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Hypoglycemia is a common adverse reaction to glucose-lowering treatment. Diabetes mellitus (DM) combined with recurrent nonsevere hypoglycemia (RH) can accelerate cognitive decline. Currently, the metabolic pattern changes in cognition-related brain regions caused by this combined effect of DM and RH (DR) remain unclear. In this study, we first characterized the metabolic profiles of the hippocampus in mice exposed to DR using non-targeted metabolomic platforms. Our results showed that DR induced a unique metabolic pattern in the hippocampus, and several significant differences in metabolite levels belonging to the histidine metabolism pathway were discovered. Based on these findings, in the follow-up experiment, we found that histidine treatment could attenuate the cognitive impairment and rescue the neuronal and synaptic damage induced by DR in the hippocampus, which are closely related to ameliorated mitochondrial injury. These findings provide new insights into the metabolic mechanisms of the hippocampus in the progression of DR, and l-histidine supplementation may be a potential metabolic therapy in the future., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Aim: The objective of the CRASH (Conversations and Reactions Around Severe Hypoglycemia) survey was to further our understanding of the characteristics, experience, behavior and conversations with healthcare professionals (HCPs) of people with diabetes (PWD) receiving insulin, and of caregivers (CGs) caring for such people, concerning hypoglycemia requiring external assistance (severe hypoglycemic events [SHEs])., Methods: CRASH was an online cross-sectional survey conducted across eight countries. PWD with self-reported type 1 (T1D) or insulin-treated type 2 (T2D) diabetes were aged≥18 years and had experienced one or more SHEs in the past 3 years; CGs were non-medical professionals aged ≥18 years, caring for PWD meeting all the above criteria except for PWD age (≥4 rather than ≥18 years). The present report is a descriptive analysis of data from France., Results: Among PWD who had ever discussed SHEs with an HCP, 38.9% of T1D PWD and 50.0% of T2D PWD reported that SHEs were discussed at every consultation; 26.3% and 8.8%, respectively, had not discussed the most recent SHE with an HCP. In total, 35.7% of T1D PWD and 53.8% of T2D PWD reported that glucagon was not available to them at the time of their most recent SHE. Only 16.9% of T1D PWD and 6.5% of T2D PWD who had discussed their most recent SHE with an HCP reported that the HCP recommended obtaining a glucagon kit or asked them to confirm that they already had one. High proportions of PWD and CGs reported that the most recent SHE had made them feel unprepared, scared and helpless and had affected mood, emotional state and activities., Conclusion: CRASH survey data from France identify a need for greater discussion about SHEs between HCPs and PWD and the CGs of such people, and reveal gaps in the diabetes education of PWDs and CGs., (Copyright © 2021 Eli Lilly and Company. Published by Elsevier Masson SAS.. All rights reserved.)

