Brain magnetic resonance imaging correlates of impaired cognition in patients with type 2 diabetes

The structural correlates of impaired cognition in type 2 diabetes are unclear. The present study compared cognition and brain magnetic resonance imaging (MRI) between type 2 diabetic patients and nondiabetic control subjects and assessed the relationship between cognition and MRI findings and blood pressure and metabolic control. The study included 113 patients and 51 control subjects. Brain MRI scans were rated for white matter lesions (WMLs), cortical and subcortical atrophy, and infarcts. Neuropsychological test scores were divided into five cognitive domains and expressed as standardized Z values. Type 2 diabetes was associated with deep WMLs (P = 0.02), cortical (P < 0.001) and subcortical (P < 0.05) atrophy, (silent) infarcts (P = 0.06), and impaired cognitive performance (attention and executive function, information-processing speed, and memory, all P < 0.05). Adjustment for hypertension did not affect the results. Within the type 2 diabetic group, cognitive function was inversely related with WMLs, atrophy, and the presence of infarcts (adjusted for age, sex, and estimated IQ), and there was a modest association with HbA1c and diabetes duration. This association was strongest for age, even more so than in control subjects. We conclude that cognitive impairments in patients with type 2 diabetes are not only associated with subcortical ischemic changes in the brain, but also with increased brain atrophy.     

Intranasal Insulin Enhanced Resting-State Functional Connectivity of Hippocampal Regions in Type 2 Diabetes

Type 2 diabetes mellitus (T2DM) alters brain function and manifests as brain atrophy. Intranasal insulin has emerged as a promising intervention for treatment of cognitive impairment. We evaluated the acute effects of intranasal insulin on resting-state brain functional connectivity in older adults with T2DM. This proof-of-concept, randomized, double-blind, placebo-controlled study evaluated the effects of a single 40 IU dose of insulin or saline in 14 diabetic and 14 control subjects. Resting-state functional connectivity between the hippocampal region and default mode network (DMN) was quantified using functional MRI (fMRI) at 3Tesla. Following insulin administration, diabetic patients demonstrated increased resting-state connectivity between the hippocampal regions and the medial frontal cortex (MFC) as compared with placebo (cluster size: right, P = 0.03) and other DMN regions. On placebo, the diabetes group had lower connectivity between the hippocampal region and the MFC as compared with control subjects (cluster size: right, P = 0.02), but on insulin, MFC connectivity was similar to control subjects. Resting-state connectivity correlated with cognitive performance. A single dose of intranasal insulin increases resting-state functional connectivity between the hippocampal regions and multiple DMN regions in older adults with T2DM. Intranasal insulin administration may modify functional connectivity among brain regions regulating memory and complex cognitive behaviors.     

Brain activation during working memory is altered in patients with type 1 diabetes during hypoglycemia

OBJECTIVE

To investigate the effects of acute hypoglycemia on working memory and brain function in patients with type 1 diabetes.

RESEARCH DESIGN AND METHODS

Using blood oxygen level–dependent (BOLD) functional magnetic resonance imaging during euglycemic (5.0 mmol/L) and hypoglycemic (2.8 mmol/L) hyperinsulinemic clamps, we compared brain activation response to a working-memory task (WMT) in type 1 diabetic subjects (n = 16) with that in age-matched nondiabetic control subjects (n = 16). Behavioral performance was assessed by percent correct responses.

RESULTS

During euglycemia, the WMT activated the bilateral frontal and parietal cortices, insula, thalamus, and cerebellum in both groups. During hypoglycemia, activation decreased in both groups but remained 80% larger in type 1 diabetic versus control subjects (P < 0.05). In type 1 diabetic subjects, higher HbA_1c was associated with lower activation in the right parahippocampal gyrus and amygdala (R² = 0.45, P < 0.002). Deactivation of the default-mode network (DMN) also was seen in both groups during euglycemia. However, during hypoglycemia, type 1 diabetic patients deactivated the DMN 70% less than control subjects (P < 0.05). Behavioral performance did not differ between glycemic conditions or groups.

