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Aims/hypothesis: Diabetes distress is one of the most frequent mental health issues identified in people with type 1 and type 2 diabetes. Little is known about the role of glucose control as a potential contributor to diabetes distress and whether the subjective perception of glucose control or the objective glycaemic parameters are more important for the experience. With the emergence of continuous glucose monitoring (CGM), this is a relevant question as glucose values are now visible in real-time. We employed a precision monitoring approach to analyse the independent associations of perceived and measured glucose control with diabetes distress on a daily basis. By using n-of-1 analyses, we aimed to identify individual contributors to diabetes distress per person and analyse the associations of these individual contributors with mental health at a 3 month follow-up., Methods: In this prospective, observational study, perceived (hypoglycaemia/hyperglycaemia/glucose variability burden) and measured glucose control (time in hypoglycaemia and hyperglycaemia, CV) were assessed daily for 17 days using an ecological momentary assessment (EMA) approach with a special EMA app and CGM, respectively. Mixed-effect regression analysis was performed, with daily diabetes distress as the dependent variable and daily perceived and CGM-measured metrics of glucose control as random factors. Individual regression coefficients of daily distress with perceived and CGM-measured metrics were correlated with levels of psychosocial well-being at a 3 month follow-up., Results: Data from 379 participants were analysed (50.9% type 1 diabetes; 49.6% female). Perceived glucose variability (t=14.360; p<0.0001) and perceived hyperglycaemia (t=13.637; p<0.0001) were the strongest predictors of daily diabetes distress, while CGM-based glucose variability was not significantly associated (t=1.070; p=0.285). There was great heterogeneity between individuals in the associations of perceived and measured glucose parameters with diabetes distress. Individuals with a stronger association between perceived glucose control and daily distress had more depressive symptoms (β=0.32), diabetes distress (β=0.39) and hypoglycaemia fear (β=0.34) at follow-up (all p<0.001). Individuals with a stronger association between CGM-measured glucose control and daily distress had higher levels of psychosocial well-being at follow-up (depressive symptoms: β=-0.31; diabetes distress: β=-0.33; hypoglycaemia fear: β=-0.27; all p<0.001) but also higher HbA 1c (β=0.12; p<0.05)., Conclusions/interpretation: Overall, subjective perceptions of glucose seem to be more influential on diabetes distress than objective CGM parameters of glycaemic control. N-of-1 analyses showed that CGM-measured and perceived glucose control had differential associations with diabetes distress and psychosocial well-being 3 months later. The results highlight the need to understand the individual drivers of diabetes distress to develop personalised interventions within a precision mental health approach., (© 2024. The Author(s).)

Aims/hypothesis: The aim of this work was to examine the impact of hypoglycaemia on daily functioning among adults with type 1 diabetes or insulin-treated type 2 diabetes, using the novel Hypo-METRICS app., Methods: For 70 consecutive days, 594 adults (type 1 diabetes, n=274; type 2 diabetes, n=320) completed brief morning and evening Hypo-METRICS 'check-ins' about their experienced hypoglycaemia and daily functioning. Participants wore a blinded glucose sensor (i.e. data unavailable to the participants) for the study duration. Days and nights with or without person-reported hypoglycaemia (PRH) and/or sensor-detected hypoglycaemia (SDH) were compared using multilevel regression models., Results: Participants submitted a mean ± SD of 86.3±12.5% morning and 90.8±10.7% evening check-ins. For both types of diabetes, SDH alone had no significant associations with the changes in daily functioning scores. However, daytime and night-time PRH (with or without SDH) were significantly associated with worsening of energy levels, mood, cognitive functioning, negative affect and fear of hypoglycaemia later that day or while asleep. In addition, night-time PRH (with or without SDH) was significantly associated with worsening of sleep quality (type 1 and type 2 diabetes) and memory (type 2 diabetes). Further, daytime PRH (with or without SDH), was associated with worsening of fear of hyperglycaemia while asleep (type 1 diabetes), memory (type 1 and type 2 diabetes) and social functioning (type 2 diabetes)., Conclusions/interpretation: This prospective, real-world study reveals impact on several domains of daily functioning following PRH but not following SDH alone. These data suggest that the observed negative impact is mainly driven by subjective awareness of hypoglycaemia (i.e. PRH), through either symptoms or sensor alerts/readings and/or the need to take action to prevent or treat episodes., (© 2024. The Author(s).)

Aims/hypothesis: Valid and reliable patient-reported outcome measures are vital for assessing disease impact, responsiveness to healthcare and the cost-effectiveness of interventions. A recent review has questioned the ability of existing measures to assess hypoglycaemia-related impacts on health-related quality of life for people with diabetes. This mixed-methods project was designed to produce a novel health-related quality of life patient-reported outcome measure in hypoglycaemia: the Hypo-RESOLVE QoL., Methods: Three studies were conducted with people with diabetes who experience hypoglycaemia. In Stage 1, a comprehensive health-related quality of life framework for hypoglycaemia was elicited from semi-structured interviews (N=31). In Stage 2, the content validity and acceptability of draft measure content were tested via three waves of cognitive debriefing interviews (N=70 people with diabetes; N=14 clinicians). In Stage 3, revised measure content was administered alongside existing generic and diabetes-related measures in a large cross-sectional observational survey to assess psychometric performance (N=1246). The final measure was developed using multiple evidence sources, incorporating stakeholder engagement., Results: A novel conceptual model of hypoglycaemia-related health-related quality of life was generated, featuring 19 themes, organised by physical, social and psychological aspects. From a draft version of 76 items, a final 14-item measure was produced with satisfactory structural (χ 2 =472.27, df=74, p<0.001; comparative fit index =0.943; root mean square error of approximation =0.069) and convergent validity with related constructs (r=0.46-0.59), internal consistency (α=0.91) and test-retest reliability (intraclass correlation coefficient =0.87)., Conclusions/interpretation: The Hypo-RESOLVE QoL is a rigorously developed patient-reported outcome measure assessing the health-related quality of life impacts of hypoglycaemia. The Hypo-RESOLVE QoL has demonstrable validity and reliability and has value for use in clinical decision-making and as a clinical trial endpoint., Data Availability: All data generated or analysed during this study are included in the published article and its online supplementary files ( https://doi.org/10.15131/shef., Data: 23295284.v2 )., (© 2024. The Author(s).)

