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Objective: People with type 2 diabetes are at increased risk of cognitive impairment but the mechanism is uncertain. Elevated glucocorticoid levels in rodents and humans are associated with cognitive impairment. We aimed to determine whether fasting cortisol levels are associated with cognitive ability and estimated lifetime cognitive change in an elderly population with type 2 diabetes.Research Design and Methods: This was a cross-sectional study of 1,066 men and women aged 60-75 years with type 2 diabetes, living in Lothian, Scotland (the Edinburgh Type 2 Diabetes Study). Cognitive abilities in memory, nonverbal reasoning, information processing speed, executive function, and mental flexibility were tested, and a general cognitive ability factor, g, was derived. Prior intelligence was estimated from vocabulary testing, and adjustment for scores on this test was used to estimate lifetime cognitive change. Relationships between fasting morning plasma cortisol levels and cognitive ability and estimated cognitive change were tested. Models were adjusted for potential confounding and/or mediating variables including metabolic and cardiovascular variables.Results: In age-adjusted analyses, higher fasting cortisol levels were not associated with current g or with performance in individual cognitive domains. However, higher fasting cortisol levels were associated with greater estimated cognitive decline in g and in tests of working memory and processing speed, independent of mood, education, metabolic variables, and cardiovascular disease (P < 0.05).Conclusions: High morning cortisol levels in elderly people with type 2 diabetes are associated with estimated age-related cognitive change. Strategies targeted at lowering cortisol action may be useful in ameliorating cognitive decline in individuals with type 2 diabetes. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To test the conclusion that there is no association between multiple episodes of severe hypoglycemia and cognitive decrements by reanalyzing the data from the Diabetes Control and Complications Trial (DCCT) with psychometrically validated cognitive factors and to conduct a novel analysis of the association between individual differences in baseline cognitive ability and episodes of severe hypoglycemia documented after baseline. RESEARCH DESIGN AND METHODS: The factor structure of cognitive ability in the neuropsychological data from the DCCT study was derived. Four cognitive factors (spatial ability, processing speed, memory, and verbal ability) were extracted. Changes in patients' cognitive scores for each year of follow-up were obtained, and paired comparisons of these change scores were performed between groups experiencing zero and five or more hypoglycemic episodes. The association between cognitive ability at baseline and number of subsequent episodes of severe hypoglycemia was also examined. RESULTS: Repeated episodes of hypoglycemia were found not to be associated with cognitive decline in any of the validated cognitive factors. No significant association was found between prospectively documented numbers of severe hypoglycemic episodes and baseline cognitive ability level. CONCLUSIONS: Repeated episodes of hypoglycemia were not related to cognitive decrement, and initial mental ability level was not associated with eventual numbers of hypoglycemic episodes in this group of patients. [ABSTRACT FROM AUTHOR]