CONCLUSIONS

BOLD activation was increased and deactivation was decreased in type 1 diabetic versus control subjects during hypoglycemia. This higher level of brain activation required by type 1 diabetic subjects to attain the same level of cognitive performance as control subjects suggests reduced cerebral efficiency in type 1 diabetes.Acute episodes of hypoglycemia are a rate-limiting adverse effect in the treatment of type 1 diabetes. When severe, they can lead to seizures and coma (1). Even mild to moderate hypoglycemia is known to impair cognitive functions, such as working memory (2,3). Working memory is used to actively maintain and manipulate information over a brief period of time and to allocate attentional resources among competing subtasks (4,5). Traditionally, working-memory performance is thought to depend primarily on a network of brain regions, including portions of the frontal and parietal lobes, thalamus, precuneus, cerebellum, and insula (6,7).Using blood oxygen level–dependent (BOLD) functional magnetic resonance imaging (fMRI), we evaluated how diabetes impacts these neural processes under euglycemic and hypoglycemic conditions when subjects were presented with a working-memory task (WMT). Diabetes is known to negatively affect working memory (8). This task evaluates functional effects that might reflect changes in brain structure and/or presage decreases in cognitive performance. A better understanding of the brain’s metabolic and physiological mechanisms underlying the cognitive functions implicated in working memory could lead to improved treatment strategies to help maintain cortical function in patients with diabetes during hypoglycemia (9).BOLD fMRI is a well-established method for examining regional brain activation in response to physiological, pharmacological, sensory, or cognitive tasks (10). Studies that have examined brain activation in response to sensory stimulation or cognitive challenges using BOLD fMRI during hypoglycemic conditions in nondiabetic subjects (11–13) have shown that hypoglycemia reduces regional brain BOLD activation. This reduction in BOLD response during hypoglycemia has been attributed to low glucose levels causing decreases in neuronal activity, glucose oxidative metabolism, cerebral blood flow, neurovascular coupling, and/or neuronal recruitment (12).Whether cognitive function in patients with type 1 diabetes is affected by hypoglycemia in the same manner as in nondiabetic individuals remains unclear because few studies using functional neural imaging have directly compared diabetic and nondiabetic subjects during the performance of cognitive tasks (14,15). If brain glucose transport or metabolism are altered in type 1 diabetes, as has been suggested in recent studies by our group (16) and others (17), then one would expect that the BOLD activation response during hypoglycemia may differ between diabetic patients compared with nondiabetic control subjects. On the basis of these findings, we hypothesized that 1) patients with type 1 diabetes would have greater BOLD activation during the performance of a WMT during hypoglycemia when compared with nondiabetic control subjects, 2) cognitive performance would deteriorate during hypoglycemia in both groups, and 3) among type 1 diabetic patients, better glycemic control (lower HbA_1c) would correlate with BOLD activation responses to the WMT during hypoglycemia. We also conducted exploratory analyses to examine deactivation patterns in the default-mode network (DMN), the regions of the brain that are more active during rest (18), because of other research by our group examining the effects of diabetes on deactivation patterns during cognitive tasks and previous research suggesting that DMN function may be altered in diseases that affect cognition, such as Alzheimer’s disease (19).     

Microvascular disease in type 1 diabetes alters brain activation: a functional magnetic resonance imaging study

Individuals with type 1 diabetes have mild performance deficits on a range of neuropsychological tests compared with nondiabetic control subjects. The mechanisms underlying this cognitive deterioration are still poorly understood, but chronic hyperglycemia is now emerging as a potential determinant, possibly through microvascular changes in the brain. In 24 type 1 diabetic patients, we tested at euglycemia and at acute hypoglycemia whether the presence of proliferative diabetic retinopathy, as a marker of microvascular disease, adversely affects the ability of the brain to respond to standardized hypoglycemia, using functional magnetic resonance imaging with a cognitive task. Patients with retinopathy, compared with patients without, showed less deactivation (hence, an increased response) in the anterior cingulate and the orbital frontal gyrus during hypoglycemia compared with euglycemia (P < 0.05). Task performance and reaction time were not significantly different for either group. We conclude that microvascular damage in the brain of patients with retinopathy caused this increased brain response to compensate for functional loss.     

Investigation of the Relationship between Type 2 Diabetes and Osteoporosis Using Bayesian Inference

This study aims to determine the prevalence of Type 2 diabetes in women with osteoporosis and estimate the odds ratio (OR) of osteoporosis in women with Type 2 diabetes using Bayesian inference. This is a case-control study design that looked into prevalence of diabetes among 582 female patients who had normal bone mineral density (BMD) and 598 female patients with osteoporosis. The subjects included women at least 30 yr of age who had their BMD measured in the lumbar spine and femoral neck using dual-energy X-ray absorptiometry at a tertiary referral center in Manila, Philippines. Prevalence of Type 2 diabetes in subjects with osteoporosis is 22.41%, whereas 19.07% of the subjects with normal BMD had diabetes. The odds of developing osteoporosis is 22.54% higher for Type 2 diabetic subjects. Patients with osteoporosis were older than subjects with normal BMD by almost 10 yr. Of the diabetic osteoporotic patients, 44.78% were physically active compared with 20.72% diabetics with normal BMD. Most of the diabetics (60.36%) with normal BMD were obese, whereas majority of diabetic osteoporotics (64.93%) have normal body mass index (BMI). Less than 10% of both diabetic osteoporotics and diabetics with normal BMD have ever undergone hormone replacement therapy. Of the 598 subjects with osteoporosis, 124 (20.74%) had suffered from fragility fractures. When controlling for physical activity and BMI, the odds of developing osteoporosis was 21.73% and 53.89% higher for Type 2 diabetics, respectively. In considering all possible confounders and effect modifiers (age, physical activity, BMI, and hormone replacement therapy) in the model which made use of a diffuse normal prior distribution, the estimate for OR (Model 1) is 0.67. A separate analysis excluding modifiable confounders (Model 2) gave the measure of association an equal likelihood of diabetes being a protective factor or a risk factor. The crude OR indicated that Type 2 diabetes is a risk factor for osteoporosis. However, when identified confounders were included in the model, the direction of the relationship changed. Considering the credible intervals (95% credible interval in both models), the study concluded that diabetes is indeed a protective factor for osteoporosis. Results of the study may have potential limitations. There are sources of bias that have been identified—selection bias where patients included in the study were referred by primary care givers for a specified reason as well as misclassification and recall biases on certain information such as type and duration of physical activity. Diabetes is a protective factor for osteoporosis in this referred population of women. However, with the well-known diabetes-related factors, that is, microvascular complications, visual acuity, and risk for fall, one should still strongly consider assessing and screening for osteoporosis and fracture risk reduction in diabetic patients.     

