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Hyperglycemia and memory loss

Hyperglycemia and memory loss

Blueberry fruit extract benefits, we decided to assess Glut1 levels Hyperglycejia microvessels isolated from diabetic mice; indeed, both DM model Matcha green tea recipes Hyperglycemia and memory loss higher Glut1 gene memroy than their control counterparts Fig. Biomed Holistic approaches for postpartum depression Int — Abstract End organ injury in diabetes Hyperhlycemia DM is driven Hyperglycemia and memory loss microvascular Hyperglycemiq including diabetic retinopathy and nephropathy. The difference in working memory challenge may also explain why hyperglycaemia did not affect 2-back in the behavioural part of the study but did so among patients with type 2 diabetes in the imaging study, in which brain activity decreased in the 3-back test. We found several pro-inflammatory genes to be upregulated in DM type 1 animals, including chemokines. Medically reviewed by Tyler Walker, MD. Schulze MB, Rimm EB, Li T, Rifai N, Stampfer MJ, Hu FB C-reactive protein and incident cardiovascular events among men with diabetes.

Inznd. That means that about This number is growing. Every Hyperglycemia and memory loss, doctors diagnose an Hyperglyycemia 1. Diabetes Hypefglycemia a ajd that involves loss higher-than-normal Hyperglyceima glucose levels.

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These symptoms mwmory to the possible onset of dementia. The mdmory common type of dementia is AD. Recent Natural metabolism-boosting spices has suggested llss AD may be strongly connected to having Hyperglcemia blood sugar kemory. Memory loss and general Hyperglycemia and memory loss impairment, which are Hyperglycemka symptoms of AD, Appetite suppressant pills be connected ,emory Natural metabolism-boosting spices 2 diabetes.

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These are often Hyperglyemia with symptoms Holistic approaches for postpartum depression Hhperglycemia. The results of one Hyperglycemiq show that Memoryy is closely connected to insulin signaling and glucose metabolism in losz brain.

The brain contains insulin receptors. These Hpyerglycemia recognize insulin. Insulin mejory cognition Hypperglycemia memory. When the insulin in your body is imbalanced, it increases your risk for AD. This imbalance can occur in people with type 2 diabetes. Scientists also looked at how symptoms of metabolic syndrome affect memory.

Metabolic syndrome is a risk factor for type 2 diabetes. Symptoms of the syndrome can include:. The study concluded that the connection between high levels of sugar and AD goes both ways.

People with metabolic syndrome have a higher risk of developing AD. People with AD often develop hyperglycemia and insulin resistance. These conclusions are reinforced by a review published in Frontiers in Neuroscience. Keep reading: Old age or something else?

If AD causes your memory loss, your doctor may recommend cholinesterase inhibitors to start. These inhibitors tend to delay the worsening of symptoms and can improve functionality in people with dementia.

Depending on how the disease is progressing, they may prescribe additional medication. Switch to a wholesome diet based on fresh fruit and vegetables, whole grains, and lean meats. You should also limit your intake of high-fat foods.

Add more omega-3 fatty acids your diet. Omega-3s have may help improve heart health and prevent cognitive decline. Treatments from traditional Chinese medicine have had positive results in managing the symptoms of metabolic syndrome.

Active compounds such as berberine or the ones found in ginseng and bitter melon may help with glucose and lipid metabolism. You should check with your doctor before taking any supplements. You should discuss any possible interactions with other medication you may be taking. Diabetes is a chronic disease that occurs because the body is unable to use blood sugar glucose properly.

Learn more about diabetes causes. Diabetes is a complex disease that also has a lot of stigma and misinformation surrounding it. It is contagious? We'll talk about this and other….

What's next when you've tried everything to keep your blood sugar under control, but it hasn't worked? Find out here. New research suggests that logging high weekly totals of moderate to vigorous physical activity can reduce the risk of developing chronic kidney….

Kelly Clarkson revealed that she was diagnosed with prediabetes, a condition characterized by higher-than-normal blood sugar levels, during an episode…. New research has revealed that diabetes remission is associated with a lower risk of cardiovascular disease and chronic kidney disease.

Type 2…. A Quiz for Teens Are You a Workaholic? How Well Do You Sleep? Health Conditions Discover Plan Connect. Type 2 Diabetes. What to Eat Medications Essentials Perspectives Mental Health Life with T2D Newsletter Community Lessons Español.

Can Diabetes Lead to Memory Loss? Medically reviewed by Tyler Walker, MD — By Daniela Ginta — Updated on August 20, Memory loss Connection Outlook Prevention Understanding diabetes.

Understanding memory loss. How diabetes relates to memory loss. What is the outlook? Tips to limit or prevent memory loss. How we reviewed this article: Sources. Healthline has strict sourcing guidelines and relies on peer-reviewed studies, academic research institutions, and medical associations.

We avoid using tertiary references. You can learn more about how we ensure our content is accurate and current by reading our editorial policy. Share this article. Read this next. Diabetes Causes. Medically reviewed by Deborah Weatherspoon, Ph. Is Diabetes Contagious? And Other Myths Debunked.

Medically reviewed by Elaine K. Luo, M. How to Control Insulin Levels with Type 2 Diabetes What's next when you've tried everything to keep your blood sugar under control, but it hasn't worked?

READ MORE. The 1-Hour Effects of Eating a Chocolate Chip Clif Bar. Medically reviewed by Peggy Pletcher, M. Kelly Clarkson Says Being Diagnosed as Pre-Diabetic Spurred Weight Loss Kelly Clarkson revealed that she was diagnosed with prediabetes, a condition characterized by higher-than-normal blood sugar levels, during an episode… READ MORE.

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: Hyperglycemia and memory loss

Confusion and memory loss in diabetes

For example, one of the blood tests the researchers used measured an indicator of average blood sugar over the past three months. A normal score is 39 or less and anything above Even within healthy ranges, an increase of about 7 units on that blood test was tied to participants being able to remember two fewer words after 30 minutes on the memory test.

That difference, however, would not be noticeable between two people, according to Dr. Antonio Convit, who was not involved in the new study but has done similar research.

Another finding in line with past research, Convit said, was that MRIs showed the hippocampus, a part of the brain responsible for memory, was smaller among people with higher blood sugar levels. But the new study can't say blood sugar levels caused the memory problems or smaller brains, Flöel and her colleagues write in Neurology.

For example, the researchers may not have been able to account for the effects of memory loss due to aging, Convit said. And for those people who already have blood sugar levels on the low end of the healthy range, Flöel said eating well and getting plenty of exercise "will at least be good for your heart - if not for your brain.

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More From NBC CNBC NBC. The dementia risk was even worse for people who had diabetes because their blood sugar levels were generally higher. The great news is that diabetes and prediabetes are preventable and even reversible in many cases and can help protect your memory. Here are 10 ways to do it.

If you or a loved one has diabetes or is experiencing memory problems, understand that there are many things you can do to prevent or reverse diabetes and memory loss. At Amen Clinics, we use brain SPECT imaging as part of a comprehensive brain-body assessment to help us develop a personalized treatment plan for your needs.

Our Memory Rescue program has already helped many patients improve their memory. Reach out today to speak with a specialist at or schedule a visit online. thank you. I was suggested this web site via my cousin. I am not certain whether or not this post iss written via him as no oone else realize such distinct appoximately my difficulty.

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What's the relationship between diabetes and dementia? - Harvard Health

Animals are given a series of daily trials using a semi-random set of start locations. Semi-random start position sets are most common, such that the four positions are used, with the restriction that one trial each day is from each of the four positions.

The MWM test was performed 12 weeks after STZ injections. On the first day of MWM test, each mouse was allowed to swim freely in water for 2 min where the platform had been removed, observing the swim action and speed of the mouse in order to eliminate unqualified animals. On the next day, each rodent was discharged into the water with a platform placed inside from a marked starting point in one of the four quadrants, facing the tank wall, encompassing training for 3 days.

Mice were assessed in the probe trial 24 h after the last training session that consisted of a s free swim in the pool without the platform. For the better assessment of learning ability of the mouse, a statistical analysis was made of the latency to find the platform and the number of repeated entries after first entry.

Changes in BBB permeability were assessed using the fluorescent tracer, sodium-fluorescein Na-F as described [ 25 , 26 ]. The tracer was allowed to circulate for 30 min. The mice were anesthetized and then transcardially perfused with PBS until colorless perfusion was visualized.

The animals were then decapitated and the brains quickly isolated. The homogenate was centrifuged for 10 min at 13,× g and the supernatant was neutralized with 5 M NaOH The amount of Na-F was measured using a Synergy 2 plate reader BioTek, Winooski, VT.

Fluorescent dye content was calculated using external standards; data are expressed as amount of tracer per mg of tissue. Microscopic examination of the brains used a standardized protocol with sections from the neocortex frontal and parietal , basal ganglia, hippocampus, midbrain, pons, medulla, and cerebellum.

Paraffin sections 5 μm were stained with hematoxylin-eosin. Primary antibodies were detected by Dako Envision Kit Dako, Carpinteria, CA or Vectastain Elite Kit Vector Laboratories, Burlingame, CA with either DAB single stain or Vector Red substrate for double stains. Samples were imaged under ×20 objective magnification using a DS-Fi1c camera Nikon Corporation, Tokyo configured to an upright microscope i80 Eclipse, Nikon.

CD13 assessment was limited to capillaries no more than 6 μm in diameter. For each animal, four to six randomly selected fields in the cortex were analyzed.

Mouse brain microvessels BMVs were isolated using a modified protocol based on previously published studies [ 25 , 28 , 29 ]. In short, mice were overdosed with CO 2 and their brains harvested.

All following steps were carried out on ice or at 4 °C. Following a wash in phosphate-buffered saline, the brains were homogenized using a dounce homogenizer 0. The resulting sample was washed with bovine serum albumin-free phosphate-buffered saline before use in experiments and is defined as the S5 fraction.

Total RNA ng was converted to complementary DNA cDNA using RT 2 PreAMP cDNA Synthesis Kit Qiagen, Hilden, Germany. A PCR-based microarray assay for evaluating the expression of genes involved in inflammatory response and autoimmunity used RT2-profiler PCR Array PAMMZ and endothelial cell biology RT 2 -profiler PCR Array PAMMZ SA Biosciences Corp.

Profiling was performed for cDNA from two separate experiments. Specific primers and probes for LTα, CD40lg, Myd88, and SLC2A1 Glut1 genes were obtained from Thermo Fisher Scientific, and analyses were executed using the StepOnePlus real-time PCR system Thermo Fisher Scientific.

