The consequences of hypoglycaemia.
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ABSTRACT:
SUBMITTER: Amiel SA
PROVIDER: S-EPMC8012317 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description: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.
| S-EPMC8012314 | biostudies-literature
Project description:INTRODUCTION:In healthy carriers of the T allele of the transcription factor 7-like 2 (TCF7L2), fasting plasma glucagon concentrations are lower compared with those with the C allele. We hypothesised that presence of the T allele is associated with a diminished glucagon response during hypoglycaemia and a higher frequency of severe hypoglycaemia (SH) in type 1 diabetes (T1DM). MATERIAL AND METHODS:This is a post hoc study of an earlier prospective observational study of SH and four mechanistic studies of physiological responses to hypoglycaemia. 269 patients with T1DM were followed in a one-year observational study. A log-linear negative binomial model was applied with events of SH as dependent variable and TCF7L2 alleles as explanatory variable. In four experimental studies including 65 people, TCF7L2 genotyping was done and plasma glucagon concentration during experimental hypoglycaemia was determined. RESULTS:Incidences of SH were TT 0.54, TC 0.98 and CC 1.01 episodes per patient-year with no significant difference between groups. During experimental hypoglycaemia, the TCF7L2 polymorphism did not influence glucagon secretion. DISCUSSION:Patients with T1DM carrying the T allele of the TCF7L2 polymorphism do not exhibit diminished glucagon response during hypoglycaemia and are not at increased risk of severe hypoglycaemia compared with carriers of the C allele.
| S-EPMC5097143 | biostudies-literature
Project description:A large number of inborn errors of metabolism present with hypoglycemia. Impairment of glucose homeostasis may arise from different biochemical pathways involving insulin secretion, fatty acid oxidation, ketone bodies formation and degradation, glycogen metabolism, fructose and galactose metabolism, branched chain aminoacids and tyrosine metabolism, mitochondrial function and glycosylation proteins mechanisms. Historically, genetic analysis consisted of highly detailed molecular testing of nominated single genes. However, more recently, the genetic heterogeneity of these conditions imposed to perform extensive molecular testing within a useful timeframe via new generation sequencing technology. Indeed, the establishment of a rapid diagnosis drives specific nutritional and medical therapies. The biochemical and clinical phenotypes are critical to guide the molecular analysis toward those clusters of genes involved in specific pathways, and address data interpretation regarding the finding of possible disease-causing variants at first reported as variants of uncertain significance in known genes or the discovery of new disease genes. Also, the trio's analysis allows genetic counseling for recurrence risk in further pregnancies. Besides, this approach is allowing to expand the phenotypic characterization of a disease when pathogenic variants give raise to unexpected clinical pictures. Multidisciplinary input and collaboration are increasingly key for addressing the analysis and interpreting the significance of the genetic results, allowing rapidly their translation from bench to bedside.
| S-EPMC9001947 | biostudies-literature
Project description:ObjectiveWhether hypoglycaemia incidentally detected during intercurrent illness in children requires an endocrine workup remains controversial. This study aimed to determine the yield of conducting a diagnostic evaluation in this setting and to compare clinical and biochemical features between patients ultimately diagnosed with a hypoglycaemic disorder and those who were not.DesignSingle-center, retrospective review of children referred to endocrinology between January 2013 and December 2018 for evaluation of hypoglycaemia (defined as plasma glucose<3.9 mmol/L (<70 mg/dL)) in the setting of acute illness.Results145 patients met eligibility criteria. A hypoglycaemia disorder was identified in 12 patients (8% of the cohort, 17% of those who underwent a diagnostic fast). There were no cases in which diagnosis was established in the absence of a diagnostic fast. Characteristics associated with identifying an underlying disorder included younger age (1.03 years (IQR: 0.05-1.54) vs 2.18 years [IQR: 1.29-3.99], p<0.001), higher bicarbonate level (22±5.5 mmol/L vs 16±3.6 mmol/L, p<0.001), lower frequency of elevated plasma or urine ketones (25% vs 92%, p=0.004) and lower frequency of other documented medical problems (17% vs 50%, p=0.03).ConclusionsThe yield of diagnostic evaluation among children with incidental detection of hypoglycaemia in the setting of illness is not insignificant. We thus recommend that all children with hypoglycaemia in the setting of illness undergo guided diagnostic evaluation. Younger age and absence of ketosis and acidosis at presentation may serve as useful predictors for establishing a diagnosis. Future studies are needed to confirm these findings.
