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Glucose regulation is associated with cognitive performance in young nondiabetic adults
Abstract
Several studies have documented an increased incidence of dementia among diabetic patients. In addition, impaired glucose regulation in both, younger and older adults, has been shown to be associated with neuropsychological deficits, particularly of episodic memory. The main purpose of this study was to examine this association in a large sample of young nondiabetic adults. All participants underwent a glucose tolerance test together with measures of insulin levels and lipids. Regression analyses revealed that glucoregulatory indices based on evoked glucose levels were significantly associated with the verbal memory performance of 122 young adults, independent of demographic and vascular risk factors. Participants were assessed after drinking glucose or saccharin, using a repeated-measures design. There was no effect of glucose on cognitive performance. Glucoregulatory indices calculated on the basis of insulin levels or fasting glucose levels explained less cognitive variability compared to indices based on evoked glucose levels. Cardiovascular risk factors were associated with hyperinsulinemia but these factors were not associated with cognitive performance in this young adult group. These findings suggest that cognitive decrements are observable in young, nondiabetic adults, prior to the onset of impaired glucose regulation and diabetes.
... tasks have been used to measure the effect of glucose upon the different aspects of memory such as word recall and retrieval, digit span, serial subtractions, and more. Each methodology found an increase in the performance level of participants in that level after the consumption of glucose (Scholey et al., 2001;Benton, 1990;Sunram-Lea et al., 2001). Messier et al., (2011have also supported the improvement in word recall and gluco-regulation. They researched both male (N= 47) and female (N=62), young non-diabetic adults (mean age: 20.8). However, they did not find any consistent associations between glucose regulation and working memory. This appears to suggest other factors may have been involved as alt ...
... This appears to suggest other factors may have been involved as alternative research has found improvements in verbal, visual and working memory (Scholey et al., 2001;Benton, 1990). The fact that they (Messier et al., 2011) may not have found anything significant could just be that as the majority of participants who volunteer to take part within these studies tend to be psychology undergraduate students, it is expected that they would already have a good memory and the ingestion of glucose would not necessarily influence their responses to the demand tasks. ...
... Gluco-regulation is an important biological process that the human body uses to survive. Without the glucose being regulated correctly, the body's insulin production can be effected (Messier, 2011). As gluco-regulation is used to modulate the glucose memory facilitation effect within memory (especially in older to elderly adults), the more glucose there is within the body and can be utilized, the better memory will be. ...
Previous research has shown that the consumption of glucose has a positive effect on working memory and attention. Research has suggested that the effect of glucose is greater in tasks of a higher cognitive demand. The current study will attempt to further investigate the impact of cognitive demand on the glucose facilitation effect. A 2x2x2 mixed design was applied. The independent variables were Drink (between subjects: placebo v glucose) x Task (between subject: easy v difficult) x Time (within subjects: pre-dose v post-dose). Fifty participants aged 18-61 were randomly allocated to the Drink and Task conditions. All participants self-reported as healthy and confirmed that they had not consumed any food for two hours. Participants completed a series of cognitive tasks at baseline (easy condition – mental fatigue, serial 3 subtractions and the RVIP task: difficult condition – mental fatigue, serial 7 subtractions and RVIP task) and then ingested their drink (25g of glucose or 105mg Saccharin). Twenty minutes later, participants completed another series of cognitive tasks (as above). No significant findings were found in the interaction of Drink x Task x Time. No significant findings were found within the Drink x Time condition. Significant findings have been found in the Task x Time condition. Mental fatigue was shown to differ between each level of the Time condition. Overall there was no evidence of glucose having an effect upon cognitive functions following the consumption of a glucose drink in a healthy volunteer sample suggesting the facilitation effect did not occur.
... Indeed, numerous studies have consistently reported that obesity is linked to cognitive deficits (Gunstad et al. 2007;Smith et al. 2011;Spyridaki et al. 2014), with the potential mechanisms being attributed to elevated energy metabolic indices (e.g. leptin, insulin and glucose; Razay & Wilcock, 1994;Vanhanen et al. 1998;Harvey, 2007;Gunstad et al. 2008;Messier et al. 2011), low-grade systemic inflammation (Smith et al. 2011), poorer prefrontal cerebral metabolism (Volkow et al. 2009) and neuronal degradation (Smith et al. 2011). ...
... However, insulin resistance (IR) results in chronic hyperinsulinaemia/chronically high insulin concentrations, which may impair cognitive functioning (Razay & Wilcock, 1994;Vanhanen et al. 1998). Most importantly, the association of glucoregulation and cognition is highly related to the function of insulin in the brain (Messier et al. 2011). Glycaemic status is sensitive to neurophysiological parameters, as evidenced by increased P3 latency and decreased serum glucose concentrations (Thomas et al. 1997) and by a significant decrease in P3 latency and enlargement in P3 amplitude after reduction of blood glucose concentrations via exercise in adults with type 2 diabetes (Kyizom et al. 2010). ...
New Findings
What is the central question of this study?
Obesity is linked to cognitive deficits, elevated energy metabolic indices and low‐grade systemic inflammation. Do the relationships between neurocognitive performance and the biochemical markers (e.g. energy metabolic indices and inflammatory cytokines) occur independently of factors known to be associated with neurocognitive dysfunction (i.e. cardiorespiratory fitness) in young adults?
What is the main finding and its importance?
Young obese adults showed poorer neuropsychological performances, aberrant neural activity and higher C‐reactive protein and energy metabolic indices. The higher leptin and C‐reactive protein concentrations showed a significant negative association with lower P3 amplitudes. However, leptin was the sole predictive factor, implicating hyperleptinaemia in the altered neurocognitive function observed in obesity.
The present study was designed to explore the neurophysiological mechanism of visuospatial attention deficits in obese adults and to examine the relationships between neurocognitive (neuropsychological and neurophysiological) performances and the biochemical markers. Thirty obese adults and 30 healthy‐weight control subjects, categorized by body mass index and percentage fat as measured with dual‐energy X‐ray absorptiometry, provided a fasting blood sample and performed a visuospatial attention protocol with concomitant electrophysiological recording. The obese group showed slower reaction times and smaller P3 amplitudes when performing the cognitive task. Even when controlling for the covariable of cardiorespiratory fitness, the results remained. In addition, the serum concentrations of insulin, glucose, leptin and C‐reactive protein were significantly higher in the obese group relative to the control group, but not those of interleukin‐6, interleukin‐1β and tumour necrosis factor‐α. Partial correlations adjusting for cardiorespiratory fitness showed that leptin and C‐reactive protein concentrations in the obese group were negatively associated with poorer neurophysiological (i.e. P3 amplitude) performance. However, the regression analysis showed that leptin was the sole predictor of P3 amplitude in the obese group. These findings indicate that the individuals with obesity exhibited neurocognitive deficits when performing the visuospatial attention task, and serum leptin concentrations could be one of the influential factors.
... Studies have shown that when examining changes in blood glucose from the start of cognitive testing until the end, those individuals who displayed decreased glucose levels performed cognitively better than individuals whose blood glucose levels stayed at similar levels or even increased [50,51]. Moreover, "poor" glucoregulators as evidenced by blood glucose levels above 7.8 mmol/L following a 75-g oral glucose tolerance test (IGT), demonstrated impaired cognitive performance in measures of executive function but not of BF specifically [52][53][54]. ...
... The most noteworthy finding from this study is that the lower the change (ie, from postprandial blood glucose) in blood glucose levels following the consumption of a 15-g glucose drink, the better the performance on the WCST. These data are largely in agreement with previous investigations on other cognitive functions [50][51][52][53][54] and extend to the domain of behavioral flexibility. Moreover, our study uniquely shows the importance of glucoregulation on cognitive performance even when a small dose of glucose has been administered to individuals in their postprandial and not fasting state. ...
Behavioral flexibility (BF) performance is influenced by both psychological and physiological factors. Recent evidence suggests that impulsivity and blood glucose can affect executive function, of which BF is a subdomain. Here, we hypothesized that impulsivity, fasting blood glucose (FBG), glucose changes (ie, glucoregulation) from postprandial blood glucose (PBG) following the intake of a 15-g glucose beverage could account for variability in BF performance. The Stroop Color-Word Test and the Wisconsin Card Sorting Test (WCST) were used as measures of BF, and the Barratt Impulsiveness Scale (BIS-11) to quantify participants' impulsivity. In Study 1, neither impulsivity nor FBG could predict performance on the Stroop or the WCST. In Study 2, we tested whether blood glucose levels following the intake of a sugary drink, and absolute changes in glucose levels following the intake of the glucose beverage could better predict BF. Results showed that impulsivity and the difference in blood glucose between time 1 (postprandial) and time 2, but not blood glucose levels at time 2 per se could account for variation in performance on the WCST but not on the Stroop task. More specifically, lower impulsivity scores on the BIS-11, and smaller differences in blood glucose levels from time 1 to time 2 predicted a decrease in the number of total and perseverative errors on the WCST. Our results show that measures of impulsivity and glucoregulation can be used to predict BF. Importantly our data extend the work on glucose and cognition to a clinically relevant domain of cognition.
... However, fewer studies have examined whether, within "healthy" or subclinical ranges of fasting blood glucose, higher levels might are associated with impaired cognition. Among young nondiabetic adults, impaired glucoregulation has been linked most consistently with memory deficits (e.g., Messier, Awad-Shimoon, Gagnon, Desrochers, & Tsiakas, 2011), but more work is needed to clarify the pathways by which obesity yields cognitive deficits prior to the manifestation of comorbid diseases, such as T2DM. ...