The study was carried out to determine the psychosocial outcomes of advanced hybrid closed-loop (AHCL) systems in children and adolescents with type 1 diabetes (T1D). Single-center and cohort study with a duration 6 months consisted of 60 children and adolescents with T1D. Standard clinical procedures, including both glycemic indicators, e.g., sensor-measured time within the 70-180 mg/dL range and glycated hemoglobin (HbA1c) levels, and psychosocial metrics were used for data collection. The psychosocial metrics included the Pediatric Quality of Life Inventory (PedsQL) 3.0 Diabetes Module for both children (8-12 years) and parents; the Quality of Life for Youth scale for adolescents (13-18 years); the Strengths and Difficulties Questionnaire (SDQ); the Hypoglycemia Fear Survey for Children (HFS-C); the Revised Child Anxiety and Depression Scale (R-CADS); and AHCLS-specific DTSEQ satisfaction and expectation survey. These metrics were evaluated at the baseline and after 6 months of AHCL use. Of the 60 children and adolescents with T1D for whom the AHCL system was utilized, 41 of them, 23 female and 18 male, completed the surveys. The mean age of the 41 children and adolescents was 12.5 ± 3.2 (min. 6.7, max. 18) years. The time spent within the target glycemic range, i.e., time-in-range (TIR), improved from 76.9 ± 9% at the baseline to 80.4 ± 5% after 6 months of AHCL system use (p = 0.03). Additionally, HbA1c levels reduced from 7.1% ± 0.7% at the baseline to 6.8% ± 0.8% after 6 months of AHCL system use (p = 0.03). The most notable decline in HbA1c was observed in participants with higher baseline HbA1c levels. All patients' HFS-C and AHCL system-specific DTSEQ satisfaction and expectation survey scores were within the normal range at the baseline and remained unchanged during the follow-up period. No significant difference was found in the R-CADS scores of children and adolescents between baseline and after 6 months of AHCL system use. However, there was a significant decrease in the R-CADS scores of the parents. Patients' PedsQL scores were high both at the baseline and after 6 months. The SDQ scores were high at baseline, and there was no significant improvement at the end of 6 months.  Conclusion: This is the first study to investigate in detail the psychosocial outcomes of AHCL system use in T1D patients and their parents. Although state-of-the-art technologies such as AHCL provide patients with more flexibility in their daily lives and information about glucose fluctuations, the AHCL resulted in a TIR above the recommended target range without a change in QOL, HFS-C, SDQ, and R-CADS scores. The scores obtained from the R-CADS conducted by the parents of the children indicated that the use of pumps caused a psychological improvement in the long term, with a significant decrease in the R-CADS scores of the children and adolescents with T1D. What is Known: • Previous studies focused on clinical outcomes of AHCL systems in pediatric T1D patients, showing glycemic control improvements. • Limited attention given to psychosocial outcomes of AHCL systems in children and adolescents with T1D. • Crucial psychosocial factors like quality of life, emotional well-being, and fear of hypoglycemia underexplored in AHCL system context. What is New: • First study to comprehensively examine psychosocial outcomes of AHCL systems in pediatric T1D patients. • Study's robust methodology sets new standard for diabetes technology research and its impact on qualiy of life., (© 2024. The Author(s).)

Hypoglycaemia (blood glucose concentration below the normal range) has been recognised as a complication of insulin treatment from the very first days of the discovery of insulin, and remains a major concern for people with diabetes, their families and healthcare professionals today. Acute hypoglycaemia stimulates a stress response that acts to restore circulating glucose, but plasma glucose concentrations can still fall too low to sustain normal brain function and cardiac rhythm. There are long-term consequences of recurrent hypoglycaemia, which are still not fully understood. This paper reviews our current understanding of the acute and cumulative consequences of hypoglycaemia in insulin-treated diabetes.

The discovery of insulin and its subsequent mass manufacture transformed the lives of people with type 1 and 2 diabetes. Insulin, however, was a drug with a 'dark side'. It brought with it the risk of iatrogenic hypoglycaemia. In this short review, the cellular consequences of recurrent hypoglycaemia, with a particular focus on the brain, are discussed. Using the ventromedial hypothalamus as an exemplar, this review highlights how recurrent hypoglycaemia has an impact on the specialised cells in the brain that are critical to the regulation of glucose homeostasis and the counterregulatory response to hypoglycaemia. In these cells, recurrent hypoglycaemia initiates a series of adaptations that ensure that they are more resilient to subsequent hypoglycaemia, but this leads to impaired hypoglycaemia awareness and a paradoxical increased risk of severe hypoglycaemia. This review also highlights how hypoglycaemia, as an oxidative stressor, may also exacerbate chronic hyperglycaemia-induced increases in oxidative stress and inflammation, leading to damage to vulnerable brain regions (and other end organs) and accelerating cognitive decline. Pre-clinical research indicates that glucose recovery following hypoglycaemia is considered a period where reactive oxygen species generation and oxidative stress are pronounced and can exacerbate the longer-term consequence of chronic hypoglycaemia. It is proposed that prior glycaemic control, hypoglycaemia and the degree of rebound hyperglycaemia interact synergistically to accelerate oxidative stress and inflammation, which may explain why increased glycaemic variability is now increasingly considered a risk factor for the complications of diabetes.

Aims/hypothesis: The aim of this work was to assess the effect of spontaneous nocturnal hypoglycaemia on quality of life and mood during subsequent days in type 1 diabetes., Methods: A total of 153 people with type 1 diabetes participated in 6 days of blinded continuous glucose monitoring while documenting hypoglycaemic symptoms, quality of life and mood, daily. Hypoglycaemia was defined by interstitial glucose ≤3.9 mmol/l (IG 3.9 ) and ≤ 3.0 mmol/l (IG 3.0 ) for ≥15 min and was classified as asymptomatic if no hypoglycaemic symptoms were reported., Results: Self-estimated quality of life assessed by the EQ-5D VAS (but not by the WHO Well-Being Index) was higher the day after asymptomatic (but not after symptomatic) hypoglycaemic nights, as compared with non-hypoglycaemic nights (IG 3.9 , p = 0.021; IG 3.0 , p = 0.048). The effect increased with lower glucose nadir and longer duration of nocturnal hypoglycaemia (IG 3.9 , p = 0.03). The finding was confined to participants with impaired hypoglycaemia awareness. There was no effect of nocturnal hypoglycaemia on mood or self-estimated effectiveness at work the following day., Conclusions/interpretation: Individuals with type 1 diabetes and impaired hypoglycaemia awareness reported higher quality of life on days preceded by nights with asymptomatic (but not symptomatic) hypoglycaemia. The effect was amplified by lower glucose nadir and longer duration of the episodes and may help explain resistance to implementation of interventions to reduce hypoglycaemia in many people with impaired hypoglycaemia awareness.

