Featured Research

from universities, journals, and other organizations

Blood-pressure drug may slow diabetes progression

Date:
March 22, 2012
Source:
University of Alabama at Birmingham
Summary:
Researchers surprised by second effect of established drug. A common high-blood-pressure medication appears to reverse the diabetes-related death of pancreatic beta cells.

A common high-blood-pressure medication appears to reverse the diabetes-related death of pancreatic beta cells, according to a University of Alabama at Birmingham study publishedMarch 22 in the journal Diabetes.

The authors argue that the findings -- while in human pancreatic islets and diabetic mice -- could have clinical implications as physicians consider that calcium channel blockers may address two major, related diseases. They also found evidence in past clinical trials that the study drug verapamil may slow diabetes.

Beta cells secrete insulin to control blood sugar levels, but begin to die as patients develop Type 1 or Type 2 diabetes. No one suspected that calcium channel blockers might reverse beta cell death because the studies that led to their FDA approval measured their effect on heart attacks, not blood sugar. UAB researchers were surprised when hints of verapamil's effect were discovered amid their effort to design a drug to shut down a protein called TXNIP.

The team had published several papers over 10 years that describe the way high blood sugar uniquely turns on the gene for TXNIP, and how excessive TXNIP-signaling in diabetes signals cells to self-destruct. Recent studies also have suggested that lowering TXNIP levels in the heart lessens the damage caused by a heart attack.

"We long have felt that finding an oral medication that inhibits beta cell TXNIP expression would represent a major breakthrough, and now we have the first study showing that a drug already proven safe in years of clinical practice may halt the development of diabetes," said Anath Shalev, M.D., director of the UAB Comprehensive Diabetes Center and senior author of the paper. "Our results are encouraging because patients with diabetes suffer from beta cell death as part of their disease, there has been no treatment targeting this problem and TXNIP-inhibition promises to reverse it."

Of the nearly 26 million adult patients with diabetes, 67 percent also have high blood pressure.

Based on its findings, the UAB team has redoubled its original effort to design a new class of TXNIP-inhibitors. In partnership with the Southern Research Institute and the Alabama Drug Discovery Alliance, they are now screening a library of 300,000 molecules, a search they hope will yield drug candidates that reverse beta cell death without affecting blood pressure.

Only when necessary

In cell studies, the team found that verapamil reduced TXNIP gene expression 50 percent. In diabetic mice, verapamil treatment maintained normal glucose level, while glucose spiked in control mice. This was accompanied by an 80 percent reduction in TXNIP levels in isolated islets of verapamil-treated animals.

Using molecular biology techniques, researchers were able to watch as expression of TXNIP, or thioredoxin-interacting protein, rose in beta cells to abnormal levels as mice became diabetic and then fell again as they received verapamil.

The team also found that treatment only reduced TXNIP gene expression when high blood sugar had driven it to abnormal levels, making the pathway "extremely attractive" as a target for drugs, Shalev said. Future treatments conceivably could return TXNIP levels to normal in diabetic patients, but leave in place the basic level of TXNIP-signaling that cells rely on to regulate life processes. The results also suggest the drug is able to slow diabetes in mice with longstanding disease and is more effective when given early.

"The debate now should begin as to whether physicians should consider verapamil an additional treatment to protect beta cells in patients with both hypertension and diabetes, similar to the use of ACE inhibitors for kidney protection," said Shalev, who also is a clinician. "As it stands, it can take years before patients with diabetes receive verapamil, possibly missing a window of opportunity. Future clinical studies need to test whether or not earlier treatment could have a profound effect on diabetes progression by saving more beta cells."

Though no one had previously established the link between calcium channel-blockers, TXNIP and beta cell death, past studies had hinted at a connection. Analysis of the INVEST trial revealed that newly diagnosed diabetes was less common in patients treated with verapamil, especially in the Hispanic population.

In addition to protecting insulin-producing cells, experiments also showed that verapamil countered insulin-resistance that makes the hormone less able to lower blood-sugar levels in diabetic patients. Theory has it that lowering TXNIP levels counters this by increasing glucose uptake in the tissues targeted by insulin (e.g. muscle and fat), a phenomenon observed in mice lacking the TXNIP gene.

