Traumatic brain injury, diabetic neuropathy and altered-psychiatric health: The fateful triangle Hadi Abou-El-Hassan a,1 , Batoul Dia b,1 , Khalil Choucair a , Stephanie A. Eid b , Farah Najdi c , Lama Baki c , Farid Talih d , Assaad A. Eid b,⇑ , Firas Kobeissy c,⇑ a Faculty of Medicine, American University of Beirut Medical Center, Beirut, Lebanon b Department of Anatomy, Cell Biology and Physiology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon c Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon d Department of Psychiatry, Faculty of Medicine, American University of Beirut Medical Center, Beirut, Lebanon article info Article history: Received 25 March 2017 Accepted 6 August 2017 abstract Traumatic brain injury is a detrimental medical condition particularly when accompanied by diabetes. There are several comorbidities going along with diabetes including, but not limited to, kidney failure, obesity, coronary artery disease, peripheral vascular disease, hypertension, stroke, neuropathies and amputations. Unlike diabetes type 1, diabetes type 2 is more common in adults who simultaneously suf- fer from other comorbid conditions making them susceptible to repetitive fall incidents and sustaining head trauma. The resulting brain insult exacerbates current psychiatric disorders such as depression and anxiety, which, in turn, increases the risk of sustaining further brain traumas. The relationship between diabetes, traumatic brain injury and psychiatric health constitutes a triad forming a non- reversible vicious cycle. At the proteomic and psychiatric levels, cellular, molecular and behavioral alter- ations have been reported with the induction of non-traumatic brain injury in diabetic models such as stroke. However, research into traumatic brain injury has not been systematically investigated. Thus, in cases of diabetic neuropathy complicated with traumatic brain injury, utilizing fine structural and ana- lytical techniques allows the identification of key biological markers that can then be used as innovative diagnostics as well as novel therapeutic targets in an attempt to treat diabetes and its sequelae especially those arising from repetitive mild brain trauma. Ó 2017 Elsevier Ltd. All rights reserved. Background Traumatic brain injury epidemiology and pathology Traumatic brain injury (TBI), defined as brain damage due to a mechanical force applied to the head, is a common neurological disorder leading to serious disability and death worldwide [1]. By the year 2020, with around 10 million annual global TBI-related deaths or hospitalizations, TBI is expected to surpass numerous human diseases. TBI is expected to become the third leading cause of death and disability leading to temporary or permanent cogni- tive deficit, physical and psychosocial impairments [1,2]. TBI is characterized by axonal injury and subsequently has a direct implication on behavioral and cognitive functions. TBI induces damage to nerve axons in many areas of the brain which can be irreversible and debilitating to TBI patients. TBI has been described as ‘‘the silent epidemic” since its consequences may not be readily apparent and many patients, especially those with mild TBI, may not be referred to the emergency departments and remain undiagnosed [3]. This damage begins within minutes after the injury and develops to hours or days, and leads to diffuse loss of synaptic terminals [4,5]. In fact, TBI can result from either a direct impact to the skull causing open or closed injury or due to acceleration/deceleration/rotational forces or penetrating object causing mechanical damage to the brain tissue. The injury can be either confined to one area of the brain or can be diffused involving more than one area [6]. Subsequently, the damage may be classi- fied as mild, moderate or severe and range from scalp contusion, skull fracture, to brain contusions and lacerations, epidural, subdu- ral and subarachnoid hemorrhage, in addition to focal or diffuse patterns of axonal injury [7]. TBI pathology includes primary and secondary insults. Primary insult is the result of the direct or indi- rect mechanical (acceleration and deceleration) forces that cause brain and BBB tissue distortion and destruction in the early post injury period [8]. Secondary insult leads to degeneration of neu- rons, glial cells, or axons due to the bimolecular and physiological http://dx.doi.org/10.1016/j.mehy.2017.08.008 0306-9877/Ó 2017 Elsevier Ltd. All rights reserved. ⇑ Corresponding authors. E-mail addresses: ae49@aub.edu.lb (A.A. Eid), firasko@gmail.com (F. Kobeissy). 1 Equal contribution. Medical Hypotheses 108 (2017) 69–80 Contents lists available at ScienceDirect Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy