Poor Control of Diabetes May be Linked to Low Vitamin D

Released: 6/21/2010 9:00 AM EDT
Source: Endocrine Society
Newswise — Vitamin D deficiency is highly prevalent in patients with Type 2 diabetes and may be associated with poor blood sugar control, according to a new study. The results will be presented Saturday at The Endocrine Society’s 92nd Annual Meeting in San Diego.
“This finding supports an active role of vitamin D in the development of Type 2 diabetes,” said study co-author Esther Krug, MD, an assistant professor of medicine at The Johns Hopkins University School of Medicine and an endocrinologist at Sinai Hospital, Baltimore.
Krug and her colleagues reviewed the medical charts of 124 patients with Type 2 diabetes who came to an endocrine outpatient clinic for specialty care from 2003 to 2008. Patients’ age ranged from 36 to 89 years. All patients had a single measurement of their serum 25-hydroxyvitamin D levels as part of their evaluation at the clinic. The researchers divided the patients into quartiles based on vitamin D level.
Despite receiving regular primary care visits before referral to the endocrine clinic, 91 percent of patients had either vitamin D deficiency (defined as a level below 15 nanograms per deciliter, or ng/dL) or insufficiency (15 to 31 ng/dL), the authors reported. Only about 6 percent of patients were taking vitamin D supplements at their first visit.
Additionally, the investigators found an inverse relationship between the patients’ blood levels of vitamin D and their hemoglobin A1c value, a measure of blood sugar control over the past several months. Lower vitamin D levels were discovered in patients with higher average blood sugars as measured by HbA1c, Krug said. Compared with whites, blacks had a higher average A1c and lower average vitamin D level.
“Since primary care providers diagnose and treat most patients with Type 2 diabetes, screening and vitamin D supplementation as part of routine primary care may improve health outcomes of this highly prevalent condition,” she said.

Many People with Diabetes Do Not Know or Heed Dangers of Hot Weather

Released: 6/21/2010 9:00 AM EDT
Source: Endocrine Society
Newswise — A new survey shows that diabetic individuals who live in a hot climate have important gaps in their “heat awareness,” or knowledge about proper diabetes self-care in hot weather, even though diabetes raises their risk of heat illness. The results of “Diabetes in the Desert: What Do Patients Know About the Heat?” will be presented Monday at The Endocrine Society’s 92nd Annual Meeting in San Diego.
Researchers from Mayo Clinic in Arizona, in collaboration with the National Ocean and Atmospheric Administration and the National Weather Service, surveyed patients at a Phoenix diabetes clinic and analyzed 152 surveys. Responses showed that people living with diabetes in hot climates need increased awareness of how heat affects their disease, said lead researcher Adrienne Nassar, MD, third-year medical resident at Mayo Clinic.
“People with diabetes have an impaired ability to sweat, which predisposes them to heat-related illness, as do uncontrolled, high blood sugars,” Nassar said. “Many patients surveyed had suboptimal glycemic control during the summer, possibly increasing their risk of dehydration.”
Past research shows that during hot weather people with diabetes have an increased number of emergency room visits, hospitalizations and deaths due to heat illness.
Yet one in five survey respondents said they would not take precautions until temperatures exceeded 100 degrees Fahrenheit. “Heat illness can take place at 80 to 90 degrees when you factor in the heat index,” Nassar said.
Only about half of the patients knew the definition of the heat index—the combination of air temperature and humidity. High humidity makes heat more dangerous because it slows the evaporation of perspiration, the way the body cools itself.
Heat also can harm the effectiveness of diabetes medications and supplies. “Oral medications as well as insulin have a therapeutic temperature range above which they lose efficacy,” Nassar said. The drug’s package insert includes information about proper temperatures for storage.
Although 73 percent of respondents had received information about the harmful effect of heat on insulin, fewer knew about the adverse effects of heat on their oral diabetes medications (39 percent) and on glucose meters (41 percent) and glucose test strips (38 percent).
Even when survey respondents knew that they should protect their diabetes medications and glucose-testing supplies from heat, an alarming proportion—37 percent—chose to leave them at home rather than risk heat exposure.
“If they are unable to check their blood sugars while they are away from home, that’s unsafe,” Nassar said.
“Increasingly more people with diabetes are living in places characterized by hot weather. Patient education focusing on diabetes management in hot climates is needed,” she said.




