Latest news & developments

Go Ahead, EAT BREAKFAST

Current guidelines recommend an eight-hour fast before a cholesterol test, which is burdensome to both patients and laboratories. Previous studies comparing cholesterol levels in fasting versus non-fasting states used selected patient populations rather than the general population.

Doctors Davinder Sidhu and Christopher Naugler at the University of Calgary in Canada conducted a study, published Nov. 12, 2012, online in the Archives of Internal Medicine, to determine the relationships between fasting times and blood lipid parameters. Researchers analyzed laboratory data from 209,180 people (53 percent female, 47 percent male) in the Calgary, Alberta, Canada area. The average age in the study was 53 years, and ranged from 0 to 103 years old. The duration of fasting time ranged from one to 16 hours and was correlated with lipid test panels (high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, total cholesterol, and triglycerides).

The length of fasting time prior to having blood drawn had little effect on blood lipid levels. The average HDL and total cholesterol varied by less than 2 percent, the average LDL varied by less than 10 percent, and the average triglycerides varied by less than 20 percent.

The authors suggested that fasting before routine blood cholesterol screenings may be unnecessary and that dropping the fasting requirement may improve patient compliance. They also noted that more studies are needed to confirm their results before moving to routine nonfasting lipid screening.

Finding little effect on blood lipid levels, researchers suggest fasting before routine blood cholesterol screenings may be unnecessary, and dropping the fasting requirement may improve patient compliance.

—Joanne McAndrews, PhD

COGNITIVE DECLINE Linked to Fat Consumption Mitigated with Exercise

Exercise might ward offcognitive decline brought on by high fat consumption. University of Minnesota researchers taught mice a memory task, then fed half the group a 40 percent fat diet and watched their cognitive function decline. Using an exercise wheel returned cognitive function to baseline within seven weeks. Non-exercising mice remained impaired. If the research holds up for humans, exercise may become an important tool in addressing Alzheimer’s disease.

Using exercise to combat high fat consumption may play critical role in addressing Alzheimer’s and memory disorders.

—Carol Bengle Gilbert

POTENTIAL TARGET for Beta Cell Protection

A protein involved in modulating programmed cell death in pancreatic beta cells could offer a therapeutic target for preserving beta cell mass and slowing the pathogenesis of diabetes.

Epidermal growth factor (EGF) stimulates cell growth, proliferation, and differentiation by binding to its receptor on cells, EGFR. Mitogen-inducible gene 6 (Mig6) is a stress response protein that can interfere with this process by binding to EGFR, downregulating its signaling. Mig6 has been viewed as a molecular brake on proliferation, so a team led by Patrick T. Fueger, PhD, of Indiana University School of Medicine in Indianapolis decided to study its role in apoptosis and endoplasmic reticulum (ER) stress.

Using adenoviral vectors to manipulate Mig6 expression in mice, they found that Mig6 overexpression exacerbated beta cell apoptosis through pathways mediated by caspase 3, a protease that plays a key role in programmed cell death. Silencing of Mig6 mitigated the apoptosis.

The high glucose and lipid levels typical of diabetes compromise the integrity of the endoplasmic reticulum in pancreatic beta cells, triggering pathways leading to cell death. The researchers suggest that Mig6 regulates pancreatic beta cell apoptosis during ER stress via a new pathway, perhaps by compromising cell survival signals mediated by growth factor receptors.

In an article in Molecular Endocrinology, they propose that targeting Mig6—preventing its induction, translation, or function—could be a strategy for increasing beta cell survival.

Mig6 regulates pancreatic beta cell apoptosis during ER stress via a new pathway, perhaps by compromising cell survival signals mediated by growth factor receptors.

—Eric Seaborg

Graves’ Orbitopathy COSTS GERMANY Up to $3.7B Annually

In a first-of-its-kind study appearing in The Journal of Clinical Endocrinology & Metabolism [jcem.endojournals.org], researchers from the Gutenberg University Medical Center in Mainz, Germany, set out to measure the direct and indirect costs of Graves’ orbitopathy (GO). The researchers estimated GO costs the German nation more than $200 million per year in direct costs and between $1.7 and $3.5 billion per year in indirect costs. The direct costs consist of treatment expenditures, while sick leave and disability payments constitute the indirect costs.

The researchers noted their estimates are low due to the study’s cross-sectional design. That design prevented consideration of the disease’s typical oneto two-year active phase in measuring direct costs and the long-term, indirect costs occurring outside the study period.

The study relied upon clinical data and cost information from 310 GO patients and 370 controls from 2005 to 2009.

In estimates that may still be low, German researchers find that Graves’ orbitopathy costs the country more than $200 million per year in treatment expenditures and between $1.7 and $3.5 billion per year in sick leave and disability payments.