Aims/hypothesis: Approximately 25% of people with type 1 diabetes have suppressed counterregulatory hormonal and symptomatic responses to insulin-induced hypoglycaemia, which renders them at increased risk of severe, disabling hypoglycaemia. This is called impaired awareness of hypoglycaemia (IAH), the cause of which is unknown. We recently proposed that IAH develops through habituation, a form of adaptive memory to preceding hypoglycaemia. Consistent with this hypothesis, we demonstrated restoration of defective counterregulatory hormonal responses to hypoglycaemia (referred to as dishabituation) in a rodent model of IAH following introduction of a novel stress stimulus (high intensity training [HIT]). In this proof-of-concept study we sought to further test this hypothesis by examining whether a single episode of HIT would amplify counterregulatory responses to subsequent hypoglycaemia in people with type 1 diabetes who had IAH (assessed by Gold score ≥4, modified Clarke score ≥4 or Dose Adjustment For Normal Eating (DAFNE) hypoglycaemia awareness rating 2 or 3). The primary outcome was the difference in adrenaline response to hypoglycaemia following both a single episode of HIT and rest., Methods: In this randomised, crossover study 12 participants aged between 18 and 55 years with type 1 diabetes for ≥5 years and an HbA 1c  <75 mmol/mol (9%) were recruited. Individuals were randomised using computer generated block randomisation to start with one episode of HIT (4 × 30 s cycle sprints [2 min recovery] at 150% of maximum wattage achieved during [Formula: see text] assessment) or rest (control). The following day they underwent a 90 min hyperinsulinaemic-hypoglycaemic clamp study at 2.5 mmol/l with measurement of hormonal counterregulatory response, symptom scores and cognitive testing (four-choice reaction time and digit symbol substitution test). Each intervention and subsequent clamp study was separated by at least 2 weeks. The participants and investigators were not blinded to the intervention or measurements during the study. The investigators were blinded to the primary outcome and blood analysis results., Results: All participants (six male and six female, age 19-54 years, median [IQR] duration of type 1 diabetes 24.5 [17.3-29.0] years, mean [SEM] HbA 1c 56 [3.67] mmol/mol; 7.3% [0.34%]) completed the study (both interventions and two clamps). In comparison with the rest study, a single episode of HIT led to a 29% increase in the adrenaline (epinephrine) response (mean [SEM]) (2286.5 [343.1] vs 2953.8 [384.9] pmol/l); a significant increase in total symptom scores (Edinburgh Hypoglycaemia Symptom Scale: 24.25 [2.960 vs 27.5 [3.9]; p<0.05), and a significant prolongation of four-choice reaction time (591.8 [22.5] vs 659.9 [39.86] ms; p<0.01] during equivalent hypoglycaemia induced the following day., Conclusions/interpretation: These findings are consistent with the hypothesis that IAH develops in people with type 1 diabetes as a habituated response and that introduction of a novel stressor can restore, at least partially, the adapted counterregulatory hormonal, symptomatic and cognitive responses to hypoglycaemia., Trial Registration: ISRCTN15236211.

Advances in technology allowing improved insulin delivery and glucose monitoring can significantly reduce the burden of hypoglycaemia when used appropriately. However, limitations of the current technology, and the skills, commitment and motivation required to use them, mean that it does not work for all people. Education and informed professional support are key to success. In the context of problematic hypoglycaemia, data suggest that newer technology has lower efficacy and uptake in those with most need. Identifying the causes of hypoglycaemia and understanding some of the underlying behavioural drivers may prove useful and psycho-educational strategies may be effective in selected individuals. Ultimately, as in many spheres of medicine, successful management of problematic hypoglycaemia depends upon matching the right treatment to the right individual.

Aims: The occurrence of hypoglycaemia is assumed to be associated with increased diabetes-related distress. We investigated the association of mild hypoglycaemia (MH) with diabetes-related distress in a large outpatient cohort with diabetes type 1 (DM1) and type 2 (DM2)., Methods: In a cross-sectional study, we recorded MH and simultaneously assessed diabetes-related distress with the PAID questionnaire in 783 people with diabetes [female 43.8 %, age 63.7 years, duration of diabetes 17.3 years, HbA1c 7.0 % (53 mmol/mol)] in an university outpatient department for metabolic diseases over a period of three months. Participants with and without MH were compared., Results: People with DM1 (n = 191) had 1.09 MH per week. Diabetes-related distress was not different comparing people with DM1 with (n = 125) and without (n = 66) MH (PAID score 18.4 ± 16.2 vs. 16.6 ± 15.0, p = 0.449). The frequency of MH per week in people with DM2 on oral antidiabetic therapy (n = 182) and with insulin therapy (n = 410) is low (0.03 vs. 0.1 episodes). People with DM2 on insulin therapy with (n = 72) and without (n = 338) MH have a comparable PAID score (17.9 ± 13.3 vs. 16.8 ± 14.9, p = 0.552). 14.4 % of those with DM1 as well as 12.5 % of those with DM2 on insulin feel hypoglycaemic events to be a "somewhat serious problem" or "serious problem"., Conclusions: In an outpatient setting, MH is not associated with increased diabetes-related distress or burden in people with DM1 or DM2.

