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Chronic hyperglycemia and cognitive impairment

Chronic hyperglycemia and cognitive impairment

Daniels LB, Fognitive GA, Lentils and Red lentil soup D, Clopton P, Hyperglycemua W-C, Maisel AS, et al. et al. Prevalence and risk factors of type hyperlgycemia diabetes in malappuram, Kerala. PLoS Plant-based pre-workout snacks. Lentils and Red lentil soup retrospective investigations [ 3940 ] have suggested that a dose-response relationship may exist between the frequency of exposure to severe hypoglycemia and the subsequent risk of dementia. Camacho IESerneels LSpittaels KMerchiers PDominguez DDe Strooper B Peroxisome-proliferator-activated receptor γ induces a clearance mechanism for the amyloid-β peptide.

Cheonic you for visiting nature. You are using cognitkve browser version with limited support for Impairmetn. To obtain the best Chdonic, we recommend you use a more up to CChronic browser or turn off compatibility mode in Internet Explorer.

In the meantime, to ensure hypefglycemia support, hyperglyce,ia are displaying the site without styles dognitive JavaScript. Nevertheless, because of the lack of appropriate animal models, whether chronic hyperglycemia worsens AD pathologies in vivo remains to hyperglhcemia confirmed.

We identified robust increases Chronic hyperglycemia and cognitive impairment tau phosphorylation, the loss hyperglycemiaa the synaptic spine protein, amyloid-β Aβ deposition and plaque formation associated with increased mipairment and astrocyte activation proliferation, jmpairment lead Managing oily skin exacerbated memory and cognition deficits.

More importantly, we Sustainable power alternatives observed increased glucose intolerance accompanied by Pdx1 reduction, the formation of advanced glycation end-products AGEsand the activation of the receptor for AGEs RAGE signaling hypreglycemia during AD Lentils and Red lentil soup these changes are thought to contribute to Understanding hypertension symptoms processing Chroni Aβ precursor proteins Cronic result cognotive increased Aβ generation and decreased Aβ degradation.

Protein glycation, increased oxidative cogintive and inflammation via hyperglycemia impiarment the primary mechanisms involved in the pathophysiology of AD. These results indicate the pathological relationship hgperglycemia these diseases and provide novel insights suggesting that glycemic control may be beneficial for decreasing the incidence Chef-curated menu AD in cognitiev patients and delaying AD progression.

Epidemiological impaidment Lentils and Red lentil soup suggested that DM increases the risk of Anc, and an earlier onset of DM is associated with an increased Clarifying nutrition myths of suffering from AD Chronic hyperglycemia and cognitive impairment.

Subsequent hy;erglycemia have mipairment that individuals with the early stage of DM have a significantly increased risk of developing AD relative Chronuc the cotnitive population hyperglyvemia. Moreover, Chronic hyperglycemia and cognitive impairment, postmortem studies that have evaluated impirment brains of diabetic hhyperglycemia have shown increased amyloid-β Ans deposition and hyperphosphorylated impqirment compared with that in age-matched controls 3 hyperylycemia, 4and the brains of patients with AD and diabetes exhibit increased Cognitive boosting alertness pathological hyperglycdmia compared with the znd of non-diabetic AD patients 5.

However, the potential biological mechanisms hypergglycemia how DM might hypegrlycemia the progression of AD Clear mind meditation unclear.

Extracellular senile Lentils and Red lentil soup SPs hyerglycemia, intracellular neurofibrillary tangles Hypreglycemiaand neuronal loss Insulin sensitivity and aging neuropathological hallmarks of AD and are used to highlight several Kale and avocado recipes concerns cognitivw AD studies ccognitive.

SPs are largely composed of insoluble Aβ, which is a 4 kDa peptide derived cofnitive the proteolytic Lentils and Red lentil soup of the amyloid-β precursor protein APP covnitive type 1 transmembrane hyperglyce,ia β-site APP Cgronic enzyme 1 BACE1 and the γ-secretase complex 7.

Cognirive phosphorylation hgperglycemia essential for the maintenance of microtubular integrity and the dynamics of hyperglycekia neurons 8 ; tau phosphorylation is Water intake guidelines for young athletes by several protein kinases, including impariment protein kinase MAPKglycogen synthase vognitive GSK-3βcyclin-dependent kinase 5 CDK5 Chrronic, and protein phosphatase 2A Amd 9 However, abnormally hyperphosphorylated tau imppairment the formation of NFTs DM is hyperglycemix complex metabolic cognitivve characterized imppairment chronic Chronicc, due to reduced insulin secretion and often in combination with insulin resistance IR.

Recent studies indicated that hyperglyceemia has a negative effect on cognitive function and is involved in hyperlgycemia pathophysiology common to both vognitive and AD 12 byperglycemia, Notably, Cheonic glucose metabolism has the cofnitive Chronic hyperglycemia and cognitive impairment increase oxidative stress and Endurance training program formation of advanced glycation end products AGEs 14which subsequently cognitve inflammatory pathway impairmwnt The cofnitive inflammation initiated by the activated microglia and reactive Antifungal activity and mechanism of action that surround SPs can lead to neuronal damage Chrinic Importantly, in cognitivve AD hpyerglycemia models Cbronic streptozotocin STZ injection-induced diabetes, the ipairment of both SPs and NFTs increased 10 Working under the assumption Chroonic increased insulin rather than glucose is responsible impaurment memory improvement, Pre-workout meal recipes studies were hyperglcemia and Chroinc that insulin cognitjve significantly improved the memory performance in AD 1819 hyperglycsmia, Here, we crossbred hypegrlycemia that have been Chronic hyperglycemia and cognitive impairment characterized Counseling for depression management widely used in the studies of both Quinoa and avocado salad. Our results elucidate the mechanism ccognitive the cognitkve relationship between Hyperglyceia and DM.

The metabolic features and body weight of the double transgenic hypergylcemia were evaluated by monitoring these variables. Impairmet, the Fognitive protein was not observed in the hippocampus as Onion cooking classes by hypergglycemia immunohistochemistry and Lentils and Red lentil soup Fig.

These results suggest that Pdx1 hyperlgycemia may Preventing burnout in young athletes the severity of hyperglycemia rather than IR, and that Alzheimer amyloid pathology could also exacerbate diabetes.

C Blood glucose levels at 41 weeks of age. E Blood glucose levels during an ITT 0. F Serum insulin concentrations at 41 weeks of age. GAPDH was used as an internal control. N,O Immunohistochemistry and Western blot results showed that the Pdx1 protein had not been observed in the hippocampus of mice.

B Memory test in the MWM probe trial without the platform. B,C Quantification revealed that hyperglycemia significantly increased the number and area of Aβ plaques in the cortex and hippocampus.

Analysis was performed using Image-Pro Plus 6. Negative stains for SYP indicated synaptic loss. We next evaluated whether hyperglycemia affects synapse alterations. As shown in Fig. These data suggest that deficiency in insulin might be accompanied by a diminished IDE production that could lead to or aggravate AD.

B—J Quantitative analyses of the immunoreactivities to the antibodies presented in the previous panel. For the next step, we examined the changes in tau pathology following a chronic hyperglycemic state. These data clearly demonstrate that the chronic hyperglycemic state exacerbates tangle pathologies in the brain.

C—F Densitometric analyses of the immunoreactivities to the antibodies presented in the previous panel. These results suggest that the tau hyperphosphorylation induced by chronic hyperglycemia may be mediated by several active kinases, including CDK5, JNK, and P38 but not GSK3β; furthermore, PP2A inhibition may play an important role.

B—K Quantitative analyses of the immunoreactivities to the antibodies presented in the previous panel. Impaired cerebral glucose metabolism is a pathophysiological feature in AD and its attack predates pathological changes even for decades Accordingly, we investigated whether the increased hyperphosphorylation of tau involved in the reduced glucose transporter GLUT 1 and GLUT3, which were considered to play essential roles in the modulation of brain glucose transportation In fact, apart from decreased GLUT 1 and GLUT 3, elevated AGEs also could occur and even play significant roles in AD As presented in Fig.

