Researchers ID Genetic Variants Linked to Increased Risk of Metabolic Syndrome

Nutrition researchers have identified five common genetic variations that increase the risk of metabolic syndrome, a group of factors linked to heart disease and diabetes. Another variant they found appeared to protect against the condition.

People with metabolic syndrome have at least three of the following symptoms: abdominal obesity, high blood triglyceride levels, lower good cholesterol (HDL), elevated blood pressure and elevated fasting blood glucose. They are four times as likely to develop heart disease and at least seven times more likely to develop diabetes as individuals without metabolic syndrome.

The investigators at Washington University School of Medicine in St. Louis looked for changes in the CD36 gene, which is located in a region of chromosome 7 that has been linked to metabolic syndrome in several genome-wide studies.

The researchers say linking changes in the CD36 gene to the risk for metabolic syndrome and abnormal levels of good cholesterol is important because as more people in the United States become obese, they also become susceptible to these problems. Better understanding of the relationships between obesity, the gene and disease risk may allow for earlier identification of individuals who are more susceptible to develop metabolic syndrome. Treatments such as medication or lifestyle changes could begin earlier, perhaps preventing or delaying future problems with diabetes or heart disease.

Senior investigator Nada A. Abumrad, Ph.D., the Dr. Robert C. Atkins Professor of Medicine and Obesity Research, first identified the CD36 protein in studies with mice. Her research has demonstrated that the protein facilitates the use of fatty acids for energy. CD36 is located on the surface of cells and distributed throughout many tissues, including fat cells, the digestive tract, heart and skeletal muscle.

The investigators focused on 36 small genetic variations, called single nucleotide polymorphisms (SNPs), in the CD36 gene. A SNP involves a single base-pair change in the DNA.

The team evaluated DNA taken from more than 2,000 African-Americans because variations in the gene are more common in individuals of African and Asian descent than in other racial groups. The researchers expect, however, that these findings also will be applicable in other populations.

“The idea was to look at the different variations in the gene and see whether they were more prevalent in people who also had elevated cholesterol, abnormal blood glucose or the other components of the metabolic syndrome,” says first author Latisha Love-Gregory, Ph.D., research instructor in the Division of Geriatrics and Nutritional Science.

Love-Gregory says the research team demonstrated an association between SNPs in the gene and metabolic syndrome.

“There is additional work to do to determine if the function of these genetic variants actually contributes to the development of type 2 diabetes or heart disease,” she explains. “We do expect that a number of different changes, in both CD36 and other genes, will be related to these diseases. What we’d like to learn, however, is whether the changes identified in the gene alter the CD36 protein in ways that change its function to make a person more vulnerable.”

The team determined that five of the SNPs they examined are more common in people who have symptoms of metabolic syndrome, but a sixth seemed to have a more favorable metabolic effect. The “protective” SNP makes people produce lower amounts of CD36 protein.

Humans have two copies of each chromosome. In this study, people who had the protective variant on only one of their copies of chromosome 7 were less susceptible to metabolic syndrome. But people with two copies of the variant, who were completely deficient in the CD36 protein, did not appear to be protected. They tended to have lower levels of HDL, the so-called good cholesterol.

“A bit less CD36 protein may improve your risk profile, but people need some CD36 function,” Abumrad says. “It’s like requiring a certain level of fat in the diet. Fatty acids are important for optimal function of many tissues — from pancreatic beta cells to skeletal muscle to the heart — but too much fat creates a problem.”

Love-Gregory and Abumrad found that many variants influenced blood levels of HDL cholesterol. Now they are taking a closer look at the relationship between CD36 and HDL cholesterol. Higher levels of HDL normally are considered positive, but because changes in the CD36 gene seem to influence HDL, the researchers want to make sure that the HDL molecule isn’t being altered in composition or function.

“We’re going to follow up on the HDL component of the study,” Love-Gregory says. “We’re also going to look for additional variants in the promoter region of the gene that controls how the gene is regulated. And we’re planning to look for evidence of these gene variants and their associations with HDL and the metabolic syndrome in other populations and ethnic groups.”

Source: Human Molecular Genetics, June, 2008

Risk of Type 1 Diabetes in Children Related to Vitamin D and Sun

Researchers have found that the risk of Type 1 diabetes in children may be strongly associated with Vitamin D and exposure to sunshine.

Low incidence of type 1 diabetes was noted in people living in equatorial regions, while higher incidence was noted in populations at higher latitudes where sunlight was scarcer.