Background and Aims: Hypoglycemia represents a relevant burden in people with diabetes. Consequences of hypoglycemia/fear of hypoglycemia on quality of life (QoL) and behaviors of patients with T1DM and T2DM were assessed., Methods and Results: HYPOS-1 was an observational retrospective study. Fear of hypoglycemia (Fear of Hypoglycemia Questionnaire, FHQ), general health status (visual analog scale of EuroQol questionnaire, EQ5D-VAS) psychological well-being (WHO-5 well being index, WHO-5), diabetes related distress (Problem Areas in Diabetes 5, PAID-5), and corrective/preventive behaviors following hypoglycemia were compared between people with and without previous experience of severe and symptomatic hypoglycemia and by tertiles of FHQ scores. A multivariate analysis was performed to identify factors associated with the likelihood of being in the third tertile of FHQ score. Overall, 2229 patients were involved. Severe hypoglycemia had statistically significant and clinically relevant (measured as effect sizes) negative impact on EQ5D-VAS, WHO-5, PAID-5, and FHQ both in T1DM and T2DM. In T2DM, symptomatic episodes had similar impact of severe hypoglycemia. Moving from the first to the third FHQ tertile, lower scores of EQ-5D VAS and WHO-5, and higher levels of PAID-5 were found. Patients in the third tertile performed more frequently corrective/preventive actions that negatively impact on metabolic control. Previous hypoglycemia, insulin treatment, female gender, age, and school education were the independent factors associated with increased likelihood to be in the third tertile., Conclusion: Not only severe but also symptomatic hypoglycemia negatively affect patient QoL, especially in T2DM. Addressing fear of hypoglycemia should be a goal of diabetes education., (Copyright © 2019 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background: The effectiveness of real-time continuous glucose monitoring (rtCGM) in avoidance of hypoglycaemia among high-risk individuals with type 1 diabetes treated with multiple daily insulin injections (MDI) is unknown. We aimed to ascertain whether the incidence and severity of hypoglycaemia can be reduced through use of rtCGM in these individuals., Methods: The HypoDE study was a 6-month, multicentre, open-label, parallel, randomised controlled trial done at 12 diabetes practices in Germany. Eligible participants had type 1 diabetes and a history of impaired hypoglycaemia awareness or severe hypoglycaemia during the previous year. All participants wore a masked rtCGM system for 28 days and were then randomly assigned to 26 weeks of unmasked rtCGM (Dexcom G5 Mobile system) or to the control group (continuing with self-monitoring of blood glucose). Block randomisation with 1:1 allocation was done centrally, with the study site as the stratifying variable. Masking of participants and study sites was not possible. Control participants wore a masked rtCGM system during the follow-up phase (weeks 22-26). The primary outcome was the baseline-adjusted number of hypoglycaemic events (defined as glucose ≤3·0 mmol/L for ≥20 min) during the follow-up phase. The full dataset analysis comprised participants who wore the rtCGM system during the baseline and follow-up phases. The intention-to-treat analysis comprised all randomised participants. This trial is registered with ClinicalTrials.gov, number NCT02671968., Findings: Between March 4, 2016, and Jan 12, 2017, 149 participants were randomly assigned (n=74 to the control group; n=75 to the rtCGM group) and 141 completed the follow-up phase (n=66 in the control group, n=75 in the rtCGM group). The mean number of hypoglycaemic events per 28 days among participants in the rtCGM group was reduced from 10·8 (SD 10·0) to 3·5 (4·7); reductions among control participants were negligible (from 14·4 [12·4] to 13·7 [11·6]). Incidence of hypoglycaemic events decreased by 72% for participants in the rtCGM group (incidence rate ratio 0·28 [95% CI 0·20-0·39], p<0·0001). 18 serious adverse events were reported: seven in the control group, ten in the rtCGM group, and one before randomisation. No event was considered to be related to the investigational device., Interpretation: Usage of rtCGM reduced the number of hypoglycaemic events in individuals with type 1 diabetes treated by MDI and with impaired hypoglycaemia awareness or severe hypoglycaemia., Funding: Dexcom Inc., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Aim: This study examines whether the short-term use of a continuous glucose monitor (CGM) can reduce the fear of hypoglycaemia in individuals with type 1 diabetes mellitus (T1DM)., Methods: Twelve participants with T1DM were fitted with a Guardian® REAL-Time CGM and assigned to either an alarm (low glucose alarm set at 4.5 mmol/L) or no alarm condition for 3 days, with both treatments administered following a counterbalanced study design. The participants completed the Hypoglycaemia Fear Survey on three separate occasions, before their CGM was fitted as well as following the alarm and no alarm conditions., Results: The alarm treatment reduced the incidence of hypoglycaemic episodes (CGM readings≤3.5 mmol/L; 1.1±0.5 versus 1.9±0.5; mean±SEM) and the relative time spent below this hypoglycaemic threshold (0.9±0.4% versus 2.6±1.0%) but did not alter the fear of hypoglycaemia (78.6±7.0, 75.8±5.2 and 79.3±5.8 at baseline and following the alarm and no alarm treatments, respectively; p>0.05). CGM overestimated blood glucose levels by 0.8±0.2 mmol/L for blood glucose readings less than, or equal to, 5 mmol/L., Conclusions: Short-term use of the Guardian® REAL-Time CGM has no clinically significant effect on fear of hypoglycaemia possibly due, in part, to the inaccuracies of CGMs at low blood glucose levels., (Copyright © 2011 Primary Care Diabetes Europe. All rights reserved.)