Well-Defined Quantity of Antioxidants in Diet Can Improve Insulin Resistance

Released: 6/21/2010 9:00 AM EDT
Source: Endocrine Society
Newswise — A diet rich in natural antioxidants improves insulin sensitivity in insulin-resistant obese adults and enhances the effect of the insulin-sensitizing drug metformin, a preliminary study from Italy finds. The results will be presented Monday at The Endocrine Society’s 92nd Annual Meeting in San Diego.
“The beneficial effects of antioxidants are known, but we have revealed for the first time one of their biological bases of action—improving hormonal action in obese subjects with the metabolic syndrome,” said principal author Antonio Mancini, MD, an endocrinology researcher at Catholic University of the Sacred Heart in Rome.
The metabolic syndrome is a cluster of metabolic risk factors for developing diabetes, heart disease and stroke. People with this syndrome cannot efficiently use insulin, the hormone that regulates glucose (sugar) in the blood.
Some evidence exists that oxidative stress may play a role in the metabolic syndrome, according to Mancini. Oxidative stress, a biochemical mechanism which can lead to damage to blood particles and to cells, results from an imbalance between an excessive amount of oxidants and decreased antioxidant defenses. Oxidative stress also plays a part in aging.
Antioxidants, which are found naturally in fruits, vegetables, legumes and nuts, include vitamins E and C, selenium and carotenoids, such as beta-carotene. Past research shows that antioxidants can prevent oxidative damage to cells and in some cases also help repair damage.
Mancini and his colleagues studied the effects of dietary antioxidants on insulin resistance, with partial financial support from MIUR, the Italian Department for University and Research. The study included 16 men and 13 women, ages 18 to 66 years, who were obese and insulin-resistant, but were not yet diabetic.
The researchers randomly assigned the subjects to one of four treatment groups. All groups ate a low-calorie, Mediterranean-type diet averaging 1,500 calories daily, containing only 25 percent from protein foods, with the rest made up of low-glycemic-index carbohydrates (carbs that do not raise blood sugar levels quickly or greatly, such as whole grains). Group A only ate this kind of diet, and group B ate the same diet plus took the drug metformin. For groups C and D, the researchers prescribed a diet enriched in antioxidant, with a calculated intake, 800 to 1,000 milligrams a day, coming from fruits and vegetables, but group D also took metformin.
Despite similar weight loss in all the groups, only the two groups receiving the antioxidant diet (groups C and D) had a significant decrease in insulin resistance, the authors reported. Group D had the best improvement in insulin resistance on some measures of insulin response to an oral glucose tolerance test, according to the abstract.
Subjects reported no adverse effects from the antioxidant diet, Mancini said. When asked about the risk of adding more antioxidants to a diet, he stated, “We think that a total antioxidant level of 800 to 1,000 milligrams a day is safe and probably not close to the maximum tolerable level.”