Photosynthesis of vitamin D3 is set in motion by ultraviolet exposure, while this form of vitamin D is also available through diet and supplements. "This is the first study, to our knowledge, to show that higher serum levels of vitamin D are associated with reduced incidence rates of type 1 diabetes worldwide," said Cedric F. Garland, Dr. P.H., professor of Family and Preventive Medicine in the UCSD School of Medicine, and a member of the Moores UCSD Cancer Center.

About 1.5 million Americans cope with type 12 diabetes every day, and type 1 diabetes ranks second only to asthma as the most chronic disease among children. Type 1 diabetes is diagnosed in some 15,000 Americans each year, and causes blindness and kidney failure in youth and middle age.

"This research suggests that childhood type 1 diabetes may be preventable with a modest intake of vitamin D3 (1000 IU/day) for children, ideally with 5 to 10 minutes of sunlight around noontime, when good weather allows," said Garland. "Infants less than a year old should not be given more than 400 IU per day without consulting a doctor. Hats and dark glasses are a good idea to wear when in the sun at any age, and can be used if the child will tolerate them."

Even after allowing for the fact that equatorial regions will have lower per capita healthcare expenditures than more developed countries, the association of UVB irradiance to incidence of type 1 diabetes remained strong. The researchers created a graph with a vertical axis for diabetes incidence rates, and a horizontal axis for latitude. The latitudes range from -60 for the southern hemisphere, to zero for the equator, to +70 for the northern hemisphere. They then plotted incidence rates for 51 regions according to latitude. The resulting chart was a parabolic curve that looks like a smile.

In the paper the researchers call for public health action to address widespread vitamin D inadequacy in U.S. children.

"This study presents strong epidemiological evidence to suggest that we may be able to prevent new cases of type 1 diabetes," said Garland. "By preventing this disease, we would prevent its many devastating consequences."

The study was published June 5, 2008 in the online version of the scientific journal Diabetologia.

FDA Warns of Cancer Risk for Regranex in Treatment of Diabetics’ Foot and Leg Ulcers

The U.S. Food and Drug Administration (FDA) has announced the addition of a boxed warning to the label of Regranex Gel 0.01% (becaplermin) to address the increased risk of cancer mortality in patients who use 3 or more tubes of the product. Regranex is a topical cream indicated for the treatment of leg and foot ulcers that are not healing in diabetic patients.

The WARNINGS section of the product has been updated to include a BOXED WARNING and a description of the epidemiologic data that is the basis for the revised label. These data come from a retrospective study that compared cancer incidence and cancer mortality among 1,622 patients exposed to Regranex to 2,809 otherwise similar patients who were not exposed. The results were consistent with no overall increase in cancer incidence among the patients exposed to Regranex. However, there was a five-fold increased risk of cancer mortality in the group exposed to three or more tubes of Regranex.

"In announcing this label change, FDA still cautions health care professionals to carefully weigh the risks and benefits of treating patients with Regranex," said Susan Walker, M.D., director of the Division of Dermatological and Dental Products. "Regranex is not recommended for patients with known malignancies."

In late March, 2008 the FDA issued an Ongoing Safety Review Communication on Regranex notifying the public that it was conducting a safety review. This follow-up communication is in keeping with FDA’s commitment to notify the public of any regulatory changes with this FDA approved product.

Regranex is a medicine that is a recombinant form of human platelet-derived growth factor which is applied directly to diabetic foot and leg ulcers that are not healing. The recombinant form of platelet growth factor has a biologic activity that is much like that produced naturally by the body. Growth factors cause cells to divide more rapidly. It is for this reason that the manufacturer continued to monitor studies begun before Regranex was approved in December 1997 for any evidence of adverse effects such as increased numbers of cancers. In a long term safety study completed in 2001, there were more deaths from cancer in people who used Regranex than in those who did not use it.

Following the report of the study completed in 2001, an additional study was performed using a health insurance database that covered the period from January, 1998 through June, 2003. This study used the database to identify two groups of patients with similar diagnoses, drug use, and use of health services, one of which used Regranex and one group that did not. The results of this study showed that deaths from cancer were higher for patients who were given three or more prescriptions for treatment with Regranex than those who were not treated with Regranex. No single type of cancer was identified, but rather deaths from all types of cancer, combined were observed.

