Changes in cardiac repolarization during clinical episodes of nocturnal hypoglycaemia in adults with Type 1 diabetes

Aims/hypothesis Experimental hypoglycaemia leads to abnormal cardiac repolarization manifest by a lengthened QT interval and caused by adrenergic stimulation. However it is less clear whether spontaneous clinical episodes lead to similar changes. We have therefore measured cardiac ventricular repolarization and counterregulatory responses in patients with Type 1 diabetes during hypoglycaemic and euglycaemic nights.Methods We studied 22 patients with Type 1 diabetes (mean age 40.4±17.2 years, duration of diabetes 17.2±9.3 years, HbA1c 8.2±1.2% overnight). Measurements were taken hourly of blood glucose, plasma potassium, catecholamines and high resolution electrocardiograms.Results Hypoglycaemia (blood glucose level <2.5 mmol/l) occurred on 7 of the 22 nights. During overnight hypoglycaemia, QTc interval increased by 27 ms (±15) above baseline, compared with 9 ms (±19) during nights with no nocturnal hypoglycaemia (p=0.034, 95%CI 2, 35). Adrenaline increased by 0.33 nmol/l (±0.21) above baseline during hypoglycaemia, compared with –0.05 nmol/l (±0.08) during euglycaemia (p=0.001, 95%CI 0.19, 0.56 nmol/l). There was no significant difference between potassium, and noradrenaline concentrations between the two groups.Conclusion/interpretation QTc interval lengthens significantly during spontaneous nocturnal hypoglycaemia. Increases are generally less than those observed during experimental hypoglycaemia and could reflect attenuated sympathoadrenal responses during clinical episodes. The clinical relevance of these changes is uncertain but is consistent with the hypothesis that clinical hypoglycaemia can cause abnormal cardiac repolarization and an attendant risk of cardiac arrhythmia.Abbreviations ECG electrocardiogram     

The impact of metabolic control and QTc prolongation on all-cause mortality in patients with type 2 diabetes and foot ulcers

Aims/hypothesis

The increased all-cause mortality in patients with chronic diabetic foot ulcers cannot fully be explained by traditional cardiovascular risk factors. The significance of heart-rate-corrected QT (QTc) prolongation, a finding often seen in these patients, is unknown. Recently, the importance of metabolic control and hypoglycaemia has been discussed. The aim of this study was to evaluate the impact of different HbA_1c levels and QTc prolongation on all-cause mortality in the high-risk population of patients with type 2 diabetes mellitus and foot ulcers.

Methods

All patients with type 2 diabetes, younger than 80 years, visiting our diabetes foot unit, with a foot ulcer duration >4 weeks, were screened for participation. Patients on dialysis were excluded. Patients were grouped according to HbA_1c level and QTc time ≤ or >?440 ms.

Results

Patients (n?=?214, median age 69.1 years) were grouped according to HbA_1c level (HbA_1c?<?7.5% [<58 mmol/mol] n?=?81, 7.5–8.9% [58–74 mmol/mol] n?=?70, >8.9% [>74 mmol/mol] n?=?63). Baseline characteristics, including use of potential hypoglycaemic drugs, were similar between groups. During the 8 years of follow-up 151 patients died (70.6%) and HbA_1c?<?7.5% (<58 mmol/mol) was strongly associated with increased mortality. The highest mortality was seen in patients with a combination of HbA_1c?<?7.5% (<58 mmol/mol) and QTc prolongation, with an 8 year mortality of 92.1% as compared with 48.8% in those with HbA_1c?<?7.5% (<58 mmol/mol) but without QTc prolongation.

Conclusion/interpretations

HbA_1c?<?7.5% (<58 mmol/mol) in a high-risk population of patients with type 2 diabetes and foot ulcers is associated with a significantly higher mortality, particularly in patients with QTc prolongation.     

Effect of exenatide QW or placebo,both added to titrated insulin glargine,in uncontrolled type 2 diabetes: The DURATION‐7 randomized study

Aims

To compare the efficacy and safety of adding the glucagon‐like peptide‐1 receptor agonist exenatide once weekly (QW) 2 mg or placebo among patients with type 2 diabetes who were inadequately controlled despite titrated insulin glargine (IG) ± metformin.

Methods

This multicentre, double‐blind study ( ClinicalTrials.gov identifier: NCT02229383) randomized (1:1) patients with persistent hyperglycaemia after an 8‐week titration phase (glycated haemoglobin [HbA1c] 7.0%‐10.5% [53‐91 mmol/mol]) to exenatide QW or placebo. The primary endpoint was HbA1c change from baseline to week 28. Secondary endpoints included body weight, 2‐hour postprandial glucose, and mean daily IG dose.

Results

Of 464 randomized patients (mean: age, 58 years; HbA1c, 8.5% [69 mmol/mol]; diabetes duration, 11.3 years), 91% completed 28 weeks. Exenatide QW + IG vs placebo + IG significantly reduced HbA1c (least‐squares mean difference, ?0.73% [?8.0 mmol/mol]; 95% confidence interval, ?0.93%, ?0.53% [?10.2, ?5.8 mmol/mol]; P < .001; final HbA1c, 7.55% [59 mmol/mol] and 8.24% [67 mmol/mol], respectively); body weight (?1.50 kg; ?2.17, ?0.84; P < .001); and 2‐hour postprandial glucose (?1.52 mmol/L [?27.5 mg/dL]; ?2.15, ?0.90 [?38.7, ?16.2]; P < .001). Significantly more exenatide QW + IG‐treated patients vs placebo + IG‐treated patients reached HbA1c <7.0% (<53 mmol/mol) (32.5% vs 7.4%; P < .001); daily IG dose increased by 2 and 4 units, respectively. Gastrointestinal and injection‐site adverse events were more frequent with exenatide QW + IG (15.1% and 7.8%, respectively) than with placebo + IG (10.8% and 3.0%, respectively); hypoglycaemia incidence was similar between the exenatide QW + IG (29.7%) and placebo + IG (29.0%) groups, with no major hypoglycaemic events.

Conclusions

Among patients with inadequate glycaemic control, exenatide QW significantly improved glucose control and decreased body weight, without increased hypoglycaemia or unexpected safety findings.     

Effect of atenolol on QTc interval lengthening during hypoglycaemia in type 1 diabetes

Aims/hypothesis Hypoglycaemia is associated with heart rate-corrected QT (QTc) interval lengthening on the ECG; this may be important in the pathogenesis of sudden overnight death in young people with diabetes. Since hypoglycaemic QTc lengthening appears to be mediated through the sympathoadrenal response, we tested the hypothesis that beta₁-blockade will prevent these changes in type 1 diabetic patients and so provide a potential therapeutic intervention.Methods We studied eight type 1 diabetic adults without cardiovascular or renal complications. Similar hypoglycaemic clamp studies were performed on two occasions, at least 4 weeks apart, but immediately before one visit subjects received atenolol 100 mg daily for 7 days. Following a 60-min euglycaemic (5 mmol/l) period, blood glucose was lowered over 30 min to 2.5 mmol/l, and held for 60 min. High-resolution ECG was recorded at baseline and at 0, 30 and 60 min during each glycaemic plateau. QT interval was measured using a semiautomated tangent method and QTc was derived from QT using the Fridericia formula.Results Mean (SD) baseline QTc was similar at both visits: control 391 (30) ms, post-atenolol 386 (34) ms; (p=0.33). Without atenolol pretreatment, QTc lengthened during hypoglycaemia to a maximum of 448 (34) ms (p<0.001). On atenolol, QTc lengthening was significantly reduced (peak QTc 413 (27) ms; p=0.004 vs control visit).Conclusions/interpretation Hypoglycaemic QTc lengthening is blunted by atenolol in patients with type 1 diabetes. Selective beta₁-blockade may help prevent sudden death, if we can identify those at high risk.     

Cardiac arrhythmia and nocturnal hypoglycaemia in type 1 diabetes—the ‘dead in bed’ syndrome revisited