Well-Defined Quantity of Antioxidants in Diet Can Improve Insulin Resistance

Released: 6/21/2010 9:00 AM EDT
Source: Endocrine Society
Newswise — A diet rich in natural antioxidants improves insulin sensitivity in insulin-resistant obese adults and enhances the effect of the insulin-sensitizing drug metformin, a preliminary study from Italy finds. The results will be presented Monday at The Endocrine Society’s 92nd Annual Meeting in San Diego.
“The beneficial effects of antioxidants are known, but we have revealed for the first time one of their biological bases of action—improving hormonal action in obese subjects with the metabolic syndrome,” said principal author Antonio Mancini, MD, an endocrinology researcher at Catholic University of the Sacred Heart in Rome.
The metabolic syndrome is a cluster of metabolic risk factors for developing diabetes, heart disease and stroke. People with this syndrome cannot efficiently use insulin, the hormone that regulates glucose (sugar) in the blood.
Some evidence exists that oxidative stress may play a role in the metabolic syndrome, according to Mancini. Oxidative stress, a biochemical mechanism which can lead to damage to blood particles and to cells, results from an imbalance between an excessive amount of oxidants and decreased antioxidant defenses. Oxidative stress also plays a part in aging.
Antioxidants, which are found naturally in fruits, vegetables, legumes and nuts, include vitamins E and C, selenium and carotenoids, such as beta-carotene. Past research shows that antioxidants can prevent oxidative damage to cells and in some cases also help repair damage.
Mancini and his colleagues studied the effects of dietary antioxidants on insulin resistance, with partial financial support from MIUR, the Italian Department for University and Research. The study included 16 men and 13 women, ages 18 to 66 years, who were obese and insulin-resistant, but were not yet diabetic.
The researchers randomly assigned the subjects to one of four treatment groups. All groups ate a low-calorie, Mediterranean-type diet averaging 1,500 calories daily, containing only 25 percent from protein foods, with the rest made up of low-glycemic-index carbohydrates (carbs that do not raise blood sugar levels quickly or greatly, such as whole grains). Group A only ate this kind of diet, and group B ate the same diet plus took the drug metformin. For groups C and D, the researchers prescribed a diet enriched in antioxidant, with a calculated intake, 800 to 1,000 milligrams a day, coming from fruits and vegetables, but group D also took metformin.
Despite similar weight loss in all the groups, only the two groups receiving the antioxidant diet (groups C and D) had a significant decrease in insulin resistance, the authors reported. Group D had the best improvement in insulin resistance on some measures of insulin response to an oral glucose tolerance test, according to the abstract.
Subjects reported no adverse effects from the antioxidant diet, Mancini said. When asked about the risk of adding more antioxidants to a diet, he stated, “We think that a total antioxidant level of 800 to 1,000 milligrams a day is safe and probably not close to the maximum tolerable level.”



Fructose Sugar Makes Maturing Human Fat Cells Fatter, Less Insulin-Sensitive

Released: 6/20/2010 2:00 PM EDT
Source: Endocrine Society
Newswise — Fructose, the sugar widely used as high-fructose corn syrup in soft drinks and processed foods, often gets some of the blame for the widespread rise in obesity. Now a laboratory study has found that when fructose is present as children’s fat cells mature, it makes more of these cells mature into fat cells in belly fat and less able to respond to insulin in both belly fat and fat located below the skin.
The results will be presented Sunday at The Endocrine Society’s 92nd Annual Meeting in San Diego by lead author Georgina Coade, a PhD student at the University of Bristol in the U.K.
“Our results suggest that high levels of fructose, which may result from eating a diet high in fructose, throughout childhood may lead to an increase in visceral [abdominal] obesity, which is associated with increased cardiometabolic risk,” Coade said.
Defined by a large waistline, abdominal obesity raises the risk of heart disease and Type 2 diabetes. The abdominal cavity contains one of two major types of fat in the body: visceral fat. The other type, subcutaneous fat, is found below the surface of the skin.
Although researchers have shown the negative effects of fructose on the fat distribution of rodents, the effects of this sugar on human adipocytes, or fat cells, are not clear, according to Coade. Therefore, she and her fellow researchers studied biopsy specimens of both subcutaneous and visceral fat from 32 healthy-weight children who had not yet gone through puberty.
From the biopsy samples, the investigators obtained preadipocytes—the precursors to fat cells that have the potential to differentiate, or mature, into fat-containing adipocytes. They then allowed the precursor cells to mature for 14 days in culture media containing normal glucose (the main sugar found in the bloodstream and the principal source of energy in the body), high glucose or high fructose. The researchers assessed cell differentiation by measuring activity of an enzyme (GPDH) and the abundance of the adipocyte fatty acid binding protein, which are both present only in mature fat cells.
Fructose, the research team found, had different effects to that of glucose and caused the fat cells to differentiate more—that is, to form more mature fat cells—but only in visceral fat.
For both types of fat cells, maturation in fructose decreased the cells’ insulin sensitivity, which is the ability to successfully take up glucose from the bloodstream into fat and muscles. Decreased insulin sensitivity is a characteristic of Type 2 diabetes.
Although prolonged exposure to fructose had a negative effect on insulin sensitivity, when Coade and her co-workers exposed mature fat cells, rather than preadipocytes, to fructose for 48 hours, the cells’ insulin sensitivity increased. The reason why is unknown. However, she said, “Fructose alters the behavior of human fat cells if it is present as the fat cells mature. We can maybe compare this [timing] to periods in children when they are making their fat.”
The London-based organization Diabetes UK helped fund this study.


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Deadly Effect of Arsenic in Drinking Water Measured in Massive Study

Released: 6/18/2010 9:00 AM EDT
Embargo expired: 6/18/2010 6:30 PM EDT
Source: University of Chicago Medical Center
Newswise — More than 20 percent of deaths in a study of 12,000 Bangladeshis were attributable to arsenic exposure from contaminated drinking water, new research reports.
The large 10-year study is the first to prospectively measure the relationship between individual exposure to arsenic and its associated mortality risk, the authors said. The data, collected by an international team from Chicago, New York, and Bangladesh, will be published early online Saturday in The Lancet.
Since the widespread installation of hand-pumped wells to tap groundwater sources in the 1970's, as many as 77 million people - about half the population of Bangladesh - have been accidentally exposed to dangerous levels of arsenic. The World Health Organization calls the exposure "the largest mass poisoning of a population in history."
The Health Effects of Arsenic Longitudinal Study (HEALS) was led by Habibul Ahsan, MD, MMedSc, Director of the Center for Cancer Epidemiology and Prevention at the University of Chicago Medical Center. Arsenic levels from well drinking-water and repeated biennial urine samples of 12,000 subjects were associated with deaths in that population over the last decade.
For the 25 percent of people exposed to the highest levels of arsenic, mortality risk increased by nearly 70 percent, the study determined. People exposed to moderate levels of the poisonous chemical also exhibited increased deaths from chronic disease, relative to those whose exposure was within WHO recommendations of 10 parts per million.
"The results of this study have important public health implications for arsenic in drinking water," the authors write. The exposure levels studied are "similar to other populations that have low-level arsenic exposure."
Arsenic is known to be a potent carcinogen and toxic to organs such as the liver, skin, kidney and the cardiovascular system. But previous studies assessing the effects of long-term drinking-water exposure to arsenic have lacked resolution, relying upon retrospective analysis and estimations of exposure on a group, rather than individual, level.
The HEALS project sought to improve upon this body of research with a prospective study, actively monitoring exposure levels in a large set of individual Bangladeshis. Nearly 12,000 subjects were recruited and tested for baseline arsenic levels in drinking water and urine between 2000 and 2002, then underwent follow-up tests approximately every 2 years thereafter.
"We set up this study to measure health effects based on individual level data so that other factors or biases that may affect our study findings were much less likely," Ahsan said. "This allowed us to examine disease quite reasonably in a more accurate way."
The collection of so many samples was no simple task. More than 100 staff members traveled to remote Bangladesh villages by foot, car, or boat to collect samples from subjects and measure arsenic levels in the water from local wells. Millions of such wells were installed by global health organizations in the 1970's to provide a supposedly cleaner source of water than that available from dirty rivers and streams.
"In Bangladesh, waterborne illnesses have gone down in the last 2 to 3 decades," Ahsan said. "Unfortunately, there is now this new problem affecting them."
While a quarter of the study's population was within the WHO-determined safe range of 10 µg/L, the upper quartile was exposed to 27 times that amount on average. Those individuals were found to be 68 percent more likely to die from a chronic disease over the time period studied, compared to individuals with exposure less than 10 µg/L, after controlling for other factors such as sex, age, body mass, blood pressure and smoking.
Subjects with moderate arsenic exposure were at a smaller yet still elevated risk of mortality. When the entire population exposed to arsenic levels above the WHO guideline was combined, 21.4 percent of all deaths and 23.5 percent of deaths from chronic disease could be attributed to arsenic exposure, the authors wrote.
An ongoing expansion of the HEALS project to 20,000 subjects hopes to clarify the deleterious effects of the lower doses, which are similar to the levels found in the groundwater of some regions in the United States, Argentina, Mexico and other countries.
"With a larger population, we can make much more definitive conclusions on whether this low dose exposure between 10 to 150 micrograms that some US populations have been exposed to are indeed deleterious, increasing cancer or even deaths," Ahsan said.
The study found no reduction in mortality risk for subjects with high baseline arsenic levels that were subsequently lowered in follow-up measurements. That suggests that the effects of chronic exposure to high levels of arsenic are not reduced even when the individual is given access to cleaner drinking water – at least not during the time surveyed by the study.
"This says that further exposure to arsenic for those individuals already exposed needs to be reduced immediately if possible," Ahsan said. "Unfortunately in a developing country such as Bangladesh, the real solution of replacing the source of drinking water from contaminated to safe water sources for 50 million people is quite a task. What is needed is for the government and international community to deal with that challenge."
The paper, "Arsenic exposure from drinking water, and all-cause and chronic-disease mortalities in Bangladesh (HEALS): a prospective cohort study," will be published online Saturday by The Lancet. Other authors include Maria Argos, Tara Kalra, Paul J. Rathouz, and Brandon Pierce of the University of Chicago; Faruque Parvez, Vesna Slavkovich, Alexander van Geen, and Joseph Graziano of Columbia University; Yu Chen of New York University; and Tariqul Islam, Alauddin Ahmed, Muhammad Rakibuz-Zaman, Rabiul Hasan, Golam Sarwar of the University of Chicago Research Office in Bangladesh. Funding for the study was provided by the National Institutes of Health.