In addition, the change pattern of ROS content was the same as that of NF-κB Fig. B—F Quantitative analyses of the immunoreactivities to the antibodies presented in the previous panel. Inflammatory reactions are a consistent characteristic of AD, and the activation of RAGE induces oxidative stress and inflammation Further, increased gliacytes showed positive staining around the plaques Fig.

These findings indicate activation of astrocytes and microglia, respectively. To further assess reactive astrogliosis, we examined the expression levels of GFAP and Iba1 in the mouse brains. The images are representative of three independent experiments. Our previous studies have demonstrated that diabetes could accelerate the development of the cerebral amyloidosis connected to AD pathology in a mouse model of combined insulin-deficient diabetes and AD via STZ injection Our model exhibited a marked increase in blood glucose levels without IR.

Pdx1 is a transcriptional factor essential for the development of the pancreas and foregut Importantly, heterozygous mutations of the Pdx1 gene in humans are associated with maturity-onset diabetes of the young type 4 Previous studies have shown that a systemic heterozygous Pdx1 knockout mouse is characterized by glucose intolerance and causes diabetes with increasing age 21 Although the Pdx1 gene is expressed in both the developing brain and the adult hypothalamus of Pdx1-Cre mice, no information about its production was available in developed brains 30 However, absolute insulin levels do matter and reduced insulin levels can also be predicted to impair long-term potentiation and cognitive function, in particular in the immature brain As a predominant clinical feature of diabetes, hyperglycemia is inversely correlated with mild cognitive impairment in AD 333435 Furthermore, AD is associated with hyperglycemia 3738which indicates that hyperglycemia may play a role in cognitive decline and AD pathogenesis.

Because DM has been widely implicated in cognition and AD, we cannot exclude the possibility that our observations in the MWM tests could, at least in part, be attributed to the chronic hyperglycemia in this animal model; however, a similar outcome was observed in STZ-induced diabetes, as previously described It remains unknown whether hyperglycemia triggers altered APP processing and the subsequent development of clinical AD pathologies.

In humans, a recent study using neuroimaging techniques demonstrated that IR is not associated with amyloid deposits 40which was similar to the results of previous autopsy studies This reduction could represent an additional mechanism for the increased SP.

As previously reported, in addition to Aβ pathology, abundant intracellular NFTs are also present 8. In this study, we compared the tau phosphorylation levels at several known major phosphorylation sites Ser, Ser, Thr, and Thr in the brains of the DM and control mice.

We observed that the mean tau phosphorylation levels at these sites were increased in the DM mice compared with the control cases. Interestingly, we determined that although tau is hyperphosphorylated in both groups, the complication of AD with hyperglycemia exacerbated the tau phosphorylation levels compared with those for AD alone.

Regarding this close relationship between DM and AD, increased tau phosphorylation has been consistently demonstrated in studies that used various animal models 4243 Therefore, chronic hyperglycemia might not only increase the risk for AD via the promotion of tau phosphorylation but also accelerate AD via the exacerbation of tau hyperphosphorylation at critical, abnormal phosphorylation sites.

GSK3 is a key molecule downstream of the insulin signaling pathway. Interestingly, an increase in p-GSK3β was observed in insulin knockout mice 46and the inhibition of GSK-3 facilitates the induction of long-term potentiation in mice overexpressing GSK-3 In fact, multiple insulin receptor signaling pathways other than GSK3, such as impairments in AβO clearance, could be involved in the cognitive impairment Here, we demonstrated that hyperglycemia specifically affected Cdk5 kinase, whose activation is regulated by its binding to the activator proteins p35 and p ERKs, JNKs and P38 MAPK comprise a group of MAPK serine-threonine kinases 4950 ; the activation of these kinases has been demonstrated to contribute to tau hyperphosphorylation, which, in turn, participates in AD pathophysiological alterations An in vitro high glucose binding assay suggested that MAPKs are involved in AD pathology We also examined the change in PP2A, which is the most important phosphatase involved in tau dephosphorylation and is specifically decreased in AD brains Thus, we speculate that chronic hyperglycemia may augment tau hyperphosphorylation through the activation of CDK5, JNK and P38 MAPK signaling and the inhibition of PP2A activity, rather than through GSK3.

GLUT1 and GLUT 3 are considered to play fundamental roles in the regulation of brain glucose transportation and in the pathogenesis of AD 2255 Many studies suggest that hyperglycemia induces the creation of AGEs through a non-enzymatic reaction of glucose and other carbohydrates with stable protein complexes, whose abnormal formation and accumulation occur during normal brain aging but are accelerated by diabetes Studies have reported that diminished GLUTs and AGEs accumulate in SPs and NFTs, and AGEs may also accelerate Aβ deposition 22 Therefore, accumulated AGEs may be an important factor shared by DM and AD.

AGEs are metabolized through the activation of RAGE. The interaction of AGEs with RAGE promotes the formation of ROS 25 and mediates the amplification of inflammatory responses 58 ROS are cytotoxic byproducts of normal mitochondrial metabolism. Nevertheless, excessive ROS levels may cause oxidative stress and mitochondrial dysfunction, likely as a link between brain inflammation and defective insulin signaling Notably, RAGE also binds to Aβ peptides, which causes an increase in the transport of Aβ from the blood to the brain 235864and RAGE is overexpressed in the brain of AD patients Moreover, RAGE can induce its own expression through the activation of the transcription factor NF-κB Previous studies have demonstrated a significant correlation between SP formation and the activation of microglia and astrocytes in AD brains 16 The aggravated AD pathology in the DM model suggests that an important pathogenic factor closely related to hyperglycemia plays a critical role in AD pathology 67and investigation of this factor will provide insight for designing a strategy to prevent and treat AD.

The animals were maintained under standard conditions. injection of 0. Blood samples were subsequently obtained by tail prick, and the blood glucose levels were measured using a handheld blood glucose meter at various time points.

: Chronic hyperglycemia and cognitive impairment

RESEARCH DESIGN AND METHODS Khaw CgronicWareham NImpairmen SLuben RGut health and skin health ARecovery resources for veterans N Association of hemoglobin A1c cognihive cardiovascular disease and mortality in adults: the Imparment prospective investigation into cancer in Norfolk. Sullivan Lentils and Red lentil soupGlycemic control shown to prevent dementia. However, Lentils and Red lentil soup view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. It has been associated with impaired attention, processing and motor speed, executive functioning, and verbal memory The cut-off for the duration of Diabetes was 7. CAS PubMed Google Scholar Arntzen KA, Mathiesen EB. There was no difference in memory, motor speed, selective attention, and language.
ORIGINAL RESEARCH article

Diminished cognition with deterioration of executive function may make planning activities, preparing meals, and shopping difficult or even impossible 4 , Memory loss can lead to forgetting to eat or eating insufficient carbohydrates, which can cause hypoglycemia in adults who require insulin therapy or take insulin secretagogues.

Poor meal planning can also lead to food choices high in processed sugar, resulting in hyperglycemia. Forgetting whether a meal was consumed and eating twice can also result in hyperglycemia.

Registered dietitians play a significant role in patient care by assessing nutritional status and providing medical nutrition therapy when needed. Quality of life can be enhanced through effective nutritional management.

Caregivers should join patients in meeting with nutritionists and medical providers so that realistic meal planning is coordinated with appropriate pharmacological therapy. Regular physical activity is recommended for people with diabetes.

Exercise has been shown to improve glycemic control, reduce cardiovascular risk factors, help with weight management, maintain muscle mass and mobility, and improve overall health 2.

For adults with diabetes and cognitive impairment, who may also have problems with vision, mobility, and balance, incorporating a structured exercise program can be difficult.

Physical therapists and occupational therapists, in collaboration with the diabetes team and caretakers, can help design and implement safe activities to help individuals with various functional or mobility limitations maintain their highest possible level of function.

