News, Notes, & Insights

Short Sprints Stave off Hypoglycemia during Exercise

To avoid the low drop in blood sugar that can occur after a session of moderate-intensity exercise, people with type 1 diabetes mellitus (T1DM) should perform short sprints before exercising, suggests a recent article in The Journal of Clinical Endocrinology & Metabolism [].

For T1DM patients, the risk of hypoglycemia while exercising can discourage adding physical activity to their lifestyles. The new study shows that starting with a 10-second sprint can reduce the risk, according to Paul A. Fournier, Ph.D., a professor in the School of Sport Science, Exercise and Health at the University of Western Australia, who led the study.

“We found in two separate studies that a 10-second sprint performed before or after moderateintensity exercise reduces the risk of post-exercise hypoglycemia for 30 minutes to two hours,” Fournier said. “However, sprinting before moderate-intensity exercise has no effect on the rate of fall in blood glucose levels during exercise.”

The team of Australian researchers studied eight young adults with T1DM who averaged 22.9 years of age and a body mass index of 26.7. All were on insulin pump therapy. A second group of young adults without diabetes served as controls. Before the exercise sessions, the participants with T1DM underwent insulin treatment and the investigators measured their glucose levels. Both groups then pedaled stationary bikes as hard as possible for 10 seconds. After different time intervals of exercise and rest, the investigators again took blood samples and measured glucose levels in both groups.

In the T1DM group, blood glucose levels increased significantly by 1.2 ± 0.2 mmol/L after the sprint and remained even during the rest period. In the group without diabetes, blood glucose levels increased significantly less than those of the T1DM patients.

Hyperthyroidism Increases Death Risk

Hyperthyroidism is an all-toocommon condition, and one that often occurs with other conditions, some fatal. Individuals with hyperthyroidism have a 21 percent higher mortality rate than people who do not have it.

Frans Brandt, M.D., at the Odense University Hospital, Denmark, led a team to find out whether the higher mortality rate derives from the hyperthyroidism itself or is because of associated conditions or genetics. Using a standardized evaluation system, they studied 4,850 singletons from Denmark with hyperthyroidism and 926 twin individuals from 625 same-sex pairs discordant for hyperthyroidism.

In their paper, to be published soon in The Journal of Clinical Endocrinology & Metabolism [jcem.], the researchers report that individuals without preexisting comorbidity at the time of hyperthyroidism diagnosis had an increased rate of death. This suggests an independent association between hyperthyroidism and mortality. In dizygotic twins, whose genomes are about as similar as those of non-twin siblings, this association persisted. The twin with hyperthyroidism had an increased risk for death. However, in monozygotic twins, whose genomes are identical, the association did not hold up.

The researchers conclude that hyperthyroidism confers a higher risk of death, separate from coexisting conditions, and that genetic confounders are also at work, predisposing certain individuals with hyperthyroidism to death. Future studies should clarify whether severity of hyperthyroidism influences the risk of death, they add.

High Triglycerides in First-Trimester Affects Pregnancy

High maternal triglyceride and total cholesterol levels in the second and third trimesters are linked to both short- and long-term complications for the mother and the infant, including preterm birth, pregnancyinduced hypertension, preeclampsia, large-for-gestational age infants, and infant death. A new study seeks to discover what effects elevated lipids have during early pregnancy to eliminate factors associated with more advanced pregnancies such as problems with the placenta or the pregnancy itself.

Tanja Vrijkotte, Ph.D., at the Academic Medical Center in Amsterdam, the Netherlands, led a team of scientists analyzing lipid profiles from 4,008 healthy pregnant women in their 12th to 14th weeks of pregnancy who participated in the Amsterdam Born Children and their Development (ABCD) cohort study. In their paper, to be published soon in The Journal of Clinical Endocrinology & Metabolism [], the researchers report that serum triglyceride level correlated with hypertension, preeclampsia, preterm birth, and large infant size, but had no effect on infant death. Total cholesterol level did not associate with adverse outcomes.

“Increasing evidence suggests that elevated plasma lipids may induce endothelial dysfunction by enhancing oxidative stress, leading to placental dysfunction,” says Vrijkotte. The researchers conclude that elevated triglycerides in early pregnancy are toxic for mother and child. Whether preconception screening could be useful to counsel for lifestyle modifications like diet and exercise remains to be studied, they add.

Ingredient in AntiBacterial Products Affects Muscle Contraction

Triclosan, the active ingredient in household products commonly marketed as “anti-bacterial,” has been shown to affect cardiac output and grip strength in mice and the swimming performance of fathead minnows—findings that have researchers at the University of California at Davis questioning how the substance may affect human and environmental health. In a three-pronged study published in the July 13, 2012, issue of the Proceedings of the National Academy of Sciences, researchers found that triclosan impaired muscle contraction by interfering with how muscle cells communicate with each other.