—Carol Bengle Gilbert

Androgen Receptor Ablation Improves Bone Marrow Grafting

Androgen deprivation therapy (ADT) has been the treatment of choice for prostate cancer and is also used adjunctively in bone marrow transplantation (BMT) to promote T-cell survival. However, ADT not only comes with significant side effects associated with loss of sex steroids, but also has proven ineffective to treat prostate cancer. What if the androgen receptor (AR) is somehow implicated here, rather than the androgen itself?

Chawnshang Chang, PhD, at the University of Rochester Medical Center, New York, led a team of scientists to uncover how thymic cellularity affects T-cell exportation and, in turn, the immune response in epithelial AR knockout mice. In their paper, to be published soon in Molecular Endocrinology, the researchers report that the mice showed both increased thymopoiesis and T-cell availability, which collectively produced a better immune response during BMT. This finding held up when a synthetic AR degradation enhancer was used.

The researchers conclude that AR signaling modulates T-cell selection and that targeting AR promotes T-cell survival. AR ablation not only improves BMT outcomes without adverse side effects but is also a promising future therapy for other AR-related diseases. “Using ASC-J9, the first AR degradation enhancer to target AR in selective cells, led to good efficacy to treat acne, wound healing, spinal and bulbar muscular atrophy, and prostate and liver cancers,” said Dr. Chang.

Androgen receptor ablation improves bone marrow transplantation outcomes without adverse side effects and holds promise as a future therapy for other AR-related diseases.

—Kelly Horvath

Lean Men Also Face DIABETES RISK Due to OSA

Obstructive sleep apnea (OSA), a disorder in which the throat muscles relax and block or narrow the airways to the lungs during sleep, has long been associated with insulin resistance and an increased risk of type 2 diabetes in people who are overweight or obese. But now a study published in the November 2012 issue of Diabetes Care by researchers at the University of Chicago suggests that the condition may increase diabetes risk in young, lean men, as well.

In the study, 52 men between the ages of 18 and 30 with body mass indexes between 18 and 25 underwent sleep studies. The next morning they took an oral glucose tolerance test in which they consumed a sugary drink and researchers measured their blood glucose and insulin concentrations at 30, 60, 90, and 120 minutes.

The researchers selected 12 men with OSA and compared them to 20 men without OSA and found that even though both groups of men had similar blood glucose levels, those with OSA had 27 percent lower insulin sensitivity and 37 percent more insulin secretion. In their conclusion, the rsearchers note that OSA may have a different effect on women because of known sex disparities in body fat distribution.

The presence of obstructive sleep apnea, in the absence of increased body fat or other cardiometabolic risk factors, may promote the development of type 2 diabetes in men.

—Terri D’Arrigo

Promising THYROID CANCER Treatments

Two compounds, decitabine and zebularine, show promise for treating thyroid tumors and should be investigated for that purpose, say researchers at the National Cancer Institute (NCI) in Bethesda, Maryland.

Decitabine is currently used to treat myelodysplastic syndrome, or MDS, a group of conditions in which the bone marrow produces misshapen blood cells. Zebularine is currently being studied for use in treating breast cancer. Both compounds were shown to affect genes that direct the growth of thyroid tumors.

In a three-pronged study appearing in the January 2013 issue of Endocrinology, researchers led by Won Gu Kim, MD, PhD, first examined human thyroid cancer tissue samples and determined that the expression of a gene called THRB is lower in people who have thyroid cancer, and that lower levels of THRB correlate to greater cancer progression. Next, the researchers bathed cancerous human thyroid and neck lymph node cells in either decitabine or zebularine and found that these agents promoted the expression of the THRB gene.

The researchers further studied decitabine’s effectiveness in slowing tumor growth in mice. They inoculated 12 mice with human thyroid cancer cells, and then separated the mice into two groups. Six mice received injections of decitabine while the remaining mice were injected with inactive solution. Tumors grew more slowly in the mice treated with decitabine than those injected with inactive solution.

Compounds decitabine and zebularine show promise for the potential treatment of thyroid tumors.

—Terri D’Arrigo

FAT-BLOCKING SODA Arrives in Japan

Pepsi has launched a product that promises to put a new spin on diet soda. The Pepsi Special on sale in Japan contains dextrin, a watersoluble fiber supplement that acts as stomach filler.

Pepsi says its new drink will “minimize the absorption of fats” or block the fat.

—Glenda Fauntleroy

Lower Stress, HIGHER FERTILITY

There may be a nugget of truth in the old wives’ tale that women trying to get pregnant should just relax. New findings on the effects of corticotropin-releasing hormone (CRH) at the ovarian follicle level suggest that lowering stress levels could increase a women’s fertility.

