SLR - July 2012 - James E. Fullwood Jr.
Reference: Christina Yang, Adriena DeVisser, Jose A. Martinez, IIia Poliakov, Alma Rosales-Hernandez, Amit Ayer, Alexander Garven, Shaila Zaver, Natalia Rincon, Kevin Xu, Ursula I. Tuor, Ann Marie Schmidt, Cory Toth. Differential impact of diabetes and hypertension in the brain: Adverse effects in white matter. Neurobiology of Disease 42 (2011) 446-358
Scientific Literature Review
Reviewed by: James E. Fullwood Jr., DPM
Residency Program: Mercy Hospital
Podiatric Relevance:
Changes to the diabetic brain have often been coined “type three diabetes.” Diabetes (DM) and hypertension (HTN) are often regarded as concomitant and together causing multiple system morbidity. It is thought that each plays a role in cognitive dysfunction and what many physicians term “central neuropathy.” Recent studies have implicated DM and HTN in accelerated dementia, gait deterioration and impairment of cognition in children. The goal of this study was to evaluate the clinical, pathological and molecular affects of white matter decay in the diabetic and hypertensive brain.
Methods:
The study design consisted of 68 male rats with known genetic mutations for diabetes and hypertension. Rat subgroups consisted of: Type 1 diabetes, Type 2 diabetes, HTN alone and combined DM and HTN; all with appropriate controls for each group. Each of the 68 underwent magnetic resonance scanning; rat weights and blood glucose were obtained prior to sacrifice. Half of each brain was used for morphological and immuno-histochemical staining. The other half was utilized for quantitative real-time reverse transcriptase polymerase chain reaction (RT-PCR), Western blot analysis and electrophoretic mobility shift assay.
Results:
Magnetic resonance imaging (MRI) of diabetic rat brains showed no significant difference between cohorts of rats within white matter regions of interest in whole brain measurements. MRI findings showed a more specific pattern of degeneration. These regions being the cerebral peduncle (proprioception/balance), subiculum (memory), corpus callosum (sex drive) and internal capsule (limb motor function). HTN rat brain MRI ratios of degeneration could be compared with the corpus callosum of diabetics but otherwise white matter was not directly affected by HTN in this rat model. MRI brain water volume measurements were nearly the same, suggesting that cerebral ischemia played little to no role in these findings. Molecular studies of mRNA by RT-PCR, and protein analysis by Westerblot showed a down regulation of myelin by products in the brain stem of diabetic rats, while the cohort with HTN alone were not subject to down regulation of mRNA markers. MRI brain perfusion values for diabetics were consistently higher than HTN rats which showed depressed perfusion levels. Immuno-histochemical analysis revealed decreased oligodendrocyte counts in all diabetic cohort white matter with increased levels of NFkBp65. Further mRNA quantification showed that high levels of RAGE and NFkBp656 are up regulated in only the diabetic rat brain.
Conclusions:
Significant changes can be seen in the diabetic rat brain verses the hypertensive rat. The effects of diabetes in the rat brain suggest a prolonged inflammatory response by creation of reactive oxygen species (ROS) thus activating NFkB then inducting the AGE/RAGE phenomenon in both Type 1 and Type 2 diabetic rats when compared to the hypertensive cohort. Limitations to this study are these rat models are subject to hypotension and do not mimic the combined effects of arterial hypertension seen in the human diabetic hypertensive patient. The effects of HTN in this study are shown to be mild at best. Further, this article does not correlate their findings to cognitive function. These results suggest there is a more central role played by hyperglycemia in white matter degeneration than hypertension in the diabetic rat model.