... Indeed, individuals with glucose levels in the prediabetes range had nearly twice as many errors on the test of inhibitory control compared with individuals with normal fasting glucose levels, regardless of whether they were normal weight or obese, implying that subclinical abnormalities in glucoregulation may negatively impact cognitive function independently of obesity. Our findings extend those of past studies examining glucoregulation-cognition relationships in healthy young adults that have either used only memory recall tests or the working memory aspect of executive function (EF; e.g., Messier et al., 2011). Our findings when using an EF test of inhibitory control indicate that certain components of EF may be more sensitive to glucoregulatory effects than others. ...
Objective:
Obesity is associated with cognitive deficits; however, the mechanisms are unclear, especially among otherwise healthy adults. Our objectives were to examine (a) whether obesity is linked to elevations in fasting glucose and (b) whether these elevations are associated with cognitive impairment among otherwise healthy young adults.
Method:
Participants were 35 normal weight adults and 35 young adults with obesity who completed a task from the Automated Neuropsychological Assessment Metrics-4 (ANAM-4). Measured body mass index (BMI) and fasting blood glucose levels (mg/dL) were examined.
Results:
Persons with obesity had higher fasting glucose levels than normal weight persons (p = .03). After applying Bonferroni correction for multiple tests, higher fasting glucose predicted less accurate performance on tests of inhibitory control: Go/No-Go Commission Errors (β = .33, p = .004). No effects were observed for sustained attention or working memory (ps ≥. 049). Persons with glucose levels in the prediabetes range had nearly twice as many errors as those with normal glucose, a large effect that was independent of BMI.
Conclusions:
Young adults who were obese but otherwise healthy had higher fasting glucose levels compared with normal weight peers. Higher glucose levels were associated with poorer cognitive performance on tests of inhibitory control, especially among individuals with prediabetes levels. Thus, subclinical elevations in blood glucose may contribute to cognitive impairment and, ultimately, greater impulsivity-well in advance of the development of chronic disease states (e.g., insulin resistance or Type 2 diabetes) and independently of excess adiposity-though prospective studies are needed to determine directionality of this relationship. (PsycINFO Database Record
... Experimental studies investigating the acute effect of hyperglycaemia on cognitive function are, by their nature, limited. Investigators have used various methods to induce hyperglycaemia in different populations over varying time frames, variations that may have contributed to their divergent results [13][14][15]. Accordingly, a standardised hyperglycaemic clamp should be the preferred method in a testing situation. Moreover, the effect of hyperglycaemia on the brain, as assessed by functional magnetic resonance imaging (fMRI), in correlation with working memory has scarcely been studied in people with type 2 diabetes. ...
How acute hyperglycaemia affects memory functions and functional brain responses in individuals with and without type 2 diabetes is unclear. Our aim was to study the association between acute hyperglycaemia and working, semantic, and episodic memory in participants with type 2 diabetes compared to a sex- and age-matched control group. We also assessed the effect of hyperglycaemia on working memory-related brain activity. A total of 36 participants with type 2 diabetes and 34 controls (mean age, 66 years) underwent hyperglycaemic clamp or placebo clamp in a blinded and randomised order. Working, episodic, and semantic memory were tested. Overall, the control group had higher working memory (mean z-score 33.15 ± 0.45) than the group with type 2 diabetes (mean z-score 31.8 ± 0.44, p = 0.042) considering both the placebo and hyperglycaemic clamps. Acute hyperglycaemia did not influence episodic, semantic, or working memory performance in either group. Twenty-two of the participants (10 cases, 12 controls, mean age 69 years) were randomly invited to undergo the same clamp procedures to challenge working memory, using 1-, 2-, and 3-back, while monitoring brain activity by blood oxygen level-dependent functional magnetic resonance imaging (fMRI). The participants with type 2 diabetes had reduced working memory during the 1- and 2-back tests. fMRI during placebo clamp revealed increased BOLD signal in the left lateral frontal cortex and the anterior cingulate cortex as a function of working memory load in both groups (3>2>1). During hyperglycaemia, controls showed a similar load-dependent fMRI response, whereas the type 2 diabetes group showed decreased BOLD response from 2- to 3-back. These results suggest that impaired glucose metabolism in the brain affects working memory, possibly by reducing activity in important frontal brain areas in persons with type 2 diabetes.
... IR has been found to adversely impact memory and executive function in mid-to late-life (majority) non-Hispanic whites without diabetes. [7][8][9][10] Nearly half of individuals 65 years and older not diagnosed with diabetes (48.3%) have preclinical alterations in glucose uptake and utilization [1]. Furthermore, Hispanics/Latinos tend to have higher rates than non-Hispanic Whites [11]. ...
Aims:
Insulin resistance (IR) adversely impacts memory and executive functioning in non-Hispanic whites without diabetes. Less is known in Hispanics/Latinos, despite the fact that Hispanics/Latinos have higher rates of insulin resistance than non-Hispanic whites. We investigated the association between IR and cognition and its variation by age.
Methods:
Data from 5987 participants 45-74 years old without diabetes from the Hispanic Community Health Study/Study of Latinos. IR was considered continuously using homeostasis model assessment for insulin resistance (HOMA-IR) and also dichotomized based on clinically relevant thresholds for hyperinsulinemia (fasting insulin > 84.73 pmol/L or HOMA-IR > 2.6) and sample-based norms (75th percentile of fasting insulin or HOMA-IR). Cognitive testing included the Brief Spanish English Verbal Learning Test (B-SEVLT), Verbal Fluency, and Digit Symbol Substitution.
Results:
There was 90% overlap in participant categorization comparing clinically relevant and sample-based thresholds. In separate fully-adjusted linear regression models, age modified the association between HOMA-IR and Digit Symbol Substitution (p = 0.02); advancing age combined with higher HOMA-IR levels resulted in higher scores. Age also modified the association between clinically relevant hyperinsulinemia and B-SEVLT recall (p = 0.03); with increasing age came worse performance for individuals with hyperinsulinemia.
Conclusion:
The relationship of IR with cognition in Hispanics/Latinos without diabetes may reflect an age- and test-dependent state.
... Although blood glucose levels affect cognitive function in normal healthy individuals [1,2], those with diabetes are at greater risks of dementia and cognitive decline compared with healthy individuals [3,4]. It has been shown that hyperglycemia [5,6] and hypoglycemic episodes [7] are associated with cognitive changes in diabetic patients, and there is no doubt that optimal glucose control is important for the prevention of cognitive decline in this patient population. ...
Diabetes is associated with cognitive decline as well as the development of dementia. Although mean blood glucose levels are typically used to assess the status of diabetic patients, glucose variability is also involved in the manifestation of macro- and microvascular complications in this population. Thus, the present study sought to determine whether visit-to-visit glucose variability contributes to cognitive decline in patients with type 2 diabetes.
The present study assessed 68 patients with type 2 diabetes using several validated neuropsychological measures. All patients had no cerebrovascular disease, history of hypoglycemia, psychiatric conditions, or other medical illnesses. Standard deviations (SDs) and coefficients of variance (CVs) of the patients' blood glucose (after fasting and 2 hours postprandial; FBS and PP2), and glycated hemoglobin (HbA1c) values were used as indices of glucose variability. The cognitive outcome parameters were transformed with z-scores and entered into a multiple linear regression model that included educational status, age, sex, vascular risk factors, and mean glucose parameters as covariates.
The mean age of the total patient population was 70.9 years; 46 (67.6%) of the patients were men, and the median follow-up duration at our endocrinology outpatient clinic was 4.8 years. The mean FBS and PP2 glucose levels of the patients were 132 mg/dL and 199 mg/dL, respectively, and the mean HbA1c level was 8.0%. A univariable analysis revealed that only the PP2 value was associated with the Mini-Mental State Examination (MMSE) score, and multivariable analysis revealed that a high SD and/or CV for PP2 glucose were associated with low scores on the Rey Complex Figure Copy test and/or the Verbal Learning Test. Additionally, a high SD and a higher CV for HbA1c level were significantly associated with low MMSE and Digit Span test scores even after adjusting for mean HbA1c values.
The present data indicate that a greater degree of visit-to-visit glucose variability influenced specific types of cognitive function in type 2 diabetic patients independently of mean blood glucose levels. Future studies should focus on whether reductions in glycemic variability will improve the cognitive decline observed in type 2 diabetic patients.
... A systematic review of the impact of glucoregulation on cognition concluded that it was clearly associated with poorer performance, especially for memory and in older people (Lamport et al., 2009); moreover, ingesting glucose was more likely to benefit those with poor glucoregulation. Indeed, the effect of glucoregulation can obscure any treatment benefit from glucose (Messier et al., 2011) . These findings could again suggest a role for elevated cortisol levels. ...
This paper reviews effects of both insufficient and excessive energy and macronutrient intake on cognition over the lifespan, including the prenatal period, infancy, childhood, and adulthood. In the brain, the hippocampus is particularly vulnerable to both protein malnutrition and energy undernutrition in utero or infancy, resulting in impaired neurogenesis and deficits in memory and spatial learning, reduced anxiety and increased impulsivity, reflected in impairments of neurotransmitter systems. Conversely, higher protein intake is associated with improved motor development but not mental development, whereas breastfeeding benefits mental development. Nevertheless, pre- and post-natal protein-energy supplementation has been shown to improve cognition in later childhood, and in adulthood, above energy alone. Similarly, n-3 essential fatty acid intake during pregnancy may have long-lasting effects on children's cognitive abilities. However, over-nutrition, particularly during gestation, may lead to metabolic programming that increases risk of cognitive impairment. In undernourished school children, breakfasts can benefit cognitive performance. In normally nourished children, benefits of breakfast are less clear; nevertheless, acutely, breakfasts lower in glycaemic index can benefit memory, whereas higher glycaemic breakfasts may improve vigilance. This difference depends on the impact of the carbohydrate on cortisol release. In adolescents and adults, moderate carbohydrate loads can benefit cognition, provided that glucoregulation is efficient. Protein intake may benefit memory by restraining task-related cortisol release. Chronically high intake of saturated fats may contribute to cognitive decline, whereas n-3 fatty acids, and perhaps reduced energy intake, may be protective. With aging populations, dietary prediction of cognition in adults is a key area for research.