Aims/hypothesis  Sudden nocturnal death in type 1 diabetes (‘dead in bed’ syndrome) is thought to be due to ECG QT prolongation with subsequent ventricular tachyarrhythmia in response to nocturnal hypoglycaemia. We investigated this theoretical mechanism using continuous ECG and continuous glucose monitoring in a group of patients with type 1 diabetes. Methods  Twenty-five patients with type 1 diabetes (age 20–50 years) underwent two separate 24 h ECG and continuous glucose monitoring periods. Patients were fully ambulant and carried out normal daily activities. Results  There were 13 episodes (26% of recordings) of nocturnal hypoglycaemia, eight of <2.2 mmol/l and five of 2.2–3.4 mmol/l. Corrected QT interval (QTc) was longer during nocturnal hypoglycaemia compared with normoglycaemic control periods (445 ± 40 vs 415 ± 23 ms; p = 0.037). Cardiac rate and rhythm disturbances (excluding sinus tachycardia) were seen in eight of the 13 nocturnal hypoglycaemia episodes (62%). These were sinus bradycardia (<40 beats/min; three episodes), ventricular ectopics (three episodes), atrial ectopics (one) and P wave abnormalities (one). Conclusions/interpretation  This study demonstrates QTc prolongation and cardiac rate/rhythm disturbances in response to episodes of nocturnal hypoglycaemia in ambulant patients with type 1 diabetes. This may support an arrhythmic basis for the ‘dead in bed’ syndrome.     

Lack of preservation of higher brain function during hypoglycaemia in patients with intensively-treated IDDM

Summary 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 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.Abbreviations IDDM Insulin-dependent diabetes mellitus     

Prolonged cardiac repolarisation during spontaneous nocturnal hypoglycaemia in children and adolescents with type 1 diabetes

Aims/hypothesis It has been postulated that hypoglycaemia-related cardiac dysrhythmia and, in particular, prolonged cardiac repolarisation, may contribute to increased mortality rates in children and adolescents with type 1 diabetes.Methods We examined the prevalence of prolonged QT interval on ECG during spontaneous hypoglycaemia in 44 type 1 diabetic subjects (aged 7–18 years), and explored the relationships between serial overnight measurements of QT interval corrected for heart rate (QTc) and serum glucose, potassium and epinephrine levels. Each subject underwent two overnight profiles; blood was sampled every 15 min for glucose measurements and hourly for potassium and epinephrine. Serial ECGs recorded half-hourly between 23.00 and 07.00 hours were available on 74 nights: 29 with spontaneous hypoglycaemia (defined as blood glucose <3.5 mmol/l) and 45 without hypoglycaemia.Results Mean overnight QTc was longer in females than in males (412 vs 400 ms, p=0.02), but was not related to age, diabetes duration or HbA₁c. Prolonged QTc (>440 ms) occurred on 20 out of 74 (27%) nights, with no significant differences between male and female subjects, and was more prevalent on nights with hypoglycaemia (13/29, 44%) than on nights without (7/45, 15%, p=0.0008). Potassium levels were lower on nights when hypoglycaemia occurred (minimum potassium 3.4 vs 3.7 mmol/l, p=0.0003) and were inversely correlated with maximum QTc (r=–0.40, p=0.03). In contrast, epinephrine levels were not higher on nights with hypoglycaemia and were not related to QTc.Conclusions/interpretation In young type 1 diabetic subjects, prolonged QTc occurred frequently with spontaneous overnight hypoglycaemia and may be related to insulin-induced hypokalaemia.     

Spontaneous hypoglycaemia after pancreas transplantation in Type 1 diabetes mellitus

Hypoglycaemia is an important complication of insulin treatment in Type 1 diabetes mellitus (DM). Pancreas transplantation couples glucose sensing and insulin secretion, attaining a distinctive advantage over insulin treatment. We tested whether successful transplantation can avoid hypoglycaemia in Type 1 DM. Combined kidney and pancreas transplanted Type 1 DM who complied with good function criteria (KP-Tx, n = 55), and isolated kidney or liver transplanted non-diabetic subjects on the same immunosuppressive regimen (CON-Tx, n = 14), underwent 1-day metabolic profiles in the first 3 years after transplantation, sampling plasma glucose (PG) and pancreatic hormones every 2 hours. KP-Tx had lower PG than CON-Tx in the night and in the morning and higher insulin concentrations throughout the day. KP-Tx had lower PG nadirs than CON-Tx (4.40 ± 0.05 vs 4.96 ± 0.16 mmol l⁻¹, ANOVA p = 0.001). Nine per cent of KP-Tx had hypoglycaemic values (PG ≤3.0 mmol l⁻¹) in the profiles, both postprandial and postabsorptive, whereas none of CON-Tx did (p < 0.02). In conclusion, after pancreas transplantation, mild hypoglycaemia is frequent, although its clinical impact is limited. Compared to insulin treatment in Type 1 DM, pancreas transplantation improves but cannot eliminate hypoglycaemia. Copyright © 1998 John Wiley & Sons, Ltd.     

Altered ventricular repolarization during hypoglycaemia in patients with diabetes

There is circumstantial evidence implicating hypoglycaemia in the sudden overnight death of young patients with insulin-dependent (Type 1) diabetes mellitus (IDDM), the mechanism of which is unknown. We have investigated the effects of hypoglycaemia on the electrocardiogram in 15 patients with diabetes (8 with IDDM and 7 with NIDDM) using a high resolution computer-based system. Patients were randomized to either 2 h of euglycaemia or hypoglycaemia (at around 3 mmol l⁻¹ ) during the afternoon, using hyperinsulinaemic glucose clamps, the two visits separated by a period of at least 4 weeks. Corrected QT interval (QTc), plasma potassium, and adrenaline were measured at baseline and at 0, 60, and 120 min. The degree of QTc lengthening (from baseline) during clamped hypoglycaemia was greater compared to the euglycaemic control period in patients with IDDM (median{range} at 60 min, 156{8 to 258 } vs 6{−3 to 28} ms, p <0.02) and NIDDM (120 min, 128{16 to 166} vs 4{ −3 to 169} ms, p <0.05). The fall in plasma potassium was greater during clamped hypoglycaemia compared to euglycaemia in those with NIDDM ( p <0.03) but not with those with IDDM ( p >0.06). The rise in plasma adrenaline was greater during clamped hypoglycaemia in both groups (IDDM p <0.02, NIDDM p <0.02) and there was a strong relationship between the rise in adrenaline and increase in QTc ( r = 0.73, p <0.0001).These data demonstrate alteration of ventricular repolarization with lengthening of the QT interval during hypoglycaemia and suggest a possible mechanism by which hypoglycaemia could cause ventricular arrhythmias. © 1997 by John Wiley & Sons, Ltd.     

Glycaemic patterns of male professional athletes with type 1 diabetes during exercise,recovery and sleep: Retrospective,observational study over an entire competitive season

Aims

To analyse glycaemic patterns of professional athletes with type 1 diabetes during a competitive season.

Materials and Methods

We analysed continuous glucose monitoring data of 12 professional male cyclists with type 1 diabetes during exercise, recovery and sleep on days with competitive exercise (CE) and non-competitive exercise (NCE). We assessed whether differences exist between CE and NCE days and analysed associations between exercise and dysglycaemia.

Results

The mean glycated haemoglobin was 50 ± 5 mmol/mol (6.7 ± 0.5%). The athletes cycled on 280.8 ± 28.1 days (entire season 332.6 ± 18.8 days). Overall, time in range (3.9-10 mmol/L) was 70.0 ± 13.7%, time in hypoglycaemia (<3.9 mmol/L) was 6.4 ± 4.7% and time in hyperglycaemia (>10 mmol/L) was 23.6 ± 12.5%. During the nights of NCE days, athletes spent 10.1 ± 7.4% of time in hypoglycaemia, particularly after exercise in the endurance zones. The CE days were characterized by a higher time in hyperglycaemia compared with NCE days (25.2 ± 12.5% vs. 22.2 ± 12.1%, p = .012). This was driven by the CE phase, where time in range dropped to 60.4 ± 13.0% and time in hyperglycaemia was elevated (38.5 ± 12.9%). Mean glucose was higher during CE compared with NCE sessions (9.6 ± 0.9 mmol/L vs. 7.8 ± 1.1 mmol/L, p < .001). The probability of hyperglycaemia during exercise was particularly increased with longer duration, higher intensity and higher variability of exercise.

Conclusions

The analysis of glycaemic patterns of professional endurance athletes revealed that overall glycaemia was generally within targets. For further improvement, athletes, team staff and caregivers may focus on hyperglycaemia during competitions and nocturnal hypoglycaemia after NCE.     

QT interval prolongation during spontaneous episodes of hypoglycaemia in type 1 diabetes: the impact of heart rate correction

Aims/hypothesis  

Prolongation of the heart rate corrected QT interval (QTc) is seen during episodes of hypoglycaemia in type 1 diabetes. We studied the relationship between spontaneous hypoglycaemia and the QT interval and hypothesised that the choice of heart rate correction affects the observed change in QTc.     

Effect of insulin degludec versus insulin glargine U100 on nocturnal glycaemia assessed by plasma glucose profiles in people with type 1 diabetes prone to nocturnal severe hypoglycaemia

Aim

To compare nocturnal glucose profiles according to hourly plasma glucose measurements during treatment with insulin degludec and insulin glargine U100 in a cohort of people with type 1 diabetes prone to nocturnal severe hypoglycaemia.

Materials and methods

The HypoDeg trial is a 2-year investigator-initiated, randomized, controlled crossover trial in 149 participants randomized to treatment with insulin degludec and insulin glargine U100 for 12 months each. The 51 participants in this predefined substudy stayed at least one night in hospital during each treatment arm for plasma glucose samples to be taken. Endpoints were glucose profiles, including mean plasma glucose, glycaemic variability and risk of hypoglycaemia.

Results

There were no differences between treatments regarding mean plasma glucose. We saw a flatter glucose profile during insulin degludec compared with insulin glargine U100 treatment, which had a nadir at 4:00 AM, with a subsequent rise. During treatment with insulin degludec, the participants had lower glycaemic variability, with an estimated treatment difference of −4.3% (95% confidence interval [CI] −8.1 to −0.5; P < 0.05). Participants treated with insulin degludec were less likely to experience nocturnal hypoglycaemia below 3.0 mmol/L (hazard ratio 0.36 [95% CI 0.17-0.73; P < 0.05]).

Conclusion

Based on nocturnal plasma glucose measurements, treatment with insulin degludec compared with insulin glargine U100 administered in the evening results in lower glycaemic variability and lower risk of nocturnal hypoglycaemia without differences in mean plasma glucose.     

Salbutamol‐induced electrophysiological changes show no correlation with electrophysiological changes during hyperinsulinaemic–hypoglycaemic clamp in young people with Type 1 diabetes

Aims

Hypoglycaemia causes QT‐interval prolongation and appears pro‐arrhythmogenic. Salbutamol, a β₂‐adrenoreceptor agonist also causes QT‐interval prolongation. We hypothesized that the magnitude of electrophysiological changes induced by salbutamol and hypoglycaemia might relate to each other and that salbutamol could be used as a non‐invasive screening tool for predicting an individual's electrophysiological response to hypoglycaemia.

Methods

Eighteen individuals with Type 1 diabetes were administered 2.5 mg of nebulized salbutamol. Participants then underwent a hyperinsulinaemic–hypoglycaemic clamp (2.5 mmol/l for 1 h). During both experiments, heart rate and serum potassium (and catecholamines during the clamp) were measured and a high‐resolution electrocardiogram (ECG) was recorded at pre‐set time points. Cardiac repolarization was measured by QT‐interval duration adjusted for heart rate (QT_c), T‐wave amplitude (T_amp), T‐peak to T‐end interval duration (T_pT_end) and T‐wave area symmetry (T_sym). The maximum changes vs. baseline in both experiments were assessed for their linear dependence.

Results

Salbutamol administration caused QT_c and T_pT_end prolongation and a decrease in T_amp and T_sym. Hypoglycaemia caused increased plasma catecholamines, hypokalaemia, QT_c and T_pT_end prolongation, and a decrease in T_amp and T_sym. No significant correlations were found between maximum changes in QT_c [r = 0.15, 95% confidence interval (95% CI) ?0.341 to 0.576; P = 0.553), T_pT_end (r = 0.075, 95% CI ?0.406 to 0.524; P = 0.767), T_sym (r = 0.355, 95% CI ?0.132 to 0.706; P = 0.149) or T_amp (r = 0.148, 95% CI ?0.347 to 0.572; P = 0.558) in either experiment.

Conclusions

Both hypoglycaemia and salbutamol caused pro‐arrhythmogenic electrophysiological changes in people with Type 1 diabetes but were not related in any given individual. Salbutamol does not appear useful in assessing an individual's electrophysiological response to hypoglycaemia.

     

Severity and multiplicity of microvascular complications are associated with QT interval prolongation in patients with type 2 diabetes

Aims/Introduction

A prolonged QT interval plays a causal role in life‐threatening arrhythmia, and becomes a risk factor for sudden cardiac death. Here, we assessed the association between microvascular complications and the QT interval in patients with type 2 diabetes.