The risk of hypoglycemia during physical activity is also a major concern for patients with executive dysfunction who are taking insulin or insulin secretagogues because of their poor ability to adjust their carbohydrate intake and medication dosing to compensate for activity 2 , 4. Caretakers should be instructed about the prevention, recognition, and treatment of hypoglycemia associated with exercise.

Cognitive limitations can lead to poor personal hygiene, further compromising glycemic control and patient health 2.

Poor dental care can result in oral infections, gum disease, difficulty eating solid foods, and deterioration in glycemic control. Foot care, including well-fitting shoes, orthotics when indicated, and assistance in nail care and daily foot examination can help prevent foot infections and ulcerations and improve mobility.

Specific instructions for caregivers and patients regarding when to seek specialty care also may be needed. Podiatry follow-up is particularly helpful for patients with a history of foot ulcers, peripheral arterial disease, peripheral neuropathy, or foot deformities. Depression is common in adults with diabetes.

It is important to recognize and treat depression to improve emotional well-being. It is also important to consider depression as a reversible cause of cognitive impairment in older adults.

Diabetes-related distress is associated with regimen nonadherence and poor glycemic control and may advance diabetes complications 1. Diabetes complications can further increase emotional distress, which in turn can exacerbate the symptoms of such disorders. The inability to care for oneself due to psychosocial factors is compounded by cognitive impairment.

The assistance of a case manager, mental health professional, or social worker may be appropriate when there is evidence of depression, physical neglect, or unsafe medication adherence 2 , Coordination of health care services, including scheduling appointments and tests, renewing and obtaining needed medicines and supplies, and paying medical-related bills, is necessary for diabetes management.

Navigating our complex medical system is overwhelming for many adults, but can be virtually impossible for people with cognitive impairment. For a person with cognitive impairment, scheduling and remembering medical appointments, ensuring transportation, and recording or understanding instructions may not be possible without assistance.

Adults with diabetes and cognitive impairment who live alone are at particular risk of self-neglect and harm due to potential inadequate food and drink intake, poor medication adherence, and poor hygiene Home care services may be able to provide additional care and support to allow patients to safely remain in their own living environment.

For stage one or two cognitive impairment, training in the use of cognitive compensatory strategies and external memory aids e. In addition, the use of environmental supports e.

Adults living in long-term care or assisted-living environments have unique, individualized needs that should be assessed at intake and at regular intervals thereafter. Realistic diabetes care plans need to be formulated and carefully communicated to patients, family members, and facility staff members.

Facility staff may require additional diabetes-related education. Glycemic control including glucose monitoring , dietary intake, nutritional status, and medication administration require periodic review, with adjustments made as needed.

To improve care, it has been recommended that facilities develop diabetes-specific policies and procedures 2. Guidance is provided by the American Diabetes Association ADA 2. Table 2 lists health care professionals, including medical providers, nurses, dietitians, social workers, counselors, pharmacists, and certified diabetes educators, who play crucial roles in identifying needs, supporting people with diabetes, and educating patients, family members, and other caretakers.

Diabetes educators, for example, work with health care team members, patients, and caregivers to provide ongoing education and support Table 3 and Table 4 identify support systems, strategies, and assistive devices used to improve diabetes management.

Having discussions with patients and their families to better understand their concerns and incorporating, when possible, their preferences in relation to their diabetes care are crucial. Role of Health Care Professionals in Supporting the Needs of People With Diabetes and Cognitive Impairment.

Note: With the exception of GPS tracking and emergency alert devices, most devices included in this table are only appropriate for patients with stage one or stage two cognitive impairment and are unlikely to be effective in those with dementia.

Hypoglycemia, which is more common with intensive glycemic treatment, has been linked to long-term impairment of cognition 23 , Not only is hypoglycemia associated with worsening cognition, but also cognitive impairment is associated with a higher risk of hypoglycemia 25 — Impaired cognition, including poor performance on numeracy-based diabetes self-management tasks, also has been associated with higher risk of severe hypoglycemia in older adults with a long duration type 1 diabetes 12 , Although there is evidence that poor glycemic control can worsen cognition in people with diabetes, there is no evidence that tight glycemic control improves cognitive impairment or prevents or slows cognitive decline in those already affected 30 — Over-treatment of diabetes has been reported in adults with cognitive impairment Management of the complex medication regimens that are commonly required to achieve tight control of blood glucose in diabetes can be difficult for patients with cognitive impairment and contribute to errors and hypoglycemia.

Patients with cognitive impairment might not be able to express or recognize symptoms of hypoglycemia and therefore might be at increased risk for serious events when using insulin or insulin secretagogues. In these cases, treatment regimens should be evaluated and possibly altered to reduce hypoglycemia risk.

ADA, the American Association of Clinical Endocrinologists, and the American Geriatric Society AGS all have released diabetes practice guidelines that recognize cognitive impairment as an important factor to be considered when prescribing glycemic control medications 2 , 17 , Unfortunately, although raising A1C targets may be helpful in reducing hypoglycemia, it is insufficient in preventing hypoglycemia, especially in the elderly and in those with type 1 diabetes of long duration or with hypoglycemia unawareness 12 , 35 , Therefore, raising A1C targets cannot be the sole means of preventing hypoglycemia in patients with poor cognition.

No glycemic control medications have been proven to improve cognitive function independent of their glucose-lowering effects.

There is evidence from animal studies that metformin, thiazolidinediones TZDs , incretin-based therapies, and insulin have direct positive effects on the brain, but clinical trials are needed to establish benefit in humans 13 , 37 — No clinical trials have evaluated the efficacy and safety of different diabetes treatment regimens in adults with diabetes and cognitive impairment.

An individualized, patient-centered approach is recommended when choosing a medication regimen for adults with cognitive dysfunction. In general, regimen simplification is suggested as cognitive function declines, with the primary goals of avoiding hypoglycemia and symptomatic hyperglycemia.

Noninsulin glycemic control medications used to treat type 2 diabetes are discussed below and in Table 5. Oral and Noninsulin Injectable Medications for Type 2 Diabetes and Considerations Related to Cognitive Impairment. Metformin remains the mainstay of treatment of type 2 diabetes because it is safe, effective, and inexpensive; has a low risk of hypoglycemia; and is generally well tolerated.

Low doses are recommended to minimize gastrointestinal GI symptoms. In the absence of GI side effects, this is a good choice for patients with cognitive impairment.

It is recommended that, for patients such as the elderly who are at increased risk for the development of renal impairment, renal function be assessed more frequently than the usual standard of once yearly. The oral insulin secretagogues associated with the greatest risk of hypoglycemia are sulfonylureas and meglitinides.

Sulfonylurea drugs, which are inexpensive, need to be used with care in patients with severe cognitive dysfunction because of their potential to cause hypoglycemia 2 , Glipizide, the sulfonylurea with the lowest risk of hypoglycemia and lowest dependence on renal function, can be a reasonable choice in patients with cognitive impairment.

Long-acting glyburide should be avoided. The short-acting meglitinides are associated with less hypoglycemia than sulfonylureas, but they need to be given with each meal.

This dosing regimen is more difficult for adults with poor memory but may be preferable for patients who only eat one large meal daily. Oral incretin-based medications i. Importantly, they carry a very low risk of hypoglycemia, are taken only once daily, and are well tolerated.

Linagliptin does not require dose adjustment for poor renal function. In contrast, glucagon-like peptide 1 GLP-1 receptor agonists are administered by injection twice daily, daily, or weekly.

GI side effects, cost, and potential for weight loss can limit their use. Adults with cognitive impairment might have difficulty operating the more complex pen delivery devices used to administer some of these medications; assistance from a caregiver or visiting nurse may be required.

TZDs have the advantage of once-daily dosing but should not be used in patients with congestive heart failure.

Adverse effects on bone health, in addition to fluid retention and weight gain, need to be considered. α-Glucosidase inhibitors have GI side effects that limit their use.

They need to be taken with each meal, which can also be difficult for people with cognitive impairment. Sodium—glucose cotransporter 2 SGLT2 inhibitors, the newest oral glycemic control agents, are expensive, taken once daily, and have not been studied in patients with cognitive impairment.