... The present results are in line with Messier et al. [32] who showed that higher blood glucose, but not insulin, was associated with poorer episodic memory in a population of 20-year-old students. Our findings are also corroborated by Sanz et al. [15] who found that neither increased fasting insulin nor insulin resistance were associated with episodic memory or semantic memory in a study population with a mean age of 50 years. ...
Elevated concentrations of plasma glucose appear to play a role in memory impairment, and it has been suggested that insulin might also have a negative effect on cognitive function. Our aim was to study whether glucose, insulin or insulin resistance are associated with episodic or semantic memory in a non-diabetic and non-demented population.
We linked and matched two population-based data sets identifying 291 participants (127 men and 164 women, mean age of 50.7 ± 8.0 years). Episodic and semantic memory functions were tested, and fasting plasma insulin, fasting plasma glucose, and 2-hour glucose were analysed along with other potential influencing factors on memory function. Since men and women display different results on memory functions they were analysed separately. Insulin resistance was calculated using the HOMA-IR method.
A higher fasting plasma glucose concentration was associated with lower episodic memory in women (r = -0.08, 95% CI -0.14; -0.01), but not in men. Plasma insulin levels and insulin resistance were not associated with episodic or semantic memory in women or in men after adjustments for age, fasting glucose, 2-hour glucose, BMI, education, smoking, cardiovascular disease, hypertension, cholesterol, and physical activity.
This indicates that fasting glucose but not insulin, might have impact on episodic memory in middle-aged women.
... Particularly relevant to the present investigation, a large body of research has shown that glucose metabolism is important for one of the major elements of self-generated thought; episodic memory [13,14]. Impairments in episodic memory has been observed in healthy younger individuals with poor glucose regulation [15], in middle aged adults [16] and also poor gluco-regulating adolescents after consuming a glucose containing drink [17,18,19], in older adults with and without Mild Cognitive Impairment [20] and in those individuals with impaired glucose tolerance and diabetes (see [14,21] for reviews). Efficient glucose regulation may be particularly important for episodic memory ability. ...
The generation of thought independent of environmental input occupies almost half of mental life and is important for skills such as creativity and planning. To understand how this ubiquitous cognitive process relates to the brain's ‘energy budget’, a cross-sectional study is carried out to examine how the capacity for mental time travel relates to the efficiency with which adults metabolize glucose, the brain’s primary source of fuel. On day 1 the ability of a group of 36 younger and 36 older individuals to metabolize glucose was assessed using the gold standard two-hour glucose tolerance test. Twenty-four hours later, the same group of participants returned to the laboratory to perform a non-demanding choice reaction time task during which experience sampling was used to assess the frequency with which they generated thoughts that were unrelated to the here and now. Analysis indicated that younger individuals who were the most efficient at metabolizing glucose exhibited mental time travel that spanned longer time periods. Given the importance of self-generated thought in daily life these results suggest that the capacity to mentally simulate events not present in the immediate environment is highly dependent on efficient glucose metabolism.
... Cognitive deficits in T2DM have been linked to multiple disease-related processes, including: (i) poor glucose control (i.e., hemoglobin A1c [HbA1c]; Ryan and Geckle, 2000;Kanaya et al., 2004;Cukierman-Yaffe et al., 2009;Maggi et al., 2009;Luchsinger et al., 2011;Tuligenga et al., 2014; for conflicting results, see Christman et al., 2011), (ii) glucose intolerance (Rizzo et al., 2010;Zhong et al., 2012b), (iii) high peripheral AGE levels (Yaffe et al., 2011), (iv) high levels of inflammatory cytokines (Marioni et al., 2010), and (v) peripheral hyperinsulinemia and insulin resistance (Bruehl et al., 2010;Zhong et al., 2012a). Even in nondiabetic adults, poorer glucoregulation has been associated with deficits and/or declines in verbal memory, working memory, processing speed, and executive function (Dahle et al., 2009;Bruehl et al., 2010;Messier et al., 2010Messier et al., , 2011Ravona-Springer et al., 2012). ...
The rising prevalence of type 2 diabetes (T2DM) and hypertension in older adults, and the deleterious effect of these conditions on cerebrovascular and brain health, is creating a growing discrepancy between the "typical" cognitive aging trajectory and a "healthy" cognitive aging trajectory. These changing health demographics make T2DM and hypertension important topics of study in their own right, and warrant attention from the perspective of cognitive aging neuroimaging research. Specifically, interpretation of individual or group differences in blood oxygenation level dependent magnetic resonance imaging (BOLD MRI) or positron emission tomography (PET H2O(15)) signals as reflective of differences in neural activation underlying a cognitive operation of interest requires assumptions of intact vascular health amongst the study participants. Without adequate screening, inclusion of individuals with T2DM or hypertension in "healthy" samples may introduce unwanted variability and bias to brain and/or cognitive measures, and increase potential for error. We conducted a systematic review of the cognitive aging neuroimaging literature to document the extent to which researchers account for these conditions. Of the 232 studies selected for review, few explicitly excluded individuals with T2DM (9%) or hypertension (13%). A large portion had exclusion criteria that made it difficult to determine whether T2DM or hypertension were excluded (44 and 37%), and many did not mention any selection criteria related to T2DM or hypertension (34 and 22%). Of all the surveyed studies, only 29% acknowledged or addressed the potential influence of intersubject vascular variability on the measured BOLD or PET signals. To reinforce the notion that individuals with T2DM and hypertension should not be overlooked as a potential source of bias, we also provide an overview of metabolic and vascular changes associated with T2DM and hypertension, as they relate to cerebrovascular and brain health.
... In contrast to Benton et al., (1994) , we found no evidence that changes in pretest blood glucose levels were related to performance. Nevertheless, Gagnon, Greenwood and Bherer (2011) recently reported that better glucoregulators (lower blood glucose area under the curves over 90 minutes) specifically made more errors during the most demanding component (switching) of a Stroop task, in agreement with previous findings (Awad, Gagnon, Desrochers, Tsiakas, and Messier, 2002; Lamport, Lawton, Mansfield and Dye, 2009; Messier, 2004; Messier, Awad-Shimoon, Gagnon, Desrochers and Tsiakas, 2011). We were unable to test this relationship here because blood glucose was only measured for 30 minutes after the drink, i.e., prior to declining glucose levels. ...
Previous research has demonstrated that glucose administration improves memory performance. These glucose facilitation effects have been most reliably demonstrated in medial temporal lobe tasks with the greatest effects found for cognitively demanding tasks. The aim of the proposed research was to first explore whether such effects might be demonstrated in a frontal lobe task. A second aim was to investigate whether any beneficial effects of glucose may arise more prominently under tasks of increasing cognitive demand. To achieve these aims, the Stroop Task was administered to participants and effects of a drink of glucose (25 g) were compared with an aspartame-sweetened control drink on performance in young adults. Results demonstrated that glucose ingestion significantly reduced RTs in the congruent and incongruent conditions. No effect on error rates was observed. Of most importance was the finding that this glucose facilitative effect was significantly greatest in the most cognitively demanding task, that is, the incongruent condition. The present results support the contention that the glucose facilitation effect is most robust under conditions of enhanced task difficulty and demonstrate that such benefits extend to frontal lobe function. (PsycINFO Database Record (c) 2013 APA, all rights reserved).
... Behavioral findings of the present study are consistent with previous reports of a relationship between attentional control performances and glucose regulation in non-diabetic individuals [22,20,30], and more of interest for the present study, between glucose regulation and dual-task performances [10]. Brain activation patterns showing a differential activation related to glucose regulation are also consistent with previous findings of increased variance in ERP signals when participants were in the glucose condition, compared to the placebo condition. ...
Glucose enhancing effects in older adults have mostly been observed for episodic memory, but have recently been found for attentional control performance. Yet, brain activation patterns underlying these effects are still unknown.
The present study examined the acute effects of glucose ingestion on prefrontal brain activation during the execution of a divided attention task in fasting non-diabetic older adults.
Twenty older adults (60 years and older) took part in the study that included two experimental sessions. After an overnight fast, participants received either a glucose drink (50 g) or a placebo (saccharin) drink, following which they completed a dual-task. During task execution, prefrontal activation was recorded with functional near-infrared spectroscopy (fNIRS). A repeated-measures design was used such that each participant served as his or her own control. The two experimental sessions were counterbalanced among participants and were performed two weeks apart.
When participants were in the glucose condition, they showed similar dual-task costs for both tasks, whereas in the placebo condition they prioritized one task over the other, with a significantly larger dual-task cost for the non-prioritized task (p<0.01). Differential brain activation was also observed in right ventral-lateral prefrontal regions for oxygenated hemoglobin and deoxygenated hemoglobin, with more activation apparent in the glucose condition (p<0.05). Furthermore, behavioral and activation data were influenced by individual differences in glucose regulation.
Glucose ingestion appears to momentarily enhance fasting seniors' capacity to coordinate more equally two concurrent tasks and this is reflected in brain activation patterns.
Background
In the past, researchers have observed a significant link between glycemia and dementia. Medial temporal atrophy (MTA) is regarded as a common marker of dementia. The correlation between glycemic variability and MTA is unclear, and it has not been determined whether glycemic variability can be utilized as a biomarker of MTA and cognitive performance.
Methods
The patients in a memory clinic who underwent brain MRI scans and cognitive assessments within the first week of their hospital visit, were enrolled. All participants underwent three fasting blood glucose and one HBA1c assessments on three self-selected days within 1 week of their first visit. The variability independent of the mean (VIM) was employed. Validated visual scales were used to rate the MTA results. The mini-mental state examination (MMSE) and Montreal Cognitive Assessment (MoCA) scales were employed to assess the cognitive functions of the participants. Spearman’s correlation and regression models were used to examine the relationship between the MMSE and MoCA scales, and also determine the link between the MRI characteristics and cognitive status, where vascular risk factors, educational status, age, gender, and mean glucose parameters served as covariates.