Objective: The objective of this study was to evaluate the impact of initiation of insulin therapy, metabolic control and structured patient education on the diabetes-related quality of life (QoL) in insulin-treated patients with type 2 diabetes mellitus., Methods: This prospective study was conducted with 71 consecutively recruited patients with insulin-treated diabetes at the University hospital. All patients participated an inpatient diabetes treatment and teaching program (DTTP) for conventional insulin therapy (mean age 68.9 years, HbA1c 10.1+/-1.4%, diabetes duration 11.2 years (range: 0-25.5 years), body-mass-index 28.7+/-5.7 kg/m(2). Diabetes-related quality of life was assessed before and 6 months after participation in the DTTP using the standardized questionnaire of Lohr analysing the subscales: social relations, physical complaints, worries about the future, dietary restrictions, fear of hypoglycaemia, and daily struggles., Results: Only patients switched on insulin therapy showed significant improvement in diabetes-related quality of life 6 months after participation in the DTTP (p=0.03), fewer physical complaints (p=0.03), fewer worries about the future (p=0.02), fewer daily struggles (p=0.01) and less fear of hypoglycaemia (p<0.001), while patients, who were already on insulin therapy showed no improvements in diabetes-related quality of life. Though, residual analysis reveals that effects on patients' QoL are mainly caused by improvements in metabolic control., Conclusions: Improvements in metabolic control have a significant effect on different diabetes-related quality of life domains in patients with diabetes mellitus., Practice Implications: Appropriate interventions resulting in better metabolic control, such as starting on insulin therapy within a structured patient education program seem to be an effective approach to improve patients' diabetes-related quality of life.

Objective: The objective of this study was to evaluate the psychometric properties of the Swedish version of the Hypoglycaemia Fear Survey (Swe-HFS) for use among Swedish-speaking patients with type 1 diabetes., Methods: The HFS was translated using the forward-backward translation method and was thereafter answered by 325 type 1 patients. The psychometric properties were investigated using exploratory factor analysis, Cronbach's alpha, content and convergent validity., Results: The factor analysis showed that a three-factor solution was reasonable with the subscales Behaviour/Avoidance (10 items), Worry (6 items) and Aloneness (4 items). Cronbach's alpha coefficient for the total score was 0.85. The result also supports the instrument's content validity and convergent validity., Conclusion: The Swedish version of the HFS appears to be a reliable and valid instrument for measuring fear of hypoglycaemia (FoH) in type 1 patients., Practice Implications: The results from this study suggest that the Swe-HFS, an instrument that is brief and easy to administer, may be valuable in clinically assessing FoH among patients with type 1 diabetes.

Objective: In many individuals with diabetes, the unpleasant symptoms and negative consequences associated with hypoglycemia may result in significant anxiety or even a fear of hypoglycemia (FoH). This fear may have significant clinical implications for diabetes management. The aim of this review is to integrate existing research on FoH (its measurement, predictors, correlates, impact and treatment) and discuss its implications for diabetes management and patient education., Methods: A literature search was conducted using Medline and Embase. The search was limited to journal articles published in English from 1985 to 2007 inclusive. Three hundred and one abstracts were reviewed and 273 were rejected on the basis of non-relevance. In addition to the 28 papers included, six additional papers were identified by further searches and were added to this review., Results: FoH appears to be a widespread phenomenon. It is measured primarily through the use of a specific scale, the Hypoglycemic Fear Survey (HFS). There are a number of factors that relate to whether an individual is likely to develop FoH including whether there is a history of hypoglycemia in an individual, length of time since first insulin treatment, and a higher level of variability in blood glucose level. FoH has been linked to both state and trait anxiety although the relationship is complex., Conclusions: There is evidence that FoH may have a significant negative impact on diabetes management, metabolic control and subsequent health outcomes. There is evidence that blood glucose (BG) awareness training and CBT can reduce levels of fear and improve disease management. More research is needed on how FoH arises and the individual variables which predict its development. In addition, well designed research is required to better understand the behavioral and medical impact of FoH, and interventions to reduce it., Practice Implications: There is some evidence to suggest that interventions including BG awareness training and cognitive behavioral therapy can reduce levels of fear and improve disease management. While many aspects of FoH require further well-designed research, it is evident that this phenomenon can have a major impact on diabetes management and needs to be specifically addressed in patient education programs.