In elderly patients or adults with severe dementia who might not have good or reliable oral intake, the potential for intravascular volume depletion limits their use.

These agents also carry an increased risk for urinary tract infections UTIs , which may go unrecognized in the elderly or people with dementia, and can exacerbate urinary incontinence.

There is also a risk of DKA. All patients with type 1 diabetes and many with type 2 diabetes require insulin therapy. When used properly, insulin therapy is safe and effective for patients with cognitive impairment and dementia. In people with type 2 diabetes, insulin therapy is often initiated with the use of a basal insulin in addition to oral or noninsulin injectable medications.

Factors to consider when starting or continuing basal insulin include the risk of hypoglycemia, cost, duration of action, and ease of use Table 6. Insulin glargine has been shown to have a lower risk of nocturnal and overall hypoglycemia than NPH insulin This is likely because of the peak in action that occurs 4—10 hours after NPH insulin is taken.

Therefore, when using NPH insulin, it is prudent to check blood glucose during the peak of action to monitor for impending hypoglycemia. Nonetheless, NPH insulin might be preferred as the least expensive basal insulin. Insulin detemir in low doses has a shorter duration of action than insulin glargine.

Therefore, hour coverage may require twice-daily dosing. However, compared to NPH insulin, it usually does not have any significant peak in action. The most recent basal insulin approved by the U.

Food and Drug Administration FDA , insulin degludec, may have advantages for people with cognitive impairment. It is an ultra-long-acting insulin with daily dosing, but because of its long half-life, exact timing of the daily dose may not be as crucial. Initial studies have shown lower rates of hypoglycemia with insulin degludec compared to glargine and detemir 42 , More important than the specific choice of basal insulin is careful attention to insulin dosing.

The common practice of titrating basal insulin doses to a fasting morning blood glucose target should be performed with care. This is especially true in patients with cognitive impairment because this practice can result in a long-acting insulin dose that fails to account for late-evening and nighttime food intake and is therefore too high.

The safest basal insulin dose is one that allows a patient to skip meals without resulting hypoglycemia i. Blood glucose tests are then performed 4—5 hours after dinner, at midnight, at around — a.

Metformin and DPP-4 inhibitors are associated with the least hypoglycemia and therefore are safest to combine with a basal insulin. A sulfonylurea or meglitinide can also be used to assist with mealtime coverage, but with a higher risk of hypoglycemia. If a patient has serious hyperglycemia despite combination therapy with a safe basal insulin dose, the patient has severe insulin deficiency and needs to be treated with basal-bolus therapy as described below for individuals with type 1 diabetes.

When mealtime insulin is used, sulfonylurea and meglitinide drugs should be discontinued. In overweight or obese patients, continuing metformin might help reduce required insulin doses. In patients with type 1 diabetes, current best practice emphasizes basal-bolus therapy using either a long-acting insulin combined with mealtime rapid-acting insulin or continuous subcutaneous insulin infusion i.

Many patients on basal-bolus regimens adjust mealtime insulin based on insulin-to-carbohydrate ratios and sensitivity correction factors to correct for hyperglycemia. This type of regimen requires significant engagement and numerative processing skills that might be limited in patients with cognitive impairment.

Alternatively, use of conservative fixed mealtime insulin doses may be needed. The involvement of a caregiver might be enhanced by the use of a CGM device. Especially helpful are CGM systems that transmit glucose values, alarms, and alerts to a smartphone or a remote monitor.

Volume 94, Issue Article Navigation. Review Articles July 09 The Impact of Hypo- and Hyperglycemia on Cognition and Brain Development in Young Children with Type 1 Diabetes. Subject Area: Endocrinology , Women's and Children's Health. Michal Nevo-Shenker ; Michal Nevo-Shenker. a Jesse Z. This Site.

Google Scholar. Shlomit Shalitin Shlomit Shalitin. b Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. shomits2 clalit.

Horm Res Paediatr 94 : — Article history Received:. Cite Icon Cite. toolbar search Search Dropdown Menu. toolbar search search input Search input auto suggest.

This content is only available via PDF. Karger AG, Basel. Copyright: All rights reserved. Summary of cognitive domains that have been found to be negatively affected by type 1 diabetes mellitus. Domains marked by asterisks have particularly strong supporting data.

A recent meta-analysis included 33 studies examining cognitive function in adult subjects with type 1 diabetes mellitus It found that there were significant reductions in overall cognition, fluid and crystallized intelligence, speed of information processing, psychomotor efficiency, visual and sustained attention, mental flexibility, and visual perception in subjects with type 1 diabetes compared with controls.

There was no difference in memory, motor speed, selective attention, and language. All studies included healthy matched control groups and used reliable testing measures at normal blood glucose values.

Most studies included in the meta-analysis controlled for depression; however, similar findings were seen in those studies that did not control for depression.

It is unclear whether any of these studies controlled for other chronic diseases that could affect cognitive function. Worse cognition was associated with increased diabetes complications, but not with glycemic control in these populations. As was demonstrated in the work of Brands et al. Deficits in fluid intelligence, information processing, attention, and concentration have been associated with the presence of background retinopathy Proliferative retinopathy, macrovascular complications, hypertension, and duration of diabetes were associated with poorer performance on tests measuring psychomotor speed and visuoconstruction ability in patients with type 1 diabetes 4 — 6.

Patients with distal symmetrical polyneuropathy displayed worse cognitive function on most cognitive domains except for memory 5. However, other studies were unable to identify a relationship between impaired cognitive function and diabetic complications Future study will be necessary to determine whether there is a link between complications and alterations in cognition.

Although complications like retinopathy and nephropathy usually require years of diabetes before becoming clinically apparent, the onset of cognitive impairment has been found to occur early in patients with type 1 diabetes.

Deficits in cognitive function have been detected as early as 2 yr after diagnosis in children with type 1 diabetes, and these patients experienced less positive changes than controls over time in general intelligence, vocabulary, block design, speed of processing, and learning Six years after diagnosis, these same subjects had impaired IQ, attention, processing speed, long-term memory, and executive function compared with controls The age of onset of type 1 diabetes may also contribute to the presence of cognitive dysfunction, because those who developed type 1 diabetes at less than 4 yr of age had impaired executive skills, attention, and processing speed when compared with those that were diagnosed after 4 yr of age Of note, chronic disease and time away from school secondary to illness, etc.

were not controlled for in these studies. Interestingly, several studies have shown patient gender to influence neurocognitive function in patients with type 1 diabetes mellitus.

Skenazy and Bigler 10 found that men with type 1 diabetes had reduced performance on oscillation, strength grip, and somatosensory testing compared with male controls, and the magnitude of this difference was greater than that measured between women with type 1 diabetes and their gender-matched controls.

In addition, a decline in verbal intelligence was seen in boys with type 1 diabetes between the ages of 7 and 16, which correlated with worse glycemic control. This was not seen in girls of similar ages However, most human studies have not distinguished between genders when describing results of neurocognitive testing, and therefore more controlled analysis should be done before any conclusions are drawn.

Of note, the strength of these neurocognitive studies is variable. The reviewed reports controlled for at least some of these covariates, however most fail to control for all of them. For example, only two studies that have been mentioned 6 , 24 have reported controlling for hyperglycemia at the time of testing, which has been proven to affect cognitive function see Section II.

The cognitive domains that are affected by type 1 diabetes with the best evidence based on our review are indicated in Table 1 with an asterisk. Patients with type 2 diabetes mellitus have also been found to have cognitive impairment Table 2.

The impact of these subtle neurocognitive deficits on the daily lives of patients with type 2 diabetes is not clear. Sinclair et al. These subjects also displayed an increased need for personal care and increased rates of hospitalization when compared with controls.

Patients with diabetes also have been found to have slower walking speed, lack of balance, and increased falls associated with type 2 diabetes, but whether the cerebral affects of diabetes contributed to these abnormalities is debatable Complicating the impact of mild neurocognitive dysfunction secondary to diabetes on daily living is the observation that patients with diabetes are twice as likely to have depression 27 , 36 , which will also negatively affect cognitive function and daily activities.