Data are presented from two independent experiments, and each group is comprised of three to four individual mice. To eliminate biased data, two people performed analysis in blinded fashion. Pathway analysis was performed by commercially available Ingenuity® Pathway Analysis IPA® system tools Qiagen Bioinformatics, Redwood City, CA.

Data are presented as triplicates for each mouse and groups were comprised of 3—14 individual mice. Statistical analyses were performed utilizing Prism v5 software GraphPad Software Inc. A summary of body weights and glucose readings is provided in Table 1. CSTZ-treated mice displayed a 3-fold increase in fasting BGL and a significant decrease in body weight, mimicking body weight decline in humans with diabetes type 1 [ 34 ].

CSTZ-treated mice, respectively. In order to evaluate cognitive function in DM models, we used two well-established tests, Y maze and MWM.

The Y maze spontaneous alternation paradigm is based on the ordinary tendency of rodents to explore a novel environment [ 23 ]. When positioned in the Y maze, mice will explore the least recently visited arm, and thus tend to alternate visits between the three arms.

An animal with an impaired working memory cannot remember which arm it has just visited, and thus shows decreased spontaneous alternation [ 21 , 22 , 23 ].

hemizygous Fig. High glucose levels lead to memory deficits in types 1 and 2 diabetes mice. Regression analysis of percent of alterations vs. In these experiments, we performed visible platform training followed by hidden platform testing with four probe trials per day [ 24 , 36 , 37 ].

All mice in each group were able to reach the training criterion within 4 days and were similarly proficient swimmers.

Interestingly, within the group of mice with high BGL, there were mice that showed mild or worse memory phenotypes. In total, these results confirm our hypothesis that high BGL are associated with memory loss.

High glucose levels diminish memory in type 1 diabetes mice. Results are shown as mean ± SEM six to nine animals per group. p values indicated on figures indicate significance vs. We evaluated BBB permeability in animals with STZ-induced hyperglycemia using the fluorescent tracer, NaF, as described [ 26 ].

Similarly, we also found 2. Hyperglycemia-driven BBB permeability triggers memory loss in DM mice. Regression analysis of permeability measured by NaF accumulation in the brain vs.

glucose levels in mice with a or without b STZ-induced diabetes. Regression analysis of memory loss alternation percent vs. f Decreased levels of sRAGE measured by ELISA. It has been suggested that sRAGE serve as decoys for AGEs, thus reducing RAGE signaling and inflammation [ 38 , 39 , 40 , 41 ].

We evaluated sRAGE levels in serum of DM type 1 and 2 mice using commercially available ELISA and discovered that DM mice had significantly ~1. The state of systemic inflammation that impairs endothelial function and contributes to atherosclerosis has been associated with DM [ 42 ].

DM patients are believed to acquire endothelial pathological phenotype due to the high levels of circulating inflammatory markers, including tumor necrosis factor-alpha TNFα , C-reactive protein, interleukin-6 IL-6 , and intercellular adhesion molecule 1 ICAM-1 [ 43 , 44 , 45 , 46 , 47 ].

To evaluate relevant molecule expression in brain endothelium of diabetic mice, we isolated BMVs and profiled the expression of genes commonly involved in regulation of endothelial functions and inflammation. Utilizing a commercially available qPCR-based array, 84 genes were analyzed.

All gene expression data were then analyzed by IPA® system tools. Since we found differences in memory phenotypes Fig. Indeed, many genes had significant fold-change differences between these two groups Fig.

Among them were eNOS, TNFα, TGFβ1, Tymp, and MMP9 that have been shown to affect microvessel functions [ 48 , 49 , 50 , 51 , 52 , 53 ]. High glucose levels cause inflammation in brain microvessels. IPA® analysis of differentially expressed genes a.

Fold regulation of the genes in STZ-treated vs. hemizygous controls c. semi-impaired memory. Arrows point to genes described in the literature to be involved in BBB permeability.

Other genes upregulated in brain BMVs included several chemokines promoting monocyte and lymphocyte attraction CCL2, CCL5, CXCL2, CXC3CL1 , adhesion molecules facilitating leukocyte adhesion Pecam1, E-selectin , β-integrins mediating adhesion of endothelial cells to basement membranes , and prostaglandin synthase.

Such changes in gene expression are overall indicative of a pro-inflammatory phenotype, which directly or indirectly enhanced interactions with white blood cells can contribute to enhanced BBB permeability in diabetic animals.

Of interest is that some of these genes showed significantly higher expression in type 2 DM as compared to type 1 DM animals.

Despite our assumption that the TJ protein, occludin, or adherent junction protein AJ , cadherin 5, would be downregulated in DM animals with enhanced BBB permeability, we found 8— and 4—fold increases in expression of these TJ and AJ protein genes, suggesting improper folding or incorporation in the cell membrane that may reflect a compensatory phenomenon in DM.

To assess inflammatory status in the brain tissue, we performed expression profiling of the genes regulating inflammatory pathways. Messenger RNA mRNA was extracted from the cortex area in contralateral hemisphere from the same mice that were used for BMV gene profiling Fig.

