Tag Archives: Dr. Kevin Chan

Traditional Asian diet lowered insulin resistance in Asian Americans

Lipidology_NP_NutritionWhy are Asian Americans at higher risk of developing type 2 diabetes than Caucasian Americans, and prone to develop the disease at lower body weights? One part of this puzzle may lie in the transition from traditional high-fiber, low-fat Asian diets to current westernized diets, which may pose extra risks for those of Asian heritage, says George King, M.D., Senior Vice President and Chief Scientific Officer at Joslin Diabetes Center and the senior author of the study.

A Joslin randomized clinical trial now has demonstrated that both Asian Americans and Caucasian Americans at risk of type 2 diabetes who adopted a rigorously controlled traditional Asian diet lowered their insulin resistance. (A leading risk factor for developing the disease, insulin resistance is a condition in which the body struggles to use the hormone insulin, which helps to metabolize sugar.)

Moreover, when both groups of participants then switched to consuming typical western fare, the Asian Americans experienced greater increases in insulin resistance than did the Caucasian Americans, says Dr. King, senior author on a paper on the study published in the journal PLOS One.

The 16-week pilot trial was completed by 24 East Asian Americans and 16 Caucasian Americans, who had an average age of 34 and were either of normal weight or overweight but not obese. All the volunteers had a family history of type 2 diabetes or another indication of diabetes risk such as gestational diabetes.

For the first eight weeks, all the participants ate a traditional high-fiber East Asian diet with 70% of calories fromcarbohydrates, 15% from protein and 15% from fat, and providing 15 g fiber/1,000 kcal. The food was prepared fresh by local chefs and delivered every two days. “Three meals and one snack were included each day, and we made sure that they were nutritious as well as very tasty,” says Ka Hei Karen Lau, a Joslin dietitian and certified diabetes educator.

For the second eight weeks, 33 of the volunteers (20 Asian Americans and 13 Caucasian Americans) transitioned to a typical low-fiber western diet with 50% of calories from carbohydrates, 16% from protein and 34% from fat, and providing 6 g fiber/1,000 kcal. Seven volunteers (4 Asian Americans and 3 Caucasian Americans) stayed on the traditional Asian diet to act as controls for the study.

Meeting with the trial participants every two weeks, the Joslin team adjusted individual diets as needed to keep their weights relatively steady, so that changes in their metabolism were not driven primarily by changes in weight.

Maintaining those steady body weights for trial participants was a challenge, King remarks. “It was almost impossible to prevent people from losing weight on the Asian diet, and that was not because the food wasn’t good!” he says. “And almost everybody gained weight on the western diet, and we had to work very hard so they didn’t gain too much.”

The researchers suggested that the combination of high fiber and low fat in the traditional diet may help to explain the decrease in insulin resistance, especially for the Asian American participants.

Additionally, those on the traditional Asian diet lowered their LDL cholesterol, a potential benefit for cardiovascular health.

“These results were very exciting for Asian Americans,” Lau says. “We are at high risk for diabetes, but we can use diet to help prevent it.”

Joslin’s Asian Clinic now promotes a traditional Asian diet and shares suitable recipes with patients.

The researchers hope to follow up the pilot trial with a larger trial that compares results of a traditional Asian diet with a westernized Asian diet and does not try to control participant weight.

Asian Americans have about 20% higher risks of developing type 2 diabetes than Caucasian Americans. More than half of the adults in the world with the disease live in Southeast Asia and the Western Pacific, the researchers pointed out, and about 10% of adults in China now suffer from diabetes.

http://www.medicalnewstoday.com/releases/282735.php

Picture courtesy to www.just-like.net

Sugar substance ‘kills’ good HDL cholesterol

LipidologyScientists at the University of Warwick have discovered that ‘good’ cholesterol is turned ‘bad’ by a sugar-derived substance.

The substance, methylglyoxal – MG, was found to damage ‘good’ HDL cholesterol, which removes excess levels of bad cholesterol from the body.

Low levels of HDL, High Density Lipoprotein, are closely linked to heart disease, with increased levels of MG being common in the elderly and those with diabetes or kidney problems.