Diabetic Retinopathy and Cognitive Decline in Older People With Type 2 Diabetes: The Edinburgh Type 2 Diabetes Study

OBJECTIVE

Cerebral microvascular disease associated with type 2 diabetes may exacerbate the effects of aging on cognitive function. A considerable homology exists between the retinal and cerebral microcirculations; a hypothesized association between diabetic retinopathy (DR) and cognitive decline was examined in older people with type 2 diabetes.

RESEARCH DESIGN AND METHODS

In the population-based Edinburgh Type 2 Diabetes Study, 1,046 men and women aged 60–75 years with type 2 diabetes underwent standard seven-field binocular digital retinal photography and a battery of seven cognitive function tests. A general cognitive ability score (g) was generated by principal components analysis. The Mill-Hill Vocabulary Scale was used to estimate premorbid cognitive ability. DR was graded using a modification of the Early Treatment of Diabetic Retinopathy Scale.

RESULTS

After age and sex adjustment, a significant relationship was observed with increasing severity of DR (none, mild, and moderate to severe) for most cognitive measures. Participants with moderate-to-severe retinopathy had the worst g and the worst performances on the individual tests. There was a significant interaction between sex and retinopathy for g. In male subjects, the associations of retinopathy with g (and with tests of verbal fluency, mental flexibility, and processing speed but not memory and nonverbal reasoning) persisted (P < 0.05) when further adjusted for vocabulary (to estimate lifetime cognitive decline), depression, sociodemographic characteristics, cardiovascular risk factors, and macrovascular disease.

CONCLUSIONS

DR was independently associated with estimated lifetime cognitive decline in older men with type 2 diabetes, supporting the hypothesis that cerebral microvascular disease may contribute to their observed accelerated age-related cognitive decline. A sex interaction with stronger findings in men requires further confirmation.Type 2 diabetes is associated with an increased risk of age-related cognitive impairment and decline in addition to higher incidences of stroke and dementia (1–3). Relatively little is known about the risk factors associated with the deleterious effects of type 2 diabetes on accelerated cognitive aging, although cerebral microvascular disease may be important (4–6). However, direct in vivo evaluation of the cerebral microcirculation is difficult and the vessels themselves are too small to permit detailed visualization with current neuroimaging methods.Retinal and cerebral small vessels share similar embryological origin, size, structure, and physiological characteristics (including the blood-brain and blood-retinal barrier) (7,8). The retinal vascular bed can be directly visualized noninvasively with retinal photography. Typical retinopathic changes associated with diabetes are associated with white matter lesions in the brain, magnetic resonance imaging (MRI)-defined cerebral infarcts, and incident stroke (9–11). We hypothesized that increasing severity of diabetic retinopathy (DR) would be associated with poorer cognitive ability and with greater cognitive decline, thus providing evidence for an effect of cerebral microvascular disease on accelerated age-related cognitive decline in people with type 2 diabetes. Previous studies have found a significant association between the presence of microaneurysms and reduced performance on measures of fluid intelligence, processing speed, and attention ability in young adults with type 1 diabetes (12) and between retinopathy and risk of cognitive impairment and decline in the general population (13–15), but to our knowledge the relationship between DR and cognition in older people with type 2 diabetes has not been examined.The aim of the present investigation was to determine the association of DR with both cognitive ability and estimated lifetime cognitive decline in a large, well-characterized sample of men and women aged 60–75 years with type 2 diabetes (the Edinburgh Type 2 Diabetes Study [ET2DS]). Cognitive function was measured using a battery of neuropsychological tests assessing major cognitive domains, and cognitive decline was estimated by using a test of vocabulary to adjust for premorbid cognitive function.     

