A look at the latest research

MOLECULE IDENTIFIED FOR BLOCKING INSULIN BREAKDOWN

Researchers at Harvard have discovered a molecule that inhibits the breakdown of insulin in mice, according to a study recently published in the journal Nature.

The identification of the insulindegrading enzyme (IDE) as a diabetes susceptibility gene could have a sizable impact on the treatment of diabetes, since it could help maintain a person’s insulin levels to lower blood sugar, say the study’s lead authors David R. Liu, PhD, and Alan Saghatelian, PhD, both of Harvard University.

The authors wrote that they discovered the physiologically active IDE inhibitor identified from a DNA-templated macrocycle library. “An X-ray structure of the macrocycle bound to IDE reveals that it engages a binding pocket away from the catalytic site,” they continued, “which explains its remarkable selectivity.” They then treated lean and obese mice with the IDE inhibitor, which showed that the inhibitor regulates the abundance and signaling of glucagon and amylin, in addition to that of insulin.

The scientists concluded that their findings demonstrate the feasibility of modulating IDE activity as a new therapeutic strategy to treat type 2 diabetes and expand an understanding of the roles of IDE in glucose and hormone regulation. “This work validates a new potential target for the treatment of diabetes,” Liu said in a university release. “What we show is that inhibiting IDE in an animal can improve glucose tolerance under conditions that mimic the intake of a meal if you administer this compound beforehand.”

ANDROGEN RESPONSE ELEMENT LINKED TO PROSTATE CANCER

Researchers in the United Kingdom may have discovered a novel approach to identifying components that affect development of prostate cancer, according to a paper recently published in Hormones and Cancer

The authors, led by Iain J. McEwan, of the University of Aberdeen, point out that the androgen receptor (AR) is a widely expressed protein, that plays a role in development of normal prostate tissue as well as prostate cancer (PCa), and mediates androgen signaling by binding to androgen response elements (AREs).

Despite the AR being “widely expressed,” that expression is poorly understood. McEwan and his team used the commonly available human prostate carcinoma cell lines LNCaP, VCaP, and DU145 to study the hormone-dependent repression of the AR gene. The scientists found that there was a primate-specific ARE in the human AR gene five prime untranslated region (5’UTR).

The authors concluded that “ARE represses transcription upon binding of activated AR, and this down-regulation is relieved by disruption of the regulatory element through mutation.” However, they noted that this ARE is specific to primates and care must be exercised “when elucidating the operation of the human AR in PCa based upon rodent promoter studies.”

THE ENDOCRINE SOCIETY’S GUIDELINES FOR ADRENAL TUMORS

The Endocrine Society has issued a Clinical Practice Guideline (CPG) for the diagnosis and treatment of pheochromocytomas and paragangliomas, rare adrenal tumors that produce epinephrine and norepinephrine and can raise the risk of cardiovascular disease and even death if left untreated. The guideline was published in the Journal of Clinical Endocrinology & Metabolism.

The Society’s task force, chaired by Jacques W.M. Lenders, MD, PhD, FRCP, of Radboud University in Nijmegen, the Netherlands, laid out recommendations that include testing the blood and urine for metanephrines, since these are byproducts left over when the body metabolizes epinephrine and norepinephrine. The CPG also recommends:

• People who are diagnosed with pheochromocytomas or paragangliomas should be involved in a shared decision-making process with their physicians to evaluate the need for genetic testing;
• A diagnostic algorithm that takes into account risk factors such as age at tumor presentation and family history should be used to establish which patients would benefit most from genetic testing and which specific gene mutations to test for;
• People with paragangliomas and those diagnosed with metastatic tumors should be tested for specific gene mutations associated with those conditions;
• Computed tomography can be used as the first choice imaging technology for determining the location of pheochromocytomas or paragangliomas for surgical treatment;
• MRI technology is to be used in specific situations, including for patients who have metastatic tumors, for detecting head and neck paragangliomas, and for patients in whom radiation exposure should be limited; and
• Another imaging technology, 18Fluorodeoxyglucose-positron emission tomography/computed tomography, can be used in patients with metastatic tumors.

“Correctly diagnosing pheochromocytomas and paragangliomas is extremely important,” Lenders said. “In addition to the strain these tumors put on the cardiovascular system, between 10% and 17% of the tumors can become malignant. Researchers have discovered that at least a third of people with these conditions have a diseasecausing genetic mutation, so early detection can benefit family members who may be at risk.”

BARIATRIC SURGERY SHOWN TO BE EFFECTIVE TREATMENT FOR T2D

A three-year-long study has shown that more than 90% of the patients who underwent bariatric surgery were able to lose 25% of their body weight and control their diabetes without the use of insulin and multiple diabetes drugs.

The article published in the New England Journal of Medicine details the results of the three-year data of the STAMPEDE trial, the largest randomized trial with one of the longest follow-ups comparing medical therapy with bariatric surgery.

Researchers led by Sangeeta Kashyap, MD, and Philip R. Schauer, MD, of the Cleveland Clinic, evaluated outcomes of 150 obese patients with uncontrolled type 2 diabetes to receive either intensive medical therapy alone or intensive medical therapy plus Roux-en-Y gastric bypass or sleeve gastrectomy. “The primary end point was a glycated hemoglobin level of 6.0% or less,” the authors wrote.

The researchers found that at “three years, the criterion for the primary end point was met by 5% of the patients in the medical therapy group, as compared with 38% of those in the gastric bypass group (p<0.001) and 24% of those in the sleeve gastrectomy group (p=0.01).” Schauer and his team concluded that three-year data show that bariatric surgery is a highly effective and durable treatment for type 2 diabetes in obese patients, enabling nearly all surgical patients to be free of insulin and many to be free of all diabetic medications three years after surgery. The study also shows that bariatric surgery patients experienced an improvement in quality of life and a reduction in the need for cardiovascular medications to control blood pressure and cholesterol compared to those receiving medical therapy.

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