Objective: To ascertain whether hypoglycemia in association with sleep deprivation causes greater cognitive dysfunction than hypoglycemia alone and protracts cognitive recovery after normoglycemia is restored., Research Design and Methods: Fourteen adults with type 1 diabetes underwent a hyperinsulinemic, hypoglycemic clamp on two separate occasions. Before one glucose clamp, the participants stayed awake overnight to induce sleep deprivation. Participants were randomized and counterbalanced to the experimental condition. Cognitive function tests were performed before and during hypoglycemia and for 90 min after restoration of normoglycemia., Results: Cognitive impairment during hypoglycemia did not differ significantly between the sleep-deprived and non-sleep-deprived conditions. However, in the sleep-deprived state, digit symbol substitution scores and choice reaction times were significantly poorer during recovery (P < 0.001) and hypoglycemia symptom scores were significantly higher (P < 0.001), even when symptoms that may have been caused by sleep deprivation, such as tiredness, were removed., Conclusions: Hypoglycemia per se produced a significant decrement in cognitive function; coexisting sleep deprivation did not have an additive effect. However, after restoration of normoglycemia, preceding sleep deprivation was associated with persistence of hypoglycemic symptoms and greater and more prolonged cognitive dysfunction during the recovery period., (© 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Objective: To examine the effects of hypoglycemia on language processing in adults with and without type 1 diabetes., Research Design and Methods: Forty adults were studied (20 with type 1 diabetes and 20 healthy volunteers) using a hyperinsulinemic glucose clamp to lower blood glucose to 2.5 mmol/L (45 mg/dL) (hypoglycemia) for 60 min, or to maintain blood glucose at 4.5 mmol/L (81 mg/dL) (euglycemia), on separate occasions. Language tests were applied to assess the effects of hypoglycemia on the relationship between working memory and language (reading span), grammatical decoding (self-paced reading), and grammatical encoding (subject-verb agreement)., Results: Hypoglycemia caused a significant deterioration in reading span (P < 0.001; η(2) = 0.37; Cohen d = 0.65) and a fall in correct responses (P = 0.005; η(2) = 0.19; Cohen d = 0.41). On the self-paced reading test, the reading time for the first sentence fragment increased during hypoglycemia (P = 0.039; η(2) = 0.11; Cohen d = 0.25). For the reading of the next fragment, hypoglycemia affected the healthy volunteer group more than the adults with type 1 diabetes (P = 0.03; η(2) = 0.12; Cohen d = 0.25). However, hypoglycemia did not significantly affect the number of errors in sentence comprehension or the time taken to answer questions. Hypoglycemia caused a deterioration of subject-verb agreement (correct responses: P = 0.011; η(2) = 0.159; Cohen d = 0.31)., Conclusions: Hypoglycemia caused a significant deterioration in reading span and in the accuracy of subject-verb agreement, both of which are practical aspects of language involved in its everyday use. Language processing is therefore impaired during moderate hypoglycemia., (© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Objective: People with type 2 diabetes are at increased risk of age-related cognitive decline and dementia. Hypoglycemia is a candidate risk factor, but the direction of association between episodes of severe hypoglycemia and cognitive decline in type 2 diabetes remains uncertain., Research Design and Methods: In the Edinburgh Type 2 Diabetes Study, cognitive function was assessed in 831 adults with type 2 diabetes (aged 60-75 years) at baseline and after 4 years. Scores on seven neuropsychological tests were combined into a standardized general ability factor g. Self-reported history of severe hypoglycemia at baseline (history of hypoglycemia) and at follow-up (incident hypoglycemia) was recorded., Results: A history of hypoglycemia was reported by 9.3% of subjects, and 10.2% reported incident hypoglycemia. Incident hypoglycemia was associated with poorer cognitive ability at baseline (age- and sex-adjusted odds ratio for lowest tertile of g 2.04 [95% CI 1.25-3.31], P = 0.004). Both history of hypoglycemia and incident hypoglycemia were also associated with greater cognitive decline during follow-up (mean follow-up g adjusted for age, sex, and baseline g -0.25 vs. 0.03 [P = 0.02] and -0.28 vs. 0.04 [P = 0.01], respectively), including after addition of vascular risk factors and cardiovascular and microvascular disease to the models (-0.23 vs. 0.03 [P = 0.04] and -0.21 vs. 0.05 [P = 0.03], respectively)., Conclusions: The relationship between cognitive impairment and hypoglycemia appeared complex, with severe hypoglycemia associated with both poorer initial cognitive ability and accelerated cognitive decline.

Objective: Acute hypoglycemia impairs cognitive function in several domains. Executive cognitive function governs organization of thoughts, prioritization of tasks, and time management. This study examined the effect of acute hypoglycemia on executive function in adults with and without diabetes., Research Design and Methods: Thirty-two adults with and without type 1 diabetes with no vascular complications or impaired awareness of hypoglycemia were studied. Two hyperinsulinemic glucose clamps were performed at least 2 weeks apart in a single-blind, counterbalanced order, maintaining blood glucose at 4.5 mmol/L (euglycemia) or 2.5 mmol/L (hypoglycemia). Executive functions were assessed with a validated test suite (Delis-Kaplan Executive Function). A general linear model (repeated-measures ANOVA) was used. Glycemic condition (euglycemia or hypoglycemia) was the within-participant factor. Between-participant factors were order of session (euglycemia-hypoglycemia or hypoglycemia-euglycemia), test battery used, and diabetes status (with or without diabetes)., Results: Compared with euglycemia, executive functions (with one exception) were significantly impaired during hypoglycemia; lower test scores were recorded with more time required for completion. Large Cohen d values (>0.8) suggest that hypoglycemia induces decrements in aspects of executive function with large effect sizes. In some tests, the performance of participants with diabetes was more impaired than those without diabetes., Conclusions: Executive cognitive function, which is necessary to carry out many everyday activities, is impaired during hypoglycemia in adults with and without type 1 diabetes. This important aspect of cognition has not received previous systematic study with respect to hypoglycemia. The effect size is large in terms of both accuracy and speed.