Supported by funding from the British Heart Foundation (BHF) and published in Nutrition and Diabetes, the researchers discovered that MG destabilises HDL and causes it to lose the properties which protect against heart disease.

HDL damaged by MG is rapidly cleared from the blood, reducing its HDL content, or remains in plasma having lost its beneficial function.

Lead researcher Dr Naila Rabbani, of the Warwick Medical School, says that: “MG damage to HDL is a new and likely important cause of low and dysfunctional HDL, and could count for up to a 10% risk of heart disease”.

There are currently no drugs that can reverse low levels of HDL, but the Warwick researchers argue that by discovering how MG damages HDL has provided new potential strategies for reducing MG levels.

Commenting on the research’s implications Dr Rabbani said:

“By understanding how MG damages HDL we can now focus on developing drugs that reduce the concentration of MG in the blood, but it not only be drugs that can help.

“We could now develop new food supplements that decrease MG by increasing the amount of a protein called glyoxalase 1, or Glo 1, which converts MG to harmless substances.

“This means that in future we have both new drugs and new foods that can help prevent and correct low HDL, all through the control of MG.”

A potentially damaging substance, MG is formed from glucose in the body. It is 40,000 times more reactive than glucose it damages arginine residue (amino acid) in HDL at functionally important site causing the particle to become unstable.

Glo1 converts MG to harmless substances and protects us. MG levels are normally kept low in the body to maintain good health but they slowly increase with ageing as Glo1 slowly becomes worn out and is only slowly replaced.

Dr Rabbani says: “We call abnormally high levels of MG ‘dicarbonyl stress‘. This occurs in some diseases – particularly diabetes, kidney dialysis, heart disease and obesity. We need sufficient Glo1 to keep MG low and keep us in good health.”

 

http://www.medicalnewstoday.com/releases/281827.php

 

Socioeconomic status and gender are associated with differences in cholesterol levels

Integrative LipidologyA long-term lifestyle study reports differences between the sexes when it comes to fat profiles associated with socioeconomic status. Research in the open access journal BMC Public Health breaks down factors associated with social class and finds surprising inequalities between men and women.

The researchers found that men in social classes (based on occupation) with manual jobs had lowercholesterol levels than their counterparts in non-manual social classes. In contrast, women’s LDL-cholesterol levels were more closely tied to their educational level than men.

The study highlights the health inequalities that exist between the social classes, and the researchers believe that future interventions should focus on men and women separately and explore the reasons for these differences, in order to promote better health.

Researchers from University of Cambridge performed a cross-sectional study as part of the European Prospective into Cancer involving 22451 participants aged 39-79 years old from the from Norfolk cohort in the UK. Each participant indicated what their alcohol consumption was and their BMI was calculated. Participants completed a survey that measured socioeconomic status using three factors: social class, education level, and the level of deprivation in the area they lived. This is the first time that socioeconomic status has been looked at assessingthese three factors independently. Blood samples were also taken to determine the following lipid levels: total cholesterol, HDL-cholesterol, triglycerides, and LDL-cholesterol.

Kay-Tee Khaw, lead researcher, says: “There is a well-recognised social gradient in cardiovascular disease. We were interested in trying to understand reasons for the observed socioeconomic inequalities in health. However, there are different measures of socioeconomic status including occupational class, educational status and residential deprivation, which may relate differently to different domains of health.”

Overall, women were found to have higher total cholesterol levels than men. In men, socioeconomic status was not initially associated with total cholesterol level, but after taking age into account, , men in manual social classes were found to have slightly lower total cholesterol than those in non-manual jobs. Women with a lower education level were found to have higher total cholesterol compared to others.

When the team looked at HDL-cholesterol levels – the ‘good’ cholesterol – they found that women had higher levels than men. Men with more education and from higher occupational classes were found to have higher levels of HDL-cholesterols, but this was not linked to the deprivation in their area. However, when the results are adjusted for alcohol consumption – which is higher in the non-manual occupation group – this association lost statistical significance.

For LDL-cholesterol – the ‘bad’ cholesterol – again women were found to have higher levels than men. Women without educational qualifications beyond the age of 15 had significantly higher LDL-cholesterol than those who did even when accounting for BMI and alcohol use. Occupational class and level of deprivation were not linked to LDL-cholesterol in women. No association was found between the three socioeconomic indices and LDL-cholesterol levels in men.