A case of a detained person (DP) suffering from insulin-dependent diabetes, who subsequently used the disorder in his defence as a reason to claim automatism, is discussed. The legal and medical history of automatism is outlined along with the present day situation. Forensic physicians should be aware when examining any diabetic that automatism may subsequently be claimed. With this in mind, the importance of relevant history taking specifically relating to diabetic control and symptoms is discussed.

Hypoglycemia has been shown to impair cognitive and psychomotor function, but it has been unclear which measures are most reliable and sensitive for detecting these effects. In a single-blind repeated measures design, healthy young adults (N=17, 8 male, mean age 27 years) performed three PC-based cognitive and psychomotor function tests: a paced auditory serial addition task (PASAT), an adaptive five-choice reaction time test (CRTT), and a manual tracking test on two occasions 4 weeks apart. In each session, a hyperinsulinemic clamp method was used during a normoglycemic (plasma glucose: 4.7 mmol/l) baseline testing period, followed in one session by a normoglycemic target testing period, and in the other session by a hypoglycemic (2.7 mmol/l) target testing period. All cognitive and psychomotor function measures showed high test-retest reliability (r ranging from.69 to.95) and sensitivity to hypoglycemia (P<.01). A new finding is that on the PASAT, hypoglycemia appears to differentially increase the rate of omission errors more than it increases false responses. Data on PASAT reaction time (RT) are also presented.

The hazardous consequences of drinking alcohol by persons receiving insulin treatment is indicated by clinical reports, but little controlled research has investigated the combination of hypoglycemia and ethanol intoxication. Ethanol's effect on spontaneous motor activity (SMA, detected by Opto-Varimax activity meters) in hypoglycemic (HG) rats was determined over a range of ethanol doses in two experiments. Combinations of insulin and ethanol were administered intraperitoneally to moderately food-deprived rats. Blood glucose was measured before and after a 30-min SMA-monitoring period. In Experiment 1, ethanol doses of 300, 600 and 1200 mg/kg were combined with insulin at doses 0.5 and 2 U/kg. A second experiment tested a narrower range of drug doses (ethanol 600 and 1200 mg/kg, insulin 1 U/kg) under slightly different procedures. After insulin treatment, blood-glucose levels dropped to approximately 40-60% of control levels and this HG was accompanied by decreased SMA. Ethanol did not influence blood-glucose levels, nor did it potentiate the HG produced by insulin. Combination of HG and the highest ethanol dose potentiated the SMA-depressant effect in both experiments, whereas lower ethanol doses partially reversed the suppression of motor activity in HG rats.

This study investigated fear of hypoglycaemia among insulin-treated Chinese patients in Hong Kong. The study employed a cross-sectional descriptive design. Using structured-interviews, the authors collected data from 120 insulin-treated adults attending a diabetes centre. Results showed that although hypoglycaemic attacks were generally mild, they were common amongst one-third of patients. Fear was predominantly low, however 15% of respondents reported high fear. In addition, fear correlated positively with time since insulin-treatment, frequency of hospitalization due to hypoglycaemia, and frequency of hypoglycaemia affecting working life. Results also showed that although all respondents were insulin-treated, 40% had undesirable metabolic control. No statistically significant differences were found between the respondents' rating of adequacy of their diabetes knowledge among three groups of respondents who had completed, defaulted or were attending an education programme. Implications for diabetes patient education and further study are discussed.

Unlabelled: This study investigated how hypoglycaemia affects mood, whether psychological characteristics mediate an emotional disturbance during hypoglycaemia. Ten IDDM patients (1 female) were studied, aged [mean (range)] 28 (20-37) years, body mass index (BMI) 23.4 (19.6-25.7) kg/m2, diabetes duration 11 (7-15) years, HbA1c 7.5 (6.0-8.7)%. Patients underwent a standardized stepwise, hypoglycaemic, hyperinsulinaemic clamp, performed in steps of 0.5 mmol/l from 4.0 mmol/l to a glucose nadir of 2.0 mmol/l. At euglycaemia, the Symptom Checklist-90 (SCL-90) was administered. The Profile of Mood States (POMS) was completed at 4.0 and 2.5 mmol/l, while the feelings chart of the COOP/WONCA was filled out at euglycaemia and all hypoglycaemic steps., Results: The t-test for the POMS demonstrated a significant increase for anger (P < 0.05). COOP/WONCA scores displayed a progressive negative change in mood for each hypoglycaemic step, albeit with a large interindividual variability. Hostility (SCL-90) significantly interacted with anger (POMS) at 2.5 mmol/l (P < 0.05)., Conclusions: Progression of hypoglycaemia negatively alters the overall mood state. IDDM patients characterised by high scores on hostility (SCL-90) apparently are more prone to experience an increase in anger (POMS) during hypoglycaemia.