| S-EPMC9923327 | biostudies-literature
Project description: Not available
| S-EPMC5643506 | biostudies-literature
Project description:AimsTo examine maternal fear of hypoglycaemia, glycaemia and pregnancy outcomes in women with impaired and normal awareness of hypoglycaemia.MethodsA pre-planned sub-study of 214 pregnant women with type 1 diabetes who participated in the CONCEPTT trial. Participants completed hypoglycaemia fear surveys (HFS-II) at baseline. Logistic regression and Poisson regression analyses were used to obtain an adjusted estimate for the rate ratio relating awareness to the number of severe hypoglycaemic episodes, and for several neonatal outcomes in relation to the total HFS-II score. The role of continuous glucose monitoring (CGM) use was examined.ResultsOverall, 30% of participants reported impaired awareness of hypoglycaemia (n = 64). Women with impaired awareness of hypoglycaemia had more episodes of severe hypoglycaemia (mean 0.44 vs. 0.08, p < 0.001) (12-34 weeks gestation) and scored higher on the HFS-II scale (43.7 vs. 36.0, p 0.008), indicating more fear of hypoglycaemia. They spent more time below range (CGM <3.5 mmol/L) and exhibited more glycaemic variability at 12 weeks gestation. Higher overall HFS-II scores were associated with a higher risk of maternal severe hypoglycaemia episodes (Rate Ratio 1.78, 95% CI 1.39-2.27). Women with impaired awareness of hypoglycaemia had less maternal weight gain but there were no differences in neonatal outcomes between women with impaired awareness of hypoglycaemia and normal hypoglycaemia awareness. Higher HFS-II scores were associated with more nephropathy (Odds Ratio 1.91, 95% CI 1.06-3.4). CGM use after 12 weeks was not associated with the number of episodes of severe hypoglycaemia (RR 0.75, 95% CI 0.49-1.15; p = 0.18).ConclusionsIn pregnant women with type 1 diabetes, impaired awareness of hypoglycaemia is associated with more maternal severe hypoglycaemia episodes and more fear of hypoglycaemia. Having impaired awareness of hypoglycaemia and/or fear of hypoglycaemia should alert clinicians to this increased risk. Reassuringly, there was no increase in adverse neonatal outcomes.
| S-EPMC9305507 | biostudies-literature
Project description:AimAdministration of N-acetyl cysteine (NAC) during hypoglycaemia will preserve the counterregulatory response to subsequent hypoglycaemia in healthy humans.MethodsThis was a randomized double-blind cross over study where humans were given either a 60-minute infusion of NAC (150 mg/kg) followed by a 4-hour infusion of NAC (50 mg/kg) or saline starting 30 minutes before the initiation of a 2-hour hypoglycaemic (HG) clamp at 8 am. After rest at euglycaemia for ~2 hours, subjects were exposed to a 2nd HG clamp at 2 pm and discharged home in euglycaemia. They returned the following day for a 3rd HG clamp at 8 am.ResultsTwenty-two subjects were enrolled. Eighteen subjects completed the entire protocol. The epinephrine response during clamp 3 (171 ± 247 pg/mL) following clamp 1 NAC infusion was lower than the response during the clamp 1 NAC infusion (538 ± 392 pg/mL) (clamp 3 to clamp 1 NAC: P = .0013). The symptom response during clamp 3 (7 ± 5) following clamp 1 NAC infusion was lower than the response during the clamp 1 NAC infusion (16 ± 10) (clamp 3 to clamp 1 NAC: P = .0003). Nine subjects experienced rash, pruritus or nausea during NAC infusion.ConclusionWe found no difference in the hormone and symptom response to experimental hypoglycaemia measured in subjects who were administered NAC as opposed to saline the day before. This observation suggests that further development of NAC as a therapy for impaired awareness of hypoglycaemia in patients with diabetes may be unwarranted.
| S-EPMC7375074 | biostudies-literature
Project description:People with type 1 diabetes and impaired awareness of hypoglycaemia (IAH) are prone to severe hypoglycaemia. Previous attempts to develop non-invasive hypoglycaemia alarm systems have shown promising results, but it is not known if such alarms can detect severe hypoglycaemia in people with IAH. We aimed to explore whether a combination of non-invasive sensors could reliably evaluate hypoglycaemia (plasma glucose (PG) minimum 2.5 mmol/L) in people with IAH. Twenty participants with type 1 diabetes and IAH underwent randomly ordered, single blinded hyperinsulinemic euglycaemic and hyperinsulinemic hypoglycaemic clamps. Sweating, skin temperature, ECG, counterregulatory hormones and symptoms of hypoglycaemia were assessed. Overall, we were not able to detect clamp-induced hypoglycaemia with sufficient sensitivity and specificity for further clinical use. As a post-hoc analysis, we stratified participants according to their ability to identify hypoglycaemic symptoms during hypoglycaemic clamps. Five out of 20 participants could identify such symptoms. These participants had a significantly higher adrenaline response to hypoglycaemia (p < 0.001) and were reliably identified by sensors. Based on our observations, a non-invasive alarm system based on measurement of sweating responses and ECG changes during hypoglycaemia might provide an alert at a plasma glucose concentration around 2.5 mmol/L if an adequate sympatho-adrenal reaction is elicited.
