A look inside the diabetic brain: Contributors to diabetes-induced brain aging

Department of Pharmacology, Physiology and Neuroscience University of South Carolina, School of Medicine, Columbia, SC 29208, USA.
Biochimica et Biophysica Acta (Impact Factor: 4.66). 12/2008; 1792(5):444-53. DOI: 10.1016/j.bbadis.2008.10.013
Source: PubMed

ABSTRACT Central nervous system (CNS) complications resulting from diabetes is a problem that is gaining more acceptance and attention. Recent evidence suggests morphological, electrophysiological and cognitive changes, often observed in the hippocampus, in diabetic individuals. Many of the CNS changes observed in diabetic patients and animal models of diabetes are reminiscent of the changes seen in normal aging. The central commonalities between diabetes-induced and age-related CNS changes have led to the theory of advanced brain aging in diabetic patients. This review summarizes the findings of the literature as they relate to the relationship between diabetes and dementia and discusses some of the potential contributors to diabetes-induced CNS impairments.

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Available from: Lawrence P Reagan, Sep 29, 2015
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    • "A recent metaanalysis showed that T1D adults perform worse on tests of full/ verbal and performance IQ, executive function, memory, spatial memory, and motor speed (Tonoli et al. 2014). This cognitive decline has been ascribed to episodes of hypoglycaemia (Auer 2004), hyperglycaemia (Wrighten et al. 2009), and C-peptide and/or insulin deficiencies (Li et al. 2005) as a pathophysiological basis. Over the last several decades much research in nondiabetic subjects has been carried out to identify the influence of acute and chronic physical exercise on cognitive function. "
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    ABSTRACT: Exercise is known to have beneficial effects on cognitive function. This effect is greatly favored by an exercise-induced increase in neurotrophic factors, such as brain-derived neurotrophic factor (BDNF) and insulin-like growth factor-1 (IGF-1), especially with high-intensity exercises (HIE). As a complication of type 1 diabetes (T1D), a cognitive decline may occur, mostly ascribed to hypoglycaemia and chronic hyperglycaemia. Therefore, the purpose of this study was to examine the effects of acute HIE on cognitive function and neurotrophins in T1D and matched controls. Ten trained T1D (8 males, 2 females) participants and their matched (by age, sex, fitness level) controls were evaluated on 2 occasions after familiarization: a maximal test to exhaustion and an HIE bout (10 intervals of 60 s at 90% of their maximal wattage followed by 60 s at 50 W). Cognitive tests and analyses of serum BDNF, IGF-1, and free insulin were performed before and after HIE and following 30 min of recovery. At baseline, cognitive performance was better in the controls compared with the T1D participants (p < 0.05). After exercise, no significant differences in cognitive performance were detected. BDNF levels were significantly higher and IGF-1 levels were significantly lower in T1D compared with the control group (p < 0.05) at all time points. Exercise increased BDNF and IGF-1 levels in a comparable percentage in both groups (p < 0.05). In conclusion, although resting levels of serum BDNF and IGF-1 were altered by T1D, comparable increasing effects on BDNF and IGF-1 in T1D and healthy participants were found. Therefore, regularly repeating acute HIE could be a promising strategy for brain health in T1D.
    Applied Physiology Nutrition and Metabolism 01/2015; 40(1). DOI:10.1139/apnm-2014-0098 · 2.34 Impact Factor
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    • "There is substantial evidence that diabetes mellitus (DM) may have a negative impact on the central nervous system, and that cognitive impairment is the most common symptom of this condition1,2,3. Hyperglycemia-associated microvascular changes in the brain are responsible for the cognitive decline in patients with type 1 diabetes mellitus (T1DM); intensive insulin therapy for the treatment of T1DM results in improved glycemic control. Additionally, insulin treatment aims toward correcting the deficits in spatial learning and memory4,5. "
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    ABSTRACT: Aim: To examine the effects of pioglitazone, a PPARγ agonist, on memory performance and brain amyloidogenesis in streptozotocin (STZ)-induced diabetic mice. Methods: ICR male mice were injected with STZ (150 mg/kg, iv) to induce experimental diabetes. Pioglitazone (9 and 18 mg·kg-1·d-1, po) was administered for 6 weeks. Passive avoidance and Morris water maze (MWM) tests were used to evaluate cognitive function. The blood glucose and serum insulin levels were detected using the glucose oxidase method and an ELISA assay, respectively. β-amyloid (Aβ), β-amyloid precursor protein (APP), β-amyloid precursor protein cleaving enzyme 1 (BACE1), NF-κB p65, the receptor for advanced glycation end products (RAGE) and PPARγ in the brains were analyzed using Western blotting assays. Results: The STZ-induced diabetic mice characterized by hyperglycemia and hypoinsulinemia performed poorly in both the passive avoidance and MWM tests, accompanied by increased Aβ1–40/Aβ1–42, APP, BACE1, NF-κB p65 and RAGE levels and decreased PPARγ level in the hippocampus and cortex. Chronic pioglitazone treatment significantly ameliorated the memory deficits and amyloidogenesis of STZ-induced diabetic mice, and suppressed expression of APP, BACE1, RAGE and NF-κB p65, and activated PPARγ in the hippocampus and cortex. However, pioglitazone did not significantly affect blood glucose and insulin levels. Conclusion: Pioglitazone ameliorates memory deficits in STZ-induced diabetic mice by reducing brain Aβ level via activation of PPARγ, which is independent of its effects on blood glucose and insulin levels. The results suggest that pioglitazone may be used for treating the cognitive dysfunction in type 1 diabetes mellitus.
    Acta Pharmacologica Sinica 03/2013; 34(4). DOI:10.1038/aps.2013.11 · 2.91 Impact Factor
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    • "However, when the ITI is increased, which more directly assesses hippocampal-dependent function, these leptin receptor deficient rats perform more poorly when compared to control rats (Winocur et al., 2005). Interestingly, Zucker rats also exhibit increases in AD-like pathology, including increases in hyper-phosphorylated tau immunoreactivity in the dentate gyrus and CA3 region of the hippocampus (Wrighten et al., 2008). Collectively, these data illustrate that hippocampal synaptic plasticity is impaired in leptin-deficient rodents. "
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    ABSTRACT: Through their well described actions in the hypothalamus, appetitive peptides such as insulin, orexin and leptin are recognized as important regulators of food intake, body weight and body composition. Beyond these metabolic activities, these peptides also are critically involved in a wide variety of activities ranging from modulation of immune and neuroendocrine function to addictive behaviors and reproduction. The neurological activities of insulin, orexin and leptin also include facilitation of hippocampal synaptic plasticity and enhancement of cognitive performance. While patients with metabolic disorders such as obesity and diabetes have greater risk of developing cognitive deficits, dementia and Alzheimer's disease (AD), the underlying mechanisms that are responsible for, or contribute to, age-related cognitive decline are poorly understood. In view of the importance of these peptides in metabolic disorders, it is not surprising that there is a greater focus on their potential role in cognitive deficits associated with aging. The goal of this review is to describe the evidence from clinical and pre-clinical studies implicating insulin, orexin and leptin in the etiology and progression of age-related cognitive decline. Collectively, these studies support the hypothesis that leptin and insulin resistance, concepts normally associated with the hypothalamus, are also applicable to the hippocampus.
    Ageing research reviews 02/2013; 12(3). DOI:10.1016/j.arr.2013.01.009 · 4.94 Impact Factor
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