Diabetes discovery challenges known research

Yale University scientists and colleagues who used the CLS share findings that could lead to a new therapeutic approach to treating diabetes.

A discovery by an international group of scientists challenges known research on diabetes and may open the door to new therapeutic approaches for the disease that affects nearly 500 million people globally.
Their research focused on pyruvate kinase, an enzyme that is involved in communication at the cell level through a process known as protein phosphorylation, which changes the shape of a protein and alters how that protein behaves.
The study is a piece of a larger project that has researchers looking at how different signals, like insulin levels, are interpreted in the liver.
“We set out to understand and characterize insulin signalling in a laboratory model, and we found some activities in that model that were contrary to the textbooks,” said Jesse Rinehart, associate professor in the Department of Cellular & Molecular Physiology at the Yale University School of Medicine.
The team’s findings were published in Cell Reports and have opened up a new area of insight and exploration in an already highly active field of research.

>Read more on the Canadian Light Source website

Image: Gassaway et al. identified a phosphorylation site on pyruvate kinase linking it to cyclin dependent kinase (CDK) function in the liver. This new site is part of a CDK pathway stimulated by insulin resistance in vivo. Structural and biochemical characterization reveled that pyruvate kinase phosphorylation does not alter enzymatic activity. Instead phosphorylation dictates cellular compartmentalization. This image depicts the “hand” of CDK reaching out to sequester PKL in the hepatocyte nucleus.
Credit: J. Rinehart and B. Gassaway.

Researchers create the first maps of two melatonin receptors essential for sleep

A better understanding of how these receptors work could enable scientists to design better therapeutics for sleep disorders, cancer and Type 2 diabetes.

An international team of researchers used an X-ray laser at the Department of Energy’s SLAC National Accelerator Laboratory to create the first detailed maps of two melatonin receptors that tell our bodies when to go to sleep or wake up, and guide other biological processes. A better understanding of how they work could enable researchers to design better drugs to combat sleep disorders, cancer and Type 2 diabetes. Their findings were published in two papers today in Nature.

The team, led by the University of Southern California, used X-rays from SLAC’s Linac Coherent Light Source (LCLS) to map the receptors, MT1 and MT2, bound to four different compounds that activate them: an insomnia drug, a drug that mixes melatonin with the antidepressant serotonin, and two melatonin analogs.

>Read more on the LCLS at SLAC website

Image: The researchers showed that both melatonin receptors contain narrow channels embedded in the cell’s fatty membranes. These channels only allow melatonin, which can exist happily in both water and fat, to pass through, preventing serotonin, which has a similar structure but is only happy in watery environments, from binding to the receptor. They also uncovered how some much larger compounds only target MT1 despite the structural similarities between the two receptors.
Credit: Greg Stewart/SLAC National Accelerator Laboratory


A new study explains the inefficacy of some diabetes drugs

Synchrotron light has been used for the first time to simulate damages due to oxidative stress on the aldose reductase protein with the aim of obtaining its activated form.

This form of the protein, related with some several diabetic complications, is insensitive to the drugs being developed, which hinders the treatment. ALBA researchers have shown that chemical changes suffered by the protein under oxidative stress are the cause of drugs inefficacy in the attempt to block aldose reductase. The team of the Synchrotron suggests a new method for drugs design considering the changes in proteins under oxidative stress, like the ones involved in diseases such as cancer, Parkinson or Alzheimer.
The protein aldose reductase has been explored as a drug target since the 1980s for its implication in diabetic complications. Now, the team of the ALBA Synchrotron, in collaboration with the Autonomous University of Barcelona, has shown the reason why some drugs against the effects of diabetes under development do not work in the attempt to block aldose reductase.
This protein has mainly detoxifying functions inside the cell but it can also transform glucose into a molecule called sorbitol. Under hyperglycemic conditions (high level of glucose in blood), this reaction increases much more and sorbitol accumulates, consuming antioxidant defenses. So, if hyperglycemia situation becomes chronic – like in diabetes -, there are unbalanced conditions inside the cell that lead to harmful oxidative stress environment.

Image: Isidro Crespo, Judith Juanhuix and Albert Castellví, at the biolaboratoy of the ALBA Synchrotron.