Many genes were significantly affected in STZ-treated mice Fig. Two of these genes, LTα TNFβ and CD40lg, have been described in the literature to be upregulated in AD or other types of dementia [ 54 , 55 , 56 , 57 ], and Myd88 to be downregulated [ 58 ].

controls Fig. Glucose transporter, Glut1 SLC2A1 , gene has been shown to be upregulated in blood vessels in mice with diabetic retinopathy [ 59 ]. Therefore, we decided to assess Glut1 levels in microvessels isolated from diabetic mice; indeed, both DM model mice showed higher Glut1 gene expression than their control counterparts Fig.

Interestingly enough, we found that in STZ-treated mice, there was a wide distribution in fold changes in gene expression. When we matched the gene expression data with our Morris water maze data Fig. Hyperglycemia causes inflammation in brain tissue and increased Glut1 expression in microvessels.

qPCR analysis of an inflammatory response array for mRNA extracted from brain tissue isolated from STZ-treated or non-treated WT mice a. qPCR data for Glut1 gene in cerebral microvessels in DM types 1 and 2 mouse models c.

qPCR was done in triplicate and results are shown as mean ± SEM three animals per group. Immunohistochemical evaluation of the cortex showed 1. non-treated mice Fig. Enhanced expression of ICAM-1 in brain endothelium in DM types 1 and 2 mouse models.

a — c Brain microvascular endothelial cells showed increased staining for ICAM-1 b , c in STZ-treated vs. control untreated mice a.

g LPS-injected mouse used as a positive control demonstrated very high levels of ICAM-1 expression [ 60 ]. Original magnification, a — g × h Semi-quantitative evaluation of ICAM-1 staining was performed as described [ 27 ]. We found that STZ-diabetic mice showed a significant decrease in pericyte presence at the BBB and enhanced microglial reaction in diabetic mice as compared to controls with normal BGL Fig.

control animals Fig. Then, we appraised expression of the TJ proteins in the cortex area and found a significant decrease in claudin-5 expression in both DM models: Evaluation of occludin expression on serial sections showed Microglial activation and decreased pericyte coverage of the BBB in DM type 1 and 2 models.

respective control mice. Original magnification was ×, and × in marked areas. Claudin-5 and occludin protein expression is decreased in BMVs in DM type 1 and 2 models.

Original magnification was × Semi-quantitative evaluation of claudin-5 c , d and occludin e , f staining was performed as described [ 27 ]. Taken together, our results suggest a causative link between BBB dysfunction and cognitive deterioration in diabetic conditions.

Cerebrovascular pathology is often found in a wide variety of cognitive impairment or dementia disorders. One of the indicators of cerebral vascular disease is BBB dysfunction [ 61 , 62 ].

The BBB serves as a selective diffusion barrier at the level of the cerebral microvascular endothelium to maintain homeostasis in the CNS by regulating ion balance, aiding in nutritional transport, and blocking influx of potentially neurotoxic molecules from the circulation [ 61 , 62 ].

DM is a metabolic disorder characterized by hyperglycemia leading to end-organ injury in various organs due to microvascular compromise cardiovascular disease, nephropathy, and retinopathy and inflammation.

Learning abilities and memory deficits have been documented in DM type 1 or type 2 patients [ 3 , 4 , 5 ], which might be due to cerebral vascular dysfunction. Association between microvascular changes and cognitive decline in DM has not been substantiated until very recently, with defects noted in blood perfusion, neuronal function, white matter microstructure, and metabolic function [ 7 , 63 ].

BBB breakdown has been suggested as one of the causes of dementia in DM and AD [ 64 ]. However, the exact mechanisms of injury, relationship between enhanced permeability and memory loss, differences between DM types 1 and 2, and therapeutic potential of BBB protective strategies in cognitive decline are currently unknown.

Here, we investigated the idea that DM types 1 and 2 decrease BBB integrity directly via effects on brain endothelium and pericytes and promote a pro-inflammatory phenotype of brain endothelium resulting in a low-level inflammation that further exacerbates barrier injury.

We used animal models of DM types 1 and 2 and found that both models mice displayed a significant increase in BGL vs. control counterparts, mimicking hyperglycemia in DM patients [ 34 , 35 ]. DM mice exhibited memory decline, confirmed by two well-established tests, Y maze and MWM [ 23 , 24 ].

DM mice showed deterioration in their abilities in acquisition and long-term spatial memory similar to recent study [ 65 ]. STZ-injected mice displayed a broad range of BGL, but only mice with the highest BGL showed significant latency in spatial memory acquisition time to reach hidden platform for the first time and to memorize platform location number of repeated entries.

Mice that showed mild or worse memory phenotypes marked as semi-impaired or impaired, respectively demonstrated significantly different gene profiling in BMVs isolated from these animals. Among deregulated genes, there were many genes involved in inflammation and barrier destabilizing molecules MMP9, eNOS, TGFβ, TNFα, Tymp [ 48 , 49 , 50 , 51 , 52 , 53 ].

Several studies have suggested that sRAGE serves as a decoy for AGEs, thus reducing RAGE signaling and inflammation [ 38 , 39 , 40 , 41 ]. We discovered that DM mice had significantly lower levels of sRAGE than control animals, suggestive of a higher potential for inflammation in DM mice.

We showed increased BBB permeability in DM type 1 and 2 animals that was significantly associated with hyperglycemia and memory deficits. These changes paralleled deregulation of genes in brain endothelium associated with BBB injury and inflammation.