A neuropeptide secreted by the hypothalamus in response to stress, CRH is a major regulator of the hypothalamicpituitary-adrenal axis. Researchers, led by Dimitris Loutradis, MD, PhD, of the University of Athens School of Medicine, Greece, decided to look at CRH’s effects on preantral mouse follicles, steroidogenesis, and embryo development, because their previous studies showed that CRH inhibits in vitro oocyte maturation in mice. When the researchers cultured preantral follicles in the presence of CRH, they found a marked reduction in estradiol and progesterone concentrations compared with controls. The addition of antalarmin, a synthetic antagonist of CRH receptor type 1, reversed the reduction of both hormone levels.

The researchers then cultured embryos, finding that exposure to CRH significantly slowed their development rates. The addition of antalarmin to these cultures yielded higher survival rates in all embryo stages.

In an article pending publication in The Journal of Clinical Endocrinology & Metabolism, researchers say they found a new mechanism by which CRH retards oocyte maturation. CRH not only interferes with nuclear maturation, but also seems to affect cytoplasmic maturation through its anti-estrogen actions. Antalarmin can reverse this mechanism, demonstrating the role of CRH in all these processes.

Because increased stress levels can induce regional CRH secretion in the ovary and fallopian tubes, where the hormone can have these interfering effects, it follows that oocyte quality and embryo development could be enhanced by lowering patient stress.

Exposure to corticotropin-releasing hormone significantly slows embryo development rates, indicating lowering patient stress could enhance oocyte quality and embryo development.

—Eric Seaborg

Metabolic Syndrome Contributes to CARDIOVASCULAR RISK with HT

Amid the controversy over the cardiovascular risks v. the overall benefits of hormone therapy (HT), Robert A. Wild, MD, MPH, PhD, at the University Health Sciences Center, in Oklahoma City, Oklahoma, led a team of scientists to investigate whether metabolic syndrome contributes to coronary event incidence with oral HT.

Using Women’s Health Initiative demographic and metabolic data to assess “baseline cardiometabolic risk status,” the team conducted a nested case-control study of 269 women without prior cardiovascular disease (CVD) and a second composed of 166 women without prior diabetes or hypertension all who developed CVD within the first 4 years of HT. Average age of participants was 66 years.

In their paper, published in Menopause: The Journal of The North American Menopause Society, the researchers report that women who had risk factors for CVD or had metabolic syndrome (defined by specific parameters) were more likely to have a coronary event on HT, possibly because of a strong circulating fatty acid–induced inflammatory response, precipitating atherosclerotic plaque rupture.

The researchers conclude that CVD risk status should be evaluated before initiating oral HT. Alternative preparations might confer greater safety and should be investigated for effect on CVD, they add.

Women with risk factors for CVD or with metabolic syndrome may be more likely to have a coronary event on HT, possibly because of a strong circulating fatty acid– induced inflammatory response, precipitating atherosclerotic plaque rupture.

—Kelly Horvath

DIABETES and OBESITY on the Brain

Hoping to discover potential therapeutic pathways to reverse the obesity and diabetes trend, Karen Ryan, PhD, and colleagues at the University of Cincinnati studied the effects of fibroblast growth factor-19 (FGF19) and its rodent ortholog, FGF15, in the brain on food intake and glucose tolerance. Their findings will be published in an upcoming issue of Endocrinology [endo.endojournals.org].

Using a male rat model, the presence of FGF-receptors 1 and 4 in the hypothalamus was confirmed, and the expression of the FGF-1 receptor mRNA was 60 percent lower in high-fat fed rats as compared with lean control animals. FGF-4 receptor mRNA was also reduced in the high-fat fed animals compared with controls. When FGF19 was directly infused into the brain via the third cerebral ventricle, 24-hour food intake and body weight decreased, and glucose tolerance was improved. In contrast, administration of an FGF-receptor inhibitor into the third cerebral ventricle increased food intake and impaired glucose tolerance.

Findings pointed to the brain as a possible target for the positive effects of FGF19 for the treatment of obesity and diabetes. They also called for more research in this area to clarify the effects on lipid and carbohydrate metabolism and interrelated pathways.

—Joanne McAndrews, PhD

Obesity Puts Boys at Higher Risk of ASTHMA

While past research has shown overweight and obese children develop asthma at greater rates than their normalweight peers, a new literature review reveals that obese boys are at the greatest risk.

Childhood obesity has reached epidemic numbers, with more than 42 million children under the age of 5 now overweight, according to the World Health Organization.

Reviewers from National Taiwan University in Taipei evaluated six studies that included 18,760 children between the ages of 6 and 18. Overweight was considered a body mass index greater than the 85th percentile on a children’s growth chart, and obesity was defined as greater than the 95th percentile.

