Groundbreaking Findings May Bring Benefits to Patients with Diabetes

About 422 million people worldwide have diabetes, and 1.5 million deaths are directly attributed to diabetes each year, according to the World Health Organization. Type 1 diabetes is a chronic condition in which the insulin-producing cells in the pancreas are damaged and no longer produce insulin; Type 2 diabetes occurs when the body becomes resistant or insensitive to insulin.

Both versions of the disease lead to elevated blood glucose levels — or blood sugar levels — which over time can lead to serious damage to the heart, blood vessels, eyes, kidneys, and nerves if not controlled by treatment. Life-saving drugs and devices have been developed for patients with diabetes, but many people still struggle with poor blood glucose control, which puts them at high risk for complications.

Now, endocrinologists at Beth Israel Deaconess Medical Center (BIDMC) have identified a key enzyme in the synthesis of a new class of lipids (or fats), called FAHFAs, which are made in human tissues and have beneficial effects on insulin sensitivity, blood sugar control and other metabolic processes. related parameters in humans and mice. The discovery, published in Natureopens the door to possible new treatments for type 1 and 2 diabetes.

“The long-term goal is to safely replace insulin-producing pancreatic beta cells in people with type 1 diabetes, but this would require a way to protect those cells from attack by the immune system,” says Barbara B. Kahn, MD, who is Vice Chair for Research Strategy in BIDMC’s Department of Medicine. “We have shown that these FAHFA lipids protect beta cells from immune attack and metabolic stress. If we could increase FAHFA levels, we think it could be beneficial for both type 1 and type 2 diabetes. Our new discovery is a breakthrough because we know for the first time how these lipids are made in mammalian tissues.”

In 2014, Kahn’s lab, in collaboration with Alan Saghatelian, now a professor at the Salk Institute, discovered the previously unknown class of lipids they called FAHFAs (which stands for fatty acid esters of hydroxy fatty acids). In humans, FAHFA levels are linked to insulin sensitivity. FAHFAs improve blood sugar control in obese, diabetic mice, a model of type 2 diabetes, and they reduce pro-inflammatory immune responses, resulting in a lower incidence of type 1 diabetes in mice. These lipids also protect the cells in humans that make insulin — known as pancreatic beta cells — from attack by immune cells and from cellular stress. In addition, the levels of these lipids are low in the serum and adipose tissue of people who are at risk for or have type 2 diabetes.

In the current study, Kahn’s lab in collaboration with Saghatelian determined that an enzyme called adipose triglyceride lipase, or ATGL, plays a key role in synthesizing the FAHFA lipids. The experiments, conducted in mice and in human and mouse cells — led by first author Rucha Patel, a BIDMC postdoctoral researcher, and second author, Anna Santoro, an instructor at BIDMC — showed that ATGL is the key biosynthetic enzyme for FAHFAs in fat tissues. Further work will examine whether ATGL is also key biosynthetic enzymes in other tissues and whether additional enzymes help synthesize the beneficial lipids.

The discovery could eventually pave the way for new therapeutic strategies for people with diabetes.

Because people who are both obese and insulin resistant have lower ATGL levels in white adipose tissue compared to lean people or people who are both obese and insulin sensitive, scientists suspect that ATGL may contribute to the reduction of FAHFAs in insulin resistant people and hence the risk. on or severity of type 2 diabetes.

“Ideally, the new findings could be used to increase levels of FAHFAs in people who are at risk for type 2 diabetes to prevent it, or to improve blood glucose control in people who already have type 2 diabetes,” said Kahn, who said: also the Minot Professor of Medicine at Harvard Medical School and a member of the National Academy of Sciences. In addition, these new findings could be used to increase FAHFA levels in people at risk for type 1 diabetes to prevent it — as we did in mice. Understanding the regulation of ATGL could lead to strategies to target these beneficial lipids in metabolic and immune-mediated diseases.”

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