled upon an observation that presenilin proteins in mammals can perform other functions besides the enzymatic ones, that is, outside its role as gamma secretase. We're now looking closely to define this moonlighting functions and determine their contribution to disease.

In moss, the mutant phenotypes suggest presenilin might play a role in signal gathering, cytoskeleton organization and/or cell wall composition and organization. Quatrano and Khandelwal are checking that out. Kopan, Chandu and others are searching for presenilin's moonlighting activities in mammalian cells.

As a developmental biologist, my job is to translate the genetic code as if it were a manufacturer's manual, and that is accomplished by gaining detailed understanding of genes and protein function, Kopan said. Unfortunately, we're doing it one gene at a time, slowly building networks, figuring out what the context is. We can't think of all of it at once. We have to look at a small subset of genes and how they work with their friends, and hope that our observations will fit together in one coherent network.

Quatrano said the collaboration between the two labs is a reflection of what the Genomic Age can do.

Today, sitting at your computer, you can data mine genomes from hundreds of microorganisms, animals, fungi, insects and plants, and you're seeing more evidence of genes being conserved in widely different organisms, Quatrano said. This collaboration is a perfect example of bringing two labs together that on the surface have nothing in common other than one protein and two people who were aware of the interests of the other. It's led to a significant contribution that hopefully will lead to further clues as to the function of presenilin.

With this study, the Kopan and Quatrano labs and others could use this outstanding plant model not only to understand some of the off target affects during Alzheimer's Disease therapy, but to unravel novel interactions and pathways in plants.

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