PHILADELPHIA—Insulin resistance—the inability of diabetics to properly process sugar—is a leading hurdle in the difficulty of treating diabetes. While lifestyle and genetic issues such as high blood pressure, being overweight and having family members with the disease are known to be risk factors for developing diabetes, the cause of insulin resistance itself has remained unanswered.
Recently, however, the investigation of certain amino acids has uncovered their link to insulin resistance by a team led by scientists from the Perelman School of Medicine at the University of Pennsylvania. The study findings, “A branched-chain amino acid metabolite drives vascular fatty acid transport and causes insulin resistance,” were published online in Nature Medicine ahead of the print issue.
Insulin plays several roles in the body, including helping muscle, fat and liver cells to absorb glucose from the blood, stimulating the liver and muscle tissue to store excess glucose and lowering blood glucose levels by reducing glucose production in the liver, according to the National Institute of Diabetes and Kidney Diseases.
Insulin resistance results when the body produces insulin, but fat, muscle and liver cells no longer respond properly to insulin, making it harder for them to absorb glucose from the blood. More insulin is needed to aid in glucose absorption, leading to increased production by the pancreas. When sufficient insulin can not be produced, it leads to a buildup of glucose in the blood, which in turn leads to type 2 diabetes. In addition, excess body fat, a risk factor that can lead to diabetes, also leads to insulin resistance, especially excess fat in skeletal muscle. One theory is that if the level of muscular fat can be reduced, then it should be possible to prevent insulin resistance.
Dr. Zoltan Arany, an associate professor of cardiovascular medicine at the University of Pennsylvania and senior author of the work, noted that their research “sought to answer a few large questions.”
“How does fat get into skeletal muscle? And how is the elevation of certain amino acids in people with diabetes related to insulin resistance? We have appreciated for over 10 years that diabetes is accompanied by elevations in the blood of branched-chain amino acids, which humans can only obtain in their diet,” Arany explained. “However, we didn’t understand how this could cause insulin resistance and diabetes. How is elevated blood sugar related to these amino acids?”
What the researchers found was that a byproduct compound of the breakdown of these amino acids, known as 3-HIB, is secreted from muscle cells and activates cells in the vascular wall to transport more fat into skeletal muscle tissue. This in turn leads to fat accumulation in the muscle, which then, in mice, results in insulin resistance. Inhibiting the synthesis of 3-HIB in muscle cells was shown to block the uptake of fat in muscle.
As noted in the paper, “Epidemiological and experimental data implicate branched-chain amino acids (BCAAs) in the development of insulin resistance, but the mechanisms that underlie this link remain unclear. Insulin resistance in skeletal muscle stems from the excess accumulation of lipid species, a process that requires blood-borne lipids to initially traverse the blood vessel wall … We found that 3-HIB is secreted from muscle cells, activates endothelial fatty acid transport, stimulates muscle fatty acid uptake in vivo and promotes lipid accumulation in muscle, leading to insulin resistance in mice.”
The bulk of the research was conducted using mouse cells, but the team also used human muscle and blood samples, and found that 3-HIB is elevated in people with type 2 diabetes.
“The discovery of this novel pathway – the way the body breaks down these amino acids that drives more fat into the muscles – opens new avenues for future research on insulin resistance, and introduces a conceptually entirely new way to target treatment for diabetes” Arany said.