From left, Aurelio Galli, PhD; Sabrina Robertson; Kevin Niswender, MD, PhD; and Michael Siuta. (Photo by Joe Howell)

Uncovering the Molecular Pathway Linking Diabetes to Brain Disorders

As a systemic disorder, diabetes is attached to a long list of comorbidities and heightened risk factors. Through public education campaigns, even laymen are now aware that diabetes is associated with a greater risk for cardiovascular disease, stroke, kidney failure, neuropathy, amputation and blindness. Newer research, however, has also uncovered a molecular link to several brain disorders ranging from Alzheimer’s and Parkinson’s to depression and schizophrenia.

A research team at Vanderbilt University Medical Center (VUSM) in Nashville has discovered a link between impaired insulin signaling in the brain and schizophrenia-like behaviors in mice. Neurobiologist Aurelio Galli, PhD, and his group were among the first to show that insulin, which governs glucose metabolism in the body, also regulates the brain’s supply of dopamine. This link is critical in that dopamine is the neurotransmitter that plays a significant role in a number of brain activities and responses including motor function, attention and reward. Disruption of dopamine signaling has been implicated in a wide array of neurological disorders linked to these activities such as Parkinson’s disease and attention deficit hyperactivity disorder.

These findings potentially impact a significant portion of the population considering nearly 8 percent of Americans are diabetic. According to the latest statistics available from the American Diabetes Association (2007 data), 23.6 million adults and children in the United States have diabetes. Of that figure, 5.7 million are undiagnosed. As alarming as it might be for nearly 24 million people to have this disease, more than twice that amount … 57 million … are considered clinically pre-diabetic. In combination, approximately one-quarter of the U.S. population is at heightened risk from diabetes.

Kevin Niswender, MD, PhD, a board certified endocrinologist and physician-scientist whose group collaborated with Galli’s researchers, noted, “We’re just now really beginning to understand how all of these different actions of insulin in the brain interact with each other.”

Together, the two VUSM teams pieced together the molecular pathway between perturbed insulin signaling in the brain and dopamine dysfunction leading to the schizophrenic-like behaviors in the mice. The results were reported this summer in PLoS Biology.

Niswender, a senior author and principal investigator on the project, noted that when the function of the important protein Akt was impaired, then mice developed behavioral abnormalities similar to those often seen in schizophrenic patients. Akt transmits insulin’s signal within cells.

The group also showed how defects in this insulin signaling disrupted the normal neurotransmitter levels in the brain. The impaired mice now had reduced dopamine and increased norepinephrine levels in the prefrontal cortex, which is the area of the brain that is critical to cognitive process. Impairment here might be linked to dementia-related disorders such as Alzheimer’s.

In the mice, the researchers discovered elevated levels of NET, a transporter protein that removes norepinephrine and dopamine from the synaptic space between neurons. The team came to believe this increased presence of NET resulted in a reduced amount of dopamine being available to regulate neurons, and that it was instead converted to norepinephrine, thus creating the imbalance. Therefore, impaired Akt function sets off a chain reaction leading to elevated NET and ultimately decreased dopamine to create a state known as hypodopaminergia.

 “Akt has long been thought to be an important modulator of schizophrenia,” stated Niswender. Now, however, he said it is becoming apparent that the protein is a key player in how insulin works in the brain on a much broader scale including impacting the areas of the brain that control reward and addictive behavior and process information into meaningful output.

Niswender noted, “It’s been known for quite some time that if you carry a diagnosis of schizophrenia, there is really a significantly elevated risk for diabetes … some estimates are four-fold. One of the confounders is that some of the medicines used to treat schizophrenia almost cause … or exacerbate … diabetes.” However, he continued, even without these medicines the increased risk to develop diabetes exists. “I think one of the really interesting things about this research is it’s beginning to point out there is a common underlying mechanism (between the two) … and that is insulin working in the brain.”

In the mice models, NET inhibitors allowed investigators to restore normal cortical dopamine levels, which led to the normalization of behaviors. Indeed, clinical trials focused on NET inhibitors were already underway in patients that have a diagnosis of schizophrenia, but this research provides new data support for that approach. Additionally, the researchers said their work suggests the insulin to Akt signaling pathway is a critical one to the function of monoamine neurotransmitters. 

In a statement that accompanied the research findings, Galli said, “Dysregulation of this 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.”

Although Niswender is quick to say this research doesn’t yet provide a treatment solution to the problem of Akt impairment, he pointed out, “I think the critical first step is understanding molecular pathways. When you understand the mechanism, it gives you new ways to treat through targeted therapies. That’s a challenge, but it’s what we’re working toward.”

Niswender concluded, “What we have looked at really is one very small, discreet piece of the puzzle. Ultimately, we’re trying to put all of these little pieces of the puzzle together … and if Akt is the major player, then trying to find ways to manipulate Akt to improve symptoms.”

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