Cognition in patients with post-bariatric hypoglycemia.

OBJECTIVE: Bariatric surgery, a highly effective treatment for obesity and associated comorbidities, may improve cognition and brain volume in parallel with cardiometabolic function. However, some post-bariatric individuals develop post-bariatric hypoglycemia (PBH), which can be frequent and severe. The impact of recurrent hypoglycemia on cognition in PBH is unknown. The objective of this study was to determine whether individuals with PBH display reduced cognitive function compared with postsurgical counterparts without hypoglycemia. METHODS: Fourteen adults with a history of Roux-en-Y gastric bypass with hypoglycemia (PBH+, n = 7) or without PBH (PBH-, n = 7) completed assessments of memory, executive function, attention, and psychomotor speed. RESULTS: PBH+ individuals displayed significantly decreased performance in category fluency (p < 0.01), category switching (p < 0.01), and category switching accuracy (p < 0.01), compared with PBH- individuals. Performance in the first (p = 0.03) and third intervals (p = 0.045) of verbal fluency was significantly lower in PBH+ individuals versus PBH- individuals. All other assessments did not differ. CONCLUSIONS: PBH+ individuals may be at greater risk for cognitive impairment compared with PBH- individuals, as suggested by impaired semantic processing and cognitive flexibility, as well as greater difficulty initiating and sustaining word retrieval.

Hyperglycemia and hyperinsulinemia effects on anterior cingulate cortex myoinositol-relation to brain network functional connectivity in healthy adults.

Brain mechanisms underlying the association of diabetes metabolic disorders-hyperglycemia and insulin resistance-with cognitive impairment are unknown. Myoinositol is a brain metabolite involved in cell osmotic balance, membrane phospholipid turnover, and second messenger neurotransmission, which affect brain function. Increased brain myoinositol and altered functional connectivity have been found in diabetes, mild cognitive impairment, and Alzheimer's disease, but the independent effects of plasma glucose and insulin on brain myoinositol and function are not characterized. We measured myoinositol concentrations in the pregenual anterior cingulate cortex (ACC), a region involved in self-reflective awareness and decision making, using proton magnetic resonance spectroscopy, and whole brain resting-state functional connectivity using fMRI, during acute hyperglycemia (with attendant hyperinsulinemia) and euglycemic-hyperinsulinemia compared with basal fasting-euglycemia (EU) in 11 healthy nondiabetic participants (5 women/6 men, means ± SD, age: 27 ± 7 yr, fasting-glucose: 5.2 ± 0.4 mmol/L, fasting-insulin: 4.9 ± 4.4 µU/mL). Brain MR data were acquired during two separate visits: 1) EU followed by a 60-min hyperglycemic-clamp (glucose: 10.7 ± 0.2 mmol/L, insulin: 33 ± 6 µU/mL); 2) EU followed by a hyperinsulinemic-euglycemic-clamp (glucose: 5.3 ± 0.1 mmol/L, insulin: 27 ± 5 µU/mL) designed to match individual insulin levels achieved during the visit 1 hyperglycemic-clamp. Myoinositol decreased by 14% during the hyperglycemic-clamp (from 7.7 ± 1.5 mmol/kg to 6.6 ± 0.8 mmol/kg, P = 0.031), and by 9% during the hyperinsulinemic-euglycemic-clamp (from 7.1 ± 0.7 mmol/kg to 6.5 ± 0.7 mmol/kg, P = 0.014), with no significant difference between the two clamps. Lower myoinositol was associated with higher functional connectivity of the thalamus and precentral cortex with insula-ACC-related networks, suggesting myoinositol is involved in insulin modulation of cognitive/emotional network function in healthy adults. Regional brain myoinositol levels may be useful biomarkers for monitoring cognitive and mood-enhancing treatment responses.NEW & NOTEWORTHY Hyperinsulinemia-related decreases of brain anterior cingulate cortex (ACC) myoinositol independent of plasma glucose levels and the association of low ACC myoinositol with increased functional connectivity between sensorimotor regions and ACC/insula-related networks suggest involvement of myoinositol in insulin-modulated brain network function in healthy adults. In diabetes, elevated brain myoinositol may be due to reduced brain insulin levels or action, rather than hyperglycemia, and may be involved in brain network dysfunctions leading to cognitive or mood disorders.

Association of Cognitive Function and Retinal Neural and Vascular Structure in Type 1 Diabetes.