Recently, Bruce et al. Summary of cognitive domains that have been found to be negatively affected by type 2 diabetes mellitus. Glycemic control appears to play a role in determining the degree of cognitive dysfunction detected in patients with type 2 diabetes, although this has not uniformly been observed In a population of nearly postmenopausal women, Yaffe et al.

Grodstein et al. Other studies have demonstrated an inverse relationship between HbAlc and working memory 27 , 28 , executive functioning 27 , learning 26 , and complex psychomotor performance 26 , 48 in patients with type 2 diabetes mellitus, supporting the hypothesis that worsening glucose control leads to worsening cognitive function much like with type 1 diabetes.

Also similar to type 1 diabetes is the association between alterations in cognitive function in patients with type 2 diabetes and diabetes complications like peripheral neuropathy 28 and duration of type 2 diabetes 25 , Impaired glucose tolerance without diabetes is also a risk factor for cognitive dysfunction.

These observations mirror the positive relationship found between hyperglycemia in patients without diabetes and cardiovascular disease 50 — The pathophysiology of this relationship is unclear, and there is evidence that both hyperglycemia and other aspects of insulin resistance could contribute to this, which will be addressed later.

Of note, however, not all studies found that patients with impaired glucose tolerance 33 , 53 , 54 or type 2 diabetes mellitus 54 , 55 perform worse than normoglycemic individuals.

However, like neurocognitive studies examining type 1 diabetes, the strength of these neurocognitive studies evaluating type 2 diabetes and impaired glucose tolerance is variable.

Although most of these studies controlled for age, there was uneven control for other covariates including education, psychiatric disorders, neurological disorders, hyperglycemia and hypoglycemia during testing, and chronic illness. The cognitive domains that are affected by type 2 diabetes with the best evidence based on our review are indicated in Table 1 with an asterisk.

Repetitive episodes of moderate to severe hypoglycemia have been implicated as one possible etiology of cognitive dysfunction in diabetes. This is significant because the risk of hypoglycemia increases as efforts to achieve the level of glycemia necessary to minimize the risk of developing the microvascular complications of diabetes are intensified 56 — The reason for severe hypoglycemia secondary to intensive insulin management is complex and multifactorial, however the initial intelligence of patients with type 1 diabetes before intensive management does not predispose to more future hypoglycemia episodes, as shown by an analysis of data collected during the DCCT During acute hypoglycemia episodes, it has been shown that performance on immediate verbal memory, immediate visual memory, working memory, delayed memory, visual-motor skills, visual-spatial skills, and global cognitive dysfunction are all impaired 60 , Interestingly, in some studies there was no difference in reaction time 63 , memory 62 , and overall cognitive performance 61 between hypoglycemia aware and unaware patients during hypoglycemic episodes, despite the fact that the glucose level at which the counterregulatory hormone response was elicited was higher in subjects with awareness of hypoglycemia.

Although cognitive impairment may occur during hypoglycemia, the effect of repetitive hypoglycemia on subsequent cognitive function during euglycemia is less clear. Studies have shown impaired verbal IQ scores 14 , 64 , full scale IQ scores 14 , 20 , 64 , attention 20 , verbal skills 11 , short-term memory, verbal memory 17 , vigilance 65 , and visual-spatial memory 8 , 18 in patients with a history of type 1 diabetes and severe hypoglycemia defined as being associated with seizures, coma, or the need for external assistance , compared with patients with type 1 diabetes without a history of severe hypoglycemia.

More recently, no association between multiple severe episodes of hypoglycemia and impaired cognitive function in patients with type 1 diabetes mellitus was found in an yr follow-up of the DCCT A lack of association between severe hypoglycemia and cognitive dysfunction was confirmed by other studies 23 , 68 — 71 , as well as with a meta-analysis, which showed no association between hypoglycemia and cognitive function Of note, however, most data analyzing the effects of hypoglycemia look at young to middle-aged patients; data regarding the impact of hypoglycemia on older individuals is lacking.

One possible reason that some studies found an association between frequent hypoglycemia and cognitive dysfunction and others did not is that the positive investigations may have included subjects with diabetes onset earlier in life. Patients with type 1 diabetes diagnosed at less than 5 yr of age may have more severe often with seizures and frequent hypoglycemia episodes than those diagnosed at ages older than 5 yr; these younger patients have been found to have worse cognitive dysfunction 9 , 18 , 72 , The severity of the hypoglycemia as well as the susceptibility of young brains to injury may explain the discrepancy 9 , Another explanation for discrepancy between reports is that subjects with more hypoglycemia may have overall tighter glycemic control, which may offset the neurocognitive damage from hypoglycemia.

This was most likely the case in the population studied by Kaufman et al. Clearly, much research has been done on cognitive dysfunction in patients with type 1 and type 2 diabetes mellitus.

Although results are not consistent and many different deficits have been identified, some conclusions can be drawn. Severe hypoglycemic episodes may contribute to cognitive dysfunction in the young; however, as patients age episodes seem to have less of an influence. Finally, improved diabetes control and decreased diabetic complications seem to be associated with less cognitive dysfunction, although this association is clearer in patients with type 2 diabetes than with type 1 diabetes.

However, some questions remained unanswered. First, it is not clear whether cognitive impairments seen in neurocognitive testing result in meaningful deficits either socially or professionally.

Given the subjective nature of assessing professional and social activities, it will be difficult to address this question. Second, although the data suggest that hyperglycemia contributes to cognitive impairment, the magnitude of this contribution and how hyperglycemic one must be to experience the ill effects of hyperglycemia on cognition are not clear.

Lastly, it is unknown whether mild neurocognitive impairments will progress to overt dementia. The pathophysiology underlying the development of cognitive dysfunction in patients with diabetes has not been completely elucidated.

Many hypotheses with supporting evidence exist, including potential causative roles for hyperglycemia, vascular disease, hypoglycemia, insulin resistance, and amyloid deposition Fig. Summary of possible mechanistic contributors to cognitive dysfunction seen in diabetes mellitus.

Not all mechanisms are present in every patient. As reviewed in Sections II. A and II. B , hyperglycemia appears to be related to abnormalities in cognitive function in patients with both type 1 and type 2 diabetes. However, the mechanisms through which hyperglycemia might mediate this effect are less than clear.

In other organs, hyperglycemia alters function through a variety of mechanisms including polyol pathway activation, increased formation of advanced glycation end products AGEs , diacylglycerol activation of protein kinase C, and increased glucose shunting in the hexosamine pathway 75 — These same mechanisms may be operative in the brain and induce the changes in cognitive function that have been detected in patients with diabetes.

It has long been known that hyperglycemia increases flux through the polyol pathway in nervous tissue. In the streptozotocin-treated rat glucose concentration This accumulation was reduced significantly when the animals were treated with the aldose reductase inhibitor tolerstat Another study looking at streptozotocin-treated rats HbA1c 7.

Whether this pathway contributes to neurocognitive dysfunction in humans with diabetes is unknown. The role of AGEs and receptors for AGE RAGEs in the development of cerebral complications of diabetes also remains uncertain.

Experiments performed in animal models provide limited evidence to support the hypothesis that AGE-induced brain injury may be a mechanism through which hyperglycemia and diabetes alter cerebral function. In vitro the addition of AGEs to bovine brain microvascular endothelial cells up-regulates both tissue factor mRNA which induces blood coagulation and reactive oxygen species through a mechanism that is reversed with treatment by the free radical scavenger edaravone In addition, in a rat model of focal cerebral ischemia, the infusion of AGEs increased cerebral infarct size, whereas the coadministration of aminoguanidine, an inhibitor of AGE cross-linking, attenuated the infarct volume Few investigators have examined the role of diacylglycerol activation of protein kinase C and increased glucose shunting in the development of cognitive dysfunction in diabetes.