Results
Four hundred sixty-one subjects completed the MMSE scale, while 447 participants completed the MoCA scale. Data analysis revealed that 47.72% of the participants were men (220/461), and the median age of the patients was 69.87 ± 5.37 years. The findings of Spearman’s correlation analysis exhibited a strong negative relationship between the VIM and MMSE score ( r = −0.729, P < 0.01), and the MoCA score ( r = −0.710, P < 0.01). The VIM was regarded as an independent risk factor for determining cognitive impairment in both the MMSE and MoCA assessments. The results were unaffected by sensitivity analysis. In addition, a non-linear relationship was observed between the VIM and MTA scores.
Conclusion
The variability in the blood glucose levels, which was presented as VIM, was related to the reduced cognitive function, which was reflected by MMSE and MoCA scales. The relationship between the VIM and the MTA score was non-linear. The VIM was positively related to the MTA score when the VIM was less than 2.42.
Effective glycaemic control is vitally important to protecting brain function, as the brain relies primarily on circulatory blood glucose crossing the blood-brain barrier for continuous energy provision. The link between poor glucoregulation and cognitive deficits is well established, specifically for declarative memory and executive functioning (Messier, European Journal of Pharmacology, 490(1–3), 33–57, 2004; Smith, Riby, Eekelen, & Foster, Neuroscience and Biobehavioral Reviews, 35(3), 770–783, 2011a). Perhaps more alarmingly, cognitive deficits can also be detected in subclinical populations (Lamport, Lawton, Mansfield, & Dye, Neuroscience and Biobehavioral Reviews, 33(3), 394–413, 2009). The prevalence of glucoregulatory disorders (e.g. diabetes and metabolic syndrome) is increasing at a phenomenal rate, as are the associated health burdens and diminished neurocognitive functioning. This chapter considers the role of glycaemic control (glucoregulation) and circulatory glucose levels on cognitive functioning. Through first considering the mechanisms of action, this chapter discusses the specific elements of cognition that appear to be susceptible to fluctuating glucose levels and decrements in glycaemic control. This chapter briefly explores clinical populations exhibiting cognitive decrements for which declining glucoregulation is a key feature of the pathology (e.g. Alzheimer’s disease). Considerations of how we might exploit glycaemic control through acute ingestion, to elicit performance enhancements and the implications/ramifications thereof are discussed. The chapter concludes by cautioning the responsible use of acute ingestion as a short-term cognitive enhancer in select populations, with strategies for stabilising and optimising glycaemic control being more effective long term to minimise glucoregulatory disorders and associated cognitive decline.
New findings:
What is the central question of this study? Does regular exercise have benefits with regard to the neurocognitive problems related to obesity and are regular-exercise-induced neurocognitive changes associated with changes in the levels of metabolic/inflammatory biomarkers? What is the main finding and its importance? Although obese individuals with regular exercise showed higher C-reactive protein levels as compared to the healthy-weight individuals, only the obese individuals with a sedentary lifestyle showed deviant neurocognitive performance and higher metabolic and tumour necrosis factor-α levels. The P3 amplitude was correlated with the levels of leptin in the obese individuals with regular activity, implicating that the potential mechanism of neurocognitive facilitation as a result of regular exercise could be reduced serum leptin levels.
Abstract:
Obesity has been shown to be highly associated with deterioration in executive functions, elevated energy metabolic indices and low-grade systemic inflammation. Exercise has the capacity to reduce these negative phenomena. This work examined the effect of regular exercise on neurocognitive deficits and metabolic/inflammatory markers in obesity. Fifty-four participants were divided into three groups: healthy-weight (HW), obesity with regular exercise (ORE) and obesity with sedentary lifestyle (OSL), according to their BMI and frequency of exercise. Dual-energy X-ray absorptiometry was applied to assess the whole-body composition of the participants. The assessment included neurocognitive measures during the Posner paradigm test and fasting blood measurements. Relative to the HW group, only the OSL group showed significantly longer reaction times and smaller P3 amplitudes, even when controlling for the cardiorespiratory fitness co-variable. Although the OSL group exhibited a greater N2 amplitude than the HW group, when controlling for cardiorespiratory fitness the difference between the two groups disappeared. The OSL group showed greater levels of metabolic indices (i.e. leptin, insulin and glucose) than the HW group. The three groups had comparable interleukin (IL)-1β and IL-6 levels. However, the ORE and OSL groups showed higher levels of C-reactive protein than the HW group. The OSL group exhibited higher tumour necrosis factor-α levels than the HW and ORE groups. P3 amplitude was negatively correlated with the levels of leptin in the ORE group. Individuals with obesity can still obtain advantages with regard to neurocognitive and metabolic/inflammatory indices through engaging in regular exercise, possibly due to reduced serum leptin levels.
The present study investigated the perceptual, attentional, and memory processes underlying face recognition deficits observed in older adults with impaired glucoregulation. Participants were categorized as good glucoregulators or poor glucoregulators on the basis of an oral glucose tolerance test. Using event-related potential (ERP) methodology, 23 participants (62–88 years) performed a 2-stimulus oddball task. Participants were asked to rate and memorize 10 “target” faces, which were then presented amongst 120 unfamiliar foils. Behavioral results indicated that good glucoregulators were significantly more accurate at recognizing target faces. ERP markers of early visual perception (P1 and N170 components) and memory formation (P3 component) were unaffected by glucoregulatory efficiency. The P2 component, an index of attentional processing, was larger and delayed in the poor glucoregulators. To the best of our knowledge, this study is the first to suggest that face recognition deficits in poor glucoregulators may be due to impairments in attentional processing.
Recently, increasing attention has been paid to diabetic encephalopathy which is one of frequent diabetic complications and affects nearly 30% diabetics. Since cognitive dysfunction from diabetic encephalopathy might develop irreversible dementia, early diagnosis and detection of this disease is of great significance for its prevention and treatment. This study is to investigate the early specific metabolites biomarkers in the urine prior to the onset of diabetic cognitive dysfunction (DCD) by using metabolomics technology. Ultra high performance liquid-flight time-mass spectrometry (UPLC-Q/TOF-MS) platform was used to analyze the urine samples from the diabetic mice which were associated with mild cognitive impairment (MCI) and non-associated with MCI at the stage of diabetes (prior to the onset of DCD), and then screened and validated the early biomarkers using OPLS-DA model and support vector machine (SVM) method. Following multivariate statistical and integration analysis, we found 7 metabolites could be accepted as early biomarkers of DCD. And the SVM results showed that the prediction accuracy is as high as 91.66%. The identities of four biomarkers were determined by mass spectrometry. The identified biomarkers were largely involved in nicotinate and nicotinamide metabolism, glutathione metabolism, tryptophan metabolism and sphingolipid metabolism. The present study firstly revealed reliable biomarkers for early diagnosis of DCD. It would provide a new insight and strategy for the early diagnosis and treatment of DCD.
Background and aims:
Older adults with type 2 diabetes mellitus (DM2) exhibit accelerated decline in some domains of cognition including verbal episodic memory. Few studies have investigated the influence of DM2 status in older adults on recognition memory for more complex stimuli such as faces. In the present study we sought to compare recognition memory performance for words, objects and faces under conditions of relatively low and high cognitive load.
Methods:
Healthy older adults with good glucoregulatory control (n = 13) and older adults with DM2 (n = 24) were administered recognition memory tasks in which stimuli (faces, objects and words) were presented under conditions of either i) low (stimulus presented without a background pattern) or ii) high (stimulus presented against a background pattern) cognitive load.
Results:
In a subsequent recognition phase, the DM2 group recognized fewer faces than healthy controls. Further, the DM2 group exhibited word recognition deficits in the low cognitive load condition.
Conclusions:
The recognition memory impairment observed in patients with DM2 has clear implications for day-to-day functioning. Although these deficits were not amplified under conditions of increased cognitive load, the present study emphasizes that recognition memory impairment for both words and more complex stimuli such as face are a feature of DM2 in older adults.
Double-Sided Incremental Forming (DSIF) uses two small, independently moving, hemispherical tools on either side of the sheet to form a desired shape by following a predefined tool path. This study was motivated by the observation that the relative tool position of the tools, specified in the tool path generation algorithm, affects the formed geometric accuracy. A methodology for defining the relative tool positioning in the tool path generation algorithm based on local part geometry is proposed using simplified Finite Element Analysis (FEA) and sample physical experiments combined with Gaussian Process modeling techniques. This approach can take into account the mechanics of deformation in DSIF explicitly and physical compliance of the DSIF machine implicitly. Physical experiments were performed to demonstrate the effectiveness of the proposed framework.
Objectives:
To investigate the relationship between glycated albumin (GA) to glycated hemoglobin (HbA1c) ratio and cognitive impairment in old age. Diabetes is associated with cognitive impairment in older people. However, the link between elevated GA/HbA1c levels and the risk of cognitive impairment in nondiabetic individuals is unclear.
Methods:
A cross-sectional study of 474 old, nondiabetic adults (192 women, mean age 73.8 years ± 6.9 SD) who had been admitted to our hospital was conducted. Glycemic measures included fasting plasma glucose (FPG), 2-hour post-prandial plasmic glucose (2hPPG), GA and HbA1c. Cognitive function was assessed using Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) at the same examination visit in which the glycemic measures were determined.
Results:
When the individuals were divided into two groups according to the median of GA/HbA1c ratio, old adults with GA/HbA1c ratio ≥ 2.53 showed lower MMSE and MoCA scores compared to those with GA/HbA1c ratio < 2.53. Univariate regression analysis showed that MMSE and MoCA scores were not correlated with HbA1c, but were inversely correlated with GA and GA/HbA1c ratio. Linear regression analysis revealed that there was a significant negative correlation between GA/HbA1c and cognitive function (β = -0.77, P < 0.01 for MoCA and β = -0.69, P < 0.05 for MMSE) even after adjustment for age, body mass index, systolic blood pressure, lipoprotein(a) and sex.