Objective: The major aims of this study were to examine (1) the association between fear of hypoglycemia (FOH) in adults with type 1 diabetes with demographic, psychological (anxiety and depression), and disease-specific clinical factors (hypoglycemia history and unawareness, A1c), including severe hypoglycemia (SH), and (2) differences in patient subgroups categorized by level of FOH and risk of SH., Research Design and Methods: Questionnaires were mailed to 764 patients with type 1 diabetes including the Swedish translation of the Hypoglycemia Fear Survey (HFS) and other psychological measures including the Perceived Stress Scale, Hospital Anxiety and Depression Scale, Anxiety Sensitivity Index, Social Phobia Scale, and Fear of Complications Scale. A questionnaire to assess hypoglycemia history was also included and A1c measures were obtained from medical records. Statistical analyses included univariate approaches, multiple stepwise linear regressions, Chi-square t tests, and ANOVAs., Results: Regressions showed that several clinical factors (SH history, frequency of nocturnal hypoglycemia, self-monitoring) were significantly associated with FOH but R (2) increased from 16.25 to 39.2 % when anxiety measures were added to the model. When patients were categorized by level of FOH (low, high) and SH risk (low, high), subgroups showed significant differences in non-diabetes-related anxiety, hypoglycemia history, self-monitoring, and glycemic control., Conclusion: There is a strong link between FOH and non-diabetes-related anxiety, as well as hypoglycemia history. Comparison of patient subgroups categorized according to level of FOH and SH risk demonstrated the complexity of FOH and identified important differences in psychological and clinical variables, which have implications for clinical interventions.

Aims/hypothesis: In diabetic children and adolescents, a history of severe hypoglycaemia (SH) has been associated with increased slow EEG activity and reduced cognition, possibly due to harmful effects of SH on the developing brain. In a group of type 1 diabetic patients with early exposure to SH, who had EEG abnormalities and reduced cognition in childhood, we have recently demonstrated that the reduced cognition may persist into adulthood. We have now assessed whether the reduced cognition was accompanied by lasting EEG abnormalities., Methods: In 1992-1993, we studied EEG and cognition in 28 diabetic children and 28 matched controls. 16 years later, we re-investigated the same participants, with 96% participation rate. Diabetic participants were classified as with (n = 9) or without (n = 18) early SH, defined as episodes with convulsions or loss of consciousness by 10 years of age. For each EEG band (delta, theta, alpha and beta) and cerebral region (frontocentral, temporal, and parietooccipital), we calculated relative amplitudes and amplitude asymmetry. We also calculated occipital alpha mean frequency, alpha peak frequency at maximum amplitude, alpha peak width, and theta regional mean frequencies. We examined whether these EEG measures, relative to age- and sex-matched controls, differed between diabetic participants with and without early SH., Results: We found no association of early SH with any of the EEG measures., Conclusions/interpretation: Childhood SH was not associated with EEG abnormalities in young type 1 diabetic adults. Our findings suggest that the reduced adulthood cognition associated with childhood exposure to SH is not accompanied by lasting EEG abnormalities.

The aim of our study was to evaluate the frequency of hypoglycaemia unawareness and the continuous glucose profile in a group of subjects with Type 1 diabetes (T1D) with repeated non-severe/severe hypoglycaemia. Twenty patients (aged 35.2 +/- 7.6 years, duration of disease 16.4 +/- 6.4 years) were included. Hypoglycaemia awareness was evaluated using questionnaires and after an acute-induced hypoglycaemia. Glucose profile was studied using 72-h continuous glucose monitoring (CGM). All subjects were classified as having hypoglycaemia unawareness by questionnaires. Four patients displayed a "normal" signs/symptoms response to hypoglycaemia. The CGM revealed 18% of the measurements <70 mg/dl and this percentage was correlated with questionnaire score (r = 0.55, P < 0.035) and with the increase in the percentage of signs/symptoms during the induced hypoglycaemia (r = -0.57, P < 0.015). In patients exhibiting an "abnormal" response during hypoglycaemia, CGM values <70 mg/dl was higher (22.6 +/- 8.4%) than in those with a "normal" response (10.2 +/- 9.0%; P < 0.028). Summarising, in subjects with T1D and repeated hypoglycaemia the frequency of impaired awareness is substantially common. Its presence is related to a high proportion of ambulatory glycaemic profile below the desirable range.

Aims/hypothesis: The aim of this analysis was to quantify the relationship between the frequency of hypoglycaemia and various glucose cut-off points for the definition of hypoglycaemia, within a range of HbA(1c) strata., Methods: Data from two trials examining insulin glargine dose titration in 12,837 type 2 diabetic participants starting insulin therapy were combined. Curves for hypoglycaemia frequency plotted against endpoint HbA(1c) level were constructed, using a range of glucose cut-off points for hypoglycaemia., Results: During the 12-week study period, 3,912 patients recorded 21,592 hypoglycaemic episodes, comprising 242 severe, 8,871 symptomatic and 12,479 asymptomatic events, corresponding to hypoglycaemia event rates of 0.10, 3.8 and 5.3 events per patient year. Increasing the hypoglycaemia cut-off point from, for instance, <3.1 to <3.9 mmol/l more than doubled the percentage of affected patients, e.g. from 17.7 to 43.3% at HbA(1c) 7.0-7.2%. At higher hypoglycaemia cut-off points the proportion of patients having only asymptomatic hypoglycaemia increased, e.g. from 30.7% at <3.1 mmol/l to 61.7% of patients at a cut-off point of <3.9 mmol/l. In sensitivity analysis, 121 of 1,756 patients with at least one self-monitored blood glucose value <3.1 mmol/l experienced severe hypoglycaemia, compared with 149 of 3,912 patients with a self-monitored blood glucose level of <3.9 mmol/l. Thus, to identify 28 more patients with severe hypoglycaemia, the number of patients experiencing only non-severe hypoglycaemia more than doubled., Conclusions/interpretation: The glucose cut-off point defining hypoglycaemia greatly affects the reported frequency of hypoglycaemia. When hypoglycaemia is to be defined by a predetermined glucose level, to have clinical relevance the cut-off should be set at a lower level than the threshold of 3.9 mmol/l proposed by the American Diabetes Association.