Shalev's team spent years establishing TXNIP as the mandatory link between high blood sugar and beta cell death. The effort reached its first milestone in 2002 in a study that demonstrated the gene for TXNIP had the greatest increase in expression -- 11-fold greater than any of the 6,000 genes expressed in pancreatic islets -- in the face of rising glucose levels. In 2005, the team identified the DNA region that turns on the TXNIP gene in response to high sugar in beta cells and later showed that the carbohydrate response element-binding protein (ChREBP) attaches to DNA there.

Their next paper in 2008 revealed that genetic deletion of TXNIP protects against Type 1 and Type 2 diabetes and too much TXNIP-signaling shuts down the Akt/Bcl-xL pathway that keeps beta cells alive.

TXNIP stands for thioredoxin-interacting protein, and the overactive TXNIP signaling seen in diabetes sharply reduces the antioxidant activity of the protein thioredoxin. The team had found previously that that higher TXNIP levels in the mitochondria of beta cells increase the chances it will pull thioredoxin off of the protein it would otherwise shut down, apoptosis-signaling kinase 1. Once free, this enzyme initiates a chain reaction that ends in beta cell death.

Shalev's team also has now shown that calcium channel-blockers inhibit signaling through the enzyme calcineurine, which increases ChREBP phosphorylation and keeps it from getting into the beta cell nucleus. With less ChREBP, extra TXNIP gene expression is shut down.

In Shalev's lab, post-doctoral fellow Guanlan Xu, Ph.D., performed all key cell studies, and research associates Junqin Chen, Ph.D., and Gu Jing, Ph.D., helped with the mouse studies and protein work. The work was supported by Juvenile Diabetes Research Foundation & JNJSI, American Diabetes Association and National Institute of Diabetes, Digestive and Kidney Diseases, part of the National Institutes of Health.


Story Source:

The above story is based on materials provided by University of Alabama at Birmingham. Note: Materials may be edited for content and length.


Journal Reference:

  1. Guanlan Xu, Junqin Chen, Gu Jing and Anath Shalev. Preventing β-Cell Loss and Diabetes With Calcium Channel Blockers. Diabetes, 2012 DOI: 10.2337/db11-0955

Cite This Page:

University of Alabama at Birmingham. "Blood-pressure drug may slow diabetes progression." ScienceDaily. ScienceDaily, 22 March 2012. <www.sciencedaily.com/releases/2012/03/120322151445.htm>.
University of Alabama at Birmingham. (2012, March 22). Blood-pressure drug may slow diabetes progression. ScienceDaily. Retrieved July 23, 2014 from www.sciencedaily.com/releases/2012/03/120322151445.htm
University of Alabama at Birmingham. "Blood-pressure drug may slow diabetes progression." ScienceDaily. www.sciencedaily.com/releases/2012/03/120322151445.htm (accessed July 23, 2014).

Share This




More Health & Medicine News

Wednesday, July 23, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Idaho Boy Helps Brother With Disabilities Complete Triathlon

Idaho Boy Helps Brother With Disabilities Complete Triathlon

Newsy (July 23, 2014) An 8-year-old boy helped his younger brother, who has a rare genetic condition that's confined him to a wheelchair, finish a triathlon. Video provided by Newsy
Powered by NewsLook.com
Stone Fruit Listeria Scare Causes Sweeping Recall

Stone Fruit Listeria Scare Causes Sweeping Recall

Newsy (July 22, 2014) The Wawona Packing Company has issued a voluntary recall on the stone fruit it distributes due to a possible Listeria outbreak. Video provided by Newsy
Powered by NewsLook.com
Huge Schizophrenia Study Finds Dozens Of New Genetic Causes

Huge Schizophrenia Study Finds Dozens Of New Genetic Causes

Newsy (July 22, 2014) The 83 new genetic markers could open dozens of new avenues for schizophrenia treatment research. Video provided by Newsy
Powered by NewsLook.com
CDC Head Concerned About a Post-Antibiotic Era

CDC Head Concerned About a Post-Antibiotic Era

AP (July 22, 2014) Sounding alarms about the growing threat of antibiotic resistance, CDC Director Tom Frieden warned Tuesday if the global community does not confront the problem soon, the world will be living in a devastating post-antibiotic era. (July 22) Video provided by AP
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile: iPhone Android Web
Follow: Facebook Twitter Google+
Subscribe: RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins