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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., (Copyright © 2015 the authors 0270-6474/15/3511013-12$15.00/0.)

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.

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.

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.), (Copyright 2007 Massachusetts Medical Society.)

Purpose: Insulin-induced hypoglycemia and its sequelae of cognitive impairment may place patients with type 1 diabetes at risk when driving and when making decisions about driving. Little is known about the factors that influence judgments of safe driving ability during hypoglycemia in these patients., Patients and Methods: Thirty men and 30 women with uncomplicated type 1 diabetes (age [mean +/- SD] 33 +/- 9 years, duration 9 +/- 3 years, hemoglobin A1c level 8.7% +/- 1.0%) underwent a stepped hypoglycemic insulin clamp. Serum glucose levels were reduced from 120 mg/dL to 80, 70, 60, 50, and then 40 mg/dL during 190 minutes. At each glucose plateau, patients completed a symptom questionnaire and neuropsychological test, estimated their glucose level, and reported whether they could drive safely., Results: The proportion of patients judging that they could drive safely decreased as serum glucose levels decreased from 70% at 120 mg/dL to 22% at 40 mg/dL. Men and middle-aged patients were more likely to consider it safe to drive during hypoglycemia than women and those under 25 years of age. Those who were symptomatic and those who recognized hypoglycemia were less likely to report safe driving ability during hypoglycemia. Most patients who were cognitively impaired appeared to recognize this and reported that they could not drive safely at a serum glucose level of 40 mg/dL., Conclusions: Adults with type 1 diabetes need educational reinforcement of safe driving habits, particularly to check glucose levels before driving. Glucose levels less than 70 mg/dL should be treated before driving. This information is as important for middle-aged, experienced drivers as it is for younger, inexperienced drivers.

Objective: To determine the effect of blood glucose awareness training (BGAT) on epinephrine and symptom responses to hypoglycemia in patients with type 1 diabetes enrolled in an intensive diabetes treatment (IDT) program., Research Design and Methods: A total of 47 subjects with uncomplicated diabetes (duration 9 +/- 3 years: HbA1c 9.0 +/- 1.2%; reference range 4-6%) enrolled in a 4-month outpatient IDT program were randomized to classes in BGAT (n = 25) (BGAT group) or cholesterol awareness (n = 22) (control group). Subjects underwent stepped hypoglycemic clamp studies before and at completion of IDT. Plasma glucose was lowered from 6.7 mmol/l (baseline) to 4.4, 3.9, 3.3, 2.8, and 2.2 mmol/l over 190 min. Symptoms, counterregulatory hormones, and ability of the subject to estimate their glucose level were assessed at each plateau. At home, subjects used a handheld computer to first estimate and then measure and record blood glucose levels for 70 trials over a 4-week period immediately before IDT and again immediately following the educational intervention., Results: HbA1c decreased in both BGAT group (9.1 +/- 1.4 to 7.9 +/- 1.1%; P < 0.001) and control group (9.0 +/- 1.1 to 7.8 +/- 0.8%; P < 0.001) (NS between groups). Frequency of hypoglycemia (< 3.9 mmol/l) increased in both groups, from 0.45 +/- 0.06 to 0.69 +/- 0.07 episodes per day (P < 0.001) in the BGAT group and from 0.50 +/- 0.08 to 0.68 +/- 0.06 episodes per day (P < 0.05) in the control group NS between groups). Epinephrine responses after IDT were greater in the BGAT group (repeated measure analysis of variance [ANOVA], F = 3.5, P < 0.05). A separate analysis of subjects n = 26) most at risk for hypoglycemia (HbA1c after IDT < 7.8% or an HbA1c improvement of > 2 percentage points) showed that frequency of hypoglycemia increased in both the groups: from 0.50 +/- 0.09 to 0.80 +/- 0.11 episodes per day (P < 0.01) in the BGAT group (n = 14) and from 0.43 +/- 0.11 to 0.75 +/- 0.07 episodes per day (P < 0.05) in the control group (n = 12) (NS between groups). However, the epinephrine response in control subjects decreased with IDT while the response in the BGAT subjects was preserved (repeated measure ANOVA, F = 4.4, P < 0.02)., Conclusions: BGAT is a useful intervention to decrease blunting of counterregulatory responses associated with improved glycemic control and may modify the severity of hypoglycemia associated with improved glycemic control in type 1 diabetes.

Objective: To increase understanding of the everyday experiences of hypoglycemia for patients with type 1 diabetes through the use of a narrative research approach., Setting: Center for diabetes treatment and research., Design: Cross-sectional assessment using a narrative research approach., Patients/participants: Twenty outpatients (aged 21-30 years) diagnosed with type 1 diabetes for at least 10 years., Measurements and Main Results: Experiences of hypoglycemia were investigated during in-depth, semistructured interviews that were tape-recorded, transcribed, and analyzed to identify common themes. Self-report measures of depression (Revised Hamilton Rating Scale for Depression) and anxiety (State-Trait Anxiety Inventory) also were administered. Subjects reported the following common themes: interpersonal conflict including fears of dependency and loss of control and problems addressing concerns about hypoglycemia with significant others; difficulty making sense of their hypoglycemic behaviors in relation to their usual ways of functioning; and perceived lack of understanding by others, including physicians, about the emotional experiences of hypoglycemia. Subjects were neither clinically depressed nor anxious., Conclusions: These findings suggest that type 1 diabetes patients' experiences of hypoglycemia negatively affect their interpersonal relationships and views of themselves. Hypoglycemia also was described as an extremely private experience that was rarely discussed with others. Patient education and professional support in the treatment of hypoglycemia are recommended to enhance treatment decision making for patients with type 1 diabetes.

In this paper we determine whether individual and family psychosocial functioning predicts the risk for recurrent acute diabetic complications. An onset-cohort of 61 children and adolescents with Type 1 diabetes received conventional diabetes care. Episodes of ketoacidosis and of severe hypoglycemia were recorded for 8 years, and glycaemic control was measured by glycohaemoglobin. Measures of psychosocial functioning of the patient and parents were obtained during the first year. Over 8 years, 28% of subjects had at least one episode of ketoacidosis, and 21% had at least one episode of hypoglycaemia. The odds of observing recurrent hypoglycaemia versus recurrent ketoacidosis was 14 times greater in boys than in girls (Fisher's exact test p < 0.05). Girls with recurrent ketoacidosis had more behaviour problems and lower social competence, they reported higher levels of family conflict, and their parents reported lower levels of family cohesion, expressiveness and organization in year one. These relationships were independent of any association with poor glycaemic control. Recurrent hypoglycaemia in boys was generally unrelated to individual and family functioning or glycohaemoglobin. Despite our small sample size, our findings are suggestive of relationships that may lead to early identification of patients who are prone to recurrent ketoacidosis, and to the development of early intervention strategies.

Background: To determine the impact of glycemic control, gender, and other relevant parameters on cognitive function during exposure to different blood glucose levels in patients with insulin-dependent diabetes mellitus (IDDM), we examined neuropsychologic function during experimentally induced periods of hyperglycemia and hypoglycemia., Methods: We studied 20 men and 22 women, aged 18 to 44 years, with IDDM duration of 3 to 14 years and HbA1 values ranging from 5.8% to 18.0% (nondiabetic range 5.4% to 7.4%). We used a controlled experimental setting involving tests of sensory perceptual processing, simple motor abilities, attention, learning and memory, language, and spatial and constructional abilities at plasma glucose levels of 2.2, 5.6, 8.9, 14.4, and 21.1 mmol/L. Patients were blind to the glucose level. Tests used at each glucose level included reaction time (simple and choice), digit vigilance, trail making part B, word recall, digit sequence learning, and verbal fluency., Results: All aspects of neuropsychologic function were diminished at 2.2 mmol/L when compared with basal levels of performance at 8.9 mmol/L, whereas no alterations were observed at 14.4 or 21.1 mmol/L. Tests involving associative learning, attention, and mental flexibility were the most affected during hypoglycemia. Glycemic control was not correlated with neuropsychologic function at any glucose level. Women demonstrated less of an impairment in neuropsychologic function than men at 2.2 mmol/L., Conclusions: Cognitive function in IDDM patients was generally well-preserved even at substantially elevated blood glucose levels. Deficits in all relevant areas of cognitive function occurred during hypoglycemia (2.2 mmol/L), irrespective of prior glycemic control, and women with IDDM were less cognitively impaired than men with IDDM during hypoglycemia.

Purpose: To investigate hypoglycemic and hyperglycemic symptoms, accuracy of estimating blood glucose, and their relation to glycemic control and counterregulatory hormone levels in insulin-dependent diabetes mellitus., Patients and Methods: During randomly ordered stepped hypoglycemic and hyperglycemic insulin clamps on two separate days, 42 patients with insulin-dependent diabetes mellitus rated the intensity of 40 moods and symptoms when glucose was 8.9, 5.6 and 2.2 mmol/L, and 8.9, 14.4 and 21.1 mmol/L. The subjects were blinded to their actual glucose levels and asked to estimate them at each step. Epinephrine, norepinephrine, cortisol, growth hormone, and glucagon were measured at each glucose plateau., Results: Cluster analysis yielded five symptom groups during hypoglycemia: autonomic symptoms, negative moods, positive moods, feeling weak/dizzy, and feeling relaxed. At 2.2 mmol/L, mean scores for all five symptom groups and 11 of 17 unclustered symptoms differed from those reported at the baseline glucose of 8.9 mmol/L (P < or = 0.05), but 34% of patients reported no awareness of autonomic symptoms. The intensity of autonomic symptoms correlated positively with HbA1 (r = .43, P < 0.01), epinephrine (r = .59, P < 0.001), norepinephrine (r = .45, P < 0.01) and cortisol (r = .62, P < 0.001), and negatively with glucose estimation error (r = -.45, P = 0.01). Six patients (15%) were unaware of both autonomic and neuroglycopenic symptoms during hypoglycemia. At 21.1 mmol/L, only 5 of 40 symptoms differed (P < 0.05) from baseline. Seventeen percent of subjects made potentially serious errors when estimating glucose at 2.2 mmol/L, and 66% at 21.1 mmol/L. Many patients experienced symptoms different from those they reported as their usual manifestations of changing glucose levels., Conclusions: Since the majority of patients made clinically serious errors in glucose estimation, and many used symptoms that did not discriminate hyperglycemia and hypoglycemia, individualized training to increase awareness of glucose-related symptoms and glucose levels may help patients reduce the frequency or severity of hyperglycemic and hypoglycemic events.

Recent research has suggested that patients with Type 1 diabetes who are in chronically poor blood glucose control perceive hyperglycaemia differently from those who are in good control. To extend these observations 181 insulin-treated patients with Type 1 or Type 2 diabetes were studied. Patients completed a self-report questionnaire which included items concerning feelings about high and low blood glucose levels and strategies for maintaining blood glucose control. Glycosylated haemoglobin levels were also measured. We hypothesized that level of blood glucose control would: (1) be associated with perceptions of hyperglycaemia and treatment strategies for managing hyperglycaemia and (2) not be associated with perceptions and strategies concerning hypoglycaemia. In comparison with those in 'acceptable' or 'poor' blood glucose control, those in 'good' control perceived symptoms of hyperglycaemia at lower blood glucose levels (p less than 0.001) and felt physically best at lower blood glucose levels (p less than 0.001). They, also began treatment for hyperglycaemia at lower glucose levels (p less than 0.05), set lower minimal (p less than 0.001) and maximal (p less than 0.001) glucose levels as treatment goals, and tested their blood glucose levels more frequently (p less than 0.05). Among Type 1 diabetic patients, those in 'good' control reported experiencing hypoglycaemia at lower glucose levels than those in 'acceptable' or 'poor' control (p less than 0.05). No differences in treatment strategies of hypoglycaemic symptoms were apparent. This study suggests an influence of patients' perceptions of symptoms and treatment in self-care of diabetes.

We examined whether fear of hypoglycemia in insulin-dependent diabetes mellitus was associated with (a) higher levels of trait anxiety and general fearfulness, (b) difficulty in differentiating symptoms of anxiety and hypoglycemia, and (c) past experience with hypoglycemia. Joslin Diabetes Center outpatients with Type I and Type II diabetes (N = 232), all requiring insulin, were surveyed. Type I patients experienced significantly more fear of hypoglycemia than Type II patients. For the Type I and Type II groups, higher scores on the Worry subscale of the Hypoglycemia Fear Survey (HFS-W) were associated with higher levels of trait anxiety and fear. Higher scores on the Behavior subscale (HFS-B) were associated with higher levels of fear. Among Type I subjects only, HFS-W scores were also positively associated with past hypoglycemic experience and with difficulty in differentiating anxiety and hypoglycemic symptoms. These latter relations remained significant even after the variance resulting from trait anxiety and fear was removed. Other significant associations with HFS-B scores were not observed.