First, the team injected anesthetized mice with triclosan at a dose equivalent to 12.5 mg/kg body weight. Within 10 minutes, the mice experienced a 25 percent reduction in cardiac function as measured by the amount of blood pumped through their hearts.

Next, the researchers gave conscious mice a 40 mg/kg dose of triclosan and administered a grip-strength test. Over the next 60 minutes, grip strength in the mice dropped an average of 18 percent.

Finally, the team exposed fathead minnow larvae to triclosan at a concentration of 0.52 µM for seven days, and observed inhibited swimming ability, predator avoidance, and endurance in the larvae.

Although mice and minnows are not men and women, the findings could indicate that triclosan poses a risk to human and environmental health, said Isaac Pessah, Ph.D., professor and chair in the Department of Molecular Biosciences, School of Veterinary Medicine.

“The doses in the mice relate to blood levels of triclosan we see in humans,” he said. “Although a normal, healthy person wouldn’t really be fazed by a temporary 10 percent, or even a 30 percent decrease in cardiac output, especially if they are not exercising or exerting themselves, it can raise a concern about what could happen for people with heart or skeletal muscle disease.”

The results in the minnow segment of the study have implications for the environment, he added. “Millions of pounds of triclosan have been produced, and it is well documented that waste treatment plants can’t remove all of it. It’s in sediment and our drinking water.”

Household products containing triclosan include hand soap, shampoo, cleaning supplies, bedding, shoes, clothes, and carpets.

Neuropeptide Linked to Renal Damage

Hypertension has been estimated to affect 30 percent of U.S. adults and is a risk factor for the development of cardiovascular and renal diseases. Homing in on potential proteins to counter this condition, Donna Wang, M.D., at Michigan State University, and her research group focused on substance P (SP), a neuropeptide that activates neurokinin 1 (NK1) receptors and affects cardiovascular and renal function. Their findings will appear in an upcoming article in Endocrinology [].

The group created a mouse model to replicate renal injury during hypertension by removing one kidney from C57BL/6 male mice and treating the animals with deoxycorticosterone (DOCA) and salt, with or without selective NK1 receptor antagonists L-733,050 and RP-67580. Renal physiology was determined five weeks following treatment. Mean arterial pressure increased in DOCAsalt–treated mice. The absence or addition of NK1 receptor antagonists had no effect on blood pressure.

The DOCA-salt–treated mice also experienced renal hypertrophy, increased urinary 8-isoprostane levels, elevated albumin excretion, and increased plasma SP levels.

In addition, renal damage (glomerulosclerosis and tubulointerstitial injury in the renal cortex), renal collagen levels, and interstitial monocyte/macrophage infiltration were more pronounced in DOCA-salttreated mice than control animals. Co-administration of the NK1 receptor antagonists alleviated all of these.

The authors noted that during experimental DOCA-salt-induced hypertension, SP levels were elevated and contributed to renal injury, a phenomenon that was blunted by NK1 receptor antagonists. However, because the DOCA-salt mouse hypertension model is not caused by excessive dietary salt intake alone, more studies are needed to examine the role of SP-mediated renal injuries in humans with salt-sensitive hypertension.

Obesity Increases Men’s Risk of Osteoporosis

A new study shows that obese men should add bone loss to the already long list of health problems caused by carrying excess body weight.

“Obesity does not protect against bone loss as previously thought and obese men are at risk for osteoporosis,” explained lead author Miriam Bredella, M.D., associate professor of radiology at Harvard Medical School in Boston. “[This is] through the accumulation of visceral fat and associated decreased growth hormone secretion and low testosterone levels.”

The researchers studied 35 obese men with an average body mass index of 36.5. To determine the effect of visceral adipose tissue (VAT), or body fat, on bone microarchitecture and mechanical properties, computed tomography (CT) was used to divide the men into two groups. Men with VAT below the group’s median were grouped into a low VAT group and those with VAT greater than the median were placed into a high VAT group. Each participant then underwent three-dimensional CT scans and endocrine tests, including measurements of testosterone, estradiol, and growth hormone (GH) levels.

In the study appearing in The Journal of Clinical Endocrinology & Metabolism [jcem.endojournals. org], Bredella and her team found that men with high VAT had weakened bone health compared with those in the low VAT group. The researchers also concluded that decreased GH, insulin-like growth factor-1, and testosterone—all characteristics of male obesity—may cause harmful damage to skeletal microarchitecture, although higher estradiol levels may offer protection.

Breast Cancer Risk Higher in Night Shift Workers

A new study may bring worrisome news to those who work at night. According to its findings, excessive use of artificial light during the night may be linked to an increased risk of breast cancer in industrialized countries where night shift work is common.