Effect of type 1 diabetes on the gender difference in coronary artery calcification: a role for insulin resistance? The Coronary Artery Calcification in Type 1 Diabetes (CACTI) Study

The objective of this is study was to examine whether estimated insulin resistance and insulin resistance-related factors are associated with coronary artery calcification (CAC) in 1,420 asymptomatic participants in the Coronary Artery Calcification in Type 1 Diabetes (CACTI) study. A total of 656 patients with type 1 diabetes and 764 control subjects aged 20-55 years were examined. CAC was assessed by electron-beam computed tomography. Insulin resistance was computed with linear regression based on an equation previously validated in clamp studies on type 1 diabetic adults. Insulin resistance was associated with CAC (OR 1.6 in type 1 diabetes and 1.4 in control subjects, P < 0.001), independent of coronary artery disease risk factors. There was a male excess of CAC in control subjects (OR 2.7, adjusted for age, smoking, and LDL and HDL cholesterol levels) and in type 1 diabetic patients (OR 2.2, adjusted for the same factors and diabetes duration). After adjusting for insulin resistance, the CAC male excess in diabetic patients decreased from OR 2.2 (P < 0.001) to 1.8 (P = 0.04). After adjustment for waist-to-hip ratio, waist circumference, or visceral fat, the gender difference in CAC was not significant in diabetic subjects. In conclusion, gender differences in insulin resistance-associated fat distribution may explain why type 1 diabetes increases coronary calcification in women relatively more than in men.     

Functional Brain Connectivity and Neurocognitive Functioning in Patients With Long-Standing Type 1 Diabetes With and Without Microvascular Complications: A Magnetoencephalography Study

OBJECTIVE

Hyperglycemia-associated microvascular disease may underlie changes in cerebral functioning and cognitive performance in patients with type 1 diabetes. Functional connectivity, an indicator of functional interactions and information exchange between brain regions, provides a measure of cerebral functioning. This study addresses functional connectivity and cognition in type 1 diabetic patients with and without proliferative retinopathy, relative to healthy control subjects, using magnetoencephalography.

RESEARCH DESIGN AND METHODS

Fluctuations in magnetic field at scalp for Δ, θ, lower and upper α, β, and lower and upper γ frequency bands were measured using magnetoencephalography. Synchronization likelihood, a measure of functional connectivity, was computed. Using neuropsychological tests, cognitive functioning was assessed and its associations with functional connectivity were determined.

RESULTS

Compared with control subjects, type 1 diabetic patients performed poorer on general cognitive ability, information processing speed, and motor speed, irrespective of their microvascular complication status. Functional connectivity, however, was lowest for type 1 diabetic patients with retinopathy, compared with type 1 diabetic patients without microvascular complications and control subjects, whereas type 1 diabetic patients without microvascular complications showed an increase relative to control subjects. Positive associations were found between functional connectivity and executive functioning, memory, information processing speed, motor speed, and attention.

CONCLUSIONS

Compared with healthy control subjects, functional connectivity and cognition differed in type 1 diabetic patients irrespective of microvascular complication status, indicating that chronic hyperglycemia, among other factors, may negatively affect brain functioning even before microvascular damage becomes manifest. The association found between synchronization likelihood and cognition suggests functional connectivity plays a significant role in cognitive functioning.Mild cognitive deterioration and changes in cerebral anatomy have been demonstrated in patients with long-standing type 1 diabetes. These cognitive disturbances are limited to slowed information processing speed, attentional functioning, and primary motor as well as psychomotor speed (1–3). Using structural magnetic resonance imaging (MRI), reductions in cerebral gray and white matter volume in type 1 diabetes compared with healthy control subjects were reported (4–6). To measure important functional changes, electroencephalography can be used. In children with type 1 diabetes, increases in slow (Δ and θ) activity, decreases in fast (α, β, and γ frequency bands) activity, and a reduction in α peak frequency were found. These functional cerebral changes were correlated with both poor glycemic control and more episodes of severe hypoglycemia (7). Compared with healthy control subjects, there was a loss of fast activity in well-controlled diabetic adults (8). These changes were unrelated to a history of severe hypoglycemic events. Although the underlying neuropathological and biological substrates are undefined, there is evidence that chronic hyperglycemia, leading to microangiopathy in the brain, may be the main cause of these cerebral complications (3,5,6,9).A relatively novel and more advanced approach to measuring brain activity is magnetoencephalography (MEG). MEG measures fluctuations of magnetic fields of the brain at the scalp. MEG has been widely used in the study of functional changes associated with neurological disorders including Alzheimer''s disease (10), Parkinson''s disease (11), brain tumors (12), and metabolic disorders such as obesity (13,14) and hepatic encephalopathy (15).With MEG data, functional connectivity can be calculated. This refers to the assumption that correlations between time series of neural activity recorded from different brain regions reflect functional interactions and information exchange between these regions (16,17). Differences in functional connectivity indicate a different way of communication between brain areas. Functional connectivity has been thought to be a core component of cognitive functioning, as most cognitive functions highly depend on interactions between distinct cerebral regions rather than on single brain regions or structures. Therefore, functional connectivity may, at least in part, explain cognitive functioning, and changes in functional connectivity might account for cognitive deterioration (18).In this study, MEG functional connectivity relative to healthy control subjects was investigated in a group of type 1 diabetic patients with proliferative retinopathy as a marker of hyperglycemia and a group of type 1 diabetic patients without microvascular complications. Furthermore, neurocognitive functioning and its association with functional connectivity was assessed. Based on earlier studies (9,19) we expected type 1 diabetic patients with proliferative retinopathy to show cognitive deterioration and lower functional connectivity compared with healthy control subjects and type 1 diabetic patients without microvascular complications.     

