Diabetes is a disease in which the pancreas either does not produce enough insulin or cells in the body fail to respond to insulin properly. Diabetic patients experience abnormally high blood sugar levels, which can lead to heart disease, stroke, kidney failure, and eye damage. The disease, which affects more than 29 million Americans, is treated with drugs that help to keep blood sugar within a normal range. Steatosis, or fatty liver, occurs in at least half of all diabetics, though the relationship between the two diseases is not clear. Steatosis can also occur in other patients, such as those with hepatitis. It is a condition in which fat accumulates in the liver, causing inflammation and damage to liver cells. Most patients with fatty liver can only be treated with lifestyle and diet changes.

In a study published in the February issue of Diabetes, Obesity and Metabolism, scientists at Weill Cornell Medicine have identified a new drug that appears to treat both of these diseases at the same time. The drug targets a specific protein, called retinoic acid receptor beta-2 (RARB2), which is critical in the development and functioning of pancreatic cells.

"This is a whole new class of drugs," said senior author Dr. Lorraine Gudas, chair of the Department of Pharmacology and the Revlon Pharmaceutical Professor of Pharmacology and Toxicology at Weill Cornell Medicine. "RARB2 is a new target for diabetes treatment. We are also excited because, currently, there is no medicine that effectively treats fatty liver, so this may be a breakthrough therapy."

The researchers studied mice with diabetes. The mice were given the new drug in their water. "We found that this drug restored normal blood sugar levels in the mice," said Dr. Xiao-Han Tang, an assistant research professor in pharmacology at Weill Cornell Medicine, who is an author on the paper. "And we also found that it reduced fatty liver symptoms."

The new drug, which has not been tested in humans, might have several advantages over current treatments. First, it is able to be taken orally, which makes it appealing for patients when compared to injectable diabetes medications. Second, it does not cause weight gain in mice. This is critical, said first author Dr. Steven Trasino, a postdoctoral fellow in pharmacology at Weill Cornell Medicine. "Some of the most commonly used anti-diabetes drugs cause weight gain, which can eventually make both diabetes and fatty liver worse. Avoiding that is a great advantage."

The ability to treat both of these diseases at once could result in major benefits to patients. "We think that this drug is a potential, potent anti-diabetic drug for humans," Dr. Tang said. "It's very exciting." Dr. Gudas and her team, which also includes Dr. Jose Jessurun, a professor of pathology and laboratory medicine and co-author of the paper, are making plans to bring this discovery to the clinic.

Obesity impairs the body's ability to use vitamin A appropriately and leads to deficiencies of the vitamin in major organs, according to new research conducted at Weill Cornell Medicine.

Vitamin A is critical to the proper functioning of many systems in the body, including vision, fetal development, reproduction, immune responses, and wound healing. Vitamin A deficiency impairs these functions, and is also implicated in increased risk of respiratory infections, diabetes, infertility, and delayed growth and bone development. Because of these wide-ranging health effects, people are advised to get adequate amounts of the vitamin either through diet (eggs, milk, meat, and some fruits and vegetables are sources) or supplementation. But the study, published Nov. 2 in Scientific Reports, shows that obesity interferes with the body's ability to use vitamin A, even with adequate intake.

"Our research shows that, even if an obese animal consumes normal amounts of vitamin A, they have deficiencies of the vitamin A in major organs," said first author Dr. Steven Trasino, a postdoctoral fellow in pharmacology at Weill Cornell Medicine. "Obesity is categorized as a state of malnutrition, typically associated with consumption of too many calories and poor intake of essential nutrients. Our data expand on that definition by showing that obesity plays a role in the body's ability to use this essential nutrient properly."

Dr. Lorraine Gudas

The researchers fed mice a diet that had normal vitamin A levels, similar to the recommendations for human vitamin A intake.

"We found that normal-weight mice are healthy on that diet, but obese mice show severe vitamin A deficiencies in their livers, kidneys and pancreas," said senior author Dr. Lorraine Gudas, chair of the Department of Pharmacology and the Revlon Pharmaceutical Professor of Pharmacology and Toxicology at Weill Cornell Medicine.

When the obese mice lost weight, their vitamin A levels returned to normal. "Something about the state of obesity is impairing the body's ability to use vitamin A correctly," Dr. Gudas said.

What was particularly remarkable to the research team, which also included Dr. Xiao-Han Tang, an assistant research professor in pharmacology, and Dr. Jose Jessurun, a professor in pathology, was that the blood levels of vitamin A in all of the mice, including the obese mice, were normal. The deficiency was only noted when the researchers took tissue samples from various organs in the mice. "We call this ‘silent vitamin A deficiency' because it would not be picked up by a standard blood test for the vitamin," Dr. Trasino said.

The new findings suggest that obesity in humans is also associated with low vitamin A levels in many organs. Such deficiencies would have corresponding health effects.

"We know that obesity is associated with many illnesses, such as poor immune response and diabetes," Dr. Gudas said. "What we don't know is why. This gives us more information for understanding how the two go together, but many puzzles remain to be solved before we fully understand why obesity leads to less vitamin A in major organs of the body."

Investigators have long sought the answer to a vexing question: What are the biological mechanisms involved in the development of type 2 diabetes? A recent study from Weill Cornell Medical College researchers suggests that the culprit may be a lack of vitamin A, which helps give rise to the cells, called beta cells, in the pancreas that produce the blood sugar-regulating hormone insulin.

The researchers found in mice models that a lack of vitamin A spurred the death of beta cells, stunting the production of insulin, which is tasked with metabolizing sugars that come from food. These findings, published Dec. 1 in The Journal of Biological Chemistry, may offer new clues into the cause of type 2 diabetes, which is characterized by insulin-resistance, and in advanced cases, inadequate numbers of insulin-producing beta cells.

When the investigators removed vitamin A from the rodents’ diet, they found that the mice began to experience massive losses of beta cells, which resulted in drops in insulin and a big increase in blood glucose. The researchers then reintroduced vitamin A into the animals’ diet and found that the number of beta cells stabilized, insulin production was higher and that blood glucose returned to normal levels.

Because patients with type 1 diabetes and those with advanced type 2 diabetes experience a loss of beta cells, there is a strong interest in developing new treatments that either preserve or replenish them. “From a therapeutic point of view, our research is a very important contribution because there are no drugs available to do this,” said first author Dr. Steven Trasino, a postdoctoral associate in the Department of Pharmacology.

Scientists have understood that vitamin A is essential for the production of insulin-producing cells during fetal development, but whether that role continued into adulthood was not known. The researchers sought to answer that question by using both normal mice and mice that had a genetically impaired ability to store vitamin A.

"While there are thousands of publications on diabetes, there hasn’t been much research on the effects of removing vitamin A from the diets of animals, acting as a model for human disease," said senior author Dr. Lorraine Gudas, chairman of the Department of Pharmacology and the Revlon Pharmaceutical Professor of Pharmacology and Toxicology at Weill Cornell. "How the removal of vitamin A causes the death of the beta cells that make insulin in the pancreas is an important question we want to answer. These beta cells in the pancreas are exquisitely sensitive to the dietary removal of vitamin A. No one has found that before."

These early-stage findings raise the question of whether vitamin A deficiency is involved in humans and animals with type 2 diabetes, either through inadequate diet or through a metabolic defect. They also spark questions about whether a synthetic analog of vitamin A could reverse the disease’s effects.

"Our study sets the platform to take these studies further into pre-clinical and clinical settings," Dr. Trasino said.