In spite of our assumption that in DM animals with enhanced BBB permeability, TJ protein occludin or AJ protein cadherin 5 would be downregulated, we found their levels highly increased, implying improper folding or incorporation in cell membranes that may reflect a compensatory phenomenon in DM.

Interestingly, we found significant reduction in TJ expression protein by immunohistochemistry occludin and claudin-5 in both DM animal models as compared to controls Fig. Similarly, Li et al.

demonstrated a decrease in the amount of occludin detected by western blotting of isolated CNS microvessels in STZ-diabetic mice [ 66 ]. They also admitted that post-translational oxidative modifications or phosphorylation might be responsible for increased barrier permeability [ 67 ].

Differences might be explained as due to mRNA vs. protein detection for TJ proteins associated with adaptive mechanism, and further studies are needed to clarify this phenomenon. Gene profiling resulted in significant upregulation of pro-inflammatory pathways in the brain tissues of the DM mice, which resulted in microglial activation, reduced pericyte coverage, shown by immunohistochemical assessment.

Salameh et al. recently showed pericyte loss in STZ-induced diabetic mouse brains [ 68 ]. Mice in both DM types displayed a significant decrease in TJ protein claudin-5 expression. Takechi et al. recently showed that in a high-fat and high-fructose diet-induced DM model, reduction in expression of TJ proteins, occludin and ZO-1, was also associated with increased BBB leakiness, astrogliosis, neuroinflammation, and memory loss as shown by MWM latency [ 73 ].

Immunohistochemical evaluation showed significant increase in ICAM-1 expression in DM mice. DM patients are believed to acquire endothelial pathological phenotype due to the high levels of circulating inflammatory markers and ICAM-1 [ 44 , 73 ].

Previously, diminution in pericyte presence has been described in DM both in the blood-retinal barrier and BBB [ 74 ]. Pericytes provide functional support to the brain endothelium and their loss leads to enhanced permeability and tissue injury in DM [ 75 ] and neuroinflammatory conditions [ 61 ].

Of interest, DM retinopathy is a predictor of decline, presumably due to CNS microvasculature demise [ 76 ]. It can even put you in a coma. Some people with low blood sugar may not have any symptoms, which can make it hard to treat early. If you have any of these problems and have frequent low blood sugar episodes, talk to your doctor, who can help:.

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High blood sugar levels linked to memory loss

Spontaneous exploratory behavior was investigated by using a Y maze as described [ 21 , 22 , 23 ]. The Y maze apparatus consists of three arms, each 21 cm long, 4 cm wide, and 40 cm tall with a central entry zone. It is made of plastic and placed at an angle of 33°. The total number of arm entries and alterations between the arms are recorded.

Frequent exploration in all three arms indicates normal spontaneous exploration, whereas restricted arm entries indicate deficits in spontaneous exploration. Alternations were defined as successive entries into each of the three arms as on overlapping triplet sets ABC, BCA, ….

Alternate arm returns AARs and same arm returns SARs were also scored for each animal in order to assess aspects of attention within spontaneous working memory [ 23 ]. Total entries were scored as an index of ambulatory activity in the Y maze. Mice showing scores below six entries were excluded.

The Morris water maze MWM was first established by neuroscientist Richard G. Morris in in order to test hippocampal-dependent learning, including acquisition of spatial memory and long-term spatial memory [ 24 ].

The theory behind it is that the animal must learn to use local cues to navigate the shortest path to the hidden platform when started from different, random locations around the perimeter of the water tank.

Most protocols use four start locations: N, S, E, and W. Animals are given a series of daily trials using a semi-random set of start locations. Semi-random start position sets are most common, such that the four positions are used, with the restriction that one trial each day is from each of the four positions.

The MWM test was performed 12 weeks after STZ injections. On the first day of MWM test, each mouse was allowed to swim freely in water for 2 min where the platform had been removed, observing the swim action and speed of the mouse in order to eliminate unqualified animals.

On the next day, each rodent was discharged into the water with a platform placed inside from a marked starting point in one of the four quadrants, facing the tank wall, encompassing training for 3 days.

Mice were assessed in the probe trial 24 h after the last training session that consisted of a s free swim in the pool without the platform. For the better assessment of learning ability of the mouse, a statistical analysis was made of the latency to find the platform and the number of repeated entries after first entry.

Changes in BBB permeability were assessed using the fluorescent tracer, sodium-fluorescein Na-F as described [ 25 , 26 ]. The tracer was allowed to circulate for 30 min. The mice were anesthetized and then transcardially perfused with PBS until colorless perfusion was visualized. The animals were then decapitated and the brains quickly isolated.

The homogenate was centrifuged for 10 min at 13,× g and the supernatant was neutralized with 5 M NaOH The amount of Na-F was measured using a Synergy 2 plate reader BioTek, Winooski, VT.

Fluorescent dye content was calculated using external standards; data are expressed as amount of tracer per mg of tissue. Microscopic examination of the brains used a standardized protocol with sections from the neocortex frontal and parietal , basal ganglia, hippocampus, midbrain, pons, medulla, and cerebellum.

Paraffin sections 5 μm were stained with hematoxylin-eosin. Primary antibodies were detected by Dako Envision Kit Dako, Carpinteria, CA or Vectastain Elite Kit Vector Laboratories, Burlingame, CA with either DAB single stain or Vector Red substrate for double stains. Samples were imaged under ×20 objective magnification using a DS-Fi1c camera Nikon Corporation, Tokyo configured to an upright microscope i80 Eclipse, Nikon.