Cognitive ability and brain structure in type 1 diabetes: relation to microangiopathy and preceding severe hypoglycemia

Type 1 diabetes is associated with chronic hyperglycemia and exposure to intermittent severe hypoglycemia. The long-term cerebral effects of these consequences of diabetes are ill defined. In this study, the history of preceding severe hypoglycemia and the presence of background retinopathy were examined in relation to cognitive ability (neuropsychological test battery) and brain structure (magnetic resonance imaging) in a cross-sectional evaluation of 74 young people with type 1 diabetes. Participants differed by their severe hypoglycemia exposure and degree of diabetic retinopathy and none had previous neuropsychological pathology. Severe hypoglycemia did not influence cognitive ability or brain structure. Background diabetic retinopathy was associated with small focal white-matter hyperintensities in the basal ganglia (33.3 vs. 4.7%, after correction for age, P = 0.005) and significant cognitive disadvantage, affecting fluid intelligence (P = 0.008, Eta(2) = 0.14), information processing (P = 0.001, Eta(2) = 0.22), and attention and concentration ability (P = 0.03, Eta(2) = 0.09). In conclusion, recurrent exposure to severe hypoglycemia alone in young people with type 1 diabetes had no detrimental impact on brain structure or function over the duration of diabetes examined. Chronic hyperglycemia (inferred by the presence of background diabetic retinopathy) may affect brain structure and function.     

Cellular immune responses to human islet proteins in antibody-positive type 2 diabetic patients.

Type 1 diabetes is a cell-mediated autoimmune disease characterized by autoantibody and peripheral blood mononuclear cell (PBMC) reactivity to islet cell proteins. Type 2 diabetes is not an autoimmune disease but rather results from both insulin resistance and a nonautoimmune insulin secretory defect. There is, however, a group of phenotypic type 2 diabetic patients who have islet autoantibodies that are similar to those of type 1 diabetic patients. In this study, we investigated, using cellular immunoblotting, whether type 2 diabetic patients positive for islet autoantibodies have PBMC responses to islet proteins. We observed that autoantibody negative (Ab-) type 2 diabetic patients (n = 9) and normal control subjects (n = 12) demonstrated PBMCs responsive to 0-3 molecular weight regions. In contrast, autoantibody positive (Ab+) type 2 diabetic patients (n = 11) demonstrated PBMC responses to 3-18 molecular weight regions, similar to that of type 1 diabetic patients (responsive to 4-18 molecular weight regions). PBMCs from over 90% of the Ab+ type 2 and type 1 diabetic patients were observed to proliferate to islet proteins in the vicinity of 97 kDa. In contrast, 65-90% of type 1 diabetic patients had responsive PBMCs for islet proteins in most of the molecular weight regions, whereas <60% of the Ab+ type 2 diabetic patients had PBMCs responsive to the same molecular weight proteins. Ab+ type 2 diabetic patients appear to be heterogeneous with respect to cellular reactivity to islet proteins. Some subjects demonstrate PBMC responses similar to those of "classic" type 1 diabetic patients, whereas others have PBMC responses potentially distinct from type 1 diabetic patients.     

Association Between Raised Inflammatory Markers and Cognitive Decline in Elderly People With Type 2 Diabetes: The Edinburgh Type 2 Diabetes Study

OBJECTIVE

To determine whether circulating levels of the inflammatory markers C-reactive protein (CRP), interleukin (IL)-6, and tumor necrosis factor (TNF)-α are associated with cognitive ability and estimated lifetime cognitive decline in an elderly population with type 2 diabetes.

RESEARCH DESIGN AND METHODS

A cross-sectional study of 1,066 men and women aged 60–75 years with type 2 diabetes and living in Lothian, Scotland (the Edinburgh Type 2 Diabetes Study), was performed. Seven cognitive tests were used to measure abilities in memory, nonverbal reasoning, information processing speed, executive function, and mental flexibility. The results were used to derive a general intelligence factor (g). A vocabulary–based test was administered as an estimate of peak prior cognitive ability. Results on the cognitive tests were assessed for statistical association with inflammatory markers measured in a venous blood sample at the time of cognitive testing.