  • Study Examines Outcomes of Lowering Homocysteine Levels With Folic Acid and Vitamin B12

    Released: 6/18/2010 1:05 PM EDT
    Embargo expired: 6/22/2010 4:00 PM EDT
    Source: American Medical Association (AMA)
    Newswise — Patients who had experienced a heart attack and lowered their blood homocysteine levels with folic acid and vitamin B12 supplementation did not have an associated lower risk of heart attack, coronary death or stroke, according to a study in the June 23/30 issue of JAMA. However, the researchers did find that folic acid supplementation did not increase the risk of cancer, which has been speculated.
    Blood homocysteine levels are positively associated with cardiovascular disease, but it is uncertain whether the association is causal, according to background information in the article. A meta-analysis of prospective studies indicated that, after adjustment for known risk factors, a 25 percent lower than usual homocysteine concentration was associated with an 11 percent lower risk of coronary heart disease and 19 percent lower risk of stroke. “Daily supplementation with folic acid typically lowers homocysteine levels by about 25 percent, and the addition of vitamin B12 lowers it by a further 7 percent,” the authors write. Other research has suggested supplementation with folic acid may offer a protective effect against stroke.
    Jane M. Armitage, F.R.C.P., of the University of Oxford, United Kingdom, and colleagues with the Study of the Effectiveness of Additional Reductions In Cholesterol and Homocysteine (SEARCH) trial assessed the effects of lowering homocysteine levels with folic acid plus vitamin B12 in 12,064 survivors of myocardial infarction (heart attack) in secondary care hospitals in the United Kingdom between 1998 and 2008. Patients were randomized to receive either 2 mg. folic acid plus 1 mg. vitamin B12 daily or matching placebos. The primary outcomes measured included first major vascular event, defined as major coronary event (coronary death, heart attack, or coronary revascularization), fatal or nonfatal stroke, or noncoronary revascularization.
    Patients who received the study vitamins reduced homocysteine by an average of 3.8 µmol/L (28 percent). During 6.7 years of follow-up, major vascular events occurred in 1,537 of 6,033 participants (25.5 percent) allocated folic acid plus vitamin B12 vs. 1,493 of 6,031 participants (24.8 percent) allocated placebo. “There was no evidence of any benefit beginning to emerge with more prolonged treatment and follow-up,” the authors write.
    Receipt of study vitamins also was not associated with a significant effect on any stroke (vitamins, 4.5 percent vs. placebo, 4.4 percent); noncoronary revascularizations (vitamins, 3.0 percent vs. placebo, 2.5 percent); or major coronary events (vitamins, 20.4 percent vs. placebo, 19.6 percent). There were no apparent differences in the numbers of deaths attributed to vascular causes or nonvascular causes.
    New primary cancers (excluding non-melanoma skin cancer) were diagnosed in 11.2 percent of the participants allocated folic acid plus vitamin B12 vs. 10.6 percent allocated placebo, with this difference not being significant.
    “Taken together with the previous homocysteine-lowering trials, the results of SEARCH indicate that folic acid supplementation has no significant adverse effects on cancer or other major health outcomes, even if it also produces no beneficial effects on cardiovascular disease. In addition, these results highlight the importance of focusing on drug treatments (e.g., aspirin, statins, and antihypertensive therapy) and lifestyle changes (in particular, stopping smoking and avoiding excessive weight gain) that are of proven benefit, rather than lowering homocysteine with folic acid-based vitamin supplements, for the prevention of cardiovascular disease,” the authors conclude.
    (JAMA. 2010;303[24]:2486-2494. Available pre-embargo to the media at www.jamamedia.org)
    Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.