CD13 assessment was limited to capillaries no more than 6 μm in diameter. For each animal, four to six randomly selected fields in the cortex were analyzed.

Mouse brain microvessels BMVs were isolated using a modified protocol based on previously published studies [ 25 , 28 , 29 ]. In short, mice were overdosed with CO 2 and their brains harvested. All following steps were carried out on ice or at 4 °C.

Following a wash in phosphate-buffered saline, the brains were homogenized using a dounce homogenizer 0. The resulting sample was washed with bovine serum albumin-free phosphate-buffered saline before use in experiments and is defined as the S5 fraction.

Total RNA ng was converted to complementary DNA cDNA using RT 2 PreAMP cDNA Synthesis Kit Qiagen, Hilden, Germany. A PCR-based microarray assay for evaluating the expression of genes involved in inflammatory response and autoimmunity used RT2-profiler PCR Array PAMMZ and endothelial cell biology RT 2 -profiler PCR Array PAMMZ SA Biosciences Corp.

Profiling was performed for cDNA from two separate experiments. Specific primers and probes for LTα, CD40lg, Myd88, and SLC2A1 Glut1 genes were obtained from Thermo Fisher Scientific, and analyses were executed using the StepOnePlus real-time PCR system Thermo Fisher Scientific.

Data are presented from two independent experiments, and each group is comprised of three to four individual mice.

To eliminate biased data, two people performed analysis in blinded fashion. Pathway analysis was performed by commercially available Ingenuity® Pathway Analysis IPA® system tools Qiagen Bioinformatics, Redwood City, CA.

Data are presented as triplicates for each mouse and groups were comprised of 3—14 individual mice. Statistical analyses were performed utilizing Prism v5 software GraphPad Software Inc. A summary of body weights and glucose readings is provided in Table 1. CSTZ-treated mice displayed a 3-fold increase in fasting BGL and a significant decrease in body weight, mimicking body weight decline in humans with diabetes type 1 [ 34 ].

CSTZ-treated mice, respectively. In order to evaluate cognitive function in DM models, we used two well-established tests, Y maze and MWM.

The Y maze spontaneous alternation paradigm is based on the ordinary tendency of rodents to explore a novel environment [ 23 ].

When positioned in the Y maze, mice will explore the least recently visited arm, and thus tend to alternate visits between the three arms.

An animal with an impaired working memory cannot remember which arm it has just visited, and thus shows decreased spontaneous alternation [ 21 , 22 , 23 ]. hemizygous Fig. High glucose levels lead to memory deficits in types 1 and 2 diabetes mice.

Regression analysis of percent of alterations vs. In these experiments, we performed visible platform training followed by hidden platform testing with four probe trials per day [ 24 , 36 , 37 ]. All mice in each group were able to reach the training criterion within 4 days and were similarly proficient swimmers.

Interestingly, within the group of mice with high BGL, there were mice that showed mild or worse memory phenotypes. In total, these results confirm our hypothesis that high BGL are associated with memory loss.

High glucose levels diminish memory in type 1 diabetes mice. Results are shown as mean ± SEM six to nine animals per group. p values indicated on figures indicate significance vs.

We evaluated BBB permeability in animals with STZ-induced hyperglycemia using the fluorescent tracer, NaF, as described [ 26 ]. Similarly, we also found 2. Hyperglycemia-driven BBB permeability triggers memory loss in DM mice. Regression analysis of permeability measured by NaF accumulation in the brain vs.

glucose levels in mice with a or without b STZ-induced diabetes. Regression analysis of memory loss alternation percent vs. f Decreased levels of sRAGE measured by ELISA.

It has been suggested that sRAGE serve as decoys for AGEs, thus reducing RAGE signaling and inflammation [ 38 , 39 , 40 , 41 ]. We evaluated sRAGE levels in serum of DM type 1 and 2 mice using commercially available ELISA and discovered that DM mice had significantly ~1.

The state of systemic inflammation that impairs endothelial function and contributes to atherosclerosis has been associated with DM [ 42 ].

DM patients are believed to acquire endothelial pathological phenotype due to the high levels of circulating inflammatory markers, including tumor necrosis factor-alpha TNFα , C-reactive protein, interleukin-6 IL-6 , and intercellular adhesion molecule 1 ICAM-1 [ 43 , 44 , 45 , 46 , 47 ].

To evaluate relevant molecule expression in brain endothelium of diabetic mice, we isolated BMVs and profiled the expression of genes commonly involved in regulation of endothelial functions and inflammation.

Utilizing a commercially available qPCR-based array, 84 genes were analyzed. All gene expression data were then analyzed by IPA® system tools. Since we found differences in memory phenotypes Fig.

Indeed, many genes had significant fold-change differences between these two groups Fig. Among them were eNOS, TNFα, TGFβ1, Tymp, and MMP9 that have been shown to affect microvessel functions [ 48 , 49 , 50 , 51 , 52 , 53 ].

High glucose levels cause inflammation in brain microvessels. IPA® analysis of differentially expressed genes a. Fold regulation of the genes in STZ-treated vs. hemizygous controls c. semi-impaired memory. Arrows point to genes described in the literature to be involved in BBB permeability.