Conclusion:
Our results indicate that even in the absence of manifest type 2 diabetes mellitus, GA/HbA1c ratio levels exert a negative influence on cognition and it may be a better predictor for cognitive impairment in the older population.
This chapter examines the failure of police, attorneys, judges, and juries to appreciate the magnitude of acute impairments of will and cognition in interrogation. The authors explore sources of enhanced susceptibility to interrogative influence triggered by the nature of the suspect’s immediate circumstances, rather than by chronic personal characteristics, which they call “acute interrogative suggestibility.” The authors consider the role of “interrogation-related regulatory decline” or IRRD in producing acute interrogative suggestibility -- that is, the decline in self-regulation resources necessary to control thinking and behavior in service of resisting interrogative influence. In particular, the authors concentrate on three common but underappreciated sources of IRRD in police interrogation, one or more of which are present in most cases involving claims of involuntary or false confession: acute emotional distress, fatigue and sleep deprivation, and glucose depletion. The chapter concludes by arguing that much more weight should be given to issues of acute sources of vulnerability to influence and suggestion than is presently the case.
We describe the localization of the recently identified glucose
transporter GLUTx1 and the regulation of GLUTx1 in the hippocampus of
diabetic and control rats. GLUTx1 mRNA and protein exhibit a unique
distribution when compared with other glucose transporter isoforms
expressed in the rat hippocampus. In particular, GLUTx1 mRNA was
detected in hippocampal pyramidal neurons and granule neurons of the
dentate gyrus as well as in nonprincipal neurons. With
immunohistochemistry, GLUTx1 protein expression is limited to neuronal
cell bodies and the most proximal dendrites, unlike GLUT3 expression
that is observed throughout the neuropil. Immunoblot analysis of
hippocampal membrane fractions revealed that GLUTx1 protein expression
is primarily localized to the intracellular compartment and exhibits
limited association with the plasma membrane. In streptozotocin
diabetic rats compared with vehicle-treated controls, quantitative
autoradiography showed increased GLUTx1 mRNA levels in pyramidal
neurons and granule neurons; up-regulation of GLUTx1 mRNA also was
found in nonprincipal cells, as shown by single-cell emulsion
autoradiography. In contrast, diabetic and control rats expressed
similar levels of hippocampal GLUTx1 protein. These results indicate
that GLUTx1 mRNA and protein have a unique expression pattern in rat
hippocampus and suggest that streptozotocin diabetes increases
steady-state mRNA levels in the absence of concomitant increases in
GLUTx1 protein expression.
The Rey and Taylor figures are two constructional and visual memory tests used interchangeably. The purpose of this study was to develop a scoring system for the Taylor figure based on the explicit guidelines established by Meyers and Meyers (1995) for the Rey figure. Younger (n = 97; mean age = 21 years) and older (n = 61; mean age = 72 years) participants' performance on the Taylor figure was scored according to the proposed scoring system and the original scoring system devised by Taylor (1989). Both scoring systems yielded comparable scores on the Taylor figure as well as comparable patterns of validity and good interrater reliabilities (0.85-0.98). Although the present system does not further improve scoring reliability, it renders both tests similar in methodology and simplifies training to evaluate the two figures. The present study also reveals the limitations of the use of the Taylor and the Rey in test-retest situations but suggests that administering the Taylor first would improve the comparability of the two figures in a test-retest situation.
To study cognitive function in an elderly population with persistent impaired glucose tolerance (IGT).
Fasting and postload 2-h plasma glucose and insulin levels were determined at baseline in a population-based sample of 1,300 people and repeated an average of 3.5 years later in 980 subjects. At follow-up, cognitive function was evaluated in subjects with persistent normal glucose tolerance (NGT; n = 506) and IGT (n = 80) with a brief neuropsychological test battery.
Subjects with persistent IGT scored lower in the Mini-Mental State Examination (MMSE) and in the Buschke Selective Reminding Test long-term memory scores. Multiple linear regression analysis revealed that age, education, and insulin levels (either fasting or 2-h value) were associated with the MMSE score in subjects with persistent IGT. Other potential risk factors for impaired cognitive function were not significantly associated with the MMSE score.
Our study showed that persistent IGT in the elderly is associated with mildly impaired cognitive function, and hyperinsulinemia may account for this association.
Central nervous system abnormalities, including cognitive and brain impairments, have been documented in adults with type 2 diabetes who also have multiple co-morbid disorders that could contribute to these observations. Assessing adolescents with type 2 diabetes will allow the evaluation of whether diabetes per se may adversely affect brain function and structure years before clinically significant vascular disease develops.
Eighteen obese adolescents with type 2 diabetes and 18 obese controls without evidence of marked insulin resistance, matched on age, sex, school grade, ethnicity, socioeconomic status, body mass index and waist circumference, completed MRI and neuropsychological evaluations.
Adolescents with type 2 diabetes performed consistently worse in all cognitive domains assessed, with the difference reaching statistical significance for estimated intellectual functioning, verbal memory and psychomotor efficiency. There were statistical trends for executive function, reading and spelling. MRI-based automated brain structural analyses revealed both reduced white matter volume and enlarged cerebrospinal fluid space in the whole brain and the frontal lobe in particular, but there was no obvious grey matter volume reduction. In addition, assessments using diffusion tensor imaging revealed reduced white and grey matter microstructural integrity.
This is the first report documenting possible brain abnormalities among obese adolescents with type 2 diabetes relative to obese adolescent controls. These abnormalities are not likely to result from education or socioeconomic bias and may result from a combination of subtle vascular changes, glucose and lipid metabolism abnormalities and subtle differences in adiposity in the absence of clinically significant vascular disease. Future efforts are needed to elucidate the underlying pathophysiological mechanisms.
Glucose enhancing effects have been observed in older adults mainly for episodic memory, but have been under-investigated for attentional functions, which are very sensitive to aging.
The present study examined the acute effects of glucose ingestion on different attentional tasks in fasting healthy older adults.
In a between-subjects design, 44 participants (60 years and older) were randomly assigned to a glucose (50 g) or saccharin (placebo) condition after 12 h of fasting. Participants were tested on neuropsychological tests of attention (trail A and B, modified Stroop) and on a computerized dual-task.
Participants in the glucose group were faster than the placebo group to complete the switching condition of the modified Stroop test (p < 0.01) and showed a smaller dual-task cost in the divided attention task (p < 0.05).
Glucose ingestion appears to momentarily enhance attentional performances in seniors who have fasted for 12 h in tasks requiring switching and dividing attention.
To determine whether the cognitive impairments observed in adults with type 2 diabetes mellitus (T2DM) exist in preclinical disease, we compared 38 adult participants with evidence of insulin resistance (IR) to 54 age-, gender-, and education-matched control participants on a battery of neuropsychological tests. We found that participants with IR had performance reductions in declarative memory and executive functioning. When we examined IR simultaneously with other biomedical indicators with which it co-occurs, only IR itself was associated with declarative memory, and hemoglobin A1c (HbA1c) was associated with executive functioning and working memory. We conclude that individuals with insulin resistance already demonstrate similar reductions in cognitive performance as those described in T2DM.
It has been suggested that the memory enhancing effect of glucose follows an inverted U-shaped curve, with 25 g resulting in optimal facilitation in healthy young adults. The aim of this study was to further investigate the dose dependency of the glucose facilitation effect in this population across different memory domains and to assess moderation by interindividual differences in glucose regulation and weight. Following a double-blind, repeated measures design, 30 participants were administered drinks containing five different doses of glucose (0 g, 15 g, 25 g, 50 g, and 60 g) and were tested across a range of memory tasks. Glycaemic response and changes in mood state were assessed following drink administration. Analysis of the data showed that glucose administration did not affect mood, but significant glucose facilitation of several memory tasks was observed. However, dose-response curves differed depending on the memory task with only performance on the long-term memory tasks adhering largely to the previously observed inverted U-shaped dose-response curve. Moderation of the response profiles by interindividual differences in glucose regulation and weight was observed. The current data suggest that dose-response function and optimal dose might depend on cognitive domain and are moderated by interindividual differences in glucose regulation and weight.
Type 2 diabetes mellitus is associated with moderate decrements in cognitive functioning, mainly in verbal memory, information-processing speed and executive functions. How this cognitive profile evolves over time is uncertain. The present study aims to provide detailed information on the evolution of cognitive decrements in type 2 diabetes over time.
Sixty-eight patients with type 2 diabetes and 38 controls matched for age, sex and estimated IQ performed an elaborate neuropsychological examination in 2002-2004 and again in 2006-2008, including 11 tasks covering five cognitive domains. Vascular and metabolic determinants were recorded. Data were analysed with repeated measures analysis of variance, including main effects for group, time and the group x time interaction.
Patients with type 2 diabetes showed moderate decrements in information-processing speed (mean difference in z scores [95% CI] -0.37 [-0.69, -0.05]) and attention and executive functions (-0.25 [-0.49, -0.01]) compared with controls at both the baseline and the 4 year follow-up examination. After 4 years both groups showed a decline in abstract reasoning (-0.16 [-0.30, -0.02]) and attention and executive functioning (-0.29 [-0.40, -0.17]), but there was no evidence for accelerated cognitive decline in the patients with type 2 diabetes as compared with controls (all p > 0.05).
In non-demented patients with type 2 diabetes, cognitive decrements are moderate in size and cognitive decline over 4 years is largely within the range of what can be viewed in normal ageing. Apparently, diabetes-related cognitive changes develop slowly over a prolonged period of time.