Materials and Methods

Patients with type 2 diabetes (n = 219) admitted to Nippon Medical School Hospital (Tokyo, Japan) for glycemic control were enrolled. QT interval was measured manually in lead II on the electrocardiogram, and corrected for heart rate using Bazett's formula (QTc). Diabetic neuropathy, retinopathy and nephropathy were assessed by neuropathic symptoms or Achilles tendon reflex, ophthalmoscopy and urinary albumin excretion, respectively.

Results

In univariate analyses, female sex (P = 0.025), duration of type 2 diabetes (P = 0.041), body mass index (P = 0.0008), systolic blood pressure (P = 0.0011) and receiving insulin therapy (P < 0.0001) were positively associated with QTc. Patients with each of the three microvascular complications had longer QTc than those without: neuropathy (P = 0.0005), retinopathy (P = 0.0019) and nephropathy (P = 0.0001). As retinopathy or nephropathy progressed, QTc became longer (P < 0.001 and P < 0.001 for trend in retinopathy and nephropathy, respectively). Furthermore, QTc was prolonged with the multiplicity of the microvascular complications (P < 0.001 for trend). Multiple regression analyses showed that neuropathy, nephropathy and the multiplicity of the microvascular complications were independently associated with QTc.

Conclusions

Patients with type 2 diabetes with severe microvascular complications might be at high risk for life‐threatening arrhythmia associated with QT interval prolongation.     

Effects of hypoglycaemia on working memory and regional cerebral blood flow in type 1 diabetes: a randomised,crossover trial

Aims/hypothesis

The aim of this randomised, crossover trial was to compare cognitive functioning and associated brain activation patterns during hypoglycaemia (plasma glucose [PG] just below 3.1 mmol/l) and euglycaemia in individuals with type 1 diabetes mellitus.

Methods

In this patient-blinded, crossover study, 26 participants with type 1 diabetes mellitus attended two randomised experimental visits: one hypoglycaemic clamp (PG 2.8?±?0.2 mmol/l, approximate duration 55 min) and one euglycaemic clamp (PG 5.5 mmol/l?±?10%). PG levels were maintained by hyperinsulinaemic glucose clamping. Cognitive functioning was assessed during hypoglycaemia and euglycaemia conditions using a modified version of the digit symbol substitution test (mDSST) and control DSST (cDSST). Simultaneously, regional cerebral blood flow (rCBF) was measured in pre-specified brain regions by six H₂ ¹⁵O-positron emission tomographies (PET) per session.

Results

Working memory was impaired during hypoglycaemia as indicated by a statistically significantly lower mDSST score (estimated treatment difference [ETD] ?0.63 [95% CI ?1.13, ?0.14], p?=?0.014) and a statistically significantly longer response time (ETD 2.86 s [7%] [95% CI 0.67, 5.05], p?=?0.013) compared with euglycaemia. During hypoglycaemia, mDSST task performance was associated with increased activity in the frontal lobe regions, superior parietal lobe and thalamus, and decreased activity in the temporal lobe regions (p?<?0.05). Working memory activation (mDSST ? cDSST) statistically significantly increased blood flow in the striatum during hypoglycaemia (ETD 0.0374% [95% CI 0.0157, 0.0590], p?=?0.002).

Conclusions/interpretation

During hypoglycaemia (mean PG 2.9 mmol/l), working memory performance was impaired. Altered performance was associated with significantly increased blood flow in the striatum, a part of the basal ganglia implicated in regulating motor functions, memory, language and emotion.

Trial registration

NCT01789593, clinicaltrials.gov

Funding

This study was funded by Novo Nordisk.

     

Hypoglycaemia induces a sustained pro-inflammatory response in people with type 1 diabetes and healthy controls

Aim

To determine the duration and the extension of the pro-inflammatory response to hypoglycaemia both in people with type 1 diabetes and healthy controls.

Materials and Methods

Adults with type 1 diabetes (n = 47) and matched controls (n = 16) underwent a hyperinsulinaemic-euglycaemic hypoglycaemic (2.8 ± 0.1 mmoL/L [49.9 ± 2.3 mg/dL]) glucose clamp. During euglycaemia, hypoglycaemia, and 1, 3 and 7 days later, blood was drawn to determine immune cell phenotype, monocyte function and circulating inflammatory markers.