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Obesity, Weight Gain in Middle Age Associated With Increased Risk of Diabetes Among Older Adults

Released: 6/18/2010 1:15 PM EDT
Embargo expired: 6/22/2010 4:00 PM EDT
Source: American Medical Association (AMA)
Newswise — For individuals 65 years of age and older, obesity, excess body fat around the waist and gaining weight after the age of 50 are associated with an increased risk of diabetes, according to a study in the June 23/30 issue of JAMA.

“Incidence of diabetes in the United States has doubled in the past 15 years, and is highest among adults 65 to 79 years of age. Approximately 70 percent of U.S. men and women 60 years of age and older are overweight or obese [BMI - body mass index 25 or greater]. Adiposity [body fat] is a well-recognized risk factor for type 2 diabetes among young and middle-aged adults, however, the relationships between different measures of body composition and diabetes in older adults [65 years of age or older] are not well described,” the authors write.
Mary L. Biggs, Ph.D., of the University of Washington, Seattle, and colleagues examined the relationship between measures of overall body fat, fat distribution, changes in these measures, and diabetes risk among 4,193 men and women 65 years of age and older. Measures of adiposity were determined when participants entered the study, and repeated 3 years later. The incidence of diabetes was ascertained based on use of antidiabetic medication or a fasting blood glucose level of 126 mg/dL or greater.
Over a median (midpoint) follow-up of 12.4 years, 339 new cases of diabetes were diagnosed among the study participants. The researchers found that BMI at baseline, BMI at 50 years of age, weight, fat mass, waist circumference, waist-hip ratio, and waist-height ratio were all strongly related to the risk of diabetes. “For each measure, there was a graded increase in the risk of diabetes with increasing quintiles of adiposity. Participants in the highest category of adiposity had an approximately 2- to 6-fold increased risk of developing diabetes compared with those in the lowest category. We found no evidence of significant statistical interaction by sex or race,” the authors write.
Also, compared with participants whose weight remained stable (plus or minus 4.4 lbs.) over the time period, those who gained 20 lbs. or more between the age of 50 years and study entry had an approximately 3-fold greater risk of developing diabetes during follow-up, regardless of their BMI at 50 years of age. Participants who were obese (BMI 30 or greater) at 50 years of age and who experienced the most weight gain (more than 20 lbs.) between the age of 50 years and study entry had 5 times the risk of developing diabetes compared with weight-stable participants with normal BMI (less than 25) at 50 years of age.
The researchers also found that participants in the highest categories of both BMI and waist circumference had more than 4 times the risk of those in the lowest category of both measures. Participants with a greater than 4 inch increase in waist size from baseline to the third follow-up visit had a 70 percent higher risk of type 2 diabetes compared with those who gained or lost 0.8 inches or less.
“Results of this study affirm the importance of maintaining optimal weight during middle age for prevention of diabetes and, while requiring confirmation, suggest that weight control remains important in reducing diabetes risk among adults 65 years of age and older,” the authors conclude.
(JAMA. 2010;303[24]:2504-2512. Available pre-embargo to the media at www.jamamedia.org)
Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.