In the breakdown of the socioeconomic status factors, the researchers did not expect to see such differences in lipid levels in occupational social class of the women, especially as their social class was based on her partner’s occupational social class. They had expected this to be similar for men and women. They speculate that this may be because men in manual social classes may have more physical activity and no differences in body mass index compared to those in non-manual social classes, whereas women in manual social classes (defined by their partners’ occupation) may not have high physical activity and had higher mean body mass index compared to those in non-manual social classes. To address this limitation the team conducted a separate analysis based on the women’s own occupation and found similar results.

Kay-Tee Khaw says: “We observed sex differences in the lipid patterns according to social class and education. The association of some adverse lipid parameters with social class and in particular, educational status in women was much stronger than for men. If we wish to reduce health inequalities we need to understand the reason for these health inequalities. Future studies need to look at men and women separately and explore the reasons for these sex differences.”

http://www.medicalnewstoday.com/releases/281685.php

 

New culprit identified in metabolic syndrome

Integrative LipidologyA new study suggests uric acid may play a role in causing metabolic syndrome, a cluster of risk factors that increases the risk of heart disease and type 2 diabetes.

Uric acid is a normal waste product removed from the body by the kidneys and intestines and released in urine and stool. Elevated levels of uric acid are known to cause gout, an accumulation of the acid in the joints. High levels also are associated with the markers of metabolic syndrome, which is characterized by obesity,high blood pressure, elevated blood sugar and high cholesterol. But it has been unclear whether uric acid itself is causing damage or is simply a byproduct of other processes that lead to dysfunctional metabolism.

Published in Nature Communications, the new research at Washington University School of Medicine in St. Louis suggests excess uric acid in the blood is no innocent bystander. Rather, it appears to be a culprit in disrupting normal metabolism.

“Uric acid may play a direct, causative role in the development of metabolic syndrome,” said first author Brian J. DeBosch, MD, PhD, an instructor in pediatrics. “Our work showed that the gut is an important clearance mechanism for uric acid, opening the door to new potential therapies for preventing or treating type 2 diabetes and metabolic syndrome.”

Recent research by the paper’s senior author, Kelle H. Moley, MD, the James P. Crane Professor of Obstetrics and Gynecology, and her collaborators has shown that a protein called GLUT9 is an important transporter of uric acid.

DeBosch, a pediatric gastroenterologist who treats patients at St. Louis Children’s Hospital, studied mice to learn what happens when GLUT9 stops working in the gut, essentially blocking the body’s ability to remove uric acid from the intestine. In this study, the kidney’s ability to remove uric acid remained normal.

Eating regular chow, mice missing GLUT9 only in the gut quickly developed elevated uric acid in the blood and urine compared with control mice. And at only 6-8 weeks of age, they developed hallmarks of metabolic syndrome: high blood pressure, elevated cholesterol, high blood insulin and fatty liver deposits, among other symptoms.

The researchers also found that the drug allopurinol, which reduces uric acid production in the body and has long been used to treat gout, improved some, but not all, of the measures of metabolic health. Treatment with the drug lowered blood pressure and total cholesterol levels.

Exposure to uric acid is impossible to avoid because it is a normal byproduct of cell turnover in the body. But there is evidence that diet may contribute to uric acid levels. Many foods contain compounds called purines that break down into uric acid. And adding to growing concerns about fructose in the diet, evidence suggests that fructose metabolism in the liver also drives uric acid production.

“Switching so heavily to fructose in foods over the past 30 years has been devastating,” Moley said. “There’s a growing feeling that uric acid is a cause, not a consequence, of metabolic syndrome. And now we know fructose directly makes uric acid in the liver. With that in mind, we are doing further research to study what happens to these mice on a high-fructose diet.”

http://www.medicalnewstoday.com/releases/280853.php

 

 

Niacin for cholesterol now linked to death risk, dangerous side effects and no benefits

Integrative LipidologyAfter 50 years of being a mainstay cholesterol therapy, niacin should no longer be prescribed for most patients due to potential increased risk of death, dangerous side effects and no benefit in reducing heart attacks and strokes, writes Northwestern Medicine® preventive cardiologist Donald Lloyd-Jones, M.D., in a New England Journal of Medicine editorial.