Results

Hypoglycaemia increased lymphocyte and monocyte counts, which remained elevated for 1 week. The proportion of CD16⁺ monocytes increased and the proportion of CD14⁺ monocytes decreased. During hypoglycaemia, monocytes released more tumour necrosis factor-α and interleukin-1β, and less interleukin-10, after ex vivo stimulation. Hypoglycaemia increased the levels of 19 circulating inflammatory proteins, including high sensitive C-reactive protein, most of which remained elevated for 1 week. The epinephrine peak in response to hypoglycaemia was positively correlated with immune cell number and phenotype, but not with the proteomic response.

Conclusions

Overall, despite differences in prior exposure to hypoglycaemia, the pattern of the inflammatory responses to hypoglycaemia did not differ between people with type 1 diabetes and healthy controls. In conclusion, hypoglycaemia induces a range of pro-inflammatory responses that are sustained for at least 1 week in people with type 1 diabetes and healthy controls.     

Glycaemia and cardiac arrhythmias in people with type 1 diabetes: A prospective observational study

Aim

To investigate the impact of hypoglycaemia, hyperglycaemia and glycaemic variability on arrhythmia susceptibility in people with type 1 diabetes.

Materials and Methods

Thirty adults with type 1 diabetes were included in a 12-month observational exploratory study. Daytime and night-time incident rate ratios (IRRs) of arrhythmias were determined for hypoglycaemia (interstitial glucose [IG] <3.9 mmol/L), hyperglycaemia (IG >10.0 mmol/L) and glycaemic variability (standard deviation and coefficient of variation).

Results

Hypoglycaemia was not associated with an increased risk of arrhythmias compared with euglycaemia and hyperglycaemia combined (IG ≥ 3.9 mmol/L). However, during daytime, a trend of increased risk of arrhythmias was observed when comparing time spent in hypoglycaemia with euglycaemia (IRR 1.08 [95% CI: 0.99-1.18] per 5 minutes). Furthermore, during daytime, both the occurrence and time spent in hyperglycaemia were associated with an increased risk of arrhythmias compared with euglycaemia (IRR 2.03 [95% CI: 1.21-3.40] and IRR 1.07 [95% CI: 1.02-1.13] per 5 minutes, respectively). Night-time hypoglycaemia and hyperglycaemia were not associated with the risk of arrhythmias. Increased glycaemic variability was not associated with an increased risk of arrhythmias during daytime, whereas a reduced risk was observed during night-time.

Conclusions

Acute hypoglycaemia and hyperglycaemia during daytime may increase the risk of arrhythmias in individuals with type 1 diabetes. However, no such associations were found during night-time, indicating diurnal differences in arrhythmia susceptibility.     

Hypoglycaemia and cardiac arrhythmias in patients with type 2 diabetes mellitus.

Improved blood glucose control by insulin treatment in patients with Type 2 (non-insulin dependent) diabetes mellitus increases the risk for hypoglycaemic episodes. Our objective was to investigate if hypoglycaemia causes electrocardiographic changes and cardiac arrhythmias in patients with Type 2 diabetes. Six insulin-treated patients with Type 2 diabetes and no known cardiac disease took part in the study. Hypoglycaemia was induced by insulin infusion aiming at a plasma glucose less than or equal to 2.0 mmol l-1 or hypoglycaemic symptoms. All patients experienced hypoglycaemic symptoms. The median lowest arterial plasma glucose was 2.0 mmol l-1. Arterial plasma adrenaline concentration increased from 0.4 +/- 0.1 (mean +/- SE) to 6.9 +/- 0.3 nmol l-1 (p less than 0.001) while serum potassium was lowered from 4.1 +/- 0.3 mmol l-1 to 3.5 +/- 0.2 mmol l-1 (p less than 0.001). The heart rate increased significantly during hypoglycaemia except in one patient who developed hypoglycaemic symptoms and a severe bradyarrhythmia at a plasma glucose of 4.4 mmol l-1. One patient developed frequent ventricular ectopic beats during hypoglycaemia while four patients showed no arrhythmia. ST-depression in ECG leads V2 and V6 was observed during hypoglycaemia in five patients (p less than 0.05) and four patients developed flattening of the T-wave. In conclusion, the study supports the hypothesis that hypoglycaemia in patients with Type 2 diabetes may be hazardous by causing cardiac arrhythmias.