RESULTS

Higher IL-6 and TNF-α levels were associated with poorer age- and sex-adjusted scores on the majority of the individual cognitive tests. They were also associated with g using standardized regression coefficients −0.074 to −0.173 (P < 0.05). After adjusting for vocabulary, education level, cardiovascular dysfunction, duration of diabetes, and glycemic control, IL-6 remained associated with three of the cognitive tests and with g.

CONCLUSIONS

In this representative population of people with type 2 diabetes, elevated circulating levels of inflammatory markers were associated with poorer cognitive ability. IL-6 levels were also associated with estimated lifetime cognitive decline.Type 2 diabetes is associated with an increased risk of cognitive impairment in older age, accelerated age-related cognitive decline, and a higher incidence of dementia (1). Identifying potentially modifiable risk factors for cognitive impairment in people with type 2 diabetes is therefore of major importance for future diabetes health care initiatives and the reduction of cognitive morbidity in the general population.The cause of cognitive impairment in type 2 diabetes is unknown, but it is most likely multifactorial. Hyperglycemia, cerebral microvascular disease, severe hypoglycemia, and an increased prevalence of macrovascular disease have all been implicated but are unlikely to explain the entire effect (2). Systemic or cerebral inflammation may also be important, and evidence of chronic inflammation has been observed in the brains of people with dementia (3). Levels of circulating inflammatory markers are elevated in people with type 2 diabetes compared with an equivalent nondiabetic population (4). Inflammatory mediators may therefore have a role in the accelerated development of cognitive impairment in people with diabetes either by a direct effect on the brain or through an influence on the development of vascular disease.The Edinburgh Type 2 Diabetes Study (ET2DS) tested the association between three markers of inflammation (C-reactive protein [CRP], interleukin [IL]-6, and tumor necrosis factor [TNF]-α) and cognitive impairment in a representative cohort of people with type 2 diabetes.     

Kidney transplantation in type 2 diabetic patients: a comparison with matched non-diabetic subjects.

BACKGROUND: Because they generally are older and frequently have co-morbidities, patients with type 2 diabetes mellitus and end-stage renal disease seldom are selected for renal transplantation. Thus, information on transplantation results from controlled studies in this high-risk category of patients is scarce. We have compared the results of kidney transplantations in type 2 diabetic patients with carefully matched non-diabetic subjects. METHODS: All first cadaveric renal transplants performed in type 2 diabetic patients from January 1, 1988 to December 31, 1998 in our centre were included. Non-diabetic controls were individually matched with diabetic patients with respect to year of transplantation, sex, age, selected immunological parameters, and graft cold ischaemia. RESULTS: We included 64 type 2 diabetic and 64 non-diabetic patients who were followed for a mean period of 37+/-27 and 41+/-31 months, respectively, after renal transplantation. Patient survival at 1 and 5 years post-transplant was 85 and 69 vs 84 and 74% (P=0.43, NS), while graft survival rates censored for patient death were 84 and 77 vs 82 and 77% for diabetic and non-diabetic subjects, respectively (P=0.52, NS). With graft survival results not censored for death with functioning graft, no significant change was seen (diabetic vs non-diabetic group: 77 and 54 vs 73 and 61%, P=0.19, NS). Age, but not the presence of diabetes, was the only factor significantly affecting patient survival when both patient groups were pooled. With regard to post-transplant complications requiring hospitalization, there was a significant difference only in the number of patients who had amputations (diabetic vs non-diabetic group: 8 vs 0, P=0.01). CONCLUSIONS: Patient and graft survival after kidney transplantation was similar in type 2 diabetic and matched non-diabetic subjects, with more amputations occurring in the diabetic group. Thus, at a single-centre level renal transplantation results almost equivalent to those in non-diabetic patients may be achieved in type 2 diabetes mellitus.     

Serum visfatin increases with progressive beta-cell deterioration

Visfatin has shown to be increased in type 2 diabetes but to be unrelated to insulin sensitivity. We hypothesized that visfatin is associated with insulin secretion in humans. To this aim, a cross-sectional study was conducted in 118 nondiabetic men and 64 (35 men and 29 women) type 2 diabetic patients. Type 1 diabetic patients with long-standing disease (n = 58; 31 men and 27 women) were also studied. In nondiabetic subjects, circulating visfatin (enzyme immunoassay) was independently associated with insulin secretion (acute insulin response to glucose [AIRg] from intravenous glucose tolerance tests) but not with insulin sensitivity (Si) or other metabolic or anthropometric parameters, and AIRg alone explained 8% of visfatin variance (beta = -0.29, P = 0.001). Circulating visfatin was increased in type 2 diabetes (mean 18 [95% CI 16-21] vs. 15 ng/ml [13-17] for type 2 diabetic and nondiabetic subjects, respectively; P = 0.017, adjusted for sex, age, and BMI), although this association was largely attenuated after accounting for HbA1c (A1C). Finally, circulating visfatin was found to be increased in patients with long-standing type 1 diabetes, even after adjusting for A1C values (37 ng/ml [34-40]; P < 0.0001, adjusted for sex, age, BMI, and A1C compared with either type 2 diabetic or nondiabetic subjects). In summary, circulating visfatin is increased with progressive beta-cell deterioration. The study of the regulation and role of visfatin in diabetes merits further consideration.     