Lloyd-Jones’s editorial is based on a large new study published in the journal that looked at adults, ages 50 to 80, with cardiovascular disease who took extended-release niacin (vitamin B3) and laropiprant (a drug that reduces face flushing caused by high doses of niacin) to see if it reduced heart attack and stroke compared to a placebo over four years. All patients in the trial were already being treated with a statin medication.

Niacin did not reduce heart attacks and stroke rates compared with a placebo. More concerning, niacin was associated with an increased trend toward death from all causes as well as significant increases in serious side effects: liver problems, excess infections, excess bleeding, gout, loss of control of blood sugar for diabetics and the development of diabetes in people who didn’t have it when the study began.

“There might be one excess death for every 200 people we put on niacin,” said Lloyd-Jones, chair of preventive medicine at Northwestern University Feinberg School of Medicine and Northwestern Memorial Hospital. “With that kind of signal, this is an unacceptable therapy for the vast majority of patients.”

“For the reduction of heart disease and stroke risk, statins remain the most important drug-based strategy by far because of their demonstrated benefit and their good safety profile,” said Lloyd-Jones, who was a member of the task force that rewrote cholesterol treatment guidelines in 2013 for the American College of Cardiology and the American Heart Association.

Niacin should be reserved only for patients at very high risk for a heart attack and stroke who can’t take statins and for whom there are no other evidence-based options, Lloyd-Jones said.

Niacin raises “good” HDL (high density lipoprotein) cholesterol levels, and having high HDL levels means a lowered risk for cardiovascular events. But clinical trials have not shown that niacin reduced the risk ofcoronary heart disease or the broader cardiovascular disease specifically by raising HDL. Niacin also produces a modest reduction in low-density lipoprotein (LDL cholesterol) and a more substantial reduction in triglyceride levels, which might be expected to lower the risk of coronary heart disease, Lloyd-Jones notes in the article.

But the new study suggests that higher HDL levels only are a sign of lowered risk for heart attacks and stroke. Raising HDL levels with niacin does not appear to impact cardiovascular outcomes nor does lowering triglyceride levels, Lloyd-Jones points out.

“The recent niacin clinical trials offer important new evidence that raising ‘good’ cholesterol (HDL) levels on top of statin therapy does not have the positive outcome that had been hoped for,” said Neil Stone, M.D., the Robert Bonow MD Professor in Cardiology at Feinberg and a cardiologist at Northwestern Memorial Hospital. “Lowering ‘bad’ cholesterol (LDL) with an optimal intensity of tolerated statins and adherence to healthy lifestyle changes remains the most effective approach to prevent strokes and heart attacks for patients at risk of cardiovascular disease.”

http://www.medicalnewstoday.com/releases/279734.php

 

The structural secrets of enzyme used to make popular anti-cholesterol drug

May_Part 2_LipidologyIn pharmaceutical production, identifying enzyme catalysts that help improve the speed and efficiency of the process can be a major boon. Figuring out exactly why a particular enzyme works so well is an altogether different quest.

Take the cholesterol-lowering drug simvastatin. First marketed commercially as Zocor, the statin drug has generated billions of dollars in annual sales. In 2011, UCLA scientists and colleagues discovered that a mutated enzyme could help produce the much sought-after pharmaceutical far more efficiently than the chemical process that had been used for years – and could do it better than the natural, non-mutated version of the enzyme. But no one quite knew why, until another team of UCLA researchers cracked the mystery.

Using a combination of experimental measurements and extensive computer simulations, the multidisciplinary team of researchers – from three chemistry, biochemistry and chemical engineering labs at UCLA – uncovered important structural features hidden in the modified enzyme that helped them unlock the secret of its efficacy. Their findings will be published in the June print edition of journal Nature Chemical Biology and are currently available online.

