Stories about: Division of Endocrinology

Two-drug approach halts lung tumors by starving them metabolically

(Illustration: Fawn Gracey)

Non-small-cell lung cancer is the leading cause of cancer death in the U.S. Roughly 1 in 4 cases are driven by the mutant KRAS oncogene. Though scientists have tried for more than three decades to target KRAS with drugs, they’ve had little success.

In a new study led by Nada Kalaany, PhD, and colleagues at Boston Children’s Hospital took a different approach, looking at what these deadly lung tumors need metabolically to live and grow. Reporting in the Proceedings of the National Academy of Sciences (PNAS), they show that a combination of two existing drugs can effectively starve tumors in a mouse model.

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Why does bariatric surgery ease diabetes?

diabetes gastric bypass

Many people who have Roux-en-Y gastric bypass surgery for obesity experience a striking but welcome side effect. In up to 80 percent of patients who also have type 2 diabetes, the diabetes abates even before they lose weight. A new study helps explain why, and suggests possible ways to combat diabetes (and obesity) without having to actually perform bariatric surgery.

“Our aim is to ‘reverse engineer’ the surgery, to find how it works and apply the mechanisms to new, less invasive treatments,” said study lead author Margaret Stefater, MD, PhD, a fellow in the lab of Nicholas Stylopoulos, MD, in a press release.

The Stylopoulos Lab, in Boston Children’s Hospital’s Division of Endocrinology, previously showed in a seminal 2013 paper that the bypass operation causes the small intestine to ramp up its sugar intake. In rodents, this appeared to account for resolution of their diabetes. Stylopoulos, together with collaborator Anita Courcoulas, MD, MPH of the University of Pittsburgh, then started an NIH-funded observational study of people undergoing Roux-en-Y gastric bypass surgery.

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News note: GIANT study homes in on obesity genes

obesity genes
Illustration: Elena Hartley

Yes, some obesity is due to genetics. The largest and most powerful study to date has pinned down 14 variants in 13 genes that carry variations associated with body mass index. They provide new clues as to why some people tend to gain weight and have more trouble losing it. Eight of the variants were in genes not previously tied to human obesity.

The study, published last month, was conducted by the Genetic Investigation of Anthropometric Traits (GIANT) consortium, an international collaboration involving more than 250 research institutions — the same group that brought us height-related genes last year. It combined genetic data from more than 700,000 people and 125 different studies to find rare or low-frequency genetic variants that tracked with obesity.

The study focused on rarer variants in the coding portions of genes, which helped pinpoint causal genes and also helped discover variants with larger effects that those previously discovered by the GIANT consortium. For example, carriers of a variant in the gene MC4R (which produces a protein that tells the brain to stop eating and to burn more energy) weigh 15 pounds more, on average, than people without the variant.

Computational analysis provided some interesting insights into what the 13 genes do. Some, for example, play a role in brain pathways that affect food intake, hunger and satiety. Other variants affect fat-cell biology and how cells expend energy.

This study provided an important confirmation of the role of the nervous system in body weight regulation,” says Joel Hirschhorn MD, PhD, a pediatric endocrinologist and researcher at Boston Children’s Hospital and the Broad Institute of MIT and Harvard, who co-led the study with Ruth Loos, PhD, of the Icahn School of Medicine at Mount Sinai. “Many of the genes from this study were not known to be associated with obesity, but our computational analysis independently implicates these new genes in strikingly similar neuronal pathways as the genes that emerged from our previous work. In addition, our approach newly highlighted a role for genes known to be important in ‘brown fat,’ a type of fat that burns energy and may help keep people lean.”

The researchers think the new findings could help focus the search for new therapeutic targets in obesity.  Read more in Nature Genetics and this press release from Mount Sinai.

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News Note: More evidence that high-glycemic diets cause obesity

a high-glycemic diet

A large genetic analysis lends credence to the idea that insulin spikes after eating high-glycemic foods promote weight gain. People genetically predisposed to produce higher than normal levels of insulin after eating processed carbohydrates — “bad carbs” like white bread, potatoes and refined sugar — were more likely to be obese, the study found.

The researchers, led by David Ludwig, MD, PhD, of Boston Children’s Hospital, Joel Hirschhorn, MD, PhD, of Boston Children’s and the Broad Institute, and Jose Florez, MD, PhD, of the Broad Institute and Massachusetts General Hospital, tapped a collection of large-scale genome-wide association studies. Analyzing data from more than 26,000 people who had glucose challenges, they identified genetic variants linked with high insulin levels 30 minutes after the challenge.

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A metabolic treatment for pancreatic cancer?

nitrogen disposal is important to pancreatic cancer
Targeting an enzyme that helps dispose of excess nitrogen curbed malignant growth of pancreatic tumors in obese mice.

Pancreatic cancer has become the third leading cause of cancer mortality. Its incidence is rising in parallel with the rise in obesity, and it’s hard to treat: five-year survival still hovers at just 8 to 9 percent. A new study published online in Nature Communications finds early success with a completely new, metabolic approach: reducing tumors’ ability to get rid of excess nitrogen.