Synthesis rate of muscle proteins,muscle functions,and amino acid kinetics in type 2 diabetes

Improvement of glycemic status by insulin is associated with profound changes in amino acid metabolism in type 1 diabetes. In contrast, a dissociation of insulin effect on glucose and amino acid metabolism has been reported in type 2 diabetes. Type 2 diabetic patients are reported to have reduced muscle oxidative enzymes and VO(2max). We investigated the effect of 11 days of intensive insulin treatment (T(2)D+) on whole-body amino acid kinetics, muscle protein synthesis rates, and muscle functions in eight type 2 diabetic subjects after withdrawing all treatments for 2 weeks (T(2)D-) and compared the results with those of weight-matched lean control subjects using stable isotopes of the amino acids. Whole-body leucine, phenylalanine and tyrosine fluxes, leucine oxidation, and plasma amino acid levels were similar in all groups, although plasma glucose levels were significantly higher in T(2)D-. Insulin treatment reduced leucine nitrogen flux and transamination rates in subjects with type 2 diabetes. Synthesis rates of muscle mitochondrial, sarcoplasmic, and mixed muscle proteins were not affected by glycemic status or insulin treatment in subjects with type 2 diabetes. Muscle strength was also unaffected by diabetes or glycemic status. In contrast, the diabetic patients showed increased tendency for muscle fatigability. Insulin treatment also failed to stimulate muscle cytochrome C oxidase activity in the diabetic patients, although it modestly elevated citrate synthase. In conclusion, improvement of glycemic status by insulin treatment did not alter whole-body amino acid turnover in type 2 diabetic subjects, but leucine nitrogen flux, transamination rates, and plasma ketoisocaproate level were decreased. Insulin treatments in subjects with type 2 diabetes had no effect on muscle mitochondrial protein synthesis and cytochrome C oxidase, a key enzyme for ATP production.     

Hypertension, proteinuria and azotaemia in diabetes

The prevalence of hypertension was evaluated in 479 white subjects with diabetes, according to the type of diabetes and the presence of persistent proteinuria as a marker for diabetic nephropathy. Hypertension was uncommon in 178 insulin dependent diabetic subjects without proteinuria (5%) (mean age 25.0 +/- 12.5 years), but occurred in 23% of 58 patients with proteinuria (mean age 28.9 +/- 14.1 years) and in 90% with azotaemia (P less than 0.00001). Among patients with non-insulin-dependent diabetes hypertension was found in 25% of 170 without renal disease (mean age 48.0 +/- 10.3 years) and in 53% of 53 (mean age 51.4 +/- 13.0 years) with proteinuria (P = 0.0002). We conclude that the prevalence of hypertension among subjects with diabetes depends on the type of diabetes, age, and the presence and severity of diabetic renal involvement.     

Prevalence of LADA and frequency of GAD antibodies in diabetic patients with end-stage renal disease and dialysis treatment in Austria.

BACKGROUND: The prevalence of individuals with latent autoimmune diabetes in adults (LADA) among diabetic patients with end-stage renal disease is unknown. Furthermore, there are no references in the literature about the persistence of glutamic acid decarboxylase antibodies (GADA) in uraemic LADA patients. The aim of the study, therefore, was to evaluate the prevalence of LADA, classified according to special features, in diabetic patients undergoing dialysis therapy as well as to find out the frequency of GADA in these patients. In addition, we investigated vascular risk factors and the prevalence of vascular diseases in each type of diabetes. METHODS: 538 patients undergoing chronic dialysis therapy from 37 Austrian dialysis centres were analysed in the study. Patients were divided into three groups: patients with type 1 or type 2 diabetes and patients with LADA. The classification of the different types of diabetes was based on the guidelines of the German Diabetes Society. We measured GADA and estimated the baseline data with reference to body mass index (BMI), age at onset of diabetes and at initiating dialysis therapy, the actual values of haemoglobin (Hb) A1c and cholesterol and the prevalence of vascular diseases by using a structured questionnaire. RESULTS: Type 1 diabetes was classified in 52 patients, type 2 diabetes in 434 and LADA in 52 (9.7%). The prevalence of positive GADA was 17.3% in the type 1 diabetic patients and 26.9% in the LADA patients. There was no positive GADA in the type 2 diabetic subjects. Age at the onset of diabetes and age at the start of dialysis were approximately the same in the LADA and the type 2 diabetic patients, while the age of the subjects with type 1 diabetes was significantly lower (P<0.001). BMI was significantly lower (25+/-3 vs 27+/-5 kg/m2) in the LADA patients than in the type 2 diabetic patients. The mean HbA1c value in the LADA patients was significantly higher than in the subjects with type 2 diabetes (P<0.01). Blood pressure (BP) was similar between LADA and type 1 or type 2 diabetes, though diastolic BP tended to be lower in the LADA patients than in the type 1 diabetics. The cholesterol levels were comparably high in each type of diabetes. In the LADA patients, the prevalence of retinopathy was lower than in the type 1 diabetics and the prevalence of stroke and angina pectoris was lower than in the type 2 diabetic patients, but the differences were not significant. CONCLUSIONS: The prevalence of LADA in diabetic patients on maintenance dialysis was 9.7%. This value is comparable to the frequency of LADA at onset of diabetes. The frequency of persisting GAD autoantibodies was 27% in the LADA patients and 17% in the type 1 diabetic patients. BMI was significantly lower in the LADA patients than in the type 2 diabetic patients, while diastolic BP only tended to be lower in the LADA patients than in the type 1 diabetics. The prevalence of vascular diseases was not significantly different between LADA and types 1 or 2 diabetes. According to our data it can be assumed that only a few uraemic patients with LADA are suitable for simultaneous pancreas-kidney transplantation.     