The review found the incidence of asthma increases by 20 percent in overweight children and by a twofold risk in obese children compared with children of normal weight. Also, gender made a significant difference in the respiratory health risk for obese children.

Obese boys were more likely than obese girls to develop asthma, with a relative risk of 2.47 compared to 1.25. The authors suggested that pulmonary mechanics, sleep disordered breathing, and leptin levels may account for the gender difference.

“Obese children might get benefit in asthma prevention if they try to lose weight,” says Yungling Leo Lee, who co-authored the article appearing in Obesity Reviews [iaso.org].

The authors concluded that health policy makers and parents should pay more attention to preventing obesity-associated risk and environments.

The incidence of asthma increases by 20 percent in overweight children and by a twofold risk in obese children compared with children of normal weight—with risk higher among boys.

—Glenda Fauntleroy

HIGH BONE MASS in Women May Signal Higher Weight

Scientists in the U.K. recently investigated the relationship between bone and fat, screening more than 219,000 dual-energy x-ray absorptiometry (DXA) scans from country’s health centers. They found 0.2 percent of the DXA scans had high bone mass.

In the new study, 153 men and women with unexplained high bone mass were recruited along with 138 of the individuals’ first-degree relatives and 39 spouses. Participants’ bone formation and reabsorption markers were also measured.

In their article published in The Journal of Clinical Endocrinology & Metabolism [jcem.endojournals. org], the researchers found that total body fat mass was about 9 kilograms higher in women with high bone mass than in the controls. Their fat mass also stayed constant with age compared with the inverse association found in the controls. The increased fat mass in males with high bone mass was less significant. Osteocalcin (a bone formation marker) was also lower in females with high bone mass than in the controls.

“The key take-home message for clinicians is that research assessing an extreme bone phenotype suggests bone acts to regulate fat metabolism, which raises the possibility that current treatments of osteoporosis may affect fat metabolism and obesity risk,” says lead investigator Celia Gregson, PhD, from the University of Bristol. Gregson added that her team is currently working to answer these questions.

In a study of men and women with high bone mass, researchers found that total body fat mass was about 9 kilograms higher in women and that their fat mass stayed constant with age.

—Glenda Fauntleroy

Prostaglandin Could Inhibit PROSTATE CANCER

Prostate cancer can often be held in check with androgen deprivation therapy, but eventually seems to break through to a “castrationresistant” form, leaving researchers to search for new treatment approaches.

Because chronic inflammation has been linked in general to carcinogenesis through increased production of reactive oxygen species, and in particular to cancerous growth in the prostate, inflammation’s role offers a promising avenue to explore for these new approaches.

A research team led by Joma J. Palvimo, PhD, of the University of Eastern Finland in Kuopio, investigated the effects of the 15-deoxy- Δ12,14-prostaglandin JΔ2 (15d-PGJΔ2 ), which has antiinflammatory properties, on the activity of androgen receptors in prostate cancer cells.

When the researchers exposed prostate cancer cells to 15d-PGJΔ2 , it repressed androgen receptor target genes and inhibited the activity of the androgen receptors, apparently by forming adducts with them. This inhibitory effect was more efficient than the effects of bicalutamide, one of the antiandrogens currently used in clinical treatment.

In an article accepted for publication inMolecular Endocrinology, the researchers conclude that 15d-PGJΔ2 is a potent and direct inhibitor of androgen receptor signaling.

Endogenous prostaglandin could provide a new approach to restricting androgen receptor activity in prostate cancer cells.

—Eric Seaborg

Quick Weight Gain in Newborns Raises HEART HEALTH RISKS

Babies who gain too much weight soon after birth may already be at risk for later health problems, a new study finds.

Researchers led by Annemieke Evelein, MD, of the Julius Center for Health Sciences and Primary Care in Utrecht, Th e Netherlands, found that weight and the growth of a child in the first three months after birth is linked with cardiovascular disease, as evident by thicker arterial walls.

In their study published in The Journal of Clinical Endocrinology & Metabolism [jcem.endojournals.org], the team used data from an ongoing Netherlands population study to look at the birth and weight of children from newborn to 3 months. Scientists checked in with 333 children at the age of 5—measuring the ratio of their weight gain rate for length gain rate (WLG) and also performing ultrasound measurements of the right carotid artery.

The results showed that the thinner the children were at birth, the stiffer the arteries were with increasing WLG. Higher WLG was linked with higher weight, height, body mass index, and waist circumference at age 5.

“Pediatricians could look for possible improvements in the environment of the baby who has established risk factors, such as asking the parents for their feeding habits,” says Evelein.

Newborns who gain weight quickly show higher weight, height, body mass index, and waist circumference by age 5, putting them at greater cardiovascular risk.

—Glenda Fauntleroy

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