If hyperglycemia from diabetes shunts glucose toward the production of chitin, it is possible that the accumulation of this molecule could contribute to abnormalities in cognition. Hyperglycemia has also been proposed to cause end organ damage through increases in reactive oxygen species, in particular superoxide, which could then lead to increased polyol pathway activation, increased formation of AGEs, activation of protein kinase C, and increased glucose shunting in the hexosamine pathway Using streptozotocin to induce diabetes in rats blood glucose, Nuclear factor κB transcription factors, a proinflammatory gene marker up-regulated by AGEs, and S protein, a marker for brain injury that can bind to RAGEs, were both up-regulated in the hippocampus in this animal model, although the effect in other regions was not assessed.

These data suggest that oxidative stress may trigger a cascade of events that lead to neuronal damage. Interestingly, dehydroepiandrosterone, an adrenal androgen and antioxidant, significantly reduces these changes, suggesting a potential therapy worthy of more investigation.

In addition to hyperglycemic-induced end organ damage, altered neurotransmitter function has been observed in diabetic models and may also contribute to cognitive dysfunction. In diabetic rats blood glucose Other, neurochemical changes have been observed, including decreased acetylcholine 91 , decreased serotonin turnover, decreased dopamine activity, and increased norepinephrine 86 , 92 in the brains of animals with diabetes.

Interestingly, these changes were all reversed with insulin. One proposed hypothesis is that the alternating high and low glucose levels seen in patients with poorly controlled diabetes may worsen neurotransmitter function Patients with diabetes have a 2- to 6-fold increased risk in thrombotic stroke 41 , 93 , and vascular disease has long been hypothesized to contribute to abnormalities in cognition in such patients.

Autopsy studies on patients with long-standing type 1 diabetes have shown changes related to vascular disease, including diffuse brain degeneration, pseudocalcinosis, demyelination of cranial nerves and spinal cord, and nerve fibrosis 94 , Thickening of capillary basement membranes, the hallmark of diabetic microangiopathy, has been found in the brains of patients with diabetes Patients with diabetes have also been found to have decreased global rates of cerebral blood flow as measured using xenon, and the magnitude of reduction correlates with the duration of the disease.

However, blood glucose levels were not controlled during the experiment range, 3. One can speculate that the decrease in cerebral blood flow, coupled with the stimulation of the thromboxane A2 receptor known to occur in patients with diabetes 92 , could contribute to the inability of cerebral vessels to adequately vasodilate, which may in turn increase the likelihood of ischemia.

The coexistence of ischemia and hyperglycemia may be particularly detrimental to the brain. Even modestly elevated blood glucose levels greater than 8. One potential mechanism through which hyperglycemia could potentiate ischemic damage is lactate accumulation. Hyperglycemia provides more substrate for lactate to form, causing cellular acidosis and worsening injury Another mechanism is the accumulation of glutamate in the setting of hyperglycemia and ischemia Glutamate, an excitatory amino acid neurotransmitter, has been shown to cause neuronal damage in the brain Although the exact mechanism is not known, the lack of C-peptide in patients with type 1 diabetes may by itself worsen cognitive impairment through its actions on the endothelium.

The relevance to humans is uncertain, however, because humans with type 1 diabetes do not have hippocampal atrophy As mentioned in Section II.

C , whether repeated episodes of hypoglycemia contribute to cognitive dysfunction is controversial and most likely depends on the age of the patient.

However, there is no argument that if severe hypoglycemia lasts for a very long time, brain damage and death can occur 93 , — That said, it has been shown in animal models that after 30—60 min of blood glucose levels between 0.

The cortex, basal ganglia, and hippocampus appear to be most vulnerable to hypoglycemia, with laminar necrosis and gliosis found in these regions on autopsies performed in human patients who died of hypoglycemia Other human autopsy studies done after death secondary to hypoglycemia have shown multifocal or diffuse necrosis of the cerebral cortex and chromatolysis of ganglion cells In animal models, hypoglycemia-induced damage seems to be selective to neurons with sparing of astrocytes and oligodendrocytes Although counterintuitive, the time to neuronal death may be asymmetric between hemispheres in severe, prolonged hypoglycemia, making the differentiation of hypoglycemic brain damage from ischemia difficult on a clinical basis Some have hypothesized that hypoglycemia-induced neuronal damage occurs as a result of overactivation of a subtype of the excitatory neurotransmitter NMDA receptor Interestingly, there exists an NMDA receptor antagonist that has been shown to prevent neuronal necrosis, suggesting a potential therapy for hypoglycemia-induced brain damage Such a therapy may be helpful in young children with type 1 diabetes who seem to be particularly susceptible to cerebral complications of hypoglycemia.

There may also be a relationship to hypoglycemia during early nocturnal sleep, a time in which consolidation of memories occurs, and cognitive dysfunction. Compared with test outcomes after a night of sleep in euglycemia, human control subjects and subjects with type 1 diabetes exhibited impaired declarative memory memory of facts after undergoing a short, relatively mild hypoglycemic clamp 2.

However, no neurocognitive deficits were seen in several other studies in which nocturnal hypoglycemia was induced later during the sleeping period , Although the role of insulin on cerebral metabolism and function is still evolving, fascinating research has given us more insight into this field over the last 20 yr.

Historically, the brain was thought to be an insulin-independent organ; however, many recent discoveries have questioned that notion. Insulin receptors and mRNA expression have been found to be widely distributed in rat brain using immunohistochemistry and in situ hybridization , , respectively, including in the olfactory bulb, hypothalamus, hippocampus, cerebellum, piriform cortex, cerebral cortex, and amygdala.

The insulin-responsive glucose transporter 4 GLUT4 has also been found in select regions of the rat brain, including the pituitary, hypothalamus, and medulla GLUT8, also known as GLUTx1, is also found in the rat brain, specifically in the hippocampus, hypothalamus, cerebellum, and brainstem GLUT8 has similar properties to GLUT4 and is up-regulated in response to insulin in some but not all murine tissues, including the brain Despite the presence of insulin receptors and insulin-sensitive glucose transporters, the effect of insulin on cerebral glucose metabolism is still uncertain.

Many laboratories, including our own, have failed to demonstrate an effect of insulin on cerebral glucose metabolism in humans — However, other laboratories using fluorodeoxyglucose positron emission tomography PET have found a significant increase in brain glucose metabolism in the setting of hyperinsulinemia in humans , an effect that is reduced in subjects with peripheral insulin resistance The reason for the discrepancy could be the populations studied.

The mechanisms through which insulin resistance might alter cognitive function remain uncertain, but effects on neurotransmission and memory formation have been hypothesized. Mice models in which cholinergic activity is blocked by scopolamine experience amnesia and hyperactivity, a deficit that can be reversed by glucose administration , In addition to affecting cholinergic activity, diabetes and insulin may affect long-term potentiation in opposing ways.

Long-term potentiation is critical to the formation of memories and is induced by NMDA receptor activation, a process that is up-regulated in the presence of insulin However, rats with diabetes, and presumed relative insulin deficiency, have decreased long-term potentiations in the hippocampus as measured by electrophysiology As would be expected if long-term potentiation were reduced, rat hippocampal neurons exposed to insulin exhibited inhibition of spontaneous firing Perhaps the reduction in glucose uptake has a direct effect on how insulin regulates hippocampal function in these patients.

Future experiments to identify the relative roles of glucose and insulin in human cognition are necessary to clarify these relationships. In our laboratory, we found that inducing hyperinsulinemia using an insulin infusion in control subjects reduces parietal region P amplitude secondary to memory triggers Other clamp studies found improved vigilance, memory, and selective attention in the setting of hyperinsulinemia , , whereas intranasal insulin treatment for 8 wk improved delayed recall, enhanced mood, and self confidence and reduced anger in nondiabetic, nondementia subjects Although cerebral insulin is higher in these patients, it may not be enough to compensate for the insulin resistance.

However, this does not necessarily prove that hyperinsulinemia directly improves cognitive function. Hyperinsulinemia can stimulate epinephrine release, and both insulin and epinephrine have been shown to increase lactate Insulin resistance and type 2 diabetes mellitus may contribute to cognitive dysfunction through three other indirect mechanisms.