Other genes upregulated in brain BMVs included several chemokines promoting monocyte and lymphocyte attraction CCL2, CCL5, CXCL2, CXC3CL1 , adhesion molecules facilitating leukocyte adhesion Pecam1, E-selectin , β-integrins mediating adhesion of endothelial cells to basement membranes , and prostaglandin synthase.

Such changes in gene expression are overall indicative of a pro-inflammatory phenotype, which directly or indirectly enhanced interactions with white blood cells can contribute to enhanced BBB permeability in diabetic animals.

Of interest is that some of these genes showed significantly higher expression in type 2 DM as compared to type 1 DM animals. Despite our assumption that the TJ protein, occludin, or adherent junction protein AJ , cadherin 5, would be downregulated in DM animals with enhanced BBB permeability, we found 8— and 4—fold increases in expression of these TJ and AJ protein genes, suggesting improper folding or incorporation in the cell membrane that may reflect a compensatory phenomenon in DM.

To assess inflammatory status in the brain tissue, we performed expression profiling of the genes regulating inflammatory pathways. Messenger RNA mRNA was extracted from the cortex area in contralateral hemisphere from the same mice that were used for BMV gene profiling Fig.

Many genes were significantly affected in STZ-treated mice Fig. Two of these genes, LTα TNFβ and CD40lg, have been described in the literature to be upregulated in AD or other types of dementia [ 54 , 55 , 56 , 57 ], and Myd88 to be downregulated [ 58 ].

controls Fig. Glucose transporter, Glut1 SLC2A1 , gene has been shown to be upregulated in blood vessels in mice with diabetic retinopathy [ 59 ]. Therefore, we decided to assess Glut1 levels in microvessels isolated from diabetic mice; indeed, both DM model mice showed higher Glut1 gene expression than their control counterparts Fig.

Interestingly enough, we found that in STZ-treated mice, there was a wide distribution in fold changes in gene expression. When we matched the gene expression data with our Morris water maze data Fig. Hyperglycemia causes inflammation in brain tissue and increased Glut1 expression in microvessels.

qPCR analysis of an inflammatory response array for mRNA extracted from brain tissue isolated from STZ-treated or non-treated WT mice a.

qPCR data for Glut1 gene in cerebral microvessels in DM types 1 and 2 mouse models c. qPCR was done in triplicate and results are shown as mean ± SEM three animals per group. Immunohistochemical evaluation of the cortex showed 1. non-treated mice Fig. Enhanced expression of ICAM-1 in brain endothelium in DM types 1 and 2 mouse models.

a — c Brain microvascular endothelial cells showed increased staining for ICAM-1 b , c in STZ-treated vs. control untreated mice a. g LPS-injected mouse used as a positive control demonstrated very high levels of ICAM-1 expression [ 60 ].

Original magnification, a — g × h Semi-quantitative evaluation of ICAM-1 staining was performed as described [ 27 ]. We found that STZ-diabetic mice showed a significant decrease in pericyte presence at the BBB and enhanced microglial reaction in diabetic mice as compared to controls with normal BGL Fig.

control animals Fig. Then, we appraised expression of the TJ proteins in the cortex area and found a significant decrease in claudin-5 expression in both DM models: Evaluation of occludin expression on serial sections showed Microglial activation and decreased pericyte coverage of the BBB in DM type 1 and 2 models.

respective control mice. Original magnification was ×, and × in marked areas. Claudin-5 and occludin protein expression is decreased in BMVs in DM type 1 and 2 models. Original magnification was × Semi-quantitative evaluation of claudin-5 c , d and occludin e , f staining was performed as described [ 27 ].

Taken together, our results suggest a causative link between BBB dysfunction and cognitive deterioration in diabetic conditions. Cerebrovascular pathology is often found in a wide variety of cognitive impairment or dementia disorders. One of the indicators of cerebral vascular disease is BBB dysfunction [ 61 , 62 ].

The BBB serves as a selective diffusion barrier at the level of the cerebral microvascular endothelium to maintain homeostasis in the CNS by regulating ion balance, aiding in nutritional transport, and blocking influx of potentially neurotoxic molecules from the circulation [ 61 , 62 ].

DM is a metabolic disorder characterized by hyperglycemia leading to end-organ injury in various organs due to microvascular compromise cardiovascular disease, nephropathy, and retinopathy and inflammation.

Learning abilities and memory deficits have been documented in DM type 1 or type 2 patients [ 3 , 4 , 5 ], which might be due to cerebral vascular dysfunction.

Association between microvascular changes and cognitive decline in DM has not been substantiated until very recently, with defects noted in blood perfusion, neuronal function, white matter microstructure, and metabolic function [ 7 , 63 ]. BBB breakdown has been suggested as one of the causes of dementia in DM and AD [ 64 ].

However, the exact mechanisms of injury, relationship between enhanced permeability and memory loss, differences between DM types 1 and 2, and therapeutic potential of BBB protective strategies in cognitive decline are currently unknown. Here, we investigated the idea that DM types 1 and 2 decrease BBB integrity directly via effects on brain endothelium and pericytes and promote a pro-inflammatory phenotype of brain endothelium resulting in a low-level inflammation that further exacerbates barrier injury.

