A look at the latest research

New Drug Approved to Treat GEP-NETs

The U.S. Food and Drug Administration recently approved a drug called Somatuline® Depot® (lanreotide) Injection 120mg for the treatment of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) in adult patients with unresectable, well- or moderately differentiated, locally advanced, or metastatic disease to improve progressionfree survival.

GEP-NETs are a rare type of cancer, affecting about five in 100,000 people in the U.S., but the prevalence of GEP-NETs has increased four- to six-fold in the last 30 years. Compounding the problem is the fact that it takes at least five years to accurately diagnose GEP-NETs (the cancer is often misdiagnosed as irritable bowel syndrome or Crohn’s disease), meaning the disease is already in the advances stages, leading to poor prognoses. The approval of Somatuline was based on a 96-week registrational Phase III, double-blind, placebo-controlled study (CLARINET®) of 204 GEP-NETs patients enrolled in 48 centers across 14 countries. Researchers led by Alexandria Phan, MD, director of GI Medical Oncology at Houston Methodist, found that the drug reduced the risk of disease progression or death by 53% versus placebo and published their findings in the New England Journal of Medicine.

“Somatuline is the first somatostatin analog to demonstrate a statistically signifi cant improvement in progression-free survival, a clinically significant endpoint in oncology that measures how long the patient continues to live with the disease without it getting any worse,” says Phan. “Somatuline offers a new weapon in our fight against this deadly disease.”

Novel Drug “Tricks” Body Into Weight Loss

Researchers at the Salk Institute for Biological Studies have developed a novel drug that “tricks” the body into thinking it has consumed calories, causing the body to begin browning white fat and lose weight, according to a study recently published in Nature Medicine.

The team, led by Michael Downes, PhD, and Ronald M. Evans, PhD, noted that bile acid released during a meal selectively activates the intestinal farnesoid X receptor (FXR) and that by “mimicking this tissue-selective eff ect, the gut-restricted FXR agonist fexaramine (Fex) robustly induces enteric fibroblast growth factor 15 (FGF15), leading to alterations in bile acid composition, but does so without activating FXR target genes in the liver.”

Fex was tested in 200 obese mice that were given the drug in solution form daily for five weeks. The team observed that the mice stopped gaining weight, lost fat, and lowered their blood sugar and cholesterol levels more than untreated mice. And since the pill is taken orally, it only works in the gut, never entering the bloodstream.

“This pill is like an imaginary meal,” Evans said in an Institute statement. “It sends out the same signals that normally happen when you eat a lot of food, so the body starts clearing out space to store it. But there are no calories and no change in appetite.”

The authors concluded that “Fex reduces diet-induced weight gain, body-wide inflammation, and hepatic glucose production, while enhancing thermogenesis and browning of white adipose tissue (WAT). These pronounced metabolic improvements suggest tissuerestricted FXR activation as a new approach in the treatment of obesity and metabolic syndrome.”

Early-Pregnancy Hyperthyroidism and High-Normal FT4 Linked to Hypertensive Disorders

Biochemical hyperthyroidism and high-normal levels of free T4 (FT4) during early pregnancy are associated with an increased risk of hypertensive disorders, according to research recently published in The Journal of Clinical Endocrinology & Metabolism.

Hypertensive disorders can cause a wide range of maternal and fetal complications, including renal failure, disseminated intravascular coagulation, cerebrovascular bleeding, intrauterine growth retardation, abruptio placentae, premature delivery, and stillbirths. The disorders affect 2% – 8% of expecting mothers, but few risk factors are known.

So the authors of the study, led by Marco Medici, MD, PhD, and Tim Korevaar, a PhD student, both of the Erasmus Medical Center in Rotterdam, The Netherlands, looked at the associations between thyroid function within the normal range, thyroid dysfunction, thyroid autoimmunity, and blood pressure (BP) as well as the risk of hypertensive disorders during pregnancy. They analyzed 5,153 Dutch women in early pregnancy with a delivery date between April 2002 and January 2006. The team measured serum TSH, FT4, and thyroperoxidase antibody (TPOAb) levels, as well as mean blood pressures and hypertensive disorders, including pregnancy-induced hypertension (n = 209) and preeclampsia (n = 136).

The scientists found that hyperthyroid mothers had a higher risk of hypertensive disorders [odds ratio (OR) 3.40 [95% confidence interval (CI) 1.46–7.91], p = .005], which was mainly due to an increased risk of pregnancy-induced hypertension [OR 4.18 (95% CI 1.57–11.1), p = .004]. Within the normal range, high-normal FT4 levels were also associated with an increased risk of hypertensive disorders [OR 1.62 (95% CI 1.06–2.47), p = .03], which was mainly due to an increased risk of preeclampsia [OR 2.06 (95% CI 1.04–4.08), p = .04].

The authors concluded that “hyperthyroidism and also high-normal FT4 levels during the early pregnancy are risk factors for the development of hypertensive disorders. These data demonstrate that even mild variation in thyroid function within the normal range can have such effects.” However, they noted that since there are only a few large studies with data on potential confounders, their results should be “replicated in an independent population.”

GLP-1 May Benefit Heart After Myocardial Infarction

The metabolic hormone glucagonlike peptide 1 (GLP-1) may help the heart heal after a myocardial infarction, according to research published in Endocrinology last month.

Investigators led by Aleksander Hinek, MD, Phd, DSc, of the Hospital for Sick Children in Ontario, Canada, noted that GLP-1 has been shown to have some “cardioprotective effects and facilitates functional recovery after myocardial infarction through GLP-1 receptor-mediated signaling in cardiomyocytes.” The antidiabetic hormone has also been demonstrated to produce long-term, sustained improvements in cardiac function. However, the reasons for these remain unclear.

Hinek and his team hypothesized that there is a possible interaction among GLP-1 and cardiac fibroblasts, which remodel the heart after a myocardial infarction, because they are less susceptible to ischemia than cardiomyocytes. “[The cardiac fibroblasts’] proliferation and production of a new extracellularmatrix (ECM) are crucial steps in the functional adaptation of the damaged myocardium,” the authors write.

The researchers treated cultures of human cardiac fibroblasts in vitro with GLP-1 peptides and found that those cultures “display a selective up-regulation in elastin gene expression and a consequent increase in elastic fibers production, in the absence of the classic GLP-1 receptor.” Moreover, the study shows that this GLP-1-induced elastogenesis is triggered through the cross-activation of the IGF-1 receptor, rather than the GLP-1 receptor.

“Because GLP-1 does not stimulate deposition of collagen I,” the authors conclude, “nor promote the proliferation or apoptosis of cultured cardiac fibroblasts, we speculate that its elastogenic effect may also contribute to the beneficial remodeling of the human heart after myocardial infarction.”

BPA Exposure during Pregnancy Linked to Oxidative Damage in Infants

Exposure to bisphenol A (BPA) during pregnancy can cause oxidative damage that may put the baby at risk of developing diabetes or heart disease later in life, according to a new study published in Endocrinology.

Researchers led by Vasantha Padmanabhan, MS, PhD, of the University of Michigan, analyzed blood samples from 24 mother and infant pairs to examine the effects of BPA exposure. The women had blood drawn during the first trimester of pregnancy to measure their BPA levels. The women were divided into two groups — those who had lower levels of BPA in their blood and those who had higher levels. The investigators also took blood samples from the umbilical cords after the babies were delivered and measured the amount of chemical byproducts created by oxidative stress.

The blood analysis revealed that the mothers exposed to higher levels of BPA and their infants showed signs of oxidative stress caused by overexposure to nitric oxidederived free radicals. The study participants had larger amounts of byproducts caused by this type of oxidative damage in their blood.

In addition to the human subjects, the researchers studied the effects of BPA on pregnancy in sheep, rats, and mice. The scientists fed the animals diets containing either high or low doses of BPA. They then measured the resulting oxidative stress on the mothers and their offspring using blood samples. The results corroborated the results in the human study.

“Whether or not BPA is harmful to human health has been vigorously debated,” Padmanabhan says. “These findings demonstrate that more studies like this one are needed to determine the disease risk of exposure to BPA. In the interim, these results indicate that pregnant women should minimize their exposure to BPA to safeguard their babies and themselves from oxidant injury.”

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