Breakthrough discovery could benefit 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 disease in which the insulin-producing cells of the pancreas have been damaged and no longer produce insulin. Type 2 diabetes occurs when the body becomes resistant or insensitive to insulin.

Both versions of the disease cause high levels of blood glucose – or blood sugar – which over time can lead to serious damage to the heart, blood vessels, eyes, kidneys and nerves if they are not controlled by treatment. Life-saving drugs and devices have been developed for patients with diabetes, but many people still struggle with poor blood sugar 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 FAHFA, which are made in human tissues and have beneficial effects on insulin sensitivity, blood glucose control and other metabolic-related parameters in humans and mice. The discovery, published in Natureopens the door to potential new treatments for types 1 and 2 diabetes.

“The long-term goal is to safely replace pancreatic insulin-producing beta cells in people with type 1 diabetes, but that would require a way to protect these cells from attack by the immune system,” he said. Barbara B. Kahn, MD, who is vice chair of research strategy in the Department of Medicine at BIDMC. “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 benefit both type 1 and type 2 diabetes. Our new discovery is a breakthrough because, for the first time, we know how these lipids are made in tissues. mammals.

In 2014, Kahn’s lab, in collaboration with Alan Saghatelian, now a professor at the Salk Institute, discovered the previously unknown class of lipids which they named FAHFA (which stands for fatty acid esters of fatty acids hydroxylated). In humans, FAHFA levels are linked to insulin sensitivity. FAHFAs improve glycemic control in obese, diabetic mice, a model of type 2 diabetes, and they reduce pro-inflammatory immune responses, which reduces the incidence of type 1 diabetes in mice. These lipids also protect the human cells that make insulin – called pancreatic islet beta cells – from immune cell attack and cellular stress. Additionally, levels of these lipids are low in the serum and fatty tissues of people at risk of or with type 2 diabetes.

In the current study, Kahn’s lab in collaboration with Saghatelian determined that an enzyme called triglyceride adipose lipase, or ATGL, plays a key role in FAHFA lipid synthesis. The experiments, conducted in mice and in human and mouse cells – led by first author Rucha Patel, postdoctoral fellow at BIDMC, and second author Anna Santoro, teacher at BIDMC – showed that ATGL is the main FAHFA biosynthetic enzyme in fats. fabrics. Further work will determine whether ATGL is also the main biosynthetic enzyme in other tissues and whether additional enzymes help synthesize beneficial lipids.

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

Because humans who are both obese and insulin resistant have lower levels of ATGL 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 FAHFA in people with insulin resistance and therefore to the risk or severity of type 2 diabetes.

“Ideally, the new findings could be used to increase FAHFA levels in people at risk for type 2 diabetes to prevent it, or to improve blood sugar control in people who already have type 2 diabetes,” said Kahn, who is also the Minot Professor of Medicine at Harvard Medical School and a Fellow of the National Academy of Sciences. “Additionally, 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 ATGL regulation could lead to strategies to augment these beneficial lipids in metabolic and immune-mediated diseases.

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