The Drug Abuse Screening Test (DAST) was designed to provide a brief instrument for clinical screening and treatment evaluation research. The 28 self-report items tap various consequences that are combined in a total DAST score to yield a quantitative index of problems related to drug misuse. Measurement properties of the DAST were evaluated using a clinical sample of 256 drug/alcohol abuse clients. The internal consistency reliability estimate was substantial at .92, and a factor analysis of item intercorrelations suggested an unidimensional scale. With respect to response style biases, the DAST was only moderately correlated with social desirability and denial. Concurrent validity was examined by correlating the DAST with background variables, frequency of drug use during the past 12 months, and indices of psychopathology. Although these findings support the usefulness of the DAST for quantifying the extent of drug involvement within a help-seeking population, further validation work is needed in other populations and settings.
This study describes the regional and cellular expression of the insulin-sensitive glucose transporter, GLUT4, in rodent brain. A combination of in situ hybridization, immunohistochemistry and immunoblot techniques was employed to localize GLUT4 mRNA and protein to the granule cells of the olfactory bulb, dentate gyrus of the hippocampus and the cerebellum, with the greatest level of expression being in the cerebellum. Estimates of the concentration of GLUT4 in cerebellar membranes indicate that this transporter isoform is present in significant amounts, relative to the other isoforms, GLUT1 and GLUT3. Cerebellar GLUT4 expression was increased in the genetically diabetic, hyperinsulinemic, db/db mouse relative to the non-diabetic control, and even higher levels were observed in db/db female than db/db male mice. Levels of expression of GLUT4 protein in cerebellum appear to respond to the level of circulating insulin, and are reduced in the hypoinsulinemic streptozotocin-diabetic rat. Exercise training also results in reduced insulin levels and comparably reduced levels of GLUT4 in the cerebellum. These studies demonstrate a chronic insulin-sensitive regulation of GLUT4 in rodent brain and raise the possibility of acute modulations of glucose uptake in these GLUT4 expressing cells.
Changes in memory performance were examined after intake of a glucose (50 g) or saccharin (50 mg) solution in fasted men and women. Glucoregulation was estimated by using a recovery index to categorize participants within each gender as having poor or good recovery. Memory was assessed with word-learning tasks in which the imagery-evoking value of the words was systematically manipulated to yield high- and low-imagery lists. The results showed that men and women characterized as having poor glucose regulation had significantly worse memory performance under the saccharin condition. This decrement was reversed by glucose ingestion. These effects were observed for both low- and high-imagery words. This study supports the hypothesis that poor glucoregulation is associated with poor memory performance even in young healthy participants and that the ingestion of glucose can improve their memory.
The oral glucose tolerance test (OGTT) has often been used to evaluate apparent insulin release and insulin resistance in various clinical settings. However, because insulin sensitivity and insulin release are interdependent, to what extent they can be predicted from an OGTT is unclear.
We studied insulin sensitivity using the euglycemic-hyperinsulinemic clamp and insulin release using the hyperglycemic clamp in 104 nondiabetic volunteers who had also undergone an OGTT. Demographic parameters (BMI, waist-to-hip ratio, age) and plasma glucose and insulin values from the OGTT were subjected to multiple linear regression to predict the metabolic clearance rate (MCR) of glucose, the insulin sensitivity index (ISI), and first-phase (1st PH) and second-phase (2nd PH) insulin release as measured with the respective clamps.
The equations predicting MCR and ISI contained BMI, insulin (120 min), and glucose (90 min) and were highly correlated with the measured MCR (r = 0.80, P < 0.00005) and ISI (r = 0.79, P < 0.00005). The equations predicting 1st PH and 2nd PH contained insulin (0 and 30 min) and glucose (30 min) and were also highly correlated with the measured 1st PH (r = 0.78, P < 0.00005) and 2nd PH (r = 0.79, P < 0.00005). The parameters predicted by our equations correlated better with the measured parameters than homeostasis model assessment for secretion and resistance, the delta30-min insulin/delta30-min glucose ratio for secretion and insulin (120 min) for insulin resistance taken from the OGTT.
We thus conclude that predicting insulin sensitivity and insulin release with reasonable accuracy from simple demographic parameters and values obtained during an OGTT is possible. The derived equations should be used in various clinical settings in which the use of clamps or the minimal model would be impractical.
Impaired glucoregulation is associated with neuropsychological deficits, particularly for tests that measure verbal declarative memory performance in older diabetic patients. The performances of 74 undergraduate students (mean age = 21 years) on several verbal declarative measures, including immediate and delayed paragraph recall, verbal free recall, and order reconstruction tasks, were correlated with glucoregulatory indices. The indices were obtained from glucose and insulin levels after a 75-g glucose load. In general, higher blood glucose levels were associated with poorer performance on all memory tests. Glucose ingestion did not interact with performance except on the most difficult task. Subjects with poorer glucoregulation showed higher evoked glucose and insulin, suggestive of a mild glucose intolerance accompanied by mild insulin insensitivity. Results suggest that poor peripheral glucoregulation has an impact on central nervous system functions.
Resistance to insulin-mediated glucose uptake is characteristic of individuals with impaired glucose intolerance or non-insulin-dependent diabetes, and it also occurs commonly in patients with high blood pressure. The physiological response to a decrease in insulin-mediated glucose uptake is an increase in insulin secretion, and as long as a state of compensatory hyperinsulinemia can be maintained, frank decompensation of glucose tolerance can be prevented. However, it is likely that the defect in insulin action and/or the associated hyperinsulinemia will lead to an increase in plasma triglyceride and a decrease in high density lipoprotein-cholesterol concentration, and high blood pressure. It seems likely that the cluster of changes associated with resistance to insulin-mediated glucose uptake comprise a syndrome, which plays an important role in the etiology and clinical course of patients with non-insulin-dependent diabetes, high blood pressure, and coronary heart disease.
Recent experiments indicate that peripheral glucose administration enhances memory in rodents and humans. This study examined the effects of glucose on memory and nonmemory measures of neuropsychological functioning in elderly humans. Healthy older adults were given a series of neuropsychological tests after drinking glucose- or saccharin-flavored lemonade. A repeated measures design using counter-balanced beverages and tests was used. Glucose enhanced performance on declarative memory tests but not on short-term or nonmemory neuropsychological measures. Glucose tolerance predicted performance on declarative memory tasks but not on other measures.
We studied cognitive function in normoglycaemic elderly subjects at different risk levels for developing non-insulin-dependent diabetes mellitus (NIDDM) and in patients with NIDDM. Risk for NIDDM was considered increased if both 2 h glucose and insulin values on oral glucose tolerance testing were higher than the median in normoglycaemic subjects, and low if the respective values were lower than the median. The increased risk group showed impairment on tests of immediate and delayed memory, attention, visuomotor speed and verbal fluency. Moreover, the increased risk group did not differ from patients with NIDDM on any cognitive tests. Our results suggest that increased risk for NIDDM is associated with widely affected cognitive function in the normoglycaemic elderly, highlighting the importance of healthy living habits.
Previous research has shown that glucose can enhance memory in animals and humans. In humans, the facilitative effect of glucose is best observed with declarative memory tasks in older subjects. While the memory-enhancing action of glucose is well established, the underlying physiological mechanisms and the specific aspects of memory that are modulated by glucose in humans are not well understood. The present study sought to examine the effects of glucose on memory in young women using a memory paradigm sensitive to specific encoding and retrieval strategies. The glucose dose was adjusted for the weight of each participant in order to generate a dose response curve covering most doses used in previous studies. The results showed that 300 mg/kg glucose enhanced the primacy effect as defined by the recall of the first five items of the lists. However, none of the doses of glucose produced changes in the recall priority given to primacy items. The effect of glucose appears to be localized on the recall primacy effect, suggesting that glucose acts on precise memory operations. This improvement, however, is independent of the order in which subjects recalled the words. Cholinergic drugs have been shown to alter the recall of the primacy part of word lists and this observation is consistent with the hypothesis that glucose acts on memory through an interaction with brain cholinergic systems.
Resistance to insulin-stimulated glucose uptake is present in the majority of patients with impaired glucose tolerance (IGT) or non-insulin-dependent diabetes mellitus (NIDDM) and in ∼25% of nonobese individuals with normal oral glucose tolerance. In these conditions, deterioration of glucose tolerance can only be prevented if the β-cell is able to increase its insulin secretory response and maintain a state of chronic hyperinsulinemia. When this goal cannot be achieved, gross decompensation of glucose homeostasis occurs. The relationship between insulin resistance, plasma insulin level, and glucose intolerance is mediated to a significant degree by changes in ambient plasma free-fatty acid (FFA) concentration. Patients with NIDDM are also resistant to insulin suppression of plasma FFA concentration, but plasma FFA concentrations can be reduced by relatively small increments in insulin concentration.Consequently, elevations of circulating plasma FFA concentration can be prevented if large amounts of insulin can be secreted. If hyperinsulinemia cannot be maintained, plasma FFA concentration will not be suppressed normally, and the resulting increase in plasma FFA concentration will lead to increased hepatic glucose production. Because these events take place in individuals who are quite resistant to insulinstimulated glucose uptake, it is apparent that even small increases in hepatic glucose production are likely to lead to significant fasting hyperglycemia under these conditions. Although hyperinsulinemia may prevent frank decompensation of glucose homeostasis in insulin-resistant individuals, this compensatory response of the endocrine pancreas is not without its price. Patients with hypertension, treated or untreated, are insulin resistant, hyperglycemic, and hyperinsulinemic. In addition, a direct relationship between plasma insulin concentration and blood pressure has been noted. Hypertension can also be produced in normal rats when they are fed a fructose-enriched diet, an intervention that also leads to the development of insulin resistance and hyperinsulinemia. The development of hypertension in normal rats by an experimental manipulation known to induce insulin resistance and hyperinsulinemia provides further support for the view that the relationship between the three variables may be a causal one. However, even if insulin resistance and hyperinsulinemia are not involved in the etiology of hypertension, it is likely that the increased risk of coronary artery disease (CAD) in patients with hypertension and the fact that this risk if not reduced with antihypertensive treatment are due to the clustering of risk factors for CAD, in addition to high blood pressure, associated with insulin resistance. These include hyperinsulinemia, IGT, increased plasma triglyceride concentration, and decreased high-density lipoprotein cholesterol concentration, all of which are associated with increased risk for CAD. It is likely that the same risk factors play a significant role in the genesis of CAD in the population as a whole. Based on these considerations the possibility is raised that resistance to insulin-stimulated glucose uptake and hyperinsulinemia are involved in the etiology and clinical course of three major related diseases— NIDDM, hypertension, and CAD.