Source: FDA, June 6, 2008

Study Shows Obesity Is a Major Risk for Heart Failure

The results of the Multiethnic Study of Atherosclerosis (MESA) identifies "the biological effects of obesity on the heart" as a serious reason for 72 million overweight Americans to worry about their health.

Senior study investigator Joao Lima, M.D., says "Even if obese people feel otherwise healthy, there are measurable and early chemical signs of damage to their heart, beyond the well-known implications for diabetes and high blood pressure. Now there is even more reason for them to lose weight, increase their physical activity and improve their eating habits."

The development of heart failure of some 7,000 mean and women, aged 45 to 84 was followed by researchers conducting the MESA study, which started in 2000. To date, of the 79 participants who developed congestive heart failure 44% were obese with a body mass index (BMI) of 30 or more. They were also found to have higher blood levels of interleukin 6, C-reactive protein and fibrinogen, key immune system proteins involved in inflammation, than non-obese adults. An 84% greater risk of developing heart failure was accounted for by a near doubling of average interleukin 6 levels.

The links between inflammation and the combination of risk factors known as the metabolic syndrome alarmed the researchers from 5 U.S. universities.

The researchers from five universities across the United States also found alarming links between inflammation and the dangerous mix of heart disease risk factors known as the metabolic syndrome. Its combined risk factors for heart disease and diabetes—high blood pressure, elevated blood glucose levels, excess abdominal fat and abnormal cholesterol levels, and particularly obesity—double a person’s chances of developing heart failure.

"More practically, physicians need to monitor their obese patients for early signs of inflammation in the heart and to use this information in determining how aggressively to treat the condition," says Lima, a professor of medicine and radiology at the Johns Hopkins University School of Medicine and its Heart Institute. "Our results showed that when the effects of other known disease risk factors—including race, age, sex, diabetes, high blood pressure, smoking, family history and blood cholesterol levels—were statistically removed from the analysis, inflammatory chemicals in the blood of obese participants stood out as key predictors of who got heart failure," says Lima.

The study found that higher levels of interleukin 6 and a tripling of average levels of C-reactive protein in study subjects increased the possibility of heart failure by 36%.

What this tells us is that both obesity and the inflammatory markers are closely tied to each other and to heart failure," says lead researcher Hossein Bahrami, M.D., M.P.H. Bahrami, a senior cardiology research fellow at Hopkins, says "the basic evidence is building the case that inflammation may be the chemical route by which obesity targets the heart, and that inflammation may play an important role in the increased risk of heart failure in obese people, especially those with the metabolic syndrome."

Each year, nearly 300,000 Americans die from heart failure.

Source: Journal of the American College of Cardiology, May 6, 2008

Gene Linked to Severe Diabetic Retinopathy and Renal Disease

Researchers have identified a gene called erythropoietin (EPO) that is linked to higher risk of severe retinopathy and nephropathy, eye and kidney diseases that often affect diabetic patients.

Diabetic retinopathy (PDR) is the most common cause of legal blindness in working-aged adults in the United States, accounting for 10% of new cases of blindness. Diabetes is also the leading cause of kidney disease, called end-stage renal disease (ESRD), in the U.S. and the Western world.

While researchers have known that these conditions in diabetic patients can be hereditary, the actual genese involved have been relatively unknown until now.

Researchers discovered the involvement of the EPO gene in a study of 1,618 people with diabetic retinopathy and end-stage renal disease, and 954 diabetes patients without any eye or kidney disease in three separate populations. Their studies demonstrate that if a person has a copy of the mutant EPO gene, they have an increased risk of developing PDR and ESRD during their lifetime.

According to Dr. Dean Li from the Program in Human Molecular Biology and Genetics at the University of Utah, while there is no proven pharmacologic treatment for diabetic vascular eye diseases, "inhibiting the growth of unwanted blood vessel growth using antibodies directed against vascular endothelial growth factor (anti-VEGF therapy) has been advocated. This genetic study suggests that future therapeutic strategies need to consider blunting the effects of erythropoietin in addition or as an alternative to an anti-VEGF strategy."

The study was led by Kang Zhang M.D., Ph.D., Director of the Division of Ophthalmic Genetics at the Moran Eye Center and Associate Professor of Ophthalmology and Visual Sciences at the University of Utah, and was published in the journal Proceedings of National Academy of Sciences.

Higher Fracture Risk for Diabetes Drugs Such as Pioglitazone and Rosiglitazone, Says Study

Insulin-sensitizing thiazolidinediones, such as pioglitazone and rosiglitazone, appear to be associated with an increased risk of fractures, according to a recent report. These two drugs account for about 21% of oral diabetes medications prescribed in the United States, and 5% of those prescribed in Europe.

