Protein Predicts Diabetes Destiny
Molecule Foretells Insulin Resistance -- May Become New Treatment Target
June 14, 2006 - Blood levels of a vitamin-A-linked protein predict insulin resistanceinsulin resistance -- an early sign of type 2 diabetesdiabetes and a risk factor for heart diseaseheart disease.
Tests for the protein may identify people on the fast track to illness in time for them to make lifestyle changes and take medications to prevent disease. It might also tell how well these preventive measures work.
Moreover, the protein -- retinol-binding-protein 4 or RBP4 -- actually causes insulin resistance in mice. If it works the same way in people, it might become a target for new diabetes drugs. (Retinol is vitamin A.)
An international research team led by Barbara B. Kahn, MD, head of the diabetes division at Beth Israel Deaconess Medical Center, reports the findings in the June 15 issue of The New England Journal of Medicine.
"Being able to determine diabetes risk well before the onset of symptoms could provide an important opportunity for patients to take preventive measures," Kahn says in a news release. "This protein could play a causal role in insulin resistance in humans, just as our lab previously showed in mice."
Insulin, made in the pancreas, is one of the body's most important hormones. It controls blood sugar levels by allowing cells in the body to take up blood sugar for energy. In the early stages of type 2 diabetes, the body becomes resistant to insulin. As blood-sugar levels rise, and sugar tolerance drops, the pancreas tries to compensate by making more and more insulin.
In addition to being a sign of diabetes, insulin resistance also leads to heart disease.
RBP4 and Diabetes
The role of RBP4 in this process isn't entirely clear. But as insulin resistanceinsulin resistance begins, fat cells start making a lot of RBP4.
In the first part of the study, the researchers found that people's RBP4 levels went up as their insulin resistance increased. This was true in obese people, people with prediabetes, and in people with type 2 diabetes. It was also true in people who had a strong family history of type 2 diabetes.
During the second part of the study, the researchers found that people with high RBP4 levels could lower them by undergoing an exercise program. When RBP4 levels went down, so did insulin resistance.
Might RBP4 be one of the causes of diabetes? It might. As fat cells make more and more RBP4, the body’s cells become insulin resistant and less able to take up sugar for energy. At the same time, liver cells think the body needs more blood sugar, so they make more and more sugar. This chain of events would lead to dangerously high blood sugar and diabetes.
Vitamin A Linked to Diabetes?
Until Kahn's team linked RBP4 to insulin resistance, the protein had only one known function. It carries vitamin A from one place to another within the body.
There's not yet any compelling evidence that too much vitamin A in the diet increases RBP4. But a cancercancer drug called fenretinide reduces RBP4 levels. In obese mice, this drug improves insulin sensitivity and sugar tolerance.
"It will be important to determine whether the dietary intake of [vitamin A] influences insulin sensitivity and whether lowering body [vitamin A] or RBP4 through the administration of fenretinide or related compounds improves insulin sensitivity in humans," Kahn and colleagues write.