CONTEXT: Cognitive dysfunction is a growing and understudied public health issue in the aging type 1 diabetic population and is difficult and time-consuming to diagnose. Studies in long duration type 1 diabetes have reported the presence of proliferative diabetic retinopathy was associated with cognitive dysfunction. OBJECTIVE: This study assessed whether structural and vascular abnormalities of the retina, representing an extension of the central nervous system, are associated with cognitive impairment and other complications of type 1 diabetes. METHODS: An observational cross-sectional study of individuals with 50 or more years of type 1 diabetes (Joslin Medalist Study) was conducted at a university hospital in the United States. The study included 129 participants with complete cognitive testing. Validated cognitive testing measures included psychomotor speed, and immediate, and delayed memory. Optical coherence tomography (OCT) and OCT angiography (OCTA) were performed to obtain neural retinal layer thicknesses and vascular density for superficial (SCP) and deep retinal capillary plexus (DCP). Multivariable modeling was adjusted for potential confounders associated with outcomes in unadjusted analyses. RESULTS: Decreased vessel density of the SCP and DCP was associated with worse delayed memory (DCP: P = .002) and dominant hand psychomotor speed (SCP: P = .01). Thinning of the retinal outer nuclear layer was associated with worse psychomotor speed both in nondominant and dominant hands (P = .01 and P = .05, respectively). Outer plexiform layer thickness was associated with delayed memory (P = .04). CONCLUSION: These findings suggest that noninvasive retinal imaging using OCT and OCTA may assist in estimating the risks for cognitive dysfunction in people with type 1 diabetes.

Acute Hyperglycemia Increases Brain Pregenual Anterior Cingulate Cortex Glutamate Concentrations in Type 1 Diabetes.

The brain mechanisms underlying the association of hyperglycemia with depressive symptoms are unknown. We hypothesized that disrupted glutamate metabolism in pregenual anterior cingulate cortex (ACC) in type 1 diabetes (T1D) without depression affects emotional processing. Using proton MRS, we measured glutamate concentrations in ACC and occipital lobe cortex (OCC) in 13 subjects with T1D without major depression (HbA1c 7.1 ± 0.7% [54 ± 7 mmol/mol]) and 11 healthy control subjects without diabetes (HbA1c 5.5 ± 0.2% [37 ± 3 mmol/mol]) during fasting euglycemia followed by a 60-min +5.5 mmol/L hyperglycemic clamp (HG). Intrinsic neuronal activity was assessed using resting-state blood oxygen level-dependent functional MRI to measure the fractional amplitude of low-frequency fluctuations in slow-4 band (fALFF4). Emotional processing and depressive symptoms were assessed using emotional tasks (emotional Stroop task, self-referent encoding task [SRET]) and clinical ratings (Hamilton Depression Rating Scale [HAM-D], Symptom Checklist-90 Revised [SCL-90-R]), respectively. During HG, ACC glutamate increased (1.2 mmol/kg, 10% P = 0.014) while ACC fALFF4 was unchanged (-0.007, -2%, P = 0.449) in the T1D group; in contrast, glutamate was unchanged (-0.2 mmol/kg, -2%, P = 0.578) while fALFF4 decreased (-0.05, -13%, P = 0.002) in the control group. OCC glutamate and fALFF4 were unchanged in both groups. T1D had longer SRET negative word response times (P = 0.017) and higher depression rating scores (HAM-D P = 0.020, SCL-90-R depression P = 0.008). Higher glutamate change tended to associate with longer emotional Stroop response times in T1D only. Brain glutamate must be tightly controlled during hyperglycemia because of the risk for neurotoxicity with excessive levels. Results suggest that ACC glutamate control mechanisms are disrupted in T1D, which affects glutamatergic neurotransmission related to emotional or cognitive processing. Increased prefrontal glutamate during acute hyperglycemic episodes could explain our previous findings of associations among chronic hyperglycemia, cortical thinning, and depressive symptoms in T1D.

Cognitive Function Deficits Associated With Long-Duration Type 1 Diabetes and Vascular Complications.

