Targeting Glucotoxicity to Improve Psychological Health After TBI

This multidisciplinary proposal addresses the FY22 TBIPHRP IIRA Focus Areas to elucidate the role of traumatic brain injury (TBI)-induced impairments in glucose metabolism in the etiology of psychological and cognitive health conditions and the potential of targeting chronic impairments in systemic and cerebral glucose metabolism for treatment. TBI is a common cause of disability and, even in mild forms, can lead to several chronic sequelae such as post-traumatic stress disorder (PTSD), depression, anxiety and memory loss. While stress hyperglycemia is a known complication in the acute phase after TBI, the development of glucose intolerance and prediabetes in the chronic phase after injury is not currently a recognized consequence of TBI. Persistent brain inflammation is believed to underlie several of the long-term complications of TBI and is thus a promising therapeutic target, but its causes are poorly understood, especially in the context of mild injuries. Our proposal is based on four key findings by the Buettner Lab. First, rats subjected to mild repeated blast TBI, which mimics repetitive injury such as service members may experience in combat from repeated explosions, develop long lasting glucose intolerance leading to recurrent high glucose after meals. Second, in independent studies of acutely and chronically diabetic rats, we found that hyperglycemia drives microglial activation and brain inflammation. Third, administration of a diabetes drug that increases urinary excretion of glucose and normalizes blood glucose, reversed the brain inflammation and improved chronic memory loss and anxiety. Fourth, insulin directly acts on the brain to lower blood glucose after a meal, but brain inflammation can lead to persistently impaired action of insulin in the brain and high blood glucose. In TBI, impaired brain responses to insulin have been observed, suggesting that impaired insulin action in the brain after TBI may account for the glucose intolerance and glucose toxicity. Taken together, these findings support the central hypothesis that impaired brain control of glucose metabolism and elevated glucose levels maintain chronic neuroinflammation in TBI in a vicious cycle. A corollary is that interventions that normalize blood glucose levels may attenuate brain inflammation and thus alleviate cognitive and behavioral complications of TBI. This hypothesis will be examined in two specific aims in collaboration with Bryan Pfister from NJIT, who has strong expertise in rodent models of TBI. In Aim 1, we will test whether suppressing the glucose intolerance and glucose toxicity improves brain inflammation along with psychological health and memory in a rat model of TBI. In Aim 2, we will test whether restoring the action of insulin in the brain normalizes glucose levels thereby attenuating brain inflammation as well as psychological and cognitive sequelae of TBI.

Impact to the Research Field: The short-term impact to the field is to identify metabolic drivers of chronic brain inflammation in TBI and to refine the understanding of mechanisms of brain control of glucose metabolism that are important to the psychological and cognitive health conditions of TBI. The long-term impact is that this work will provide new insights into a role of peripheral metabolism in driving brain inflammation. Such knowledge may have broad clinical relevance that transcends TBI, and may apply to other neuropsychiatric conditions such as Alzheimer's disease and chronic stress that are also associated with altered glucose metabolism.

Impact to Patient Care: The short-term impact of this research is to provide the medical field and the general population with the knowledge that an association between TBI and prediabetes exists and that brain toxicity driven by high glucose may increase vulnerability to psychological and cognitive complications after a brain injury. Subjects with a history of TBI may need to be counseled about their increased risk of diabetes and the need to implement lifestyle changes. The association is especially important to recognize in individuals who suffered mild TBI and are often missed at long-term follow up. The long-term impact to patient care is that our studies may create the basis for clinical trials to test whether the diabetes drug tested in this proposal is effective to prevent prediabetes and improve psychological and cognitive health in TBI survivors.