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PART 2 of a series on new diabetes research at the Lunenfeld 
 
Possible links between metabolic abnormalities and psychiatric illnesses
Similar to type 2 diabetes, several psychiatric and neurodegenerative disorders are also associated with obesity, sedentary lifestyle and genetic predisposition.
 
Psychiatric disorders can be a risk factor for, as well as a complication of, diabetes, obesity and metabolic syndrome (a group of risk factors that together increase the risk for coronary artery disease and stroke). And antipsychotic medications, widely used to treat a variety of psychiatric conditions, are also associated with diabetes and obesity.
 
It is believed that abnormal glucose metabolism and chronic hyperglycemia may affect the memory process, neurotransmitter status, neuronal structure and survival, and disrupt neuronal circuits in the brain responsible for emotions, motivation, as well as eating behaviours. 
 
So what’s the connection? The answer might lie in common factors of molecular-genetic predisposition, metabolic regulation, alterations in the neurotransmitter functions associated with psychiatric illnesses and their treatment, unique and common psychosocial variables (e.g., stress, and early-life social trauma such as abuse), or a combination of these.
 
The role of GSK-3
At the molecular level, the enzyme glycogen synthase kinase-3 (GSK-3) is a direct target of the drug lithium (commonly used to treat bipolar disorder), as well as other anti-depressant, anti-psychotic and insulin-mimetic drugs and has an essential role in many signaling pathways. This cellular master-switch regulates the function of transcription factors, structural and metabolic proteins, and has important effects in the brain including memory formation, neurogenesis, neuroinflammation and metabolism.
 
Abnormal activity of GSK-3 has been found in patients with Alzheimer’s disease, bipolar disorder, and schizophrenia. GSK-3 activity is naturally suppressed by insulin, but is elevated in fat and muscle tissues obtained from people with type II diabetes.
 
To explore these links further, Dr. Oksana Kaidanovich-Beilin, a post-doctoral Fellow in Dr. Jim Woodgett’s lab, is working to better understand the molecular mechanisms behind the connection between brain function and peripheral metabolism, and the role of GSK-3. Her goal is to assess how peripheral glucose metabolism is affected by mood, and vice versa.
 
“There are strong clinical data to support that some psychiatric disorders are independent risk factors for diabetes and obesity,” said Dr. Kaidanovich-Beilin. “In addition, second- generation anti-psychotic drugs induce side effects including metabolic syndrome. We are also intrigued that GSK-3 has been implicated in the pathogenesis of both metabolic and psychiatric disorders.”
 
“Since Dr. Woodgett’s lab has been working on this kinase for the past 20 years, we have decided to apply our systems to explore the mechanism of how the same enzyme can be simultaneously involved in regulating peripheral metabolism and essential brain functions, and whether or not targeting GSK-3 itself or related pathways may affect both conditions.”
 
In an innovative model, Dr. Kaidanovich-Beilin and her colleagues generated a “double-knock-out” mouse in which GSK-3 alpha and beta (the two GSK-3 genes) were genetically  inactivated in a specific brain region (the forebrain/limbic system) following administration of a certain drug.
 
“In our pilot study, we discovered that the mice display anti-depressant like behaviours after GSK is switched off in this specific region of the brain,” said Dr. Kaidanovich-Beilin. “Moreover, these mice have reduced body weight and are resistant to high fat diet-induced insulin resistance. It is still an ongoing project, but we have promising results and this allows us to explore how mood may be important in modifying our metabolism.”
 
In essence, Dr. Kaidanovich-Beilin suggests that targeting glucose metabolism may be a new way to improve mood in disorders including depression and schizophrenia.
 
She is collaborating with Dr. Roger McIntyre, Associate Professor of Psychiatry and Pharmacology at the University of Toronto and Head of the Mood Disorders Psychopharmacology Unit at the University Health Network. Dr. McIntyre’s research involves identifying metabolic complications associated with the use of psychotropic medications, the impact of associated medical complications on the course of mood disorders, and the effect of glucose metabolism and regulation on cognitive functioning. His new approach is focused on evaluating if insulin can help regulate moods in people with bipolar disorder. Click here to read the National Post article on this topic, published in March 2011.
 
Emerging evidence shows dual role of GSK-3 in the liver
Prital Patel, a Masters student in Dr. Woodgett’s lab, is assessing the function of GSK-3 in liver and adipose (fat) tissue. Using a genetic model where GSK-3 was completely inactivated in just the hepatocytes of the liver, she and a colleague, Dr. Satish Patel, found that the liver grew uncontrollably.
 
“GSK-3 opposes the effects of insulin by suppressing glucose absorption by cells,” says Prital. “Therefore to treat diabetes, researchers are looking at targeting and inhibiting it, thereby making insulin more efficient for improved glucose control. This is especially important because GSK-3 activity has been found to higher in the adipose tissue and muscle of people with diabetes.”
 
Prital’s ongoing project assesses the dual role for GSK-3 in the liver: tissue regeneration, as well as in metabolizing short-term deposits of glucose (as glycogen). GSK-3 controls the enzyme involved in the rate-limiting step of glycogen synthesis. Inhibition of GSK-3 would therefore provide cells a mechanism to take glucose out of the bloodstream and store it in both the liver and muscle, preventing damage to vasculature brought about by hyperglycemia.
 
A protein called beta-catenin has also been implicated as an important target in regeneration of the liver. Since GSK-3 is also a major regulator of the levels of this protein in cells, Prital is also examining the effects of inactivating both GSK-3 and beta-catenin in combination.  
 
“GSK-3 is a very exciting protein to be working on, since it controls many signalling pathways and is involved in determining cell fate,” says Prital. “So far our results have shown that GSK-3 is also important in the development of adipose tissues, as well as in improving insulin- stimulated glucose uptake.”
 
The Woodgett lab is working to determine isoform-specific effects of GSK-3 in each of the major insulin-sensitive tissues, namely the liver, muscle and adipose tissue.
 
 
 

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