OBJECTIVE: Patients with type 1 diabetes now live long enough to experience cognitive decline. During middle age, they show mild cognitive deficits, but it is unknown whether severity increases with aging or whether cognitive profiles are similar to those of age-matched peers with and without diabetes. RESEARCH DESIGN AND METHODS: We tested and compared cognition in 82 individuals with 50 or more years of type 1 diabetes (Medalists), 31 age-matched individuals with type 2 diabetes, and 30 age-matched control subjects without diabetes. Medical histories and biospecimens were collected. We also evaluated the association of complications with cognition in Medalists only. RESULTS: Compared with control subjects, both individuals with type 1 diabetes and individuals with type 2 diabetes performed worse on immediate and delayed recall (P ≤ 0.002) and psychomotor speed in both hands (P ≤ 0.01) and showed a trend toward worse executive function (P = 0.05). In Medalists, cardiovascular disease was associated with decreased executive function and proliferative diabetic retinopathy with slower psychomotor speed. CONCLUSIONS: Both patients with type 1 and patients with type 2 diabetes showed overall worse cognition than control subjects. Further, in Medalists, a relationship between complications and cognition was seen. Although both groups with diabetes showed similar deficit patterns, the underlying mechanisms may be different. Now that patients with type 1 diabetes are living longer, efforts should be made to evaluate cognition and to identify modifying behaviors to slow decline.

Prefronto-temporal white matter microstructural alterations 20 years after the diagnosis of type 1 diabetes mellitus.

OBJECTIVE: Microvascular pathophysiology that uniquely manifests as white matter (WM) abnormalities is often implicated in type 1 diabetes mellitus (T1DM)-related central nervous system (CNS) complications. This study sought to identify regional WM abnormalities in young adults diagnosed with T1DM and further examine their association with cognitive and emotional dysfunction. RESEARCH DESIGN AND METHODS: Diffusion tensor images (DTI) obtained from 34 young adults with T1DM for ≥15 years (mean duration, 20.9 years), and 16 age- and sex-matched healthy control subjects were analyzed using tract-based spatial statistics. Fractional anisotropy (FA) values of the whole brain were analyzed, and their associations with memory function and depressive symptoms were assessed. RESULTS: Whole brain voxel-wise analyses showed that T1DM-related FA reductions were most prominent within the fronto-temporo-parietal regions of the brain. Reduced FA values in the bilateral superior longitudinal fasciculi, at which group differences were most prominent, correlated with lower working memory performance in young adults with T1DM (left, P < .001; right, P = .009). Subsyndromal depressive symptoms were also associated with lower FA values in the right inferior fronto-occipital fasciculus (P = .004). CONCLUSION: Widespread WM microstructural abnormalities in the fronto-temporo-parietal brain regions, which are associated with emotional and cognitive dysfunction, may be a contributing factor to the neural mechanisms underlying T1DM-related CNS complications, thus affecting the quality of life in young adults with T1DM.

Functional Connectivity of Insula, Basal Ganglia, and Prefrontal Executive Control Networks during Hypoglycemia in Type 1 Diabetes.

Human brain networks mediating interoceptive, behavioral, and cognitive aspects of glycemic control are not well studied. Using group independent component analysis with dual-regression approach of functional magnetic resonance imaging data, we examined the functional connectivity changes of large-scale resting state networks during sequential euglycemic-hypoglycemic clamp studies in patients with type 1 diabetes and nondiabetic controls and how these changes during hypoglycemia were related to symptoms of hypoglycemia awareness and to concurrent glycosylated hemoglobin (HbA1c) levels. During hypoglycemia, diabetic patients showed increased functional connectivity of the right anterior insula and the prefrontal cortex within the executive control network, which was associated with higher HbA1c. Controls showed decreased functional connectivity of the right anterior insula with the cerebellum/basal ganglia network and of temporal regions within the temporal pole network and increased functional connectivity in the default mode and sensorimotor networks. Functional connectivity reductions in the right basal ganglia were correlated with increases of self-reported hypoglycemic symptoms in controls but not in patients. Resting state networks that showed different group functional connectivity during hypoglycemia may be most sensitive to glycemic environment, and their connectivity patterns may have adapted to repeated glycemic excursions present in type 1 diabetes. Our results suggest that basal ganglia and insula mediation of interoceptive awareness during hypoglycemia is altered in type 1 diabetes. These changes could be neuroplastic adaptations to frequent hypoglycemic experiences. Functional connectivity changes in the insula and prefrontal cognitive networks could also reflect an adaptation to changes in brain metabolic pathways associated with chronic hyperglycemia. SIGNIFICANCE STATEMENT: The major factor limiting improved glucose control in type 1 diabetes is the significant increase in hypoglycemia associated with insulin treatment. Repeated exposure to hypoglycemia alters patients' ability to recognize the autonomic and neuroglycopenic symptoms associated with low plasma glucose levels. We examined brain resting state networks during the induction of hypoglycemia in diabetic and control subjects and found differences in networks involved in sensorimotor function, cognition, and interoceptive awareness that were related to chronic levels of glycemic control. These findings identify brain regions that are sensitive to variations in plasma glucose levels and may also provide a basis for understanding the mechanisms underlying the increased incidence of cognitive impairment and affective disorders seen in patients with diabetes.