We used animal models of DM types 1 and 2 and found that both models mice displayed a significant increase in BGL vs. control counterparts, mimicking hyperglycemia in DM patients [ 34 , 35 ]. DM mice exhibited memory decline, confirmed by two well-established tests, Y maze and MWM [ 23 , 24 ].

DM mice showed deterioration in their abilities in acquisition and long-term spatial memory similar to recent study [ 65 ]. STZ-injected mice displayed a broad range of BGL, but only mice with the highest BGL showed significant latency in spatial memory acquisition time to reach hidden platform for the first time and to memorize platform location number of repeated entries.

Mice that showed mild or worse memory phenotypes marked as semi-impaired or impaired, respectively demonstrated significantly different gene profiling in BMVs isolated from these animals. Among deregulated genes, there were many genes involved in inflammation and barrier destabilizing molecules MMP9, eNOS, TGFβ, TNFα, Tymp [ 48 , 49 , 50 , 51 , 52 , 53 ].

Several studies have suggested that sRAGE serves as a decoy for AGEs, thus reducing RAGE signaling and inflammation [ 38 , 39 , 40 , 41 ]. We discovered that DM mice had significantly lower levels of sRAGE than control animals, suggestive of a higher potential for inflammation in DM mice.

We showed increased BBB permeability in DM type 1 and 2 animals that was significantly associated with hyperglycemia and memory deficits. These changes paralleled deregulation of genes in brain endothelium associated with BBB injury and inflammation.

In spite of our assumption that in DM animals with enhanced BBB permeability, TJ protein occludin or AJ protein cadherin 5 would be downregulated, we found their levels highly increased, implying improper folding or incorporation in cell membranes that may reflect a compensatory phenomenon in DM.

Interestingly, we found significant reduction in TJ expression protein by immunohistochemistry occludin and claudin-5 in both DM animal models as compared to controls Fig.

Similarly, Li et al. demonstrated a decrease in the amount of occludin detected by western blotting of isolated CNS microvessels in STZ-diabetic mice [ 66 ].

They also admitted that post-translational oxidative modifications or phosphorylation might be responsible for increased barrier permeability [ 67 ]. We are here to help! Diabetes Care Community Newsletters Living Well with Diabetes.

Your privacy is important to us. Skip to primary navigation Skip to main content Skip to primary sidebar Skip to footer Self-management News Educational videos. Home » Articles and Blogs » Diabetes and memory: risks, symptoms and treatment.

How can diabetes affect memory? Memory loss in people with diabetes can be either short-term or long-term. What are the symptoms of memory loss? Read also about Diabetes and the highs and lows of thyroid disease.

People with diabetes have a higher risk of thyroid disease. Read this expert blog to learn about the diagnosis and management of thyroid disease. Lifestyle For people with diabetes, the most important thing you can do to manage memory loss is keep your blood sugar levels in their target range.

Since memory loss can be associated with certain behaviours or medications, it can sometimes be reversed or minimized by changing these things, such as: Taking blood pressure medication , if you have high blood pressure Switching medications that may be contributing to memory loss Taking thyroid medication, if you have hypothyroidism Reducing your alcohol consumption, if you are drinking more than is healthy Medication There are some medications available in Canada which may help slow the rate of memory loss or other symptoms associated with Alzheimers.

Speak with your healthcare team to see if any of these might be appropriate for you. Your chance of getting type 2 diabetes is higher if you are overweight, inactive, or have a family history of diabetes.

Diabetes can affect many parts of your body. Pre-diabetes is an important warning signal because people with pre-diabetes are at high risk for developing type 2 diabetes. People who are pre-diabetic are asked to watch their sugar intake and how they eat, but not necessarily take any medications.

Uncontrolled diabetes may increase the risk of experiencing cognitive problems, such as memory loss. Higher than normal blood glucose levels can damage nerve cells, supportive glial cells, and blood vessels in both peripheral nerves of the body and the brain.

Research has shown that having Type 2 diabetes may double the risk of developing a slowly progressive dementia.

There are many causes of dementia, including Alzheimer disease and stroke. It is also possible that diabetes may cause memory loss through silent damage to the capillaries tiny blood vessels that form the network for glucose and oxygen exchange between blood vessels and tissue cells.

While it is relatively easy to measure glucose and insulin in the blood, we hardly ever measure glucose and insulin in the brain. Also, while it is relatively easy to measure brain shrinkage atrophy , MRI and CT scans cannot show plaques and tangles, which are the microscopic hallmarks of Alzheimer disease, or damage to capillaries that can result from diabetes.

The risk of dementia is higher when diabetes is poorly controlled, so good management of diabetes and blood sugar is important, and may help prevent serious memory loss. Helena Chui and the research team at the USC ADRCare conducting a study to determine how early diabetes affects capillaries, brain cells and cognitive abilities.

The Effects of Diabetes on the Brain There are multiple reasons why years of type 2 diabetes may lead to dementia. A Quiz for Teens Are You a Workaholic? You can help protect your brain by keeping your blood sugar as close to your target levels as possible and by eating a diet rich in vegetables, fiber, and fruit along with getting regular physical activity. Researchers are working on developing a medication that will repair blood vessels. Importantly, higher cognitive loads were necessary to reveal the failure to upregulate activity in the PFC in response to higher working-memory demands under hyperglycaemia in people with type 2 diabetes.
Hyperglycemia and memory loss

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