Aims/hypothesis: Hypoglycaemia unawareness in type 1 diabetes increases the risk of severe hypoglycaemia and impairs quality of life for people with diabetes. To explore the central mechanisms of hypoglycaemia awareness, we used [11C]-3-O-methyl-D-glucose (CMG) positron emission tomography (PET) to measure changes in global and regional brain glucose metabolism between euglycaemia and hypoglycaemia in aware and unaware diabetic subjects., Materials and Methods: Twelve men with type 1 diabetes, of whom six were characterised as aware and six as unaware of hypoglycaemia, underwent two CMG-PET brain scans while plasma glucose was controlled by insulin and glucose infusion either at euglycaemia (5 mmol/l) or at hypoglycaemia (2.6 mmol/l) in random order., Results: With hypoglycaemia, symptoms and sweating occurred only in the aware group. Brain glucose content fell in both groups (p=0.0002; aware, 1.18+/-0.45 to 0.02+/-0.2 mmol/l; unaware, 1.07+/-0.46 to 0.19+/-0.23 mmol/l), with a relative increase in tracer uptake in prefrontal cortical regions, including the anterior cingulate. No detectable differences were found between groups in global brain glucose transport parameters (K1, k2). The cerebral metabolic rate for glucose (CMRglc) showed a relative rise in the aware subjects (11.839+/-2.432 to 13.958+/-2.372) and a fall in the unaware subjects (from 12.457+/-1.938 to 10.16+/-0.801 micromol 100 g(-1) min(-1), p=0.043)., Conclusions/interpretation: Hypoglycaemia is associated with reduced brain glucose content in aware and unaware subjects, with a relative preservation of metabolism in areas associated with sympathetic activation. The relative rise in global glucose metabolic rate seen in aware subjects during hypoglycaemia contrasted with the relative fall in the unaware subjects and suggests that cortical neuronal activation is a necessary correlate of the state of hypoglycaemia awareness.

Aims/hypothesis: We have previously shown a strong relationship between high angiotensin-converting enzyme (ACE) activity, presence of the deletion (D) allele of the ACEgene and recall of severe hypoglycaemic events in patients with Type 1 diabetes. This study was carried out to assess this relationship prospectively., Methods: We followed 171 adult outpatients with Type 1 diabetes in a one-year observational study with the recording of severe hypoglycaemia. Participants were characterised by serum ACE activity and ACE genotype and not treated with ACE inhibitors or angiotensin II receptor antagonists., Results: There was a positive relationship between serum ACE activity and rate of severe hypoglycaemia with a 2.7 times higher rate in the fourth quartile of ACE activity compared to the first quartile (p=0.0007). A similar relationship was observed for the subset of episodes with coma (2.9 times higher rate in fourth quartile compared to first quartile; p=0.048). The impact of serum ACE activity was most pronounced in C-peptide negative subjects (4.2 times higher rate in fourth quartile compared to first quartile; p=0.003), and in this subgroup carriers of the D allele of the ACEgene had higher rates of severe hypoglycaemia compared to the group homozygous for the insertion (I) allele. In a multiple regression analysis high serum ACE activity and impaired awareness of hypoglycaemia were identified as the only significant predictors of severe hypoglycemia., Conclusion: High ACE activity and the presence of the D allele of the ACE gene predict a high rate of severe hypoglycaemia in Type 1 diabetes.

Aims/hypothesis: The aim of this study was to establish the effect of a rate of decreasing plasma glucose concentrations on responses to hypoglycaemia, i.e. release of counterregulatory hormones, perception of symptoms, deterioration of cognitive function, and rates of forearm noradrenaline spillover, in the postprandial condition and in the sitting position., Methods: We studied 11 subjects with Type I (insulin-dependent) diabetes mellitus, twice during clamped insulin-induced hypoglycaemia (2.4 mmol/l) after eating in the sitting position. On one occasion, plasma glucose was decreased at the rate of 0.1+/-0.003 mmol x min(-1) x l(-1) (fast fall), on the other at the rate of 0.03+/-0.001 mmol x min(-1) x l(-1) (slow fall). Subjects underwent a control euglycaemic clamp study as well., Results: In response to fast-fall as compared to slow-fall hypoglycaemia, which was about 30 min longer, cognitive tasks were performed as follows: Trail-Making B, PASAT 2 s, Digit Vigilance Test and Verbal Memory deteriorated more, adrenaline increased less (2.8+/-0.5 vs 3.5+/-0.7 nmol/l, p=0.03), forearm noradrenaline spillover was greater (6.5+/-1.0 vs 5.2+/-0.4 pmol x min(-1) x 100 ml(-1), p=0.04), and symptoms were no different. After recovery from hypoglycaemia, cognitive function was still deteriorated compared to the baseline with no difference between fast and slow-fall hypoglycaemia. The evident response of glucagon to postprandial hypoglycaemia contrasted with the blunted or absent response in the fasting state., Conclusion/interpretation: In the postprandial condition and sitting position, fast-fall hypoglycaemia is more dangerous than slow-fall, because it deteriorates cognitive function more, and activates responses of counterregulatory hormones less than slow-fall hypoglycaemia.

Unawareness of hypoglycaemia (reduced ability/failure to recognize hypoglycaemia symptoms at the physiological threshold of 3.0 mmol/l) occurs frequently in type 1 diabetes mellitus, and patients are then at risk for severe hypoglycaemia. Unawareness of hypoglycaemia is the result of earlier frequent episodes of hypoglycaemia (iatrogenic). Likewise, a history of hypoglycaemia induces unawareness, while meticulous prevention of hypoglycaemia can reverse hypoglycaemia unawareness. Therefore, it is essential that insulin therapy regimens for type 1 diabetes mellitus be designed not only to maintain near-normoglycaemia, but also to minimize hypoglycaemia. Such a goal is feasible as long as (1) a rational plan of insulin therapy is adopted, including appropriate use of the short-acting insulin analogue lispro, (2) blood glucose is properly monitored, (3) blood glucose targets are individualized, and (4) education programs are widely implemented.

Hypoglycaemic events are frequent complications of insulin-dependent diabetes mellitus in children. The signs and symptoms referred to by young children can be difficult to understand and often seem to be different from those described by their parents. We analysed the hypoglycaemic symptoms described by a group of patients and their parents. We studied 40 pairs consisting of a parent and a diabetic child by using a structured questionnaire with 27 items concerning different symptoms of hypoglycaemia. The mean+/-SD age of the children was 10.4+/-2.4 years, with duration of disease 6.2+/-2.1 years and their HbA1c was 8.2 2.0%. For the statistical analysis we used the principal component analysis. All the children followed a multiple injection regimen. The frequency and intensity of the hypoglycaemic signs described by patients and parents were similar both for neuroglycopenic (uncoordination, confusion, odd behaviour, dizziness) and autonomic symptoms (trembling, sweating, pounding heart, hunger). Moreover, our questionnaire showed a high frequency of behavioural changes. In conclusion, from the analysis of the questionnaires collected, we found that both parents and children gave almost the same score to the symptoms observed. This means that there is a concordance between the symptoms reported by the children and those reported by their parents.

