The long-term goal of this project is to improve neurological health of diabetics by decreasing the severity and incidence of cerebral ischemia in diabetics. Cerebral ischemia and heart disease are the most serious complications of diabetes, accounting for more than 84% of the mortality among diabetics. Epidemiological studies of cerebral ischemia suggest that diabetes increases both the risk of incidence and exacerbates the consequences of cerebral ischemia. Hyperglycemia is one of the contributing factors. In clinical studies, intensive anti-diabetic therapy was able to delay the onset and slow the progression of secondary complications of diabetes. The major side-effect of intensive diabetic therapy is hypoglycemia. Several reports described hypoglycemic episodes in type 1 and type 2 diabetics receiving intensive therapy. Using the streptozotocin-diabetic rat, we observed that recurrent hypoglycemia (RH) renders the insulin-treated diabetic (ITD) rat brain more sensitive to global cerebral ischemia and results in greater brain damage. Presently, we are proposing to investigate the mechanism by which RH increases ischemic damage in ITD. In preliminary studies we observed that the intra-ischemic extracellular pH drop was enhanced, and the levels of glucose transporters (GLUTs) 1 and 3 were increased in the hippocampus of ITD rats subjected to RH. We hypothesize that in the insulin-treated diabetic brain, increased glucose transporter levels following RH lead to increased intra-ischemic acidosis, sensitizing the brain towards the enhancement of cerebral ischemia-induced damage. The following specific objectives are proposed to test the central hypothesis: 1) To determine how RH increases cerebral ischemic damage in ITD rats;2) To determine the mechanism by which the larger intra-ischemic pH drop in RH-exposed ITD rats increases cerebral ischemic damage;and 3) To determine the mechanism by which RH increases GLUT1 and GLUT3 levels in the hippocampus of ITD rats. We expect these studies to provide insight into the mechanism by which RH increases ischemic damage in diabetics. Understanding this mechanism will help improve outcome following cerebral ischemia.

Public Health Relevance

Diabetes is a risk factor for cerebral ischemia and heart disease. A major side effect of intensive therapy for diabetics is intermittent low blood glucose levels (hypoglycemia). Our results indicate that intermittent hypoglycemic episodes preceding an ischemic attack result in increased brain damage in diabetics. We propose to determine the mechanisms by which hypoglycemic episodes cause increased susceptibility to cerebral ischemic damage in diabetics.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Brain Injury and Neurovascular Pathologies Study Section (BINP)
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Bosetti, Francesca
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University of Miami School of Medicine
Schools of Medicine
Coral Gables
United States
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Rehni, Ashish K; Dave, Kunjan R (2018) Impact of Hypoglycemia on Brain Metabolism During Diabetes. Mol Neurobiol 55:9075-9088
Smith, Logan; Chakraborty, Diya; Bhattacharya, Pallab et al. (2018) Exposure to hypoglycemia and risk of stroke. Ann N Y Acad Sci 1431:25-34
Rehni, Ashish K; Dave, Kunjan R (2018) Ameliorative potential of conditioning on ischemia-reperfusion injury in diabetes. Cond Med 1:105-115
Shukla, Vibha; Fuchs, Perry; Liu, Allen et al. (2018) Recurrent Hypoglycemia Exacerbates Cerebral Ischemic Damage in Diabetic Rats via Enhanced Post-Ischemic Mitochondrial Dysfunction. Transl Stroke Res :
Rehni, Ashish K; Shukla, Vibha; Perez-Pinzon, Miguel A et al. (2018) Acidosis mediates recurrent hypoglycemia-induced increase in ischemic brain injury in treated diabetic rats. Neuropharmacology 135:192-201
Rehni, Ashish K; Liu, Allen; Perez-Pinzon, Miguel A et al. (2017) Diabetic aggravation of stroke and animal models. Exp Neurol 292:63-79
Klingbeil, Kyle D; Koch, Sebastian; Dave, Kunjan R (2017) Potential link between post-acute ischemic stroke exposure to hypoglycemia and hemorrhagic transformation. Int J Stroke :1747493017743797
Shukla, Vibha; Shakya, Akhalesh Kumar; Perez-Pinzon, Miguel A et al. (2017) Cerebral ischemic damage in diabetes: an inflammatory perspective. J Neuroinflammation 14:21
Koronowski, Kevin B; Dave, Kunjan R; Saul, Isabel et al. (2015) Resveratrol Preconditioning Induces a Novel Extended Window of Ischemic Tolerance in the Mouse Brain. Stroke 46:2293-8
Cohan, Charles H; Neumann, Jake T; Dave, Kunjan R et al. (2015) Effect of cardiac arrest on cognitive impairment and hippocampal plasticity in middle-aged rats. PLoS One 10:e0124918

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