The researchers, led by Nada Kalaany, PhD, of Boston Children’s Hospital’s Division of Endocrinology and the Broad Institute of MIT and Harvard, provide evidence that targeting the enzyme arginase 2 (ARG2) can curb pancreatic tumor growth, especially in people who are obese.

“We found that highly malignant pancreatic tumors are very dependent on the nitrogen metabolism pathway,” says Kalaany.

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Why I’m tall and you’re short: GIANT effort finds rare, potent height genes

height genes that make us tall or short

Height is the “poster child” of complex genetic traits, meaning that it’s influenced by multiple genetic variants working together. Because height is easy to measure, it’s a relatively simple model for understanding traits produced by not one gene, but many.

“Mastering the complex genetics of height may give us a blueprint for studying multifactorial disorders that have eluded our complete understanding, such as diabetes and heart disease,” says Joel Hirschhorn, MD, PhD, a pediatric endocrinologist and researcher at Boston Children’s Hospital and the Broad Institute of MIT and Harvard.

Hirschhorn chairs the Genetic Investigation of Anthropometric Traits (GIANT) Consortium, an international group that’s just probed more deeply into the genetics of height than ever before. Its findings, reported today in Nature, reveal previously unknown biological pathways tied to height.

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Potential cure for diabetes may be in the stomach

diabetes stomach beta cells
The yellow-green cells in this “mini-stomach” are capable of making insulin. The mini-organ was made from biopsied cells from mouse stomachs, with reprogramming factors added.

If only there were a cure. David Breault, MD, PhD, associate chief of the Division of Endocrinology at Boston Children’s Hospital, was seeing patient after patient with Type I diabetes. Children facing lifetimes of insulin injections, special diets and the threat of long-term complications including blindness, heart disease and kidney failure.

Breault knew that patients with type I diabetes mysteriously destroy their own insulin-producing beta cells. He had read reports of researchers transplanting beta cells to supplement insulin. These transplants, even when successful, required powerful immunosuppressant medications to prevent patients’ immune systems from attacking the donor cells.

But Breault was also aware that investigators had, for a decade, been looking to stem cells as the source of a constantly renewing supply of beta cells. Advancing that promise, he has now found a way to convert patients’ own cells — from the stomach and intestine — into beta cells that produce insulin.

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Could targeting specific neurons in the hypothalamus relieve anxiety?

anxiety hypothalamus
(Ichiban Yada/Sketchport.com)

Anxiety disorders are the most common mental illness in the U.S., but lack an ideal treatment. The current drugs, SSRIs and benzodiazepines, have many side effects. More recently developed treatments seek to block corticotropin-releasing hormone (CRH), the classic stress hormone that activates our “fight or flight” response; in people with anxiety, CRH gets activated at the wrong time or too intensely.

But in clinical trials, results have been disappointing: of the eight completed phase II and III trials of CRH antagonists for depression or anxiety, six have been published, with largely negative findings, says Joseph Majzoub, MD, of the Division of Endocrinology at Boston Children’s Hospital.

Rong Zhang, PhD, who works in Majzoub’s research lab, had a hunch that blocking CRH throughout the brain, as was done in these trials, isn’t the best approach. “Blocking CRH receptors all over the brain doesn’t work,” she says. “We think the effects work against each other somehow. It may be that CRH has different effects depending on where in the brain it is produced.”

Today in Molecular Psychiatry, Zhang, Majzoub and colleagues demonstrate that certain neurons in the hypothalamus play a central, previously unknown role in triggering anxiety. When they used genetic tricks to selectively remove the CRH gene from about 1,000 of these neurons in mice, the effect was startling — they erased the animals’ natural fears.

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Could Burmese pythons shed light on diabetes?

Burmese pythons diabetes

Originally from Southeast Asia, Burmese pythons are perhaps best known in the U.S. for the havoc they’ve been creating in the Everglades. Kept as pets and released into the wild, they can grow to nearly 20 feet long, and are hunting animals like marsh rabbits toward extinction (a problem Florida is trying to address with an annual Python Removal Competition).

But in the lab, at a diminutive 3 feet in length, Burmese pythons may hold valuable lessons about diabetes.

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Can we bypass the bypass to treat diabetes?

Diagram of Roux-en-Y gastric bypass
Gastric bypass surgery creates a small pouch in the stomach and connects it directly to the small intestine. Why does it help type 2 diabetes? (Wikimedia Commons)

Research shows that gastric bypass surgery, aside from inducing weight loss, resolves type 2 diabetes. Though weight loss and improved diabetes often go hand-in-hand, patients who undergo gastric bypass usually end up seeing an improvement in their type 2 diabetes even before they lose weight.

But why? To investigate, a research team led by Nicholas Stylopoulos, MD, of Boston Children’s Hospital’s Division of Endocrinology, spent a year studying rats and observed that after gastric bypass surgery, the way in which the small intestine processes glucose changes. They saw the intestine using and disposing of glucose, and showed that it thereby regulates blood glucose levels in the rest of the body, helping to resolve type 2 diabetes.

Basically, as the team reported recently in Science, the small intestine—widely believed to be a passive organ—is actually a major contributor to the body’s metabolism.

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