Severe hypoglycaemia with cognitive dysfunction is 3 times more common in intensively, rather than conventionally, treated insulin-dependent diabetes mellitus (IDDM). To investigate the effect of diabetes control on higher brain function during acute hypoglycaemia, we studied one of the earliest detectable changes in cognitive function, i.e. the four-choice reaction time, and symptomatic and hormonal responses during euglycaemic and hypoglycaemic clamping in human subjects. There were no changes in symptoms or counterregulatory hormones and four-choice reaction time was stable during 220 min of euglycaemic insulin clamping in five men with IDDM, with a coefficient of variation of less than 2.2% (1% for accuracy) for the cognitive function test. During stepped hypoglycaemic clamping however, hormonal responses and subjective awareness of hypoglycaemia occurred in all groups but started at much lower blood glucose concentrations in eight intensively-treated diabetic subjects (Group 1) than in ten conventionally-treated (Group 2) or in eight non-diabetic subjects (Group 3). For example, for adrenaline, plasma glucose thresholds were 2.7 +/- 0.2 vs 3.4 +/- 0.2 and 3.2 +/- 0.1 mmol/l, respectively, p < 0.05, Group 1 vs Groups 2 or 3 and for subjective awareness of hypoglycaemia 2.3 +/- 0.2 vs 3.0 +/- 0.1 and 3.2 +/- 0.1 mmol/l, p < or = 0.003), as in previous studies. In contrast, deterioration in reaction time occurred at 3.2 +/- 0.3, 3.2 +/- 0.2 and 3.0 +/- 0.2 mmol/l, respectively (p = NS), thus occurring at higher glucose levels than subjective awareness in the intensively-treated subjects only. The altered hierarchy of responses to hypoglycaemia in well-controlled intensively-treated diabetes explains the increased risk of severe hypoglycaemia without warning seen in such patients.

Hypoglycaemia unawareness, is a major risk factor for severe hypoglycaemia and a contraindication to the therapeutic goal of near-normoglycaemia in IDDM. We tested two hypotheses, first, that hypoglycaemia unawareness is reversible as long as hypoglycaemia is meticulously prevented by careful intensive insulin therapy in patients with short and long IDDM duration, and that such a result can be maintained long-term. Second, that intensive insulin therapy which strictly prevents hypoglycaemia, can maintain long-term near-normoglycaemia. We studied 21 IDDM patients with hypoglycaemia unawareness and frequent mild/severe hypoglycaemia episodes while on "conventional" insulin therapy, and 20 nondiabetic control subjects. Neuroendocrine and symptom responses, and deterioration in cognitive function were assessed in a stepped hypoglycaemia clamp before, and again after 2 weeks, 3 months and 1 year of either intensive insulin therapy which meticulously prevented hypoglycaemia (based on physiologic insulin replacement and continuous education, experimental group, EXP, n = 16), or maintenance of the original "conventional" therapy (control group, CON, n = 5). At entry to the study, all 21 IDDM-patients had subnormal neuroendocrine and symptom responses, and less deterioration of cognitive function during hypoglycaemia. After intensive insulin therapy in EXP, the frequency of hypoglycaemia decreased from 0.5 +/- 0.05 to 0.045 +/- 0.02 episodes/patient-day; HbA1c increased from 5.83 +/- 0.18 to 6.94 +/- 0.13% (range in non-diabetic subjects 3.8-5.5%) over a 1-year period; all counterregulatory hormone and symptom responses to hypoglycaemia improved between 2 weeks and 3 months with the exception of glucagon which improved at 1 year; and cognitive function deteriorated further as early as 2 weeks (p < 0.05). The improvement in responses was maintained at 1 year. The improvement in plasma adrenaline and symptom responses inversely correlated with IDDM duration. In contrast, in CON, neither frequency of hypoglycaemia, nor neuroendocrine responses to hypoglycaemia improved. Thus, meticulous prevention of hypoglycaemia by intensive insulin therapy reverses hypoglycaemia unawareness even in patients with long-term IDDM, and is compatible with long-term near-normoglycaemia. Because carefully conducted intensive insulin therapy reduces, not increases the frequency of moderate/severe hypoglycaemia, intensive insulin therapy should be extended to the majority of IDDM patients in whom it is desirable to prevent/delay the onset/progression of microvascular complications.

To assess the relative roles of insulin and hypoglycaemia on induction of neuroendocrine responses, symptoms and deterioration of cognitive function (12 cognitive tests) during progressive decreases in plasma glucose, and to quantitate glycaemic thresholds, 22 normal, non-diabetic subjects (11 males, 11 females) were studied on four occasions: prolonged fast (n = 8, saline euglycaemia study, SA-EU), stepped hypoglycaemia (plasma glucose plateaus of 4.3, 3.7, 3 and 2.3 mmol/l) or euglycaemia during insulin infusion at 1 and 2 mU.kg-1.min-1 (n = 22, high-insulin hypoglycaemia and euglycaemia studies, HI-INS-HYPO and HI-INS-EU, respectively), and stepped hypoglycaemia during infusion of insulin at 0.35 mU.kg-1.min-1 (n = 9, low-insulin hypoglycaemia study, LO-INS-HYPO). Insulin per se (SA-EU vs HI-INS-EU), suppressed plasma glucagon (approximately 20%) and pancreatic polypeptide (approximately 30%), whereas it increased plasma noradrenaline (approximately 10%, p < 0.05). Hypoglycaemia per se (HI-INS-HYPO vs HI-INS-EU) induced responses of counterregulatory hormones (CR-HORM), symptoms and deteriorated cognitive function. With the exception of suppression of endogenous insulin secretion, which had the lowest glycaemic threshold of 4.44 +/- 0.06 mmol/l, pancreatic polypeptide, glucagon, growth hormone, adrenaline and cortisol had similar glycaemic thresholds (approximately 3.8-3.6 mmol/l); noradrenaline (3.1 +/- 0.0 mmol/l), autonomic (3.05 +/- 0.06 mmol/l) and neuroglycopenic (3.05 +/- 0.05 mmol/l) symptoms had higher thresholds. All 12 tests of cognitive function deteriorated at a glycaemic threshold of 2.45 +/- 0.06 mmol/l, but 7 out of 12 tests were already abnormal at a glycaemic threshold of 2.89 +/- 0.06 mmol/l. Although all CR-HORM had a similar glycaemic threshold, the lag time of response (the time required for a given parameter to increase) of glucagon (15 +/- 1 min) and growth hormone (14 +/- 3 min) was shorter than adrenaline (19 +/- 3 min) and cortisol (39 +/- 4 min) (p < 0.05). With the exception of glucagon (which was suppressed) and noradrenaline (which was stimulated), insulin per se (HI-INS-HYPO vs LO-INS-HYPO) did not affect the responses of CR-HORM, and did not influence the symptoms or the cognitive function during hypoglycaemia. Despite lower responses of glucagon, adrenaline and growth hormone (but not thresholds) in females than males, females were less insulin sensitive than males during stepped hypoglycaemia.

