Researchers have identified a mechanism underlying insulin resistance in adolescents with obesity. The findings, published in The Journal of Clinical Investigation, present a targetable pathway that could one day allow clinicians to intervene and prevent the onset of type 2 diabetes.

The number of youths with obesity has skyrocketed over the past several decades, and in turn, so have diseases previously associated with older age groups, such as heart disease and type 2 diabetes.

In a new study, Yale researchers observed how adolescents with obesity responded to insulin. Typically, insulin halts fat breakdown in adipose tissue—the connective tissue commonly known as “body fat.” But the researchers found that in adolescents who were insulin-resistant, insulin’s ability to block fat breakdown was impaired compared with those without insulin resistance.

“If fat cells don’t respond to insulin by stopping this breakdown process, the fat gets secreted into other tissues and causes a whole host of diseases,” explains Aaron Slusher, PhD, former associate research scientist at Yale School of Medicine (YSM) and the study’s first author.

Future medications that target this pathway and block the fat secretion from the liver could potentially prevent insulin-resistant adolescents from developing type 2 diabetes, the authors say.

“Adolescence is an especially vulnerable time in life to develop type 2 diabetes,” says Nicola Santoro, MD, PhD, associate professor of pediatrics at YSM and the study’s second author. “Our study is a big step forward in understanding how insulin works—and how when it is not working correctly in fat tissue, it can lead eventually to type 2 diabetes.”

The findings follow previously made discoveries from preclinical animal research conducted by Gerald Shulman, MD, PhD, George R. Cowgill Professor of Medicine (Endocrinology) at YSM and co-author of the study.

“Stopping the flux of fat from adipose tissue to other tissues would be key to reduce the rates of the cardiometabolic complications of obesity,” Santoro says.

Lipolysis is not suppressed in youth with obesity

For the study, the researchers took biopsies of the layer of adipose tissue beneath the skin from 30 adolescents with obesity—17 of whom were insulin-resistant—before and during infusions of insulin. They excluded potential participants if they had previously been diagnosed with type 2 diabetes.

To determine insulin resistance, they used an oral glucose tolerance test—a clinical test that is typically used to diagnose prediabetes and diabetes and involves measuring blood sugar levels before and after drinking a glucose solution. Subjects whose blood glucose levels took longer to return to normal were classified as insulin-resistant.

The team took the biopsies both before and after two insulin infusions—the first at a low concentration of insulin for two hours, followed by a second, higher concentration for an additional two hours. Meanwhile, the researchers looked for proteins associated with lipolysis—the process through which the body breaks down fat.

“When the participants initially came into the lab, they had done an overnight fast,” says Slusher. “When you’re in a fasted state, your fat cells are undergoing a process in which they allow fat to be excreted so that it can travel around and provide energy to other parts of the body. Insulin infusion mimics a signal to the body that it has been fed, which typically stops lipolysis and facilitates the storage of fat.”

In adolescents who were insulin-resistant, insulin was unable to inhibit the breakdown of fat, largely because insulin failed to activate the main enzyme regulating fat breakdown in adipose tissue. As a result, excess fatty acids continued to flow into other tissues, which may help explain why some adolescents with obesity develop type 2 diabetes.

“We are seeing a well-characterized mechanism respond differently in two distinct populations of children with obesity,” Slusher says.

Future research focuses on type 2 diabetes prevention

When Sonia Caprio, MD, professor of pediatrics (endocrinology) at YSM and senior author of the study, began treating children in the early ’90s, childhood obesity was not common. “But little by little, we saw an increase in the prevalence of obesity—and it became very concerning to us,” she says. “By the beginning of the 2000s, we realized kids were being diagnosed with type 2 diabetes, which was—at least in our clinic—previously unheard of.”

The team hopes their identification of this altered mechanism can help researchers better understand how to therapeutically intervene.

“We can see if interventions—such as dietary changes or physical activity interventions, or perhaps a new pharmacologic agent—impact this target favorably,” says Slusher. “Then, we can hopefully design a strategy to make these youth more sensitive to insulin signaling and mitigate negative downstream consequences.”

Caprio’s laboratory is currently studying how drugs such as semaglutide—currently used for weight loss and treating type 2 diabetes—improve insulin sensitivity and prevent type 2 diabetes in youth. “I want to stop the onset of type 2 diabetes—that’s our goal,” she says.

The research reported in this news article was supported by the National Institutes of Health (awards R01HD02801625A1, T32DK007058, R01DK124272, RO1DK119968, R01MD015974, RO1DK113984, P3DK045735, RO1DK133143, and RC2DK120534) and Yale University. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Additional support was provided by the Robert E. Leet and Clara Guthrie Patterson Trust Mentored Research Award.