Keto diet works best in small doses, researchers find

In continuation of  my update on keto diet

A ketogenic diet—which provides 99 percent of calories from fat and protein and only 1 percent from carbohydrates—produces health benefits in the short term, but negative effects after about a week, Yale researchers found in a study of mice.

The results offer early indications that the keto diet could, over limited time periods, improve human health by lowering diabetes risk and inflammation. They also represent an important first step toward possible clinical trials in humans.

The keto diet has become increasingly popular as celebrities, including Gwyneth Paltrow, Lebron James, and Kim Kardashian, have touted it as a weight-loss regimen.

In the Yale study, published in the Jan. 20 issue of Nature Metabolism, researchers found that the positive and negative effects of the diet both relate to immune cells called gamma delta T-cells, tissue-protective cells that lower diabetes risk and inflammation.

A keto diet tricks the body into burning fat, said lead author Vishwa Deep Dixit of the Yale School of Medicine. When the body's glucose level is reduced due to the diet's low carbohydrate content, the body acts as if it is in a starvation state—although it is not—and begins burning fats instead of carbohydrates. This process in turn yields chemicals called ketone bodies as an alternative source of fuel. When the body burns ketone bodies, tissue-protective gamma delta T-cells expand throughout the body.

This reduces diabetes risk and inflammation, and improves the body's metabolism, said Dixit, the Waldemar Von Zedtwitz Professor of Comparative Medicine and of Immunobiology. After a week on the keto diet, he said, mice show a reduction in blood sugar levels and inflammation.

But when the body is in this "starving-not-starving" mode, fat storage is also happening simultaneously with fat breakdown, the researchers found. When mice continue to eat the high-fat, low-carb diet beyond one week, Dixit said, they consume more fat than they can burn, and develop diabetes and obesity.

"They lose the protective gamma delta T-cells in the fat," he said.

Long-term clinical studies in humans are still necessary to validate the anecdotal claims of keto's health benefits.

"Before such a diet can be prescribed, a large clinical trial in controlled conditions is necessary to understand the mechanism behind metabolic and immunological benefits or any potential harm to individuals who are overweight and pre-diabetic," Dixit said.

There are good reasons to pursue further study: According to the Centers for Disease Control, approximately 84 million American adults—or more than one out of three—have prediabetes (increased blood sugar levels), putting them at higher risk of developing type 2 diabetes, heart disease, and stroke. More than 90 percent of people with this condition don't know they have it.

"Obesity and type 2 diabetes are lifestyle diseases," Dixit said. "Diet allows people a way to be in control."

With the latest findings, researchers now better understand the mechanisms at work in bodies sustained on the keto diet, and why the diet may bring health benefits over limited time periods.

"Our findings highlight the interplay between metabolism and the immune system, and how it coordinates maintenance of healthy tissue function," said Emily Goldberg, the postdoctoral fellow in comparative medicine who discovered that the keto diet expands gamma-delta T cells in mice.

If the ideal length of the diet for health benefits in humans is a subject for later studies, Dixit said, discovering that keto is better in small doses is good news, he said: "Who wants to be on a diet forever?"

https://www.nature.com/articles/s42255-019-0160-6

Diabetes drug metformin could help reduce toxic acid levels linked to MSUD

In continuation of my update on metformin 

Maple Syrup Urine Disease (MSUD) is a rare inherited metabolic disorder involving the dysfunction of an enzyme which breaks down three essential amino acids: leucine, isoleucine and valine. Left untreated, infants die from a toxic buildup of resulting keto-acids within weeks of birth. Those who are diagnosed early can live a normal life, but are forced to eat a very controlled, formula-based diet. The only proven treatment for the disease, which is characterized by sweet-smelling urine, is a liver transplant. Publishing in Scientific Reports, researchers at the Buck Institute show that the widely-used diabetes drug metformin reduces the toxic acid levels associated with MSUD in both skin cells derived from MSUD patients and in mice. The discovery offers the possibility of a new treatment for a disorder identified 1 in 180,000 births.

Senior author and Buck faculty Arvind Ramanathan, PhD, says metformin reduced the levels of toxic ketoisocaproic acid (KIC) in patient-derived fibroblasts by 20 to 50 percent and significantly reduced KIC levels in the skeletal muscle of mice bred to have the disease by 69 percent. "We think there is a clear path to a clinical trial and we are hoping that physicians who treat MSUD patients will start pushing in that direction," he said. "There is a definite need for novel interventions."

Ramanathan, who specializes in metabolomics, came to the MUSD discovery as he was studying various compounds and the enzymes they impact in the context of aging. The work could provide a mechanistic explanation for metformin's success in controlling diabetes and possibly extending healthspan in both animals and humans. The research also highlights similarities between a rare pediatric disease and normal aging - and shows how studying one can inform the other.

Researchers studied the enzyme BCKDH, which is defective in MSUD and also decreases in activity with normal aging. Ramanathan says decreased BCKDH is implicated in obesity and diabetes; he believes it may be involved in a number of other age-related conditions as well. Ramanathan also studied an enzyme upstream of BCKDH - called BCAT. He says in MSUD, BCAT converts leucine, isoleucine and valine to toxic ketones in the mitochondria of skeletal muscle -resulting in the muscle weakness and atrophy associated with MUSD. "We think the same process may be afoot with age-related sarcopenia and frailty," he said. "Interestingly, metformin interacts with BCAT and in our MSUD mice treatment with metformin significantly reduced toxic acid buildup in the skeletal muscle."

"This is a prime example how aging research can have a significant impact on people at any age and the work also highlights the value of studying drugs already approved by the FDA," said Brian Kennedy, PhD, senior co-author and Buck Institute CEO. "In this case, we hope our discovery will help those living with MUSD. We plan on building on these insights to further our research aimed at extending the healthy years of life for all of us."