This study was undertaken to identify the relationship between the raw scores obtained on the Rey Complex Figure Test (CFT) under four different administration procedures; additionally, the effects of the administration procedures on the Recognition Trial (Meyers & Meyers, 1994) were examined. The Recognition Trial is a new instrument, developed to assess recognition of various parts of the CFT. Many authors have presented a variety of administration procedures; however, there are no studies that examine the relationship of the various administration procedures. The administration procedures used were as follows: (1) Copy, Immediate recall, 30-min recall, and Recognition Trial; (2) Copy, 3-min recall, 30-min recall, Recognition Trial; (3) Copy, Immediate recall, 3-min recall, 30-min recall, Recognition Trial; (4) Copy, 30-min recall, Recognition Trial. The results of the study indicate no significant difference in the 30-min recall score or on the Recognition Trial if an immediate/short-term recall was given; however, if no immediate/short-term recall was given, there was a difference in the 30-min recall score and the Recognition Trial. There was no significant difference in a time period from immediate to 3 min on the 30-min recall score.
Administered complex tests of declarative memory, working memory, procedural learning, and response generation and inhibition to 27 younger adults (14 men and 13 women; aged 19–28 yrs) and 32 older adults (16 men and 16 women; aged 58–77 yrs) following ingestion of saccharin or glucose. Glucose administration (GLA) significantly enhanced performance on the declarative memory measure paragraph recall for older men and younger men whose blood glucose returned to similar levels. Younger men whose blood glucose levels were lowest 60 min after glucose ingestion showed memory deterioration. GLA did not affect paragraph recall for the other groups, nor were effects noted for any group for most other cognitive measures. Results suggest that the effects of GLA are primarily restricted to declarative memory independent of task complexity, and that age, sex, and glucoregulatory response may influence hyperglycemic memory enhancement. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
The record blank enables the examiner to conduct the test without consulting the manual except for scoring and norms, and to record the responses for each item. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
The revision of the Wechsler-Bellevue Adult Intelligence Scale retains the type of item categories but has numerous changes in the items. Standardization is based on a stratified sample of 1700 adults ages 16 to 64. Additional norms are given for ages above 64 based on a different group of subjects. Reliabilities for verbal, performance and full scale IQ's are .96, .93, and .97, and for the subtests range from .65 to .96. Manual includes directions for administering, IQ tables, and scaled score tables. Officially the title is to be abbreviated WAIS. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Cognitive dysfunction in type 1 and type 2 diabetes share many similarities, but important differences do exist. A primary distinguishing feature of type 2 diabetes is that people with this disorder often (but not invariably) do poorly on measures of learning and memory, whereas deficits in these domains are rarely seen in people with type 1 diabetes. Chronic hyperglycaemia and microvascular disease contribute to cognitive dysfunction in both type 1 and type 2 diabetes, and both disorders are associated with mental and motor slowing and decrements of similar magnitude on measures of attention and executive functioning. Additionally, both types are characterised by neural slowing, increased cortical atrophy, microstructural abnormalities in white matter tracts, and similar, but not identical, changes in concentrations of brain neurometabolites. Disconcertingly, the rapid rise in obesity and type 2 diabetes in all age groups might result in a substantial increase in prevalence of diabetes-related cognitive dysfunction.
There is an increasing body of research investigating whether abnormal glucose tolerance is associated with cognitive impairments, the evidence from which is equivocal. A systematic search of the literature identified twenty-three studies which assessed either clinically defined impaired glucose tolerance (IGT) or variance in glucose tolerance within the clinically defined normal range (NGT). The findings suggest that poor glucose tolerance is associated with cognitive impairments, with decrements in verbal memory being most prevalent. However, the evidence for decrements in other domains was weak. The NGT studies report a stronger glucose tolerance–cognition association than the IGT studies, which is likely to be due to the greater number of glucose tolerance parameters and the more sensitive cognitive tests in the NGT studies compared to the IGT studies. It is also speculated that the negative cognitive impact of abnormalities in glucose tolerance increases with age, and that glucose consumption is most beneficial to individuals with poor glucose tolerance compared to individuals with normal glucose tolerance. The role of potential mechanisms are discussed.
Recent studies suggest that glucose enhances memory in rodents and humans. The present experiment investigated the effects of glucose on memory performance and blood glucose changes in young adults (19-25 years). Subjects ingested (300 ml beverage) three doses of glucose (0, 30, 100 g) in a random, double-blind, triple crossover design. Thirty minutes post-glucose, subjects were shown nouns on a computer monitor and then administered recall and recognition memory tests. Blood samples were drawn at regular intervals. There was no effect of glucose on memory performance, and plasma glucose measures did not correlate with memory test scores. Statistical power was adequate to detect a medium effect. The results contradict the hypothesis that glucose enhances memory performance in young, healthy normal adults.
The concentration of immunoreactive insulin (IRI) extracted from the olfactory bulb, hypothalamus, hippocampus, cerebral cortex, amygdala, midbrain, and hindbrain was significantly lower in obese (fa/fa) and heterozygous (Fa/fa) Zucker rats in comparison to lean (Fa/Fa) Zucker rats. This deficit in brain IRI content was most severe in the hypothalamus and olfactory bulb and was independent of severe obesity since the marked reduction of brain IRI content was also found in heterozygous rats which possessed only one copy of the fa allele. These results demonstrate that in the 2-3 month-old female Zucker rat, the fa allele is associated with defective regulation of insulin in the brain.
Resistance to insulin-mediated glucose uptake is characteristic of individuals with impaired glucose intolerance or non-insulin-dependent diabetes, and it also occurs commonly in patients with high blood pressure. The physiological response to a decrease in insulin-mediated glucose uptake is an increase in insulin secretion, and as long as a state of compensatory hyperinsulinemia can be maintained, frank decompensation of glucose tolerance can be prevented. However, it is likely that the defect in insulin action and/or the associated hyperinsulinemia will lead to an increase in plasma triglyceride and a decrease in high density lipoprotein-cholesterol concentration, and high blood pressure. It seems likely that the cluster of changes associated with resistance to insulin-mediated glucose uptake comprise a syndrome, which plays an important role in the etiology and clinical course of patients with non-insulin-dependent diabetes, high blood pressure, and coronary heart disease.
Type II (non-insulin-dependent) diabetes may be associated with impaired cognitive function. A detailed search of the literature has identified 19 controlled studies in which cognitive function in type II diabetes has been examined. The studies vary widely with respect to the nature of the diabetic populations studied and the psychological tests used. Thirteen studies demonstrated that the diabetic individuals performed more poorly in at least one aspect of cognitive function. The most commonly affected cognitive ability was verbal memory. Psychomotor ability and frontal lobe function were affected less consistently. The remaining six studies showed no differences in cognitive ability between subjects with type II diabetes and nondiabetic control subjects, but none had adequate statistical power to detect a between-group difference in cognitive ability of 0.5 of a standard deviation (a medium effect size). These findings are consistent with type II diabetes being associated with an increased risk of cognitive dysfunction. However, the widespread differences in methodology between the studies should lead to a cautious interpretation of their conclusions. The etiology of any cognitive decrement in type II diabetes is likely to result from an interaction between metabolic abnormalities intrinsic to diabetes, diabetes-specific complications, and other diabetes-related disorders.
We examined changes in cognitive performance following the intake of a glucose (50 g) or saccharin solution (50 mg) in fasted elderly male and female subjects. Glucoregulation was estimated using a recovery index that was used to categorize subjects within each sex as having poor or good recovery. Elderly males with poor recovery performed worse on the Logical Memory subtest of the Wechsler Memory Scale and on the free recall or recognition parts of a work list task. The item analysis of the Logical Memory subtest showed that male subjects with poor recovery remembered less of the last items of the paragraphs after drinking saccharin while the first items were equally remembered by both groups. Glucose improved the performance of the males with good regulation for the first seven items while the performance of males with poor regulation decreased for those items under glucose. The present study support the notion that peripheral glucoregulation can influence memory performance and that the ingestion of glucose can influence certain aspects of memory functioning.
We set out to examine the evidence for an association between cognitive impairment or dementia and the presence of Type 2 diabetes mellitus (DM). We also sought evidence of potential mechanisms for such an association.
A literature search of three databases was performed and the reference lists of the papers so identified were examined, using English language papers only.
We found evidence of cross-sectional and prospective associations between Type 2 DM and cognitive impairment, probably both for memory and executive function. There is also evidence for an elevated risk of both vascular dementia and Alzheimer's disease in Type 2 DM albeit with strong interaction of other factors such as hypertension, dyslipidaemia and apolipoprotein E phenotype. Both vascular and non-vascular factors are likely to play a role in dementia in diabetes.
Current classification structures for dementia may not be adequate in diabetes, where mixed pathogenesis is likely. Further research into the mechanisms of cognitive impairment in Type 2 DM may allow us to challenge the concept of dementia, at least in these patients, as an irremediable disease.