Objective: Macrovascular disease may contribute to increased risk of accelerated cognitive decline in patients with type 2 diabetes. We aimed to determine associations of measures of macrovascular disease with cognitive change in a cognitively healthy older population with type 2 diabetes., Research Design and Methods: Eight hundred thirty-one men and women (aged 60-75 years) attended two waves of the prospective Edinburgh Type 2 Diabetes Study (ET2DS). At baseline, clinical and subclinical macrovascular disease was measured, including cardiovascular event history, carotid intima-media thickness (cIMT), ankle brachial index (ABI), and serum N-terminal probrain natriuretic peptide (NT-proBNP). Seven neuropsychological tests were administered at baseline and after 4 years; scores were combined to a standardized general ability factor (g). Adjustment of follow-up g for baseline g assessed 4-year cognitive change. Adjustment for vocabulary (estimated premorbid ability) was used to estimate lifetime cognitive change., Results: Measures of cognitive decline were significantly associated with stroke, NT-proBNP, ABI, and cIMT, but not with nonstroke vascular events. The association of stroke with increased estimated lifetime cognitive decline (standardized β, -0.12) and of subclinical markers with actual 4-year decline (standardized β, -0.12, 0.12, and -0.15 for NT-proBNP, ABI, and cIMT, respectively) reached the Bonferroni-adjusted level of statistical significance (P < 0.006). Results altered only slightly on adjustment for vascular risk factors., Conclusions: Stroke and subclinical markers of cardiac stress and generalized atherosclerosis are associated with cognitive decline in older patients with type 2 diabetes. Further investigation into the potential use of subclinical vascular disease markers in predicting cognitive decline is warranted.

OBJECTIVE To examine the effects of acute insulin-induced hypoglycemia on spatial cognitive abilities in adult humans with type 1 diabetes. RESEARCH DESIGN AND METHODS Sixteen adults with type 1 diabetes underwent two counterbalanced experimental sessions: euglycemia (blood glucose 4.5 mmol/l [81 mg/dl]) and hypoglycemia (2.5 mmol/l [45 mg/dl]). Arterialized blood glucose levels were maintained using a hyperinsulinemic glucose clamp technique. During each session, subjects underwent detailed assessment of spatial abilities from the Kit of Factor-Referenced Cognitive Tests and two tests of general cognitive function. RESULTS Spatial ability performance deteriorated significantly during hypoglycemia. Results for the Hidden Patterns, Card Rotations, Paper Folding, and Maze Tracing tests were all impaired significantly (P < or = 0.001) during hypoglycemia, as were results for the Cube Comparisons Test (P = 0.03). The Map Memory Test was not significantly affected by hypoglycemia. CONCLUSIONS Hypoglycemia is a common side effect of insulin therapy in individuals with type 1 diabetes, and spatial abilities are of critical importance in day-to-day functioning. The deterioration in spatial abilities observed during modest experimental hypoglycemia provides novel information on the cerebral hazards of hypoglycemia that has potential relevance to everyday activities.

Objective: Children who develop type 1 diabetes before age 7 years (early-onset diabetes; EOD) have comparatively poorer cognitive abilities. Whether this relates to psychosocial consequences of chronic illness or organic factors related to diabetes and its complications remains unresolved. We hypothesized that if differences in neuroradiological structure and cognitive ability coexisted in those who had EOD, then an organic component to their etiology was likely., Research Design and Methods: A cohort of 71 young adults with long-duration type 1 diabetes diagnosed during childhood or adolescence participated in a cross-sectional evaluation of cognitive ability (neuropsychological test battery) and brain structure (magnetic resonance imaging). Diabetes onset age, preceding severe hypoglycemia exposure, retinopathy status, and diabetes duration were examined as potential correlates of cognitive and neuroradiological differences. No participants had previous neuropsychological pathology., Results: In EOD participants (n = 26), current intellectual ability (Wechsler Adult Intelligence Scale-Revised performance IQ; P = 0.03) and information processing ability (Choice Reaction Time; P = 0.006) were comparatively poorer than was observed in those with later- onset diabetes (n = 45). Furthermore, lateral ventricular volumes were 37% greater (P = 0.002) and ventricular atrophy was more prevalent (61 vs. 20%; P = 0.01) in the EOD group than in those who had later-onset type 1 diabetes., Conclusions: An early childhood onset of type 1 diabetes was associated with mild central brain atrophy and significant differences in intellectual performance in adulthood, implying that neurodevelopment may be adversely affected by EOD. The differences observed in brain structure support an organic contribution to their etiology but do not exclude a coexistent contribution of psychosocial factors.

Objective: To examine the effects of acute hyperglycemia on cognitive function and mood in people with type 2 diabetes., Research Design and Methods: Twenty subjects with type 2 diabetes, median age 61.5 years (range 53.1-72.0), known duration of diabetes 5.9 years (range 2.8-11.2), BMI 29.8 kg/m2 (range 22.0-34.6), and HbA1c 7.5% (range 6.7-8.4) were studied. Treatment modalities varied from antidiabetic medications to insulin. A hyperinsulinemic glucose clamp was used to maintain arterialized blood glucose at either 4.5 (euglycemia) or 16.5 mmol/l (hyperglycemia) on two occasions in a randomized and counterbalanced fashion. Tests of information processing, immediate and delayed memory, working memory, and attention were administered, along with a mood questionnaire, during each experimental condition., Results: Speed of information processing, working memory, and some aspects of attention were impaired during acute hyperglycemia. Subjects were significantly more dysphoric during hyperglycemia, with reduced energetic arousal and increased sadness and anxiety., Conclusions: During acute hyperglycemia, cognitive function was impaired and mood state deteriorated in a group of people with type 2 diabetes. These findings are of practical importance because intermittent or chronic hyperglycemia is common in people with type 2 diabetes and may interfere with many daily activities through adverse effects on cognitive function and mood., (Copyright 2004 American Diabetes Association)

Objective: To examine the effects of acute insulin-induced hypoglycemia on short-term, delayed, and working memory in individuals with type 1 diabetes., Research Design and Methods: A hyperinsulinemic glucose clamp was used to maintain arterialized blood glucose level at either 4.5 mmol/l (euglycemia) or 2.5 mmol/l (hypoglycemia) on two separate occasions in 16 adults with type 1 diabetes. The participants completed tests of immediate and delayed verbal memory, immediate and delayed visual memory, and working memory during each experimental condition. Two other mental tests, the Trail Making B Test and the Digit Symbol Test, were also administered., Results: Performance in tests of immediate verbal and immediate visual memory was significantly impaired during hypoglycemia. The effect of hypoglycemia on working memory and delayed memory was more profound. Performance in the nonmemory tests, the Trail Making B Test, and the Digit Symbol Test also deteriorated during hypoglycemia., Conclusions: All of the memory systems examined in the present study were affected significantly by acute hypoglycemia, particularly working memory and delayed memory. Mild (self-treated) hypoglycemia is common in individuals with insulin-treated diabetes; therefore, these observed effects of hypoglycemia on memory are of potential clinical importance because they could interfere with many everyday activities.

Objective: Experimentally induced hypoglycemia in humans causes progressive but reversible cognitive dysfunction, but it is not known to what extent neuropsychological tests index abilities of cognitive functioning that are important in everyday life. This study examines the effects of acute insulin-induced hypoglycemia on attention and intelligence in nondiabetic humans., Research Design and Methods: A hyperinsulinemic glucose clamp was used to achieve controlled euglycemia (4.50 [0.22] mmol/l) and hypoglycemia (blood glucose 2.59 [0.19] mmol/l) in 20 healthy volunteers. Subjects were studied on two occasions in a counterbalanced order. During each study condition, subjects completed parallel tests of cognitive function. Cognitive function was assessed by the Test of Everyday Attention and Raven's Progressive Matrices., Results: Hypoglycemia induced a significant deterioration in tests sensitive to both visual and auditory selective attention. During hypoglycemia, attentional flexibility deteriorated and speed of information processing was delayed. Sustained attention was preserved and intelligence scores did not deteriorate during hypoglycemia., Conclusions: During hypoglycemia, a significant deterioration occurs in attentional abilities, whereas fluid intelligence is preserved. On the basis of these results, it can be surmised that many complex attention tasks relevant to everyday life are impaired during moderate hypoglycemia.

Objective: Acute hypoglycemia in humans impairs cognitive functions and alters mood states. The time required for cognitive functions and moods to return to normal after an acute episode of severe hypoglycemia is unknown., Research Design and Methods: Cognitive functions and moods were studied prospectively in 20 subjects with insulin-treated diabetes who had recently experienced a spontaneous episode of severe hypoglycemia ("hypo" subjects) and 20 matched control subjects with insulin-treated diabetes who had not experienced severe hypoglycemia during the preceding year. The hypo subjects had a history of a greater number of episodes of severe hypoglycemia (P = 0.000). Cognitive function tests and mood scales were administered at 1.5, 9, and 30 days after the severe hypoglycemia and at similar intervals for the control subjects., Results: For most of the cognitive tests, no evidence of a "hangover" effect of the acute hypoglycemia on cognitive function was observed (P > 0.05). A trend was noted for levels of hedonic tone (P = 0.082) and energetic arousal (P = 0.053) to improve with time in the hypo subjects but not in the control subjects. However, the hypo subjects had chronically elevated levels of depression (P = 0.011) and anxiety (P = 0.049) and persistently performed more poorly in several cognitive tests, such as the Digit Symbol Test (P = 0.009) and the Stroop Task (P = 0.007)., Conclusions: These results suggest that, in general, recovery from any acute cognitive decrement after severe hypoglycemia was complete by 1.5 days. The cognitive decrements and altered mood states noted in the hypo subjects may be persistent and may be a consequence of previous exposure to recurrent episodes of severe hypoglycemia.

Objective: Previous studies of a cohort of 100 patients with IDDM have shown that a history of recurrent severe hypoglycemia is associated with a modest impairment of cognitive function. The aim of the present study was to determine whether IDDM patients with and without a history of severe hypoglycemia have lesions in the brain that are identifiable by magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) and to investigate the putative relationship of any structural brain abnormalities with cognitive function., Research Design and Methods: MRI and MRS of the brain were performed in 22 patients from the original cohort. Eleven IDDM patients with no history of severe hypoglycemia (group A) were compared with 11 IDDM patients who had a history of five or more episodes of severe hypoglycemia (group B)., Results: Nine patients (41%) had abnormal scans. Two types of abnormalities were observed: high-intensity rounded lesions, > 3 mm in diameters, distributed in the periventricular white matter (leukoaraiosis) in four patients; and cortical atrophy in five patients. Five patients in group B had cortical atrophy, whereas no patient in group A demonstrated this feature (P < 0.05). MRS of the frontal and parietal lobes showed no differences in the N-acetyl aspartate/creatine or N-acetyl aspartate/choline ratios between groups A and B. Patients with cortical atrophy showed a nonsignificant trend toward reduced performance on Rapid Visual Information Processing., Conclusions: Brain abnormalities demonstrated by MRI are common in patients with IDDM of long duration and are suggestive of premature aging of the brain. IDDM per se may be an important pathogenic factor, but a significant association was observed between a history of recurrent severe hypoglycemia and cortical atrophy, which may be related to the modest impairment of cognitive function that has been reported previously.

Objective: To examine the symptoms of hypoglycemia in children with insulin-dependent diabetes, from the perspective both of the child and of the child's parents, and to compare the symptom reporting of the diabetic children with that of adult diabetic patients., Research Design and Methods: Interviews were conducted with 100 parents and 43 of their children. The frequency and intensity of symptoms of hypoglycemia were documented using a structured interview and classified into groups using Principal Components Analysis (PCA)., Results: Diabetic children and their parents showed close agreement concerning the relative frequency and the intensity of symptoms reported. PCA of the symptom reports showed that diabetic children and their parents identified the same distinct subgroups of hypoglycemia-related symptoms: behavioral disturbance and autonomic-neuroglycopenic subgroups., Conclusions: Hypoglycemic symptoms in children with diabetes clearly differ from those experienced by insulin-treated adults and, in particular, include behavioral changes as primary features of a low blood glucose. These observations have important implications for parental education on hypoglycemia.