Longitudinal Assessment of Neuroanatomical and Cognitive Differences in Young Children With Type 1 Diabetes: Association With Hyperglycemia

Significant regional differences in gray and white matter volume and subtle cognitive differences between young diabetic and nondiabetic children have been observed. Here, we assessed whether these differences change over time and the relation with dysglycemia. Children ages 4 to <10 years with (n = 144) and without (n = 72) type 1 diabetes (T1D) had high-resolution structural MRI and comprehensive neurocognitive tests at baseline and 18 months and continuous glucose monitoring and HbA_1c performed quarterly for 18 months. There were no differences in cognitive and executive function scores between groups at 18 months. However, children with diabetes had slower total gray and white matter growth than control subjects. Gray matter regions (left precuneus, right temporal, frontal, and parietal lobes and right medial-frontal cortex) showed lesser growth in diabetes, as did white matter areas (splenium of the corpus callosum, bilateral superior-parietal lobe, bilateral anterior forceps, and inferior-frontal fasciculus). These changes were associated with higher cumulative hyperglycemia and glucose variability but not with hypoglycemia. Young children with T1D have significant differences in total and regional gray and white matter growth in brain regions involved in complex sensorimotor processing and cognition compared with age-matched control subjects over 18 months, suggesting that chronic hyperglycemia may be detrimental to the developing brain.     

Molecular and biochemical trajectories from diabetes to Alzheimer's disease: A critical appraisal

Diabetes mellitus(DM), a metabolic disorder is a major orchestra influencing brain and behavioral responses via direct or indirect mechanisms. Many lines of evidence suggest that diabetic patients apparently face severe brain complications, but the story is far from being fully understood. Type 2 diabetes, an ever increasing epidemic and its chronic brain complications are implicated in the development of Alzheimer's disease(AD). Evidences from clinical and experimental studies suggest that insulin draws a clear trajectory from the peripheral system to the central nervous system. This review is a spot light on striking pathological, bio-chemical, molecular and behavioral commonalities of AD and DM. Incidence of cognitive decline in diabetic patients and diabetic symptoms in AD patients has brought the concept of brain diabetes to attention. Brain diabetes reflects insulin resistant brain state with oxidative stress, cognitive impairment, activation of various inflammatory cascade and mitochondrial vulnerability as a shared footprint of AD and DM. It has become extremely important for the investigators to understand the patho-physiology of brain complications in diabetes and put intensive pursuits for therapeutic interventions. Although, decades of research have yielded a range of molecules with potential beneficial effects, but they are yet to meet the expectations.     

Task-Induced Brain Activity Patterns in Type 2 Diabetes: A Potential Biomarker for Cognitive Decline

Patients with type 2 diabetes demonstrate reduced functional connectivity within the resting state default mode network (DMN), which may signal heightened risk for cognitive decline. In other populations at risk for cognitive decline, additional magnetic resonance imaging abnormalities are evident during task performance, including impaired deactivation of the DMN and reduced activation of task-relevant regions. We investigated whether middle-aged type 2 diabetic patients show these brain activity patterns during encoding and recognition tasks. Compared with control participants, we observed both reduced 1) activation of the dorsolateral prefrontal cortex during encoding and 2) deactivation of the DMN during recognition in type 2 diabetic patients, despite normal cognition. During recognition, activation in several task-relevant regions, including the dorsolateral prefrontal cortex and DMN regions, was positively correlated with HbA_1c and insulin resistance, suggesting that these important markers of glucose metabolism impact the brain’s response to a cognitive challenge. Plasma glucose ≥11 mmol/L was associated with impaired deactivation of the DMN, suggesting that acute hyperglycemia contributes to brain abnormalities. Since elderly type 2 diabetic patients often demonstrate cognitive impairments, it is possible that these task-induced brain activity patterns observed in middle age may signal impending cognitive decline.