OBJECTIVETo determine whether impaired awareness of hypoglycemia (IAH) can be improved and severe hypoglycemia (SH) prevented in type 1 diabetes, we compared an insulin pump (continuous subcutaneous insulin infusion [CSII]) with multiple daily injections (MDIs) and adjuvant real-time continuous glucose monitoring (RT) with conventional self-monitoring of blood glucose (SMBG). RESEARCH DESIGN AND METHODSA 24-week 2 3 2 factorial randomized controlled trial in adults with type 1 diabetes and IAH was conducted. All received comparable education, support, and congruent therapeutic targets aimed at rigorous avoidance of biochemical hypoglycemia without relaxing overall control. Primary end point was between-intervention difference in 24-week hypoglycemia awareness (Gold score). RESULTSA total of 96 participants (mean diabetes duration 29 years) were randomized. Overall, biochemical hypoglycemia (£3.0 mmol/L) decreased (53 6 63 to 24 6 56 min/24 h; P = 0.004 [t test]) without deterioration in HbA 1c . Hypoglycemia awareness improved (5.1 6 1.1 to 4.1 6 1.6; P = 0.0001 [t test]) with decreased SH (8.9 6 13.4 to 0.8 6 1.8 episodes/patient-year; P = 0.0001 [t test]). At 24 weeks, there was no significant difference in awareness comparing CSII with MDI (4.1 6 1.6 vs. 4.2 6 1.7; difference 0.1; 95% CI 20.6 to 0.8) and RT with SMBG (4.3 6 1.6 vs. 4.0 6 1.7; difference 20.3; 95% CI 21.0 to 0.4). Between-group analyses demonstrated comparable reductions in SH, fear of hypoglycemia, and insulin doses with equivalent HbA 1c . Treatment satisfaction was higher with CSII than MDI (32 6 3 vs. 29 6 6; P = 0.0003 [t test]), but comparable with SMBG and RT (30 6 5 vs. 30 6 5; P = 0.79 [t test]). CONCLUSIONSHypoglycemia awareness can be improved and recurrent SH prevented in longstanding type 1 diabetes without relaxing HbA 1c . Similar biomedical outcomes can be attained with conventional MDI and SMBG regimens compared with CSII/RT, although satisfaction was higher with CSII.

Summary Background We assessed whether overnight home use of automated closed loop insulin delivery (artificial pancreas) improves glucose control. Methods We studied 24 adults with type 1 diabetes in a multicentre crossover study design comparing four weeks of overnight closed loop using a model predictive control algorithm to direct insulin delivery, with four weeks of insulin pump therapy in which participants used real-time display of continuous glucose monitoring independent of their pumps as control. Primary outcome was time when glucose was in the target range of 3·9 and 8·0mmol/l between midnight to 07:00. Analyses were by intention to treat. Trial registration ClinicalTrials.gov NCT01440140. Findings Closed loop was utilised over median 8·3 (interquartile range 6·0, 9·6)hours on 555nights (86%). Proportion of time when overnight glucose was in target range was significantly higher during closed loop compared to control by 13·5% (95% CI, 7·3–19·7; p<0·001). Mean overnight glucose (8·2±0·9 vs. 9·0±1·3mmol/l; p=0·005) and time spent above target (44·3%±11·9 vs. 57·1%±15·6; p=0·001) were significantly lower during closed loop. Time spent below target was low and comparable [1·8%(0·6, 3·6) vs. 2·1%(0·7, 3·9); p=0·28]. Lower mean overnight glucose was brought about by increased overnight insulin delivery [6·4 (4·5, 8·1) vs. 4·9 (3·7, 6·3)units; p<0·001) without changing the total daily insulin amount [34·5 (29·3, 48·4) vs. 35·4 (29·7, 45·2)units; p=0·32]. No severe hypoglycaemia episodes occurred during control period and two during closed loop not related to algorithm instructions. Interpretation Unsupervised overnight closed loop at home is feasible and may improve glucose control in adults with type 1 diabetes.

Optimized insulin replacement and glucose monitoring underpinned by hypoglycemia-focused structured education should be provided to all with type 1 diabetes complicated by impaired awareness of hypoglycemia.

Hypoglycemia is associated with increased cardiovascular mortality in trials of intensive therapy in type 2 diabetes mellitus (T2DM). We previously observed an increase in arrhythmias during spontaneous prolonged hypoglycemia in patients with T2DM. We examined changes in cardiac autonomic function and repolarization during sustained experimental hypoglycemia. Twelve adults with T2DM and 11 age- and BMI-matched control participants without diabetes underwent paired hyperinsulinemic clamps separated by 4 weeks. Glucose was maintained at euglycemia (6.0 mmol/L) or hypoglycemia (2.5 mmol/L) for 1 h. Heart rate, blood pressure, and heart rate variability were assessed every 30 min and corrected QT intervals and T-wave morphology every 60 min. Heart rate initially increased in participants with T2DM but then fell toward baseline despite maintained hypoglycemia at 1 h accompanied by reactivation of vagal tone. In control participants, vagal tone remained depressed during sustained hypoglycemia. Participants with T2DM exhibited greater heterogeneity of repolarization during hypoglycemia as demonstrated by T-wave symmetry and principal component analysis ratio compared with control participants. Epinephrine levels during hypoglycemia were similar between groups. Cardiac autonomic regulation during hypoglycemia appears to be time dependent. Individuals with T2DM demonstrate greater repolarization abnormalities for a given hypoglycemic stimulus despite comparable sympathoadrenal responses. These mechanisms could contribute to arrhythmias during clinical hypoglycemic episodes.

Hypoglycemia has been linked to persistent increases in cardiovascular (CV) mortality