Diabetes drug could work against Alzheimer's, animal study suggests

ScienceDaily (Nov. 24, 2010) ? Metformin, a drug used in type 2-diabetes might have the potential to also act against Alzheimer's disease. This has been shown in a study from scientists of the German Center for Neurodegenerative Diseases (DZNE), the University of Dundee and the Max-Planck-Institute for Molecular Genetics.

The researchers have found out that the diabetes drug metformin counteracts alterations of the cell structure protein Tau in mice nerve cells. These alterations are a main cause of the Alzheimer's disease. Moreover, they uncovered the molecular mechanism of metformin in this process.

"If we can confirm that metformin shows also an effect in humans, it is certainly a good candidate for an effective therapy on Alzheimer's diseases," says Sybille Krauß from DZNE.

Their results have been published in the Proceedings of the National Academy of Sciences (Nov. 22, 2010).

Alzheimer's disease is a form of dementia that affects almost exclusively elderly people. Today, about 700,000 people are suffering from Alzheimer's disease in Germany. Neurons in their brains die, leading to cognitive impairment. At the molecular level, the disease is characterized amongst others by the formation of Tau protein deposits in nerve cells. Tau is a molecule that usually binds to the supportive cytoskeleton and performs a function in the transport system of the cell. In Alzheimer's disease, Tau is tipped too strongly with phosphate groups. This phosphorylation causes removal of Tau from the cytoskeleton and aggregation.

To counteract this problem, researchers aimed at regulating the protein PP2A. This protein is normally responsible for removing phosphate groups from Tau protein. In Alzheimer's disease, PP2A is not active enough -- leading to an increased phosphorylation and deposition of Tau. The scientists around Sybille Krauß and Susann Schweiger (University of Dundee) therefore looked for a drug that increases the activity of PP2A. "So far there is no drug on the market that targets the formation of tau aggregates," says Krauß.

In cell culture experiments with mouse nerve cells, the researchers showed that metformin directly protects PP2A against degradation by preventing the binding to special degradation proteins. This mechanism of metformin has been unknown so far. In addition, an increase in PP2A activity leads to a reduction in Tau phosphorylation. In a next step, the scientists added metformin to drinking water of healthy mice. This also led to a reduction of Tau-phoshorylation in brain cells. In further experiments, the researchers now intend to investigate, whether metformin prevents the deposition of tau proteins also in mouse models of Alzheimer's disease and improves cognitive performance of the animals. The effect in humans will then be tested in clinical studies. There is no risk of unexpected side effects, due to the fact that the drug is already used against diabetes.

Editor's Note: This article is not intended to provide medical advice, diagnosis or treatment.

Story Source:

The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Helmholtz Association of German Research Centres.

Journal Reference:

E. Kickstein, S. Krauss, P. Thornhill, D. Rutschow, R. Zeller, J. Sharkey, R. Williamson, M. Fuchs, A. Kohler, H. Glossmann, R. Schneider, C. Sutherland, S. Schweiger. Biguanide metformin acts on tau phosphorylation via mTOR/protein phosphatase 2A (PP2A) signaling. Proceedings of the National Academy of Sciences, 2010; DOI: 10.1073/pnas.0912793107

Note: If no author is given, the source is cited instead.

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New clues to origin of diabetes: Mutant gene protein can derail normal insulin production in animal pancreatic beta cells

ScienceDaily (Oct. 12, 2010) ? University of Michigan scientists have identified events inside insulin-producing pancreatic cells that set the stage for a neonatal form of non-autoimmune type 1 diabetes, and may play a role in type 2 diabetes as well. The results point to a potential target for drugs to protect normally functioning proteins essential for producing insulin.

A study published online in the journal PLoS ONE shows that certain insulin gene mutations involved in neonatal diabetes cause a portion of the proinsulin proteins in the pancreas' beta cells to misfold. Proinsulin proteins are the precursors of insulin, which the body needs to regulate blood sugar levels. Crucially, the misfolded mutant proteins cause normal proinsulin proteins in beta cells to misfold as well, the scientists found in studies of mouse and rat beta cells.