Chronic hyperglycaemia and recurrent severe hypoglycaemia have both been implicated as causing cerebral damage in patients with diabetes. Although cognitive dysfunction and intellectual impairment have been demonstrated in patients with recurrent severe hypoglycaemia, structural correlates have not been described, and it is not known whether specific functional changes occur in the brains of affected patients. Regional cerebral blood flow was estimated by SPECT with 99mTechnetium Exametazime in 20 patients with IDDM. Ten patients had never experienced severe hypoglycaemia and 10 had a history of recurrent severe hypoglycaemia. Patient results were compared with 20 age- and sex-matched healthy volunteers. We observed differences between the two patient groups and the control group. Tracer uptake was greater in diabetic patients in the superior pre-frontal cortex. This effect was particularly pronounced in the group who had a history of previous severe hypoglycaemia. Patients with a history of recurrent hypoglycaemia also had a relative reduction in tracer uptake to the calcarine cortex. This suggests an alteration in the pattern of baseline regional cerebral blood flow in diabetic patients with frontal excess and relative posterior reduction in cerebral blood flow.

The allocation of hypoglycaemic symptoms to autonomic or neuroglycopenic groups tends to occur on an a priori basis. In view of the practical need for clear symptom markers of hypoglycaemia more scientific approaches must be pursued. Substantial evidence is presented from two large scale studies we performed which support a three factor model of hypoglycaemic symptomatology, based on the statistical associations discovered among symptoms reported by diabetic patients. Study 1 involved 295 insulin-treated out-patients and found that 11 key hypoglycaemic symptoms segregated into three clear factors: autonomic (sweating, palpitation, shaking and hunger) neuroglycopenic (confusion, drowsiness, odd behaviour, speech difficulty and incoordination), and malaise (nausea and headache). The three factors were validated on a separate group of 303 insulin-treated diabetic out-patients. Confirmatory factor analyses showed that the three factor model was the optimal model for explaining symptom covariance in each group. A multi-sample confirmatory factor analysis tested the rigorous assumptions that the relative loadings of symptoms on factors across groups were equal, and that the residual variance for each symptom was identical across groups. These assumptions were successful, indicating that the three factor model was replicated in detail across these two large samples. It is suggested that the results indicate valid groupings of symptoms that may be used in future research and in clinical practice.

To examine the long-term effects of recurrent severe hypoglycaemia and other biomedical complications on mental efficiency, a battery of cognitive tests was administered to 142 Type 1 (insulin-dependent) diabetic adult patients (age 33.5 +/- 5.6 years; mean +/- SD) and 100 demographically similar non-diabetic control subjects. All diabetic subjects had been diagnosed before the age of 17 years. Diabetic subjects with one or more complications (distal symmetrical polyneuropathy; advanced background or proliferative retinopathy; overt nephropathy; one or more episodes of severe hypoglycaemia) performed significantly (p < 0.001) more poorly than non-diabetic control subjects on tests requiring sustained attention, rapid analysis of visuospatial detail, and hand eye co-ordination. Regression analyses indicated that the best biomedical predictor of cognitive test performance was a diagnosis of polyneuropathy. Although severe recurrent hypoglycaemia was not associated with performance on any test, the neuropathy x recurrent hypoglycaemia interaction term was significant. These results suggest that in adults with Type 1 diabetes of long duration, recurrent hypoglycaemia does not appear to influence cognitive performance directly, but may interact with neuropathy to exaggerate or otherwise magnify the extent of neurobehavioural dysfunction.

A low blood glucose level is associated with impairment of higher cerebral function and an increase in cerebral blood flow. This study examined whether there are differences in the physiological responses to hypoglycaemia between the cerebral hemispheres. Eight healthy men participated in two hyperinsulinaemic glucose clamp studies: after 60 min at 4.5 mmol/l, blood glucose was either lowered to 2.0 mmol/l and "clamped" there for 60 min (hypoglycaemia) or continuously maintained at 4.5 mmol/l (euglycaemia). Cardiac output, middle cerebral artery velocity (transcranial Doppler) and cerebral blood flow (133-xenon inhalation) were measured during the studies. Neuropsychological tests were used to determine whether hypoglycaemia caused differential impairment of hemispheric cognitive function. Hypoglycaemia was associated with symmetrical impairment of cognitive function in both cerebral hemispheres and a rise in cardiac output (from 5.5 [0.2] to 8.7 [0.2] l.min-1, p < 0.0001, mean [standard error]), middle cerebral artery velocity (from 55 [2.6] to 64 [2.8] cm.s-1, p < 0.002), and global cerebral blood flow (from 56 [2.6] to 69 [2.9] ml.100 g-1.min-1, p < 0.005 compared to pre-insulin values). There were no differences in the blood flow response during hypoglycaemia between hemispheres and the increase in blood flow did not correlate with either the change in cardiac output or rise in plasma catecholamine levels. After 120 min of hyperinsulinaemic, euglycaemia, global cerebral blood flow rose significantly above baseline (from 58 [2.4] to 63 [2.2] ml.100 g-1.min-1, p < 0.05). In conclusion, using the techniques described, the physiological and cognitive responses of each cerebral hemisphere to hypoglycaemia were symmetrical.(ABSTRACT TRUNCATED AT 250 WORDS)

Unlabelled: Eight Type 1 (insulin-dependent) diabetic patients with no diabetic complications were studied on two consecutive and one subsequent overnight occasions. The aim was to evaluate the influence of nocturnal hypoglycaemia on neuropsychological and reaction time tests the following morning. Hypoglycaemia was induced by i.v. insulin infusion, blood glucose nadir was 1.5 +/- 0.3 mmol/l. Duration of hypoglycaemia (blood glucose less than 3 mmol/l) was 101 +/- 38 min. Whole night sleep statistics for all patients showed no statistical differences between the normoglycaemic and hypoglycaemic nights, however, there was a tendency of prolongation of the second sleep cycle in the nights with hypoglycaemia. Each patient was used as his own control and periods with blood glucose concentration less than 3 mmol/l were compared to exactly the same periods in nights with blood glucose level over 5 mmol/l. During hypoglycaemia the amount of deep sleep was reduced and replaced by superficial sleep and arousals of short duration. Further, the reduction in deep sleep was replaced later at night. Neuropsychological test scores and reaction time measurements in the morning showed no differences between the normoglycaemic and hypoglycaemic nights., In Conclusion: despite sleep disturbances, nocturnal hypoglycaemia did not impair cognitive function the following morning in Type 1 (insulin-dependent) diabetic patients.