Investigators Perfect New Version of Blood-Regulator Thrombin

Released: 6/18/2010 11:45 AM EDT
Source: Saint Louis University Medical Center
Newswise — In research led by a Saint Louis University investigator, molecular biologists have discovered a way to harness the enzyme thrombin’s anti-blood clotting properties. The finding opens the door to new medications that will treat diseases related to thrombosis, the presence of blood clots in blood vessels, which is responsible for nearly a third of all deaths in the U.S.
“Thrombosis is one of the most prevalent causes of fatal disease,” said lead researcher Enrico Di Cera, M.D., chair of the department of biochemistry and molecular biology at Saint Louis University School of Medicine. “If we could develop an anti-thrombotic drug that didn’t carry a risk of hemorrhage, it would revolutionize the treatment of cardiovascular disease, the leading cause of death in the U.S. and Western world.
“This research carries us closer to that goal.”
Blood clotting has long ensured our survival, stopping blood loss after an injury. On the other hand, if triggered in the wrong conditions, clotting can lead to debilitating or fatal conditions like heart attack, stroke and deep vein thrombosis.
Funded by the National Institutes of Health, and published in the June 18, 2010 edition of The Journal of Biological Chemistry (Vol. 285. No. 25), researchers zeroed in on thrombin, a vitamin K-dependent enzyme key to blood coagulation.
An unusual enzyme, thrombin performs distinct and even opposing functions, acting as a pro-coagulant, pro-thrombotic but also as an anti-coagulant factor depending on which target protein – fibrinogen, PAR1 or protein C – becomes activated in the blood. Researchers studied thrombin to decipher the structure-function code that enables this protein to do so many different things.
Tackling this problem far below the level of tissue and organs, molecular biologists looked deep inside the structure, examining thrombin’s amino acids to note how they behave and interact with each other.
Using protein engineering, researchers produced mutations in the enzyme’s amino acid sequence, carefully taking out pieces and replacing them, a few at a time, to find the exact locations that influence the function of thrombin. Once they found these “hot spots,” researchers went even further – trying each of the 20 natural amino acids to see which mutation would allow them to turn on and off the pro-coagulant, pro-thrombotic and anti-coagulant functions.
“We asked the question, what if we can take this enzyme and dissociate the functions, allowing only the function we want?” said Di Cera.
In earlier research, Di Cera’s team did just that. They engineered thrombin to promote activity toward protein C – the anticoagulant target protein – and minimize activity toward fibrinogen and PAR1 – the procoagulant and prothrombotic targets.
“In 2000, we engineered a thrombin mutant with potent anticoagulant properties both in vitro and in vivo and we are moving this mutant to a phase I trial,” said Di Cera. “In this study, however, we pressed further. We wanted to optimize this mutant to completely abrogate activity toward fibrinogen and PAR1.”
“With this research we optimized the mutant so that there is no clotting at all. Furthermore, we generated a new mutant with exclusive prothrombotic activity, thereby demonstrating that the individual functions of thrombin can be dissociated by replacing a single amino acid in the protein.”
Once clinical trials are performed, researchers hope to have developed an alternative to heparin, a blood thinner that is used to prevent blood clots and is often used before surgery, but which also causes allergic reactions, dosage challenges and bleeding.
“Heparin is a brute-force remedy that shuts down all thrombin functions, including its beneficial anti-coagulant role,” said Di Cera. “Our approach is a new strategy that like a smart bomb only targets the functions we want to turn off.”
Established in 1836, Saint Louis University School of Medicine has the distinction of awarding the first medical degree west of the Mississippi River. The school educates physicians and biomedical scientists, conducts medical research, and provides health care on a local, national and international level. Research at the school seeks new cures and treatments in five key areas: cancer, liver disease, heart/lung disease, aging and brain disease, and infectious disease.

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SLU, Saint Louis University, St. Louis University, Thrombin, Thrombosis, Di Cera, Enrico Di Cera, Blood Clotting, Blood Clot Prevention, Anticoagulant, Heparin

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