Researchers led by Lulu Mao, Ph.D., and Steven M. Hill, Ph.D., of the Tulane University School of Medicine in New Orleans investigated the molecular reasons that disruption of the body’s natural circadian rhythms may be linked to breast cancer invasion and metastasis. According to the study, the incidence of breast cancer is five times higher in nations where people are exposed to “light-atnight” than in underdeveloped countries. The World Health Organization has designated night-shift work and light-at-night exposure as a potential carcinogen.

The study suggested that the association between the disruption of circadian rhythms by exposure to light at night and the increased breast cancer risk resulted from the disruption of the circadian rhythm of glycogen synthase kinase 3ß(GSK3ß). GSK3ß is an enzyme critical in metabolism, cell proliferation, and invasion/metastasis. Disruption of its circadian rhythm perturbs the nocturnal surge of pineal melatonin (MLT), the biological timing signal.

The researchers report in Molecular Endocrinology [] that this disruption of the MLT circadian rhythm by light at night “has signifi- cant and far-reaching biological consequences.”

Age-Based Reference Ranges Proposed for Androgens

Sometimes treatment guidelines that sound straightforward can be hard to follow in practice. For example, current guidelines recommend that men with symptomatic androgen deficiency and low testosterone levels are candidates for testosterone supplementation. However, because testosterone levels decline with age, particularly after 40, it’s been hard to pin down what constitutes an age-appropriate normal level and one that is low enough to justify supplementation.

A research team led by Bu Beng Yeap, M.B.B.S., Ph.D., of the School of Medicine and Pharmacology, University of Western Australia, Fremantle Hospital Unit, in Fremantle, Australia, attempted to establish reference ranges in healthy men age 70 years or older for testosterone and two of its downstream products: dihydrotestosterone (DHT), an even more potent ligand for stimulating action at the androgen receptor, and estradiol, which exerts action via the estrogen receptor. The researchers measured early morning samples from 3,690 community-dwelling men aged 70–89 years in the Western Australia city of Perth.

Levels of all three steroids declined with age. Lower testosterone and lower DHT were associated with higher body mass index, higher waist-to-hip ratio, dyslipidemia, and diabetes. Lower estradiol was associated with diabetes. An apparent association of low testosterone with cardiovascular disease was attenuated after adjustment for other variables

When the 2.5th percentiles for testosterone, DHT, and estradiol in 394 very healthy older men were used as thresholds, low testosterone or DHT was associated with frailty, diabetes, and cardiovascular disease in the cohort as a whole. Based on their findings, the researchers proposed that levels at the 2.5th percentile or lower provided an ageappropriate threshold for defining a low level of each androgen. For their reference group, this percentile represented levels of 6.4 nmol/L for testosterone (184 ng/dL), 0.49 nmol/L for DHT, and 28 pmol/L for estradiol.

In an upcoming article in The Journal of Clinical Endocrinology & Metabolism [jcem.endojournals. org], the researchers suggest that additional studies could test the applicability of their proposed thresholds to improving the treatment of older men.

Infant Antibiotic Use Could Raise Obesity Risk

Treating infants with antibiotics in their first few months of life could raise their risk of obesity later, a new study indicates.

U.S. farmers routinely give low-dose antibiotics to cattle and chickens to hasten fattening them for market. The earlier in life that the exposure begins, the greater the weight gain, so a research team led by Leonardo Trasande, M.D., M.P.P., of New York University School of Medicine in New York City, inquired whether antibiotics could have the same effect in humans.

Using data from more than 11,000 children in the United Kingdom’s Avon Longitudinal Study of Parents and Children, the researchers examined the association of antibiotic exposure during three time periods during the first two years of life with increases in body mass over the first seven years.

They found that exposure to antibiotics during the first 6 months was associated with increases in body mass from 10 to 38 months, when the effect peaked. By age seven, the increase had largely disappeared. Exposure in the period of 6–14 months showed no association. Those exposed in the 15- to 23-month timeframe did not show consistently higher BMI until age seven, when exposure was associated with a small body mass index increase.

The researchers note that the size of the increase was modest in most individuals, but spread over the population, the effect could be another factor contributing to the obesity epidemic.

The findings echo the results of a recent analysis of the Danish National Birth Cohort, which found that children of normalweight mothers exposed to antibiotics during their first six months had an increased risk of being overweight at age seven.

The findings give another indication of the importance of intestinal bacteria in maintaining a healthy metabolism, and in their article in the International Journal of Obesity, the researchers point to the first six months of life as a window of special vulnerability to disruption.