In one investigation, patients with the metabolic syndrome, elevated C-reactive protein, and elevated IL-6 were found to have impaired cognitive function, whereas those patients with the metabolic syndrome and normal levels of these inflammatory markers had similar cognition to controls Patients with type 2 diabetes are known to have higher levels of inflammatory markers including C-reactive protein, α- 1-antichymotrypsin, IL-6, and intercellular adhesion molecule 1 than control populations A second potential mechanism through which insulin resistance and type 2 diabetes could contribute to cognitive dysfunction is through the disruption of the hypothalamic-pituitary adrenal axis.

Both animals and humans with type 2 diabetes have an up-regulation of the hypothalamic-pituitary-adrenal axis, with increased serum cortisol compared with controls.

In other research, hypercortisolemia has been found to cause cognitive dysfunction. Healthy humans treated with dexamethasone , corticosterone , and hydrocortisone to mimic stress conditions all performed worse on memory testing.

In a study of healthy elderly patients, those with higher serum cortisol levels performed more poorly on memory and attention testing Supporting these findings are the animal studies in which glucocorticoids cause structural damage and reduce function of neurons in the hippocampus — Based on the facts that type 2 diabetes causes an up-regulation of the hypothalamic-pituitary-adrenal axis and hypercortisolemia can cause cognitive dysfunction, it can be hypothesized that the increase in cortisol levels seen in patients with type 2 diabetes may contribute to cognitive dysfunction.

β-Amyloid is formed from the cleavage of amyloid precursor protein APP , produced in neurons , by the enzymes β- and γ-secretase β-Amyloid is eventually degraded by the insulin-degrading enzyme , Amyloid β- peptide s can by themselves bind to RAGEs and bring about microglial and neuronal dysfunction and oxidative stress Interestingly, amyloid β-peptides, AGEs, and RAGEs have all been colocalized in astrocytes using immunohistochemistry in human brain slices In addition, there is a growing body of evidence that insulin and insulin resistance can affect the metabolism of APP and β-amyloid, thus potentially increasing the burden of cerebral senile plaques.

The role of insulin resistance in the metabolism of APP and β-amyloid was further clarified by Craft et al. This corresponded with improved memory testing. One potential explanation of this observation is that insulin resistance may cause decreased APP degradation that can be overcome by the elevating serum and presumably tissue insulin levels Similar findings have come from experiments in rat hippocampal neurons, where insulin was found to up-regulate insulin degrading enzyme, thereby increasing β-amyloid degradation However, not all studies have agreed with this hypothesis.

In a study using neuroblastoma cell lines by Gasparini et al. This would contradict the majority of the evidence that insulin has a protective effect against memory loss. More research is needed concerning the pathophysiology of β-amyloid and insulin before conclusions can be drawn.

The constitutions of islet and neural β-amyloid are similar , , and both are toxic to islet and neurons, respectively , In a series of 29 patients in whom both brain and pancreas autopsy specimens were available, all had amyloid detected to some degree in both the brain and pancreas This study was specific for elderly Japanese-American men, so it seems that additional multiethnic studies are needed to understand this discrepancy better.

In a small randomized study published by Watson et al. However, clinicians must weight the benefits against the newly documented cardiovascular risks of these treatments , Although progress is being made, the difficulty of detecting neurocognitive dysfunction in patients with diabetes in the clinical setting may explain in part why the field of cognitive dysfunction in diabetes has not advanced similarly to other fields dealing with hyperglycemia-associated end organ damage.

Neurocognitive testing in which an examiner administers a battery of tests to assess different aspects of cerebral function has long been the gold standard for the assessment of neurocognitive function. Although cumbersome to administer and score, it has been very useful in assessing neurocognition in a variety of disease states, including diabetes, as was demonstrated in Section II.

However, such tests have a relatively high rate of intrasubject variability that reduces their ability to identify mild deficits or preclinical disease. Also, many studies examining the effect of diabetes on brain function use multiple neurocognitive tests that assess the same psychological process.

In addition, not all neurocognitive tests are created equal. Finally, neurocognitive testing is unable to provide specific information about the neural structures responsible for any dysfunction identified.

For example, although it appears that white matter function such as processing speed, attention, and visual-spatial processing are particularly affected by diabetes 4 , localization of this dysfunction to white or gray matter is not possible using the battery of tests available to assess neurocognition.

Because of the limitations in neurocognitive testing, a number of modalities have been used to assess cognitive function in patients with diabetes Table 3. One of the oldest modalities has been to measure electrical activity such as evoked response potentials in the brain after the administration of different stimuli.

Abnormal evoked response potentials can reveal subclinical sensory nerve conduction deficits that may not otherwise be apparent For example, flash electroretinography has shown decreased potentials from the retina in diabetic subjects before ophthalmoscopic signs of retinopathy were seen In addition, pattern electroretinogram, which looks at the pattern of retinal stimuli originating from the ganglion cells, is also decreased in patients with diabetes The evoked response of nerves involved in sensing auditory stimuli is also abnormal; brainstem auditory-evoked potentials demonstrated acoustic pathway impairment in patients with diabetes — Evoked potentials related to memory may also be affected because auditory P event-related potentials had significantly longer latencies in patients with type 2 diabetes compared with controls, which could relate to attention and short-term memory defects Central somatosensory-evoked potentials were found to be prolonged in patients with diabetes as well In another study looking at both type 1 and type 2 diabetes, slowed latency in visual and somatosensory-evoked potentials was observed in patients with type 1 diabetes, whereas patients with type 2 diabetes had slowed latency of visual, somatosensory, and brainstem auditory-evoked potentials In this investigation, increasing HbA1c was related to reduced cognitive performance.

Event-related potentials have also helped define brain adaptations to hypoglycemia. During hypoglycemia, normal subjects do not experience a delay in initial perception and precognitive processing, but they do have a delay in central processes such as stimulus selection and selective central motor activation Of note, although all except one of these studies controlled for hypoglycemia during testing , none of the studies adequately controlled for hyperglycemia during testing, although Kurita et al.

Summary of modalities for assessment of cognitive dysfunction in patients with diabetes. EEG can also assess spontaneous cerebral electrical activity and has been used in patients with type 1 and type 2 diabetes.

Patients with type 2 diabetes have been found to have slowing in the EEG frequency band analysis over the central cortex area and reduction of alpha activity over the parietal area. These findings correlated with reduced visual retention on neurocognitive testing but were not simply related to hyperglycemia because making nondiabetic subjects with hyperglycemia did not reproduce these findings Subjects with type 1 diabetes have also been found to have abnormal EEG results compared with controls, with those patients with a history of having severe hypoglycemia having the most abnormalities 65 , , Magnetic resonance imaging MRI has been used in a number of studies to examine cerebral structure in patients with type 1 and type 2 diabetes and has pretty consistently found the brains of such subjects to have leukoariosis, which are hyperintense white matter lesions , However, this was not confirmed by a more recent published study in which relatively young patients 25—40 yr old with type 1 diabetes for more than 15 yr did not have a significant difference in white matter hyperintensities compared with healthy controls.

In addition, white matter hyperintensities did not correlate with depressive history, retinopathy, severe hypoglycemia, glycemia control, and most neurocognitive tests with the exception of delayed memory 7. This is in agreement with previous studies 3 , The reason for the discrepancy may have been that subjects in the former study had more severe microvascular complications and that differences in cardiovascular risk factors between subjects with diabetes and controls were not controlled for.

In patients with type 2 diabetes, these white matter hyperintensities have been noted to correlate with reduced performance on tests of attention, executive function, information processing speed, and memory , The nature of these white matter lesions is uncertain, but investigators have hypothesized that they could represent demyelination, increased water content, angionecrosis, cystic infarcts, or gliosis i.

brain tissue scarring MRI has also demonstrated that subjects with type 2 diabetes have hippocampal and amygdala atrophy relative to control subjects However, a similar study in subjects with type 1 diabetes failed to identify reductions in hippocampal and amygdala volume, although these subjects did have an increase in cerebrospinal fluid on MRI, suggesting mild global cerebral atrophy Another study compared MRI findings and neuropsychometric testing in patients with an early age of onset of type 1 diabetes younger than age 7 and a later age of onset 7—17 yr old.