| S-EPMC6170450 | biostudies-literature
Project description:Aims/hypothesisThe aims of this study were to assess cognitions relating to hypoglycaemia in adults with type 1 diabetes and impaired awareness of hypoglycaemia before and after the multimodal HypoCOMPaSS intervention, and to determine cognitive predictors of incomplete response (one or more severe hypoglycaemic episodes over 24 months).MethodsThis analysis included 91 adults with type 1 diabetes and impaired awareness of hypoglycaemia who completed the Attitudes to Awareness of Hypoglycaemia (A2A) questionnaire before, 24 weeks and 24 months after the intervention, which comprised a short psycho-educational programme with optimisation of insulin therapy and glucose monitoring.ResultsThe age and diabetes duration of the participants were 48±12 and 29±12 years, respectively (mean±SD). At baseline, 91% reported one or more severe hypoglycaemic episodes over the preceding 12 months; this decreased to <20% at 24 weeks and after 24 months (p=0.001). The attitudinal barrier 'hyperglycaemia avoidance prioritised' (η2p=0.250, p=0.001) decreased from baseline to 24 weeks, and this decrease was maintained at 24 months (mean±SD=5.3±0.3 vs 4.3±0.3 vs 4.0±0.3). The decrease in 'asymptomatic hypoglycaemia normalised' from baseline (η2p=0.113, p=0.045) was significant at 24 weeks (1.5±0.3 vs 0.8±0.2). Predictors of incomplete hypoglycaemia response (one or more further episodes of severe hypoglycaemia) were higher baseline rates of severe hypoglycaemia, higher baseline scores for 'asymptomatic hypoglycaemia normalised', reduced change in 'asymptomatic hypoglycaemia normalised' scores at 24 weeks, and lower baseline 'hypoglycaemia concern minimised' scores (all p<0.05).Conclusions/interpretationParticipation in the HypoCOMPaSS RCT was associated with improvements in hypoglycaemia-associated cognitions, with 'hyperglycaemia avoidance prioritised' most prevalent. Incomplete prevention of subsequent severe hypoglycaemia episodes was associated with persistence of the cognition 'asymptomatic hypoglycaemia normalised'. Understanding and addressing cognitive barriers to hypoglycaemia avoidance is important in individuals prone to severe hypoglycaemia episodes.Clinical trials registrationwww.isrctn.org : ISRCTN52164803 and https://eudract.ema.europa.eu : EudraCT2009-015396-27.
| S-EPMC9947080 | biostudies-literature
Project description:AIMS/HYPOTHESIS:Impaired awareness of hypoglycaemia (IAH) in type 1 diabetes increases the risk of severe hypoglycaemia sixfold and can be resistant to intervention. We explored the impact of IAH on central responses to hypoglycaemia to investigate the mechanisms underlying barriers to therapeutic intervention. METHODS:We conducted [15O]water positron emission tomography studies of regional brain perfusion during euglycaemia (target 5 mmol/l), hypoglycaemia (achieved level, 2.4 mmol/l) and recovery (target 5 mmol/l) in 17 men with type 1 diabetes: eight with IAH, and nine with intact hypoglycaemia awareness (HA). RESULTS:Hypoglycaemia with HA was associated with increased activation in brain regions including the thalamus, insula, globus pallidus (GP), anterior cingulate cortex (ACC), orbital cortex, dorsolateral frontal (DLF) cortex, angular gyrus and amygdala; deactivation occurred in the temporal and parahippocampal regions. IAH was associated with reduced catecholamine and symptom responses to hypoglycaemia vs HA (incremental AUC: autonomic scores, 26.2 ± 35.5 vs 422.7 ± 237.1; neuroglycopenic scores, 34.8 ± 88.8 vs 478.9 ± 311.1; both p < 0.002). There were subtle differences (p < 0.005, k ≥ 50 voxels) in brain activation at hypoglycaemia, including early differences in the right central operculum, bilateral medial orbital (MO) cortex, and left posterior DLF cortex, with additional differences in the ACC, right GP and post- and pre-central gyri in established hypoglycaemia, and lack of deactivation in temporal regions in established hypoglycaemia. CONCLUSIONS/INTERPRETATION:Differences in activation in the post- and pre-central gyri may be expected in people with reduced subjective responses to hypoglycaemia. Alterations in the activity of regions involved in the drive to eat (operculum), emotional salience (MO cortex), aversion (GP) and recall (temporal) suggest differences in the perceived importance and urgency of responses to hypoglycaemia in IAH compared with HA, which may be key to the persistence of the condition.
| S-EPMC6445483 | biostudies-literature