Aspirin Use, Bleeding Risk, and Diabetes

A daily, low-dose aspirin may help keep the cardiologist away, but it is more likely to send users to the hospital with a hemorrhage in the gut or the brain than previously thought, say researchers in Italy. After comparing nearly 6 years of records from 186,425 patients who took low-dose aspirin daily with records from an equal number of patients who did not, the researchers found that daily aspirin use increased the risk of gastrointestinal bleeding 55 percent and the risk of intracranial bleeding 54 percent. These findings, published in the June 6, 2012, issue of JAMA suggest that major bleeding events, with or without aspirin use, prompt hospitalization five times more often than found in previous studies, an indication that the real-life risk is much greater than indicated in clinical trials.

The team also observed that diabetes increases the risk of bleeding 36 percent, regardless of aspirin use. When analyzing data only from patients who did not take aspirin, the team found that diabetes increased the risk of gastrointestinal bleeding 59 percent and intracranial bleeding 64 percent.

Doctors must weigh the benefits of daily aspirin therapy against the risks when discussing treatment with their patients who are at risk for heart disease or stroke. The Italian team determined that for people who already have a 10- to 20-percent risk of having a heart attack in the next 10 years, the risks and benefits of taking lowdose aspirin daily are roughly equal. For every 1,000 people treated each year, aspirin therapy was associated with two excess cases of bleeding, but it also prevented two cardiovascular events such as heart attack.

In their conclusion, the Italian researchers write: “diabetes might represent a different population in terms of both expected benefits and risks associated with antiplatelet therapy.”

Ghrelin Receptor Reverses Cardiomyopathy

Restriction and restoration of blood to the heart—ischemia and reperfusion, respectively— reduce cardiomyocyte action potential (AP) amplitude, possibly by affecting intracellular calcium, sodium, and potassium levels, and augment reactive oxygen species (ROS), stress, and cell death. Among in vitro models of blood flow, the growth hormone secretagogue (GHS) ghrelin, which is prevalent in cardiomyocytes, and its synthetic analog hexarelin have been shown to be cardioprotective.

Led by Chen Chen, M.D., Ph.D., at the University of Queensland, Brisbane, Australia, scientists set out to determine whether the protection from ghrelin and hexarelin derives from their influence on ion channels and APs and to identify their role in the apoptosis pathway. The team induced a 20-minute ischemia in adult mice hearts and then reperfused the hearts with a solution containing either ghrelin or hexarelin for 30 minutes (controls were reperfused for 70 minutes), either before or after the ischemic episode. A subset of reperfused hearts also received ghrelin receptor 1a (GHSR1a) antagonist. In their paper to be published soon in Endocrinology [], the researchers report normal APs in treated cardiomyocytes, except those given the GHS-R1a antagonist.

The researchers conclude that ghrelin and hexarelin restore intracellular ion handling and act as ROS scavengers to protect cardiomyocytes both pre- and post-ischemia via GHSR1a activation. “Ischemic heart disease is a leading cause of mortality, but has no effective drug treatment,” says Dr. Chen. “Our laboratory is now in the process of demonstrating the protective effect of hexarelin among in vivo disease models, in view of developing effective drug treatment for this disease.”

Gene Linked to Dwarfism Disorder

Researchers have tied a particular gene and gene product to a form of dwarfism, and have even found evidence in zebrafish that backs up their finding of a disrupted developmental pathway.

Microcephalic primordial dwarfism (MPD) is a rare and severe disorder in which growth failure begins in utero. It is associated with defects in single genes involved in fundamental cellular processes, including the functions of centrosomes. These genes encode the cytoplasmic microtubule-organizing centers integral to cell division, cell polarity, and cell cycle control.

Researchers led by Andrew Dauber, M.D., M.M.Sc., of Children’s Hospital Boston and Harvard University, and Vivian Hwa, Ph.D., of Oregon Health & Science University in Portland , searched for the genetic origin of MPD in two sisters with a subtype of the disorder that included severe intellectual disabilities. They performed a whole exome sequence analysis, which they crossreferenced with a growth plate gene expression data set. This approach led them to focus on mutations in the NIN gene on chromosome 14q22.1. The NIN gene product is ninein, a key centrosomal protein important to the process of asymmetric cell division.

The researchers then studied zebrafish in which they had engineered the genetic knockdown of ninein function. This knockdown showed that ninein is essential for the early formation and patterning of the brain. In fact, knockdown in the fish led to specific, MPD-like defi- ciencies of brain and skull development, including a deformed cranium with a small, squared skull reminiscent of the phenotype in humans. The results indicate a developmental role for ninein apart from its role in cell division, a finding consistent with evidence from mouse knockdown experiments that also show an essential role for ninein during neural development.

In an article to be published in The Journal of Clinical Endocrinology & Metabolism [], the researchers say this role of NIN in the development of MPD provides important clues for further research on the role of this and related genes in human growth and development.

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