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 HbA1c 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.

Cerebral white matter integrity and resting-state functional connectivity in middle-aged patients with type 2 diabetes.

Early detection of brain abnormalities at the preclinical stage can be useful for developing preventive interventions to abate cognitive decline. We examined whether middle-aged type 2 diabetic patients show reduced white matter integrity in fiber tracts important for cognition and whether this abnormality is related to preestablished altered resting-state functional connectivity in the default mode network (DMN). Diabetic and nondiabetic participants underwent diffusion tensor imaging, functional magnetic resonance imaging, and cognitive assessment. Multiple diffusion measures were calculated using streamline tractography, and correlations with DMN functional connectivity were determined. Diabetic patients showed lower fractional anisotropy (FA) (a measure of white matter integrity) in the cingulum bundle and uncinate fasciculus. Control subjects showed stronger functional connectivity than patients between the posterior cingulate and both left fusiform and medial frontal gyri. FA of the cingulum bundle was correlated with functional connectivity between the posterior cingulate and medial frontal gyrus for combined groups. Thus, middle-aged patients with type 2 diabetes show white matter abnormalities that correlate with disrupted functional connectivity in the DMN, suggesting that common mechanisms may underlie structural and functional connectivity. Detecting brain abnormalities in middle age enables implementation of therapies to slow progression of neuropathology.

Network-level structural abnormalities of cerebral cortex in type 1 diabetes mellitus.

Type 1 diabetes mellitus (T1DM) usually begins in childhood and adolescence and causes lifelong damage to several major organs including the brain. Despite increasing evidence of T1DM-induced structural deficits in cortical regions implicated in higher cognitive and emotional functions, little is known whether and how the structural connectivity between these regions is altered in the T1DM brain. Using inter-regional covariance of cortical thickness measurements from high-resolution T1-weighted magnetic resonance data, we examined the topological organizations of cortical structural networks in 81 T1DM patients and 38 healthy subjects. We found a relative absence of hierarchically high-level hubs in the prefrontal lobe of T1DM patients, which suggests ineffective top-down control of the prefrontal cortex in T1DM. Furthermore, inter-network connections between the strategic/executive control system and systems subserving other cortical functions including language and mnemonic/emotional processing were also less integrated in T1DM patients than in healthy individuals. The current results provide structural evidence for T1DM-related dysfunctional cortical organization, which specifically underlie the top-down cognitive control of language, memory, and emotion.

Prefrontal cortical deficits in type 1 diabetes mellitus: brain correlates of comorbid depression.

CONTEXT Neural substrates that may be responsible for the high prevalence of depression in type 1 diabetes mellitus (T1DM) have not yet been elucidated. OBJECTIVE To investigate neuroanatomic correlates of depression in T1DM. DESIGN Case-control study using high-resolution brain magnetic resonance images. SETTINGS Joslin Diabetes Center and McLean Hospital, Massachusetts, and Seoul National University Hospital, South Korea. PARTICIPANTS A total of 125 patients with T1DM (44 subjects with ≥1 previous depressive episodes [T1DM-depression group] and 81 subjects who had never experienced depressive episodes [T1DM-only group]), 23 subjects without T1DM but with 1 or more previous depressive episodes (depression group), and 38 healthy subjects (control group). MAIN OUTCOME MEASURES Spatial distributions of cortical thickness for each diagnostic group were compared with the control group using a surface-based approach. Among patients with T1DM, associations between metabolic control measures and cortical thickness deficits were examined. RESULTS Thickness reduction in the bilateral superior prefrontal cortical regions was observed in the T1DM-depression, T1DM-only, and depression groups relative to the control group at corrected P < .01. Conjunction analyses demonstrated that thickness reductions related to the influence of T1DM and those related to past depressive episode influence were observed primarily in the superior prefrontal cortical region. Long-term glycemic control levels were associated with superior prefrontal cortical deficits in patients with T1DM (ß = -0.19, P = .02). CONCLUSIONS This study provides evidence that thickness reduction of prefrontal cortical regions in patients with T1DM, as modified by long-term glycemic control, could contribute to the increased risk for comorbid depression.

