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Metabolomic associations of impaired awareness of hypoglycaemia in type 1 diabetes.

ABSTRACT: This study investigates impaired awareness of hypoglycaemia (IAH), a complication of insulin therapy affecting 20-40% of individuals with type 1 diabetes. The exact pathophysiology is unclear, therefore we sought to identify metabolic signatures in IAH to elucidate potential pathophysiological pathways. Plasma samples from 578 individuals of the Dutch type 1 diabetes biomarker cohort, 67 with IAH and 108 without IAH (NAH) were analysed using the targeted metabolomics Biocrates AbsoluteIDQ p180 assay. Eleven metabolites were significantly associated with IAH. Genome-wide association studies of these 11 metabolites identified significant single nucleotide polymorphisms (SNPs) in C22:1-OH and phosphatidylcholine diacyl C36:6. After adjusting for the SNPs, 11 sphingomyelins and phosphatidylcholines were significantly higher in the IAH group in comparison to NAH. These metabolites are important components of the cell membrane and have been implicated to play a role in cell signalling in diabetes. These findings demonstrate the potential role of phosphatidylcholine and sphingomyelins in IAH.

SUBMITTER: Varkevisser RDM

PROVIDER: S-EPMC10891160 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

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Metabolomic associations of impaired awareness of hypoglycaemia in type 1 diabetes.

Varkevisser R D M RDM Cecil A A Prehn C C Mul D D Aanstoot H J HJ Paterson A D AD Wolffenbuttel B H R BHR van der Klauw M M MM

Scientific reports 20240223 1

This study investigates impaired awareness of hypoglycaemia (IAH), a complication of insulin therapy affecting 20-40% of individuals with type 1 diabetes. The exact pathophysiology is unclear, therefore we sought to identify metabolic signatures in IAH to elucidate potential pathophysiological pathways. Plasma samples from 578 individuals of the Dutch type 1 diabetes biomarker cohort, 67 with IAH and 108 without IAH (NAH) were analysed using the targeted metabolomics Biocrates AbsoluteIDQ p180 a ...[more]

PMID: 38396205

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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.

Project description:IntroductionClarke, Gold and Pedersen are validated methods to assess awareness of hypoglycaemia. Identifying impaired awareness of hypoglycaemia (IAH) is critical for supporting people with structured education and diabetes technologies, to reduce harm of hypoglycaemia. This study compares the Clarke score, Gold score and Pedersen methods and their correlations with features of hypoglycaemia unawareness and patient characteristics, to evaluate the accuracy of the methods in identifying IAH.MethodsThis retrospective, observational questionnaire-based study collected routine clinical data from 100 people with type 1 diabetes. The questionnaire included the three validated scoring methods, frequency of severe and nocturnal hypoglycaemia, knowledge and worry of hypoglycaemia and hypoglycaemia symptom scores using the Edinburgh Hypoglycaemia Scale. Data were analysed for IAH prevalence and the associations with features of IAH. The concordance of Clarke, Gold and Pedersen methods was evaluated using Spearman's correlation coefficient.ResultsThe prevalence of IAH in this cohort identified by Clarke, Gold and Pedersen methods was 18%, 19% and 61% respectively. The mean autonomic symptom score in people with IAH was significantly reduced using the Clarke method (P = 0.0002) but not on Gold (P = 0.12) and Pedersen methods (P = 0.79). For people with IAH assessed using the Clarke method, scores for night-time worry regarding hypoglycaemia (P = 0.04) and self-reported frequency of nocturnal hypoglycaemia (P = 0.001) were increased. Spearman's correlation coefficients between Pedersen and Clarke and Pedersen and Gold were Rs = 0.555 (P < 0.001) and Rs = 0.645 (P < 0.001) respectively. A moderate association was observed between Clarke and Gold Rs = 0.5669 (P < 0.001).ConclusionWhilst Clarke and Gold methods determined a similar prevalence of IAH, people identified with IAH assessed by the Clarke method had a significant association with the features and characteristics of IAH, including reduced autonomic symptoms. This study suggests that performing more than one score is important for a reliable risk assessment of IAH.

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.

Project description:ObjectiveCopeptin, a marker for stress mirroring vasopressin concentrations, has been shown to increase upon insulin-induced hypoglycaemia in patients after transsphenoidal surgery of pituitary adenomas. Patients with type 1 diabetes mellitus are prone to hypoglycaemia, but no data about copeptin levels upon hypoglycaemia are available. Furthermore, the perception of hypoglycaemia can vary from total unawareness to disabling episodes. The aim of this study was to investigate whether copeptin increases upon hypoglycaemia in patients with type 1 diabetes mellitus and is associated with the degree of hypoglycaemia awareness.Materials and methodsIn this prospective observational study, 17 patients with type 1 diabetes underwent a standardized insulin infusion test. Blood sampling for glucose and copeptin was performed at baseline and after 60 minutes (min). To assess hypoglycaemia associated symptoms the Mood and Symptom Questionnaire (MSQ) was conducted at baseline and after 60 min.ResultsDuring insulin infusion, blood glucose decreased from 5.1 (SD±0.2) to 3.0 (±0.5) mmol/L at 60 min (p<0.001). Copeptin concentrations increased from 3.2 (±1.7) to 3.8 (±1.9) pmol/L (p = 0.03). Mood and Symptoms Questionnaire scores increased from 14 (±3.0) to 18 (±5.8), (p = 0.006). Patients with good hypoglycaemia awareness had an increase in copeptin from 3.0 (±1.8) to 4.2 (±2.4) pmol/L (p = 0.03) in contrast to patients more unaware of hypoglycaemia who only showed an increase in copeptin from 3.3 (±1.6) to 3.6 (±1.4) pmol/L (p = 0.4). There was a trend to a larger copeptin increase in patients aware of hypoglycemia compared to patients unaware of hypoglycemia (p = 0.074).ConclusionCopeptin increases in patients with type 1 diabetes upon insulin induced hypoglycaemia. Interestingly, the copeptin increase seems associated with the degree of hypoglycaemia awareness. This hypothesis warrants further verification.Trial registrationClinicalTrials.gov NCT00515801.

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Metabolomic associations of impaired awareness of hypoglycaemia in type 1 diabetes.

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Metabolomic associations of impaired awareness of hypoglycaemia in type 1 diabetes.

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