We examined the structure-activity relationships of isocoumarins, phthalides and stilbenes isolated from Hydrangeae Dulcis Folium and related compounds for the inhibition of histamine release in rat peritoneal mast cells. The activities of isocoumarins such as thunberginols A and B were more potent than those of dihydroisocoumarins such as hydrangenol and thunberginol G. The double bond at the 3-position seemed to be essential to potentiate the activity. The hydroxyl groups at the 8-, 3'- and 4'-positions of isocoumarin were essential for the activity, while the hydroxyl group at the 6-position was scarcely needed. Since the activities of benzylidenephthalides such as thunberginol F were more potent than those of hydramacrophyllols A and B, the presence of a double bond at the 3-position was needed to increase the activity. Moreover, the hydroxyl group at the 8-position was essential for the activity. On the time course study, thunberginols A, B and F completely inhibited histamine release by pretreatment at 100 microM for 1 to 15 min, whereas DSCG inhibited histamine release only following 1-min pretreatment at 1000 microM. These results suggested that the mechanisms of the inhibitory effect of thunberginols are different from that of DSCG.
Insulin resistance plays an important role in the pathophysiology of diabetes and is associated with obesity and other cardiovascular risk factors. The "gold standard" glucose clamp and minimal model analysis are two established methods for determining insulin sensitivity in vivo, but neither is easily implemented in large studies. Thus, it is of interest to develop a simple, accurate method for assessing insulin sensitivity that is useful for clinical investigations. We performed both hyperinsulinemic isoglycemic glucose clamp and insulin-modified frequently sampled iv glucose tolerance tests on 28 nonobese, 13 obese, and 15 type 2 diabetic subjects. We obtained correlations between indexes of insulin sensitivity from glucose clamp studies (SI(Clamp)) and minimal model analysis (SI(MM)) that were comparable to previous reports (r = 0.57). We performed a sensitivity analysis on our data and discovered that physiological steady state values [i.e. fasting insulin (I(0)) and glucose (G(0))] contain critical information about insulin sensitivity. We defined a quantitative insulin sensitivity check index (QUICKI = 1/[log(I(0)) + log(G(0))]) that has substantially better correlation with SI(Clamp) (r = 0.78) than the correlation we observed between SI(MM) and SI(Clamp). Moreover, we observed a comparable overall correlation between QUICKI and SI(Clamp) in a totally independent group of 21 obese and 14 nonobese subjects from another institution. We conclude that QUICKI is an index of insulin sensitivity obtained from a fasting blood sample that may be useful for clinical research.
A glucose drink has been shown to improve memory in persons with poor glucose regulation and poor cognition.
The objective of this study was to determine 1) whether an association between cognition and glucose regulation is apparent in healthy seniors and 2) the effects of dietary carbohydrates on cognition.
After an overnight fast, 10 men and 10 women (aged 60-82 y) consumed 50 g carbohydrate as glucose, potatoes, or barley or a placebo on 4 separate mornings. Cognitive tests were administered 15, 60, and 105 min after ingestion of the carbohydrate. Plasma glucose and serum insulin were measured.
In a multiple regression analysis, poor baseline (placebo) verbal declarative memory (immediate and 20-min delayed paragraph recall and word list recall) and visuomotor task performance were predicted by poor beta cell function, high incremental area under the glucose curve, low insulin resistance, and low body mass index. The difference in plasma glucose after food consumption [glucose > potatoes > barley > placebo (P: < 0.03)] did not predict performance. Although overall performance did not differ with consumption of the different test foods, baseline score and beta cell function correlated with improvements in immediate and delayed paragraph recall for all 3 carbohydrates (compared with placebo); the poorer the baseline memory or beta cell function, the greater the improvement (correlation between beta cell function and improvement in delayed paragraph recall: r > -0.50, P: < 0.03). Poor beta cell function correlated with improvement for all carbohydrates in visuomotor task performance but not on an attention task.
Glucose regulation was associated with cognitive performance in elderly subjects with normal glucose tolerance. Dietary carbohydrates (potatoes and barley) enhanced cognition in subjects with poor memories or beta cell function independently of plasma glucose.
Insulin transported from plasma into the central nervous system (CNS) is hypothesized to contribute to the negative feedback regulation of body adiposity. Because CNS insulin uptake is likely mediated by insulin receptors, physiological interventions that impair insulin action in the periphery might also reduce the efficiency of CNS insulin uptake and predispose to weight gain. We hypothesized that high-fat feeding, which both reduces insulin sensitivity in peripheral tissues and favors weight gain, reduces the efficiency of insulin uptake from plasma into the CNS. To test this hypothesis, we estimated parameters for cerebrospinal fluid (CSF) insulin uptake and clearance during an intravenous insulin infusion using compartmental modeling in 10 dogs before and after 7 weeks of high-fat feeding. These parameters, together with 24-h plasma insulin levels measured during ad libitum feeding, also permitted estimates of relative CNS insulin concentrations. The percent changes of adiposity, body weight, and food intake after high-fat feeding were each inversely associated with the percent changes of the parameter k1k2, which reflects the efficiency of CNS insulin uptake from plasma (r = -0.74, -0.69, -0.63; P = 0.015, 0.03, and 0.05, respectively). These findings were supported by a non-model-based calculation of CNS insulin uptake: the CSF-to-plasma insulin ratio during the insulin infusion. This ratio changed in association with changes of k1k2 (r = 0.84, P = 0.002), body weight (r = -0.66, P = 0.04), and relative adiposity (r = -0.72, P = 0.02). By comparison, changes in insulin sensitivity, according to minimal model analysis, were not associated with changes in k1k2, suggesting that these parameters are not regulated in parallel. During high-fat feeding, there was a 60% reduction of the estimated CNS insulin level (P = 0.04), and this estimate was inversely associated with percent changes in body weight (r = -0.71, P = 0.03). These results demonstrate that increased food intake and weight gain during high-fat feeding are associated with and may be causally related to reduced insulin delivery into the CNS.
Insulin is the principal hormone of metabolic regulation. Reduced responses to insulin constitute an underlying feature of type 2 diabetes. It is, therefore, incumbent on those who work in this area (as well as many others) to characterize this response, in as simple and consistent a way as possible, so that this measure can be used both in the investigational and clinical setting. This type of approach, although eminently useful, is necessarily an oversimplification. Not only does insulin sensitivity change in pathological situations, but also in normal physiology. Tissue-specific, metabolite-specific, as well as process-specific responses may be expected to occur. Variations also occur in time-depending on the physiological state of the individual (e.g. pregnancy, aging) or following diurnal rhythms. It is perhaps remarkable that any consistent assessment of overall insulin sensitivity can be made. The observation that this can often be achieved has led to hypotheses suggesting that sensitivity to insulin is primarily determined at a single site (tissue, metabolite). At the same time, there are many discussions about the inconsistencies inherent in different approaches to the measurement of this parameter, suggesting that some of these variants, metabolic or otherwise, could lead to the low correlation between methods sometimes seen. Nevertheless, most methods used in the assessment of insulin sensitivity examine the response to insulin of a single metabolite, glucose, primarily in the muscle and liver, and under fasting conditions and should, therefore, demonstrate insulin sensitivity that is comparable among methods.
As one of the most extensively studied protein hormones, insulin and its receptor have been known to play key roles in a variety of important biological functions. Until recent years, the functions of insulin and insulin receptor (IR) in the central nervous system (CNS) have largely remained unclear. IR is abundantly expressed in several specific brain regions that govern fundamental behaviors such as food intake, reproduction and high cognition. The IR from the periphery and CNS exhibit differences in both structure and function. In addition to that from the peripheral system, locally synthesized insulin in the brain has also been identified. Accumulated evidence has demonstrated that insulin/IR plays important roles in associative learning, as suggested by results from both interventive and correlative studies. Interruption of insulin production and IR activity causes deficits in learning and memory formation. Abnormal insulin/IR levels and activities are seen in Alzheimer's dementia, whereas administration of insulin significantly improves the cognitive performance of these patients. The synaptic bases for the action of insulin/IR include modifying neurotransmitter release processes at various types of presynaptic terminals and modulating the activities of both excitatory and inhibitory postsynaptic receptors such as NMDA and GABA receptors, respectively. At the molecular level, insulin/IR participates in regulation of learning and memory via activation of specific signaling pathways, one of which is shown to be associated with the formation of long-term memory and is composed of intracellular molecules including the shc, Grb-r/SOS, Ras/Raf, and MEK/MAP kinases. Cross-talk with another IR pathway involving IRS1, PI3 kinase, and protein kinase C, as well as with the non-receptor tyrosine kinase pp60c-src, may also be associated with memory processing.
Poor glucose tolerance and memory deficits, short of dementia, often accompanies aging. The purpose of this study was to ascertain whether, among nondiabetic, nondemented middle-aged and elderly individuals, poorer glucose tolerance is associated with reductions in memory performance and smaller hippocampal volumes. We studied 30 subjects who were evaluated consecutively in an outpatient research setting. The composition of the participant group was 57% female and 68.6 +/- 7.5 years of age; the participants had an average education of 16.2 +/- 2.3 years, a score on the Mini Mental State Examination of 28.6 +/- 1.5, a glycosylated hemoglobin (HbA1C) of 5.88 +/- 0.74%, and a body mass index of 24.9 +/- 4.1 kg/m(2). Glucose tolerance was measured by an i.v. glucose tolerance test. Memory was tested by using the Wechsler Paragraphs recall tests at the time of administering the i.v. glucose tolerance test. The hippocampus and other brain volumes were measured by using validated methods on standardized MRIs. Decreased peripheral glucose regulation was associated with decreased general cognitive performance, memory impairments, and atrophy of the hippocampus, a brain area that is key for learning and memory. These associations were independent of age and Mini Mental State Examination scores. Therefore, these data suggest that metabolic substrate delivery may influence hippocampal structure and function. This observation may bring to light a mechanism for aging brain injury that may have substantial medical impact, given the large number of elderly individuals with impaired glucose metabolism.