The class of drugs is a relatively new and effective class of oral antidiabetic agents that have gained wide use in clinical conditions characterized by insulin resistance, the study authors note. Other recent studies have suggested that these therapies may have unfavorable effects on bone, resulting in slower bone formation and faster bone loss.

According to the study, individuals who were currently taking rosiglitazone and pioglitazone had approximately 2x or 3x the likelihood of hip and other non-spine fractures than those who did not take these drugs. The odds for fracture were increased among patients who took the drugs for approximately 12 to 18 months and the risk was highest for those with two or more years of therapy.

Source: Archives of Internal Medicine, April 28, 2008

Insulin Research May Lead to Longer, Healthier Life

Insulin can affect aging and lifespan, a previously unknown outcome which could provide a means of gene manipulation capable of lengthening lives and making people healthier.

In a recent paper, researchers from the Joslin Diabetes Center note that Insulin inhibits a master gene regulator protein called SKN-1, whose activity increases lifespan. SKN-1 also controls what is called the Phase 2 detoxification pathway, a network of genes that defends cells and tissue against oxidative stress—damage caused by elevated levels of free radicals (byproducts of metabolism)—and various environmental toxins. This new research result was validated in experiments on the digestive system of C.elegans, a microscopic worm often used as a model organism.

"We’ve found something new that insulin does and it has to be considered when we think about how insulin is affecting our cells and bodies," said Dr. T. Keith Blackwell, senior investigator at Joslin and author of the paper. "This has implications for basic biology since under some circumstances insulin may reduce defense against the damaging effects of oxidative stress more than we realize."

Enhancing the activity of SKN-1 may lead to increased resistance to chronic diseases and influence longevity, said Dr. Keith, and the work could be important as it relates to diabetes and the many problems associated with the disease, particularly vascular and renal complications.

"The major implication is that we have found something new that affects lifespan and aging, and an important new effect that insulin and/or a related hormone called insulin-like growth factor-1 may have in some tissues," said Blackwell. "The implications go far beyond diabetes."

A gene regulator protein called FOXO is important in diabetes metabolism, tumor suppression and stem cell maintenance, a fact known since the 1990’s. FOXO controls a number of genes involved in stress resistance, and studies in C.elegans demonstrated that diminished insulin signaling increased activity of a FOXO protein called DAF-16, leading to greater stress resistance and longer life.

The Joselin research adds to knowledge about insulin and its effects on gene pathways, while putting SKN-1 next to FOXO as a second master gene regulator that is inhibited by insulin signaling. According to the paper, insulin’s effect on SKN-1 occurs independently of its effect on DAF-16.

The paper was published in the March 21, 2008 issue of Cell.

Not Enough Doctors to Treat Increasing Number of Obese and Diabetic Children

The number of diabetic and obese children is growing so rapidly that there aren’t enough doctors to treat the kids. According to a recent study by University of Michigan’s C.S. Mott Hospital, there is only one board-certified pediatric endocrinologist per 290 children with diabetes. The ratio of obese children to board-certified endocrinologists is 17,000 to 1. The rate if childhood obesity in the United States meanwhile has more than doubled in the past 20 years, with a corresponding increase in the number of children at risk for type 1and type 2 diabetes.

"Although the American Diabetes Association recommends that all children with diabetes be cared for by a pediatric endocrinologist as part of a diabetes team, there is a current shortage of pediatric endocrinologists in this country," says study lead author Joyce Lee, M.D., MPH, a pediatric endocrinologist and member of the Child Health Evaluation and Research (CHEAR) Unit in the U-M Division of General Pediatrics. "This problem will likely only worsen due to the recent epidemic of childhood obesity."

The 16.5% of American children aged 6 to 19 who are obese are at risk for ‘adult’ diseases such as type 2 diabetes, elevated blood pressure and high cholesterol. As a result more children than ever are being referred to pediatric endocrinologists for screening, evaluation and management. "But even if just a small fraction of obese children are referred to a pediatric endocrinologist for evaluation", says Lee, " the overall ratio of one pediatric endocrinologist to 17,000 obese children makes providing the necessary care extremely challenging." Dr. Lee is assistant professor in the Department of Pediatrics and Communicable Diseases at the U-M Medical School.