How the enzyme catalyst was first discovered

Simvastatin was already in widespread use when scientists found that a natural enzyme called LovD, originally harvested from a mold found in soil, could react and produce a drug similar to simvastatin. Yet as a catalyst, its rate of reaction was too low for commercial manufacturing.

So UCLA professor Yi Tang collaborated with scientists at Codexis Inc., a developer of industrial enzymes, and used a process called “directed evolution” to create a mutated version of the enzyme that was better, faster and more stable for industrial use.

“Directed evolution is a laboratory technique that mimics the natural evolution process but in a much more rapid fashion,” said Tang, who holds dual appointments in the department of chemistry and biochemistry and the department of chemical and biomolecular engineering.

Tang’s laboratory and the Codexis team created randomly mutated versions of LovD, each with a slightly different sequence of amino acids that altered its basic form and function. The team then selected those enzymes most capable of producing simvastatin and repeated the process to further enhance their reactivity.

After nine rounds of directed evolution, they had identified a mutated enzyme they called LovD9, which deviates from the original LovD enzyme through 29 distinct mutations and which produces simvastatin 1,000 times more efficiently than the natural enzyme.

“Simvastatin has several complicated structural features, so trying to synthesize it chemically takes time and money,” said Gonzalo Jiménez-Osés, a UCLA postdoctoral scholar and the paper’s first author. “If you can produce these compounds in a straightforward manner, it is a huge improvement for drug production.”

Prior to the development of the LovD9 enzyme, simvastatin had been produced through a multistep process involving expensive and hazardous chemical reagents and solvents; the introduction of LovD9 into the manufacturing process in 2012 changed all this, resulting in a far more efficient and environmentally friendly alternative to the chemical manufacturing procedure.

“Because it is an enzymatic process, no toxic chemicals or excess organic solvent are used,” said Tang, who received the EPA’s Presidential Green Chemistry Challenge Award in 2012 for his work with Codexis.

While making simvastatin using LovD9 provided clear advantages, the reasons why the mutated enzyme worked so much better than the natural one remained unclear. So Tang turned to colleagues Kendall Houk and Todd Yeates, both professors of chemistry and biochemistry at UCLA, to see if they could combine their expertise to come up with an explanation.

Cracking the structural mystery

“There are many different examples of directed evolution being used to produce catalysts that enhance the speed of commercial or synthetic processes, but the fact that you have a good catalyst doesn’t give you any information about how it works,” Houk said.

To determine the molecular structures of both LovD and LovD9, Yeates’ laboratory grew protein crystals from each enzyme and scattered X-rays off of them in a process called X-ray crystallography. These measurements gave Yeates an in-depth look at the molecular architecture of the enzymes, yet both appeared virtually identical, with no obvious structural variations to explain why LovD9 was more efficient.

While the two enzymes might appear similar when in solid crystal form, they behave quite differently when immersed in water, Houk said. The enzymes are composed of long chains of amino acids that can rotate and twist when allowed to move freely, yet this complex motion cannot be easily observed through laboratory experiments.

To quantify these minute molecular fluctuations, Houk and Jiménez-Osés used a computer program that simulates how the mutated and natural enzymes undergo internal motions when dissolved in water, and how this motion will influence the ability of the enzymes to cause the transformation that synthesizes simvastatin.

Determining why the mutated LovD9 enzyme works better than its natural counterpart involved simulating the movement of the complex enzyme in a fluid environment over a period just microseconds long. A microsecond may seem like a very short amount of time, but computations for the motion of such a large molecule required massive computing resources, Houk said.

The team was able to harness the tremendous amount of computing power necessary for these calculations by using the National Science Foundation-sponsored Anton supercomputer designed by the D. E. Shaw Research laboratory and located at the Pittsburgh Supercomputing Center.

“In the machines that we have for our routine calculations, each of the simulations in this timescale takes more than one month,” Jiménez-Osés said. “Using Anton, we can do the same amount of calculations in one day. It is a huge improvement.”

From the results of their computer simulations, Houk and Jiménez-Osés determined that part of what makes the mutated enzyme so effective is that it can function without the involvement of an additional protein that is required by the natural enzyme. Also, the mutated enzyme moves and twists in such a way that it remains in a configuration beneficial for simvastatin production far more often than its natural counterpart.

