When Aging-Onset Diabetes Is Coming Across With Alzheimer Disease: Comparable Pathogenesis And Therapy.
ABSTRACT Diabetes Mellitus is a metabolic disorder that is characterized by high blood glucose because of the insulin-resistance and insulin-deficiency in Type 2,while the insulin deficiency due to destruction of islet cells in the pancreas in Type 1 . The development of type 2 diabetes is caused by a combination of lifestyle and genetic factors. Aging patients with diabetes are at increased risk of developing cognitive and memory dysfunctions,which is one of the significant symptoms of Alzheimer Disease(AD). Also, over 2/3 of AD patients were clinically indentified with impairment of glucose. Cognitive dysfunction would be associated with poor self-care ability in diabetes patients.This review will briefly summarize the current knowledge of the pathogenesis of these two diseases and highlight similarities in their pathophysiologies .Furthermore, we will shortly discuss recent progress in the insulin-targeted strategy, aiming to explore the inner linkage between these two diseases in aging populations.
- SourceAvailable from: Noé Alvarado-Vásquez
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- "The diversity of factors previously proposed (Aβ, glucose, insulin, etc.) as the origin of AD makes it difficult to find the central mechanisms that cause the disease (Baptista et al., 2013; Boudina et al., 2007; Liu et al., 2006; Russell et al., 2002). However, an increasing number of works support the role of hyperglycemia as a risk factor for the development of neuronal damage (Tomlinson and Gardiner, 2008) and starting point of Alzheimer disease (Tang et al., 2013). Nevertheless, it is still an issue of strong debate how a high glucose concentration could favor brain damage in the presence or absence of Aβ in individuals at risk of developing AD. "
ABSTRACT: Diabetes mellitus (DM) is considered a risk factor for the development of Alzheimer disease (AD); however, how DM favors evolution of AD is still insufficiently understood. Hyperglycemia in DM is associated to an increase in mitochondrial reactive oxygen species (ROS) generation, as well as damage of hippocampal cells, reflected by changes in morphological and mitochondrial functionality. Similar mitochondrial damage has been observed when amyloid beta (Aβ) accumulates in the brain of AD patients. In DM, the excess of glucose in the brain induces higher activity of the hexosamine biosynthesis pathway (HBP), it synthesizes UDP-N-acetylglucosamine (UDP-GlcNAc), which is used by O-linked N-acetylglucosamine transferase (OGT) to catalyze O-GlcNAcylation of numerous proteins. Although O-GlcNAcylation plays an important role in maintaining structure and cellular functionality, chronic activity of this pathway has been associated with insulin resistance and hyperglycemia-induced glucose toxicity. Three different forms of OGT are known: nucleocytoplasmic (ncOGT), short (sOGT), and mitochondrial (mOGT). Previous reports showed that overexpression of ncOGT is not toxic to the cell; in contrast, overexpression of mOGT is associated with cellular apoptosis. In this work, we suggest that hyperglycemia in the diabetic patient could induce greater expression and activity of mOGT, modifying the structure and functionality of mitochondria in hippocampal cells, accelerating neuronal damage, and favoring the start of AD. In consequence, mOGT activity could be a key point for AD development in patients with DM.Experimental Gerontology 08/2014; DOI:10.1016/j.exger.2014.08.008 · 3.53 Impact Factor
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- "Administering insulin and Hsp70 can reduce amyloid accumulation in the brain (Tang et al. 2013; Huang et al. 2014; Bobkova et al. 2013). Like aging, t2DM accelerates the loss of genome-protecting telomeres (Garagnani et al. 2013; Balasubramanyam et al. 2007) because preservation of telomeres is dependent on a functioning cell stress response (Strub et al. 2008). "
ABSTRACT: Organisms have evolved to survive rigorous environments and are not prepared to thrive in a world of caloric excess and sedentary behavior. A realization that physical exercise (or lack of it) plays a pivotal role in both the pathogenesis and therapy of type 2 diabetes mellitus (t2DM) has led to the provocative concept of therapeutic exercise mimetics. A decade ago, we attempted to simulate the beneficial effects of exercise by treating t2DM patients with 3 weeks of daily hyperthermia, induced by hot tub immersion. The short-term intervention had remarkable success, with a 1 % drop in HbA1, a trend toward weight loss, and improvement in diabetic neuropathic symptoms. An explanation for the beneficial effects of exercise and hyperthermia centers upon their ability to induce the cellular stress response (the heat shock response) and restore cellular homeostasis. Impaired stress response precedes major metabolic defects associated with t2DM and may be a near seminal event in the pathogenesis of the disease, tipping the balance from health into disease. Heat shock protein inducers share metabolic pathways associated with exercise with activation of AMPK, PGC1-a, and sirtuins. Diabetic therapies that induce the stress response, whether via heat, bioactive compounds, or genetic manipulation, improve or prevent all of the morbidities and comorbidities associated with the disease. The agents reduce insulin resistance, inflammatory cytokines, visceral adiposity, and body weight while increasing mitochondrial activity, normalizing membrane structure and lipid composition, and preserving organ function. Therapies restoring the stress response can re-tip the balance from disease into health and address the multifaceted defects associated with the disease.Cell Stress and Chaperones 02/2014; 19(4). DOI:10.1007/s12192-014-0493-8 · 2.54 Impact Factor
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- "Aging patients with Type 2 diabetes (T2D) are at a high risk of developing cognitive and memory impairments including some of Alzheimer disease 0 s (AD) most significant symptoms . In recent years it has become evident that some characteristics of AD are regulated by insulin-like growth factor signaling cascades . "
ABSTRACT: Diabetes is a high risk factor for dementia and has been shown in transgenic animals to cause a potentiation of indices that are pre-symptomatic of Alzheimer's disease. To further elucidate the underlying mechanisms linking inflammatory events elicited in the brain during oxidative stress and diabetes, we monitored the anti-inflammatory effects of the thioredoxin mimetic (TxM) peptides, Ac-Cys-Pro-Cys-amide (CB3) and Ac-Cys-Gly-Pro-Cys-amide (CB4) in the brain of male leptin-receptor-deficient Zucker Diabetic Fatty (ZDF) rats and human neuroblastoma SH-5HY5 cells. Daily i.p injection of CB3 to ZDF rats inhibited the phosphorylation of the MAP kinases, c-jun NH2-terminal kinase (JNK) and p38 MAP kinases (p38MAPK), and prevented the expression of thioredoxin-interacting-protein (TXNIP/TBP-2) in ZDF rat brain. Although plasma glucose/insulin remained high, CB3 also increased the phosphorylation of AMP-ribose activating kinase (AMPK) and inhibited p70S6K kinase in the brain. Both CB3 and CB4 reversed apoptosis induced by inhibiting thioredoxin reductase as monitored by decreasing caspase 3 cleavage and PARP dissociation in SH-SY5Y cells. The decrease in JNK and p38MAPK activity in the absence of a change in plasma glucose implies a decrease in oxidative or inflammatory stress in the ZDF rat brain. CB3 not only attenuated MAPK phosphorylation and activated AMPK in the brain, but it also diminished apoptotic markers, most likely acting via the MAPK-AMPK-mTOR pathway. These results were correlated with CB3 and CB4 inhibiting inflammation progression and protection from oxidative stress induced apoptosis in human neuronal cells. We suggest that Trx1 mimetic peptides could become beneficial for preventing neurological disorders associated with diabetes.01/2014; 2(1). DOI:10.1016/j.redox.2013.12.018