"Once the 'good' proinsulin turns 'bad,' it cannot be made into insulin and so the beta cells, and then the whole animal, become insulin deficient. The insulin deficiency causes diabetes and from there, things get worse and worse," says Peter Arvan, M.D., Ph.D., the study's senior author. He directs the Michigan Comprehensive Diabetes Center and is William and Delores Brehm Professor and chief of Metabolism, Endocrinology and Diabetes at the U-M Medical School.

Significance

"We want to see how the mechanism we found in this rare form of neonatal diabetes applies to other forms of diabetes," says Ming Liu, M.D., Ph.D., the study's first author and a research assistant professor of internal medicine at the U-M Medical School.

Diabetes researchers know that protein misfolding in beta cells also occurs on a smaller scale in mice and people without diabetes, and at higher levels in type 2 diabetes, Arvan says. In type 2 diabetes, people develop reduced sensitivity to insulin, causing beta cells to work overtime and eventually fail. In non-autoimmune type 1, diabetes results when genetic mutations cause insufficient production of insulin from pancreatic beta cells.

"In all diabetes, beta cells don't perform to the level needed," says Arvan. "It's possible that the beta cell failure of type 2 diabetes also has a critical protein folding component," he says. "The question is, can you reach a point in ordinary diabetes where misfolding causes the problem we have identified?"

Research details

In lab dish cultures of normal rat and mice beta cells, the scientists introduced single gene mutations known to be involved in various types of neonatal diabetes. They consistently found that misfolding occurred in normal proinsulin protein when mutant proinsulin protein was present. They also observed the same aberrant events in the pancreatic beta cells of Akita mice, a mouse model with the same mutation that occurs in a human family with neonatal diabetes.

Context

Proteins, which are molecules made of amino acids arranged in a certain order determined by genes, normally fold into specific shapes. But sometimes misfolding occurs. Protein folding is a phenomenon that has drawn a lot of recent attention from scientists who believe it plays a role in several common diseases.

Diabetes researchers currently lack a clear picture of why beta cells in the pancreas fail in diabetes. Many researchers look at stress and the stress response from the beta cells' endoplasmic reticulum or ER, a structure that transports materials within the cell. Stress in this structure occurs in diabetes, along with reduced beta cell mass.

Arvan and Liu found in the study that each of the mutations they examined led to ER stress and the ER stress response in beta cells, but that these ER events alone could not block insulin production in normal beta cells and do not appear to be the origin of the insulin deficiency. They hypothesize that protein misfolding events first block insulin production and cause insulin deficiency, leading to diabetes.

What's next

Uncovering the earliest events in the molecular mechanism of the disease may help diabetes researchers discover new therapies, the authors say. New drugs that could emerge would be at least several years away.

"It may be possible to find a way to modulate the environment in the endoplasmic reticulum to let the normal protein fold quickly, before the abnormal protein can act," says Liu.

Additional authors: Leena Haataja, Jordan Wright, U-M Medical School; Nalinda P. Wickramasinghe, Qing-Xin Hua, Nelson F. Phillips, Michael A. Weiss, Case Western Reserve University; Fabrizio Barbetti, University of Tor Vergata, Rome, Italy.

Funding: National Institutes of Health

Editor's Note: This article is not intended to provide medical advice, diagnosis or treatment.

Story Source:

The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by University of Michigan Health System.

Journal Reference:

Matthias G. von Herrath, Ming Liu, Leena Haataja, Jordan Wright, Nalinda P. Wickramasinghe, Qing-Xin Hua, Nelson F. Phillips, Fabrizio Barbetti, Michael A. Weiss, Peter Arvan. Mutant INS-Gene Induced Diabetes of Youth: Proinsulin Cysteine Residues Impose Dominant-Negative Inhibition on Wild-Type Proinsulin Transport. PLoS ONE, 2010; 5 (10): e13333 DOI: 10.1371/journal.pone.0013333

Note: If no author is given, the source is cited instead.

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