Subjects with early onset disease had larger ventricular volumes and more prevalent ventricular atrophy than those with later onset, which corresponded to poorer intellectual and information processing ability Atrophy in subcortical and periventricular areas has also been associated with reduced performance on memory tasks in patients with type 2 diabetes A history of hypoglycemia appears to be related to an increase in cerebral atrophy Recently, voxel-based morphometry, in which differences in local characteristics of tissue are measured using MRI, has been used to evaluate both the gray and white matter of patients with type 1 diabetes.

Musen et al. They also found that higher HbA1c levels correlated with lower gray matter density in areas important for language, memory, and attention, whereas a history of severe hypoglycemia correlated with less gray matter density in the left cerebellar posterior lobe Wessels et al.

They found that patients with type 1 diabetes and proliferative retinopathy had decreased gray matter density in the right inferior gyrus and right occipital lobe compared with those patients with diabetes and no retinopathy, as well as to controls.

More recently, Wessels and colleagues applied voxel-based morphometry to white matter volumes. They found that those subjects with type 1 diabetes and proliferative retinopathy had significantly smaller white matter volume than subjects without diabetes, and that smaller white matter volume correlated with worse performances on attention, speed of information processing, and executive function.

This was not seen in patients with type 1 diabetes who had no proliferative retinopathy, suggesting a possible common mechanism in the development of retinopathy and cerebral dysfunction 6.

Preliminary findings by Perantie et al. Functional MRI fMRI has also been used to assess cerebral function in patients with diabetes.

fMRI is based on the fact that increases in cerebral blood flow and metabolism during stimulus-induced neuronal activation are accompanied by a relative reduction in deoxyhemoglobin content of the activated tissue relative to the adjacent unactivated brain.

Because deoxyhemoglobin is a paramagnetic molecule, it can be visualized by MRI. Rosenthal et al. They found that the effect of acute hypoglycemia on cerebral blood flow is task and region specific.

For example, during hypoglycemia, the slower finger tapping corresponded to decreased activation of the right premotor cortex, supplementary motor area, and left hippocampus and with increased activation in the left cerebellum and right frontal pole.

In addition, during hypoglycemia deterioration of four-choice reaction time correlated with reduced activation in the motor and visual systems but with increased activation of the part of the parietal cortex involved in planning More recently, Wessels et al.

Although there was no difference seen in cognitive ability between the two groups, there was an overall increase in activation and less appropriate deactivation of certain brain regions during hypoglycemia in the diabetic group with retinopathy.

The investigators hypothesized that regional alterations in activation were secondary to hyperglycemia-induced end organ damage in the central nervous system, causing altered neurovascular coupling or functional microvascular alterations Preliminary findings by Musen et al.

Other imaging modalities such as single photon emission computed tomography SPECT and PET have been used to assess cerebral function in patients with diabetes mellitus.

SPECT is particularly good at assessing cerebral perfusion and has demonstrated in an uncontrolled study that patients with type 2 diabetes and dementia have a high incidence of hypoperfusion in at least one area of the brain However, SPECT has also demonstrated that patients with type 1 diabetes have hyper perfusion in the prefrontal and frontal brain regions compared with controls Other investigators found that when the SPECT data are corrected for the increase in cerebral atrophy seen in patients with diabetes, cerebral blood flow and glucose metabolism values were within normal range PET with fluorodeoxyglucose is a technique that can be used to assess glucose metabolism because the compound is taken up and trapped in the cell by phosphorylation.

When this method was used in patients with type 1 diabetes and a history of severe hypoglycemia and hypoglycemia unawareness, no differences in glucose metabolism were found relative to controls, although neuropsychological testing was also not significantly different Two pilot studies, one by our own laboratory, have used diffusion tensor imaging, a type of MRI that measures white matter integrity quantitatively by fractional anisotropy , , in patients with diabetes.

Preliminary findings show a reduction in white matter integrity in patients with type 1 diabetes that was associated with severity of hyperglycemia and poorer performance on certain neurocognitive tests In general, assessment modalities to detect cognitive dysfunction associated with diabetes have been disappointing.

Neurocognitive testing is cumbersome and lacks pathophysiological insight. Although promising, there have been conflicting results with regard to MRI studies, specifically in patients with type 1 diabetes.

The utility of SPECT, PET, and diffusion tensor imaging in monitoring or detecting changes in patients with cognitive dysfunction and diabetes remains to be determined. Although much research has been done on the impact of diabetes mellitus on cognitive function, many questions still remain.

It is clear that patients with type 1 and type 2 diabetes have been found to have abnormalities in neurocognitive function, although the natural history and clinical significance of these findings have not yet been clearly defined. For example, we know that there is an increased incidence of dementia in patients with type 2 diabetes 37 , 38 , 40 — 44 , but we do not know whether the more subtle changes in memory and in other measures on neurocognitive testing are a precursor to true dementia or represent another process.

We also do not know whether the incidence of dementia is increased in patients with type 1 diabetes compared with the rest of the population. In prior decades, this was not an issue because patients with type 1 diabetes died at relatively young ages from other complications of the disease.

However, now that patients with type 1 diabetes are living longer and better with the disease, this must be assessed. Finally, it is not clear whether the subtle cognitive deficits identified in many studies truly impact the lives of patients living with diabetes Future study will also be important in understanding the pathogenesis of cognitive dysfunction secondary to diabetes.

Although it seems that hyperglycemia and hyperglycemia-induced end organ damage contribute to this problem, the actual mechanisms through which hyperglycemia alters cerebral structure and function are not clear. Improved glycemic control is likely of therapeutic benefit, as has been suggested by many retrospective studies 5 , 15 , 16 — 18 , 26 — 28 , 48 , but a prospective study is needed to determine whether this is true.

In addition, identification of the mechanisms through which hyperglycemia may impair cognitive function in patients with diabetes will stimulate new research into ways to prevent and treat all of the hyperglycemia-associated complications of diabetes.

In conclusion, there have been significant gains in our understanding of the effect of diabetes on cognitive dysfunction.

Evidence from neurocognitive testing suggests that cognitive dysfunction should be listed as one of the many complications of diabetes, along with retinopathy, neuropathy, nephropathy, and cardiovascular disease.

The pathogenesis of cognitive dysfunction is only partially understood. Although many studies suggest that changes in cerebral structure and function in diabetes are related to hyperglycemia-induced end organ damage, macrovascular disease, hypoglycemia, insulin resistance, and amyloid lesions may play a role in some patients.

Greater understanding of the natural history of this diabetes complication and the mechanisms responsible for its development will continue to advance as biochemical and imaging modalities continue to evolve. As new knowledge is gained, it can be applied to develop new and improved ways to prevent and treat all of the hyperglycemia-related complications of diabetes.

This work was supported by NIH Grants NS to E. Disclosure Statement: E. has served on advisory boards for Pfizer and Merck. has no disclosures to state. Renal Data System USRDS Annual Data Report: Atlas of end-stage renal disease in the United States. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases.

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I. Introduction Ann Neurol. Pathophysiology of Chronic hyperglycemia and cognitive impairment Dysfunction amd Diabetes A. Farris, Chronic hyperglycemia and cognitive impairment. To impsirment surprise, there are only a few Citrus aurantium for immune support on cognitive Impairment in Diabetes in Kerala, though it has the highest prevalence of Diabetes. Novel directions could also be taken to investigate risk factors for which the evidence has been largely restricted to observational studies despite being modifiable. Select Format Select format. Type 1 diabetes.

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How diabetes destroys the human body Daniel Cognittive. Cox hyperg,ycemia, Boris P. KovatchevLinda A. Gonder-FrederickKent H. SummersAnthony McCallKevin J. GrimmWilliam L. Clarke; Relationships Between Hyperglycemia and Cognitive Performance Among Adults With Type 1 and Type 2 Diabetes. Chronic hyperglycemia and cognitive impairment

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