Resting-state brain functional connectivity is altered in type 2 diabetes.

Type 2 diabetes mellitus (T2DM) is a risk factor for Alzheimer disease (AD). Populations at risk for AD show altered brain activity in the default mode network (DMN) before cognitive dysfunction. We evaluated this brain pattern in T2DM patients. We compared T2DM patients (n = 10, age = 56 ± 2.2 years, fasting plasma glucose [FPG] = 8.4 ± 1.3 mmol/L, HbA(1c) = 7.5 ± 0.54%) with nondiabetic age-matched control subjects (n = 11, age = 54 ± 1.8 years, FPG = 4.8 ± 0.2 mmol/L) using resting-state functional magnetic resonance imaging to evaluate functional connectivity strength among DMN regions. We also evaluated hippocampal volume, cognition, and insulin sensitivity by homeostasis model assessment of insulin resistance (HOMA-IR). Control subjects showed stronger correlations versus T2DM patients in the DMN between the seed (posterior cingulate) and bilateral middle temporal gyrus (ß = 0.67 vs. 0.43), the right inferior and left medial frontal gyri (ß = 0.75 vs. 0.54), and the left thalamus (ß = 0.59 vs. 0.37), respectively, with no group differences in cognition or hippocampal size. In T2DM patients, HOMA-IR was inversely correlated with functional connectivity in the right inferior frontal gyrus and precuneus. T2DM patients showed reduced functional connectivity in the DMN compared with control subjects, which was associated with insulin resistance in selected brain regions, but there were no group effects of brain structure or cognition.

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 (R(2) = 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.

Altered prefrontal glutamate-glutamine-gamma-aminobutyric acid levels and relation to low cognitive performance and depressive symptoms in type 1 diabetes mellitus.

CONTEXT: Neural substrates for low cognitive performance and depression, common long-term central nervous system-related changes in patients with type 1 diabetes mellitus, have not yet been studied. OBJECTIVE: To investigate whether prefrontal glutamate levels are higher in patients with type 1 diabetes and whether an elevation is related to lower cognitive performance and depression. DESIGN: Cross-sectional study. SETTING: General clinical research center. PARTICIPANTS: One hundred twenty-three patients with adult type 1 diabetes with varying degrees of lifetime glycemic control and 38 healthy participants. MAIN OUTCOME MEASURES: With the use of proton magnetic resonance spectroscopy, prefrontal glutamate-glutamine-gamma-aminobutyric acid (Glx) levels were compared between patients and control subjects. Relationships between prefrontal Glx levels and cognitive function and between Glx levels and mild depressive symptoms were assessed in patients with type 1 diabetes. RESULTS: Prefrontal Glx concentrations were 9.0% (0.742 mmol/L; P = .005) higher in adult patients with type 1 diabetes than in healthy control subjects. There were positive linear trends for the effects of lifetime glycemic control on prefrontal Glx levels (P for trend = .002). Cognitive performances in memory, executive function, and psychomotor speed were lower in patients (P = .003, .01, and <.001, respectively) than in control subjects. Higher prefrontal Glx concentrations in patients were associated with lower performance in assessment of global cognitive function (0.11 change in z score per 1-mmol/L increase in Glx) as well as with mild depression. CONCLUSIONS: The high prefrontal glutamate levels documented in this study may play an important role in the genesis of the low cognitive performance and mild depression frequently observed in patients with type 1 diabetes. Therapeutic options that alter glutamatergic neurotransmission may be of benefit in treating central nervous system-related changes in patients with adult type 1 diabetes.

Impact of diabetes and its treatment on cognitive function among adolescents who participated in the Diabetes Control and Complications Trial.

OBJECTIVE: The purpose of this study was to evaluate whether severe hypoglycemia or intensive therapy affects cognitive performance over time in a subgroup of patients who were aged 13-19 years at entry in the Diabetes Control and Complications Trial (DCCT). RESEARCH DESIGN AND METHODS: This was a longitudinal study involving 249 patients with type 1 diabetes who were between 13 and 19 years old when they were randomly assigned in the DCCT. Scores on a comprehensive battery of cognitive tests obtained during the Epidemiology of Diabetes Interventions and Complications follow-up study, approximately 18 years later, were compared with baseline performance. We assessed the effects of the original DCCT treatment group assignment, mean A1C values, and frequency of severe hypoglycemic events on eight domains of cognition. RESULTS: There were a total of 294 reported episodes of coma or seizure. Neither frequency of hypoglycemia nor previous treatment group was associated with decline on any cognitive domain. As in a previous analysis of the entire study cohort, higher A1C values were associated with declines in the psychomotor and mental efficiency domain (P < 0.01); however, the previous finding of improved motor speed with lower A1C values was not replicated in this subgroup analysis. CONCLUSIONS: Despite relatively high rates of severe hypoglycemia, cognitive function did not decline over an extended period of time in the youngest cohort of patients with type 1 diabetes.

