When the body does not properly manage insulin levels, diabetes and other metabolic disorders are familiar outcomes. That hormonal imbalance, however, has also been linked to a higher risk for psychiatric disorders, such as schizophrenia. And a new study has uncovered a potential pathway by which this metabolic hormone can upset the balance of a key neurotransmitter.

"We know that people with diabetes have an increased incidence of mood and other psychiatric disorders," Kevin Niswender, an endocrinologist at Vanderbilt University Medical Center and coauthor of the study, said in a prepared statement. Previous researchers, including Aurelio Galli, a neurobiologist at Vanderbilt, had found that insulin was affecting more than blood sugar levels.

"Something goes wrong in the brain because insulin isn't signaling the way that it normally does," Galli, a coauthor of the new paper, published online June 8 in the journal PLoS Biology, said in a prepared statement. Although schizophrenia is a complex disease that is thought to have a variety of individual genetic and epigenetic causes, these researchers and others have proposed that a common thread is too little dopamine, a neurotransmitter that is involved in movement, reward and motivation.

But just how, molecularly, insulin and dopamine dysfunctions might be linked has yet to be settled.

In the new study, the researchers focused on the protein kinase Akt, which plays a role in cell signaling and has been linked to schizophrenia as well as to diabetes and obesity. It is controlled by hormones, neurotransmitter receptors and growth factors. To study Akt's possible role in schizophrenia and its relation to insulin dysregulation, the researchers created a line of transgenic mice that had poor Akt signaling, leading to schizophrenia-like behaviors.

The researchers also found that the modified mice had increased transportation of another neurotransmitter norepinephrine (which also acts as a stress hormone) and a deficit of dopamine in their brains, a condition known as hypodopaminergia.

"We believe the excess [norepinephrine transporters are] sucking away all of the dopamine and converting it to norepinephrine, creating this situation of hypodopaminergia in the cortex," Galli said.

And when the researchers inhibited the norepinephrine transporter in these Akt knock-out mice, "we could reverse the cortical hypodopaminergia and behavioral deficits," they noted in the study.

"Taken together, this work supports the potential for targeting both Akt and the norepinephrine transporter for treating dopamine-related mood disorders," the researchers concluded. They also point out clinical trials are already testing norepinephrine transporter blockers for their effectiveness in restoring dopamine balance in schizophrenics.

The molecular pathway might also shed some light on behavioral issues associated with diabetes and other insulin-related metabolic disorders. "We thought that those co-morbidities might explain why some patients have trouble taking care of their diabetes," Niswender said.

Image of dopamine pathways in the brain courtesy of Wikimedia Commons/NIDA