Available pediatric endocrinologists are so few in relation to the number of children at risk that they cannot see even a fraction of the children with diabetes or at risk for the disease. "The epidemic of childhood obesity has undoubtedly created new challenges for our health care, and we need to reassess the current system to ensure children with diabetes or at risk for diabetes receive appropriate care," Lee notes.

Pediatric endocrinologists currently do not have the capabilities to see even a fraction of the large number of children with diabetes or at risk for diabetes. "The epidemic of childhood obesity has undoubtedly created new challenges for our health care, and we need to reassess the current system to ensure children with diabetes or at risk for diabetes receive appropriate care," Lee notes.

Using data from the American Board of Pediatrics and the National Survey of Children’s Health, Lee and her colleagues compared the number of board certified pediatric endocrinologists by region to obese children and children with diabetes in those same areas.

Their research revealed that there are an estimated 229,249 children with diabetes, and only 790 board-certified pediatric endocrinologists in the country. And, in two states—Montana and Wyoming—there are no board-certified pediatric endocrinologists.

The study was published in the March, 2008 issue of The Journal of Pediatrics.

Diabetes On Increase Among Older Americans

The number of Americans aged 65 and older diagnosed with diabetes increased by 23% between 1994-1995 and, and 2003-2004.

"The prevalence of diabetes mellitus is increasing, in part because of population aging, but also in younger persons," the report notes. The high rate of existing diabetes also contributes to a high rate of diabetes-related complications and premature death. According to the authors, "awareness of the importance of active monitoring and management of diabetes has become more widespread; however, adherence to recommended practices remains low."

Medicare data for patients diagnosed with diabetes during 1964 (33,164), 1999 (931,722) and 2003 (40,058) was analyzed by Dr. Frank A. Sloan, Ph.D., and colleagues at the Duke University Medical Center, Durham, North Carolina. A comparison of this data was run with that of two control groups made up of people without diabetes but of similar race and ethnicity to those with the disease. Death and complications associated with diabetes such as cardiovascular, cerebrovascular, ophthalmic, renal, and lower extremities were recorded.

"The annual incidence of diabetes increased by 23 percent between 1994 to 1995 and 2003 to 2004, and prevalence increased by 62 percent," the authors write. The death rate after diagnosis decreased by 8.3% compared with people who did not have the disease.

"Complication rates among persons diagnosed as having diabetes generally increased or stayed the same compared with those in the control groups during 1994 to 2004 except for ophthalmic diseases associated with diabetes," the authors note. "In some cases, most notably renal events, including the most serious complications, there were increases in prevalence in both the diabetes and control groups."

The authors emphasized that diabetes created a 90% adverse outcome, with coronary heart failure, heart attack, and stroke prevalent, concluding that the problem of providing medical care for people over 65 with diagnosed diabets and paying for it, is growing rapidly.

Source: Archives of Internal Medicine, January 29, 2008

Gastric Inhibitory Polypeptide (GIP) Can Reverse Diabetes and Promote Weight Loss

A new study was designed to find whether prolonged receptor antagonism using daily injections of GIP was capable of reversing diet-induced obesity and related metabolic abnormalities in an animal model.

The 8-week old mice selected for the study were given access to drinking water and a high fat diet—20% protein and 35% protein, percent of total energy 26.15kg/g. Control mice were fed a standard rodent maintenance diet—10% fat, 30% protein, 60% carbohydrate, percent of total energy of 12.99.

Before the study, mice were fed a high-fat diet for 160 days. Another set of mice were given a high-fat diet for 112 days before measuring circulating GIP and GLP-1 levels. For both samples, obesity and diabetes were unmistakably evident.

Among the key findings were that consumption of the high-fat diet produced progressive weight gain and elevations of plasma and gyrated hemoglobin, resulting in impaired insulin sensitivity and glucose intolerance within 10 days. (Pro3)GIP countered many of the detrimental effects of high fat diet on body weight and indices of glucose and lipid metabolism.

This study showed that blocking GIP activity using (Pro3)GIP in mice with established, high fat diet-induced obesity and diabetes results in significant weight loss, improvement of insulin resistance and amelioration of diabetes. These findings represent an interesting new approach to the treatment of obesity and metabolic disturbances.

Nigel Irwin, PH.D., of the research team said that possible parallels exist with the benefits of gastric bypass surgery in treating gross obesity and diabetes in people. In this procedure nutrients surgically bypass the area of the small intestine, resulting in a deficiency of circulating GIP.

Source: American Physiological Society (APS)