These calculations enabled the research team to understand how mutations located far from the active part of the enzyme can improve its performance.

“The directed evolution changes the nature of the amino acids that are in the protein,” Houk said. “The molecular dynamics simulations allowed us to trace how these changes in amino acids altered the structure of the protein and made it appropriate for use as a catalyst.”

In the case of LovD9, these small differences make the reaction to manufacture simvastatin vastly more efficient. Now that they know which structural features in the mutated enzyme help improve simvastatin production, the team hopes to directly engineer an enzyme with similar properties without resorting to the more random directed evolution process.

“What was special about this study is that we analyzed what happened during directed evolution in order to try to understand how these improvements are made within the protein,” Yeates said. “We hope in the future that it might be possible to make better enzymes in rational ways by understanding how it occurs in random ways.”

The mystery behind the mutated LovD9 enzyme may have remained unsolved without an extraordinary degree of collaboration between chemistry and biochemistry researchers across departments at UCLA.

“This project could not have been completed without four groups coming together to try and solve a problem that is really challenging by combining their different specialties and techniques,” Jiménez-Osés said. “By piecing together this puzzle from biochemical, engineering, structural, and molecular dynamics angles, it was possible to come to a fairly cohesive picture about how the directed evolution process worked in this case,” Yeates added.

http://www.medicalnewstoday.com/releases/276809.php

Cancer spreads with help from ‘bad’ cholesterol

May_Part 1_LipidologyOnce cancer starts to spread to other parts of the body – a process called metastasis – it becomes much more difficult to treat. Now in a world first, an international study published in the journal Cell Reports and led by the University of Sydney in Australia identifies “bad” cholesterol as an important culprit in metastasis.

Cancer happens when normal cells start to behave abnormally, grow out of control and multiply to form lumps called tumors. If untreated, cancer cells can escape their primary tumors, travel to other parts of the body and grow into secondary cancers or metastases. Metastases are the major cause of death from cancer.

If we are to significantly improve cancer treatment, we need a better understanding of metastasis. One of the areas researchers are keenly investigating is what helps cancer cells escape primary tumors and set up new sites elsewhere in the body.

We already know that most of the cells in the body stick to each other because they have velcro-like molecules on their surfaces called integrins. In recent years, researchers have discovered that integrins help cancer cells to escape tumors and settle elsewhere in the body.

For instance, in 2012, Medical News Today learned of a study published in The Journal of Cell Biology that explained why migrating cancer cells often express integrins that provide better traction. The study revealed how a lipid-converting enzyme called DGK-Alpha helps cancer cells gain traction and mobilize.

So an important question in cancer research is how to block integrins so they stop cancer cells from moving and spreading. Some inhibitors of integrin have been developed, but they are not suitable for clinical use, say the researchers behind this new study.

‘Bad’ cholesterol helps integrins move, ‘good’ cholesterol keeps them inside cells

Researchers have discovered that integrins can move from the surface of cells to the inside, and thatcholesterol, one of the major lipids in the body, is needed to keep integrins on the surface of cancer cells. But the underlying mechanisms, until now, have been somewhat unclear.

Thomas Grewal, a senior author of this latest study and an associate professor in the Faculty of Pharmacy at Sydney, says they identified “that ‘bad’ (low density lipoprotein or LDL) cholesterol controls the trafficking of tiny vessels which also contain these integrins, and this has huge effects on the ability of cancer cells to move and spread throughout the body.”

He says they found high levels of “bad” cholesterol seem to help the integrins in cancer cells to move around, and in contrast, high levels of ‘good’ (high density lipoprotein or HDL) cholesterol seem to keep the integrins inside cells.

He and his colleagues conclude that fine-tuning of cholesterol levels could be a way to influence cancer cell migration and invasion.

Knowing “how to manipulate and lower ‘bad’ cholesterol could significantly help to reduce the ability of cancer cells to spread,” says Prof. Grewal, who with co-senior author Carlos Enrich, a professor in the Faculty of Medicine at the University of Barcelona in Spain, has been working on the link between cholesterol and cancer for 15 years.

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http://www.medicalnewstoday.com/articles/276606.php