Cognition and brain imaging in type 1 diabetes.

Type 1 diabetes has mild effects on cognition that are influenced by age of onset, hyperglycemia, and hypoglycemic episodes. Some of these changes occur quite early in the disease course. Studies using relatively new brain imaging techniques have also shown brain changes in adults and children that appear to be influenced by metabolic abnormalities present in diabetes. Early detections of brain changes may be early indicators of subsequent cognitive abnormalities.

Regional brain activation during hypoglycemia in type 1 diabetes.

CONTEXT: Mechanisms underlying the brain response to hypoglycemia are not well understood. OBJECTIVE: Our objective was to determine the blood glucose level at which the hypothalamus and other brain regions are activated in response to hypoglycemia in type 1 diabetic patients and control subjects. DESIGN: This was a cross-sectional study evaluating brain activity using functional magnetic resonance imaging in conjunction with a hyperinsulinemic hypoglycemic clamp to lower glucose from euglycemia (90 mg/dl) to hypoglycemia (50 mg/dl). SETTING: The study was performed at the Brain Imaging Center in the McLean Hospital. STUDY PARTICIPANTS: Seven type 1 diabetic patients between 18 and 50 yr old and six matched control subjects were included in the study. INTERVENTION: Hyperinsulinemic hypoglycemic clamp was performed. MAIN OUTCOME MEASURES: Blood glucose level at peak hypothalamic activation, amount of regional brain activity during hypoglycemia in both groups, and difference in regional brain activation between groups were calculated. RESULTS: The hypothalamic region activates at 68 +/- 9 mg/dl in control subjects and 76 +/- 8 mg/dl in diabetic patients during hypoglycemia induction. Brainstem, anterior cingulate cortex, uncus, and putamen were activated in both groups (P < 0.001). Each group also activated unique brain areas not active in the other group. CONCLUSIONS: This application of functional magnetic resonance imaging can be used to identify the glucose level at which the hypothalamus is triggered in response to hypoglycemia and whether this threshold differs across patient populations. This study suggests that a core network of brain regions is recruited during hypoglycemia in both diabetic patients and control subjects.

Long-term effect of diabetes and its treatment on cognitive function.

BACKGROUND: Long-standing concern about the effects of type 1 diabetes on cognitive ability has increased with the use of therapies designed to bring glucose levels close to the nondiabetic range and the attendant increased risk of severe hypoglycemia. METHODS: A total of 1144 patients with type 1 diabetes enrolled in the Diabetes Control and Complications Trial (DCCT) and its follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study were examined on entry to the DCCT (at mean age 27 years) and a mean of 18 years later with the same comprehensive battery of cognitive tests. Glycated hemoglobin levels were measured and the frequency of severe hypoglycemic events leading to coma or seizures was recorded during the follow-up period. We assessed the effects of original DCCT treatment-group assignment, mean glycated hemoglobin values, and frequency of hypoglycemic events on measures of cognitive ability, with adjustment for age at baseline, sex, years of education, length of follow-up, visual acuity, self-reported sensory loss due to peripheral neuropathy, and (to control for the effects of practice) the number of cognitive tests taken in the interval since the start of the DCCT. RESULTS: Forty percent of the cohort reported having had at least one hypoglycemic coma or seizure. Neither frequency of severe hypoglycemia nor previous treatment-group assignment was associated with decline in any cognitive domain. Higher glycated hemoglobin values were associated with moderate declines in motor speed (P=0.001) and psychomotor efficiency (P<0.001), but no other cognitive domain was affected. CONCLUSIONS: No evidence of substantial long-term declines in cognitive function was found in a large group of patients with type 1 diabetes who were carefully followed for an average of 18 years, despite relatively high rates of recurrent severe hypoglycemia. (ClinicalTrials.gov number, NCT00360893.)