Objective: To assess the possible influence of personality on self-reported awareness, symptoms, and fear of hypoglycemia and also to identify the relationship among these self-reported measures using formal structural equation modeling., Research Design and Methods: A structured questionnaire, which included questions about sociodemographic details, awareness of the onset of hypoglycemia, and a list of symptoms of hypoglycemia, was completed by 305 consecutive insulin-treated diabetic patients attending the diabetic clinic at the Royal Infirmary of Edinburgh. They also completed the Hypoglycemia Fear Survey (HFS), and personality was assessed using the short form of the shortened Eysenck Personality Questionnaire-Revised (EPQ-R). Formal structural equation modeling was performed using the following variables: awareness, autonomic symptoms, neuroglycopenic symptoms, severe hypoglycemic episodes in the last year, worry and behavior (from the HFS), and extroversion and neuroticism (from the short EPQ-R). This allowed a model to be constructed that expressed the putative causal associations among the variables that could be tested statistically., Results: Of the 302 patients who had experienced hypoglycemia, 111 (37%) reported reduced awareness, and these patients scored higher on the worry subscale of the HFS (reduced awareness: 41 +/- 12 vs. normal awareness: 34 +/- 12, P < 0.001). The patients with reduced awareness scored higher for neuroticism than did the patients with normal awareness (reduced awareness: 6.1 +/- 3.4 vs. normal awareness: 4.9 +/- 3.3, P < 0.01) and scored lower for extroversion (reduced awareness: 5.8 +/- 3.7 vs. normal awareness: 7.1 +/- 3.7, P < 0.01). In the structural equation modeling exercise, neuroticism was a significant putative determinant of many of the other variables., Conclusions: Personality was the major determinant of the variance that could be accounted for in this study and influenced self-reported symptoms, awareness, and fear of hypoglycemia. Personality factors may, therefore, influence self-reports from patients, particularly when soft measures, such as symptoms, are assessed and even when using validated clinical questionnaires. This finding stresses the importance of using additional evidence, such as reports from relatives, to substantiate reports from patients of loss of hypoglycemia awareness.

Objective: This study allocated the symptoms identified during acute hypoglycemia objectively to the autonomic or neuroglycopenic groups of symptoms by the use of factor analysis., Research Design and Methods: Twenty-five nondiabetic subjects, 14 newly diagnosed insulin-dependent diabetic patients, and 16 insulin-dependent diabetic patients with diabetes greater than 4 yr duration were studied. Acute hypoglycemia was induced with insulin (2.5 mU.kg-1 body wt.min-1 i.v.), and symptoms of hypoglycemia were recorded with a seven-point scale at regular time points throughout the studies. Factor analysis of the symptom scores at the time of the acute autonomic reaction with principal component analysis followed by Varimax rotation was used to separate those symptoms that might belong to neuroglycopenic and autonomic groups., Results: Hypoglycemia was induced to a mean +/- SE plasma glucose nadir of 1.3 +/- 0.1 mM in nondiabetic subjects, to 2.0 +/- 0.3 mM in newly diagnosed diabetic patients, and 1.4 +/- 0.2 mM in patients with diabetes of greater than 4 yr duration. The most frequently reported autonomic symptoms were sweating, trembling, and warmness, and the most frequently reported neuroglycopenic symptoms were inability to concentrate, weakness, and drowsiness. Neuroglycopenic symptoms were reported more commonly at the onset of hypoglycemia, which was identified by the development of symptoms. Factor analysis grouped trembling, anxiety, sweating, warmness, and nausea together, and this grouping was labeled an autonomic factor. A second factor was identified that included dizziness, confusion, tiredness, difficulty in speaking, shivering, drowsiness, and inability to concentrate, which was labeled a neuroglycopenic factor., Conclusions: This study demonstrated the high frequency with which neuroglycopenic symptoms occur at the onset of hypoglycemia and the symptoms that could be used by an individual patient as a warning of the development of acute hypoglycemia, although the rapid reduction of plasma glucose is faster than experienced by the ambulant diabetic patient. Factor analysis assisted with the allocation of symptoms to either the autonomic or neuroglycopenic groupings, but the allocation of some symptoms remained undefined, and care must be taken when assessing symptoms such as hunger, weakness, blurred vision, and drowsiness when comparing the frequency of autonomic versus neuroglycopenic symptoms. To reduce the confusion resulting from the use of different symptom questionnaires in studies of hypoglycemia, a sample questionnaire is presented, the development of which was assisted by our analysis.