Defects in insulin action – which occur in diabetes and obesity – could directly contribute to psychiatric disorders like schizophrenia. Vanderbilt University Medical Center investigators Aurelio Galli, Kevin Niswender, and colleagues have discovered a molecular link between impaired insulin signaling in the brain and schizophrenia-like behaviors in mice. The findings, publishing next week in the online, open-access journal PLoS Biology, offer a new perspective on the psychiatric and cognitive disorders that affect patients with diabetes and suggest new strategies for treating these conditions.
"We know that people with diabetes have an increased incidence of mood and other psychiatric disorders," said endocrinologist Niswender, M.D., Ph.D. "And we thought that those co-morbidities might explain why some patients have trouble taking care of their diabetes."
Galli's group was among the first to show that insulin – the hormone that governs glucose metabolism in the body – also regulates the brain's supply of dopamine – a neurotransmitter with roles in motor activity, attention and reward. Disrupted dopamine signaling has been implicated in brain disorders including depression, Parkinson's disease, schizophrenia and attention-deficit hyperactivity disorder.
Now, Galli, Niswender, and colleagues have pieced together the molecular pathway between perturbed insulin signaling in the brain and dopamine dysfunction leading to schizophrenia-like behaviors. The researchers developed mice with an insulin-signaling defect only in neurons. They found that the mice have behavioral abnormalities similar to those frequently seen in patients with schizophrenia. They also showed how defects in insulin signaling disrupt neurotransmitter levels in the brain – the mice have reduced dopamine and elevated norepinephrine in the prefrontal cortex, an important area for cognitive processes. These changes resulted from elevated levels of the transporter protein (NET) that removes norepinephrine and dopamine from the synaptic space between neurons.
By treating the mice with NET inhibitors (drugs that block NET activity), the investigators were able to restore normal dopamine levels and behaviors. Clinical trials of NET inhibitors in patients with schizophrenia are already under way and these new data provide mechanistic support for this approach. Understanding the molecular link between insulin action and dopamine balance offers the potential for novel therapeutic approaches.
"Dysregulation of this insulin-signaling pathway – because of type 1 diabetes, because of a high-fat diet, because of drugs of abuse, because of genetic variations – may put a person on the road to neuropsychiatric disorders," Galli said.