To determine whether the degree of previous glycaemic control may modify cognitive responses to hypoglycaemia, the glycaemic thresholds for, and magnitude of cognitive dysfunction as assessed by P300 event-related potentials as well as subjective and hormonal responses during hypoglycaemia were evaluated. Hypoglycaemia was induced by intravenous insulin infusion in 18 Type 1 (insulin-dependent) diabetic patients, 7 of whom were strictly controlled (HbA1c: 6.3 +/- 0.3%; mean +/- SEM; Group 1) and 11 of whom were poorly controlled (HbA1c: 9.1 +/- 0.4%; Group 2). Within 60 min, mean blood glucose declined from 5.6 and 5.7 mmol/l (baseline) to a nadir of 1.6 and 1.8 mmol/l followed by an increase to 5.6 and 4.3 mmol/l after 120 min in Group 1 and 2, respectively. There was no significant difference between the groups in regard to P300 latency at baseline, but between 50 and 70 min a significant prolongation of this component was noted in Group 2 as compared with Group 1 at blood glucose levels between 1.6 and 2.3 mmol/l (p less than 0.05). The glycaemic thresholds at which a significant increase of P300 latency over baseline was first noted were 1.6 +/- 0.2 mmol/l in Group 1 and 3.5 +/- 0.2 mmol/l in Group 2 (p less than 0.05). The glucose thresholds at which this prolongation was no longer demonstrable were 1.9 +/- 0.1 mmol/l in Group 1 and 3.8 +/- 1.4 mmol/l in Group 2, respectively (p less than 0.05). The glycaemic threshold at which the P300 amplitude was first significantly reduced was 2.2 mmol/l in Group 2, whereas no such reduction was observed in Group 1.(ABSTRACT TRUNCATED AT 250 WORDS)

To examine the hypothesis that episodes of severe hypoglycaemia may cause cumulative cognitive impairment. 100 Type 1 (insulin-dependent) diabetic patients were examined. Their age range was 25-52 years, and the onset of diabetes had occurred after the age of 19 years. Patients with evidence of organic brain disease, including cerebrovascular disease, were excluded. A questionnaire was used to assess the number, frequency and severity of hypoglycaemic episodes experienced during treatment with insulin and the accuracy of this retrospective information was verified from general practice and hospital case-notes. A detailed neuropsychological assessment was undertaken, including tests of pre-morbid and present IQ (Wechsler-Revised), memory and information-processing speed. Significant correlations were observed between the frequency of severe hypoglycaemia and the magnitude of intellectual decline, Performance IQ, inspection time and reaction time (patients with the more frequent hypoglycaemia had poorer performance). Two sub-groups of patients were identified on the basis of their experience of severe hypoglycaemia, and were balanced for pre-morbid IQ, age and duration of diabetes. One sub-group (n = 23) had never experienced severe hypoglycaemia (Group A), whilst the other sub-group (n = 24) had suffered at least five episodes of severe hypoglycaemia (Group B). Group B had greater intellectual impairment than Group A, and Group B also had a significantly slower mean reaction time and higher reaction time variance when compared with Group A.

Seventeen Type 1 (insulin-dependent) diabetic patients with a history of recurrent and severe hypoglycaemia and Type 1 diabetic patients with no severe hypoglycaemia were compared as regarded performances in tests of neuropsychological functioning. To test the hypothesis that recurrent severe hypoglycaemia gives rise to permanent cognitive impairment, the study group was selected among those patients who had met with repeated attacks over the last three years or more as identified by a questionnaire among almost 600 insulin-treated diabetic patients. The comparison group without known severe reactions were comparable to the study group with respect to type of diabetes, sex, age, age at onset, duration of diabetes, socio-economic parameters, and prevalence of neuropathy and retinopathy. The results indicate that Type 1 diabetic patients with recurrent severe hypoglycaemia scored lower than those without severe hypoglycaemia in tests of motor ability, short-term and associative memory and visuospatial tasks assessing ability in general problem-solving. Type 1 diabetic patients with severe hypoglycaemia also displayed a higher frequency of perspective reversals suggesting frontal-lobe involvement. These data can be interpreted in two ways. One interpretation implies that the cognitive impairment of Type 1 diabetic patients with severe hypoglycaemia reflects a selection factor, the other that recurrent episodes of severe hypoglycaemia result in permanent cognitive impairment.

In diabetes, loss of awareness of and a defective hormonal response to hypoglycaemia have been associated with long disease duration, improved glycaemic control and possibly a change in insulin species. In contrast it is assumed that normal subjects always have symptoms when their blood glucose is low. We have tested this in 7 normal subjects at 3 levels of blood glucose (4.5, 3.5 and 3.0 mmol/l) using a hyperinsulinaemic glucose clamp with a euglycaemic (4.5 mmol/l) clamp as a control. After 60 min at a blood glucose of 3.5 mmol/l adrenaline and glucagon increased slightly but significantly, whereas cortisol, growth hormone and pancreatic polypeptide were unchanged. As soon as glucose was lowered to 3.0 mmol/l adrenaline increased to 1.10 nmol/l and rose further to 1.43 nmol/l after 60 min. Glucagon secretion increased similarly but other counter-regulatory hormones were significantly raised only after 60 min at 3.0 mmol/l. Awareness of hypoglycaemia (symptom score) increased after 40 min at a blood glucose of 3.0 mmol/l but after 60 min decreased to baseline levels with loss of awareness in 5 subjects. Reaction time improved in parallel with the change in symptom score. Thus, despite high levels of adrenaline, normal subjects lose awareness during sustained mild hypoglycaemia. Improved reaction time may reflect cerebral adaptation.