Hypoglycaemia without warning is a dangerous complication of insulin-dependent diabetes mellitus and it limits the use of intensified insulin therapy to reduce chronic diabetic complications. To investigate the possibility of restoring awareness; symptomatic, cognitive, and hormonal responses to controlled hypoglycaemia were studied in insulin-dependent diabetic patients with long disease duration (6 with good glycaemic control and 6 with poor control) before and after hypoglycaemia avoidance. At the start of the study, all had loss of hypoglycaemia awareness. Responses to the initial challenge were small (pooled area under curve [AUC] adrenaline 5.75 [SE 0.07] nmol/L per 260 min, pooled AUC symptom score 80 [1.3]) and only started when plasma glucose was significantly lower than the 2.8 (0.1) mmol/L at which cognitive function deteriorated. After 4.1 (1.1) months' scrupulous hypoglycaemia avoidance, hormone and symptom responses to the challenge were increased (AUC adrenaline 15.9 [0.1] nmol/L per 260 min, p = 0.01; AUC symptom score 275 [7], p < 0.001), starting at plasma glucose concentrations significantly higher than that causing cognitive dysfunction. Glycosylated haemoglobin did not deteriorate significantly. We conclude that the normal hierarchy of subjective awareness before cognitive dysfunction during hypoglycaemia can be restored by avoiding hypoglycaemia. This is independent of disease duration or initial metabolic control.

Reactive hypoglycemia is a relatively uncommon meal-induced hypoglycemic disorder. Most patients with adrenergic-mediated symptoms have a diagnosis other than reactive hypoglycemia. In many patients with this self-diagnosis, other disorders can be attributed as a cause for symptoms, especially neuropsychiatric disease. The continued use of the terminology "functional hypoglycemia" only contributes vagueness to our correct understanding of this metabolic condition. There are a number of conditions associated with postprandial hypoglycemia. One category is the reactive hypoglycemias, which occur in patients with diabetes mellitus (diabetes reactive hypoglycemia), gastrointestinal dysfunction (alimentary reactive hypoglycemia), hormonal deficiency states (hormonal reactive hypoglycemia), and a large patient group characterized as having idiopathic reactive hypoglycemia. Of these causes the alimentary, hormonal, and diabetic patients are less disputed, whereas the idiopathic reactive hypoglycemic group has been referred to as a "nondisease" group. Characteristic alterations in insulin secretion accompany each of these conditions. In bona fide patients, dysinsulinism or hyperinsulinism usually accounts for the hypoglycemia. Some patients may have increased insulin sensitivity, but this association is doubtful or very rare. Patients with this meal-related eating disorder are characterized as ingesting excessive quantities of refined carbohydrate. In the research setting, the disorder can easily be elicited with the oral glucose tolerance test. However, to establish clinical relevance, the hypoglycemia needs documentation in the home setting with measurements of blood glucose during a postpradial symptomatic episode. The reactive hypoglycemic patients are frequently confused with patients with underlying psychiatric illness. Both syndromes are similar, with adrenergic-mediated symptoms and a common characteristic personality as noted on Minnesota Multiphasic Personality Inventory (MMPI) testing. Patients with bona fide meal-related reactive hypoglycemia should be treated primarily with dietary restriction of refined carbohydrates; other patients may require medications.

Artifactual hypoglycemia results from either improper collection of blood samples or interfering substances in the blood. Such artifacts should be easily detected and avoided. Factitious hypoglycemia, on the other hand, results from deliberate subterfuge by the patient and may thus elude proper diagnosis for some time. The most common cause of factitious hypoglycemia is surreptitious injection of insulin, and this is best diagnosed by the triad of hypoglycemia, inappropriately high insulin levels, and low C-peptide levels. Persons with diabetes may also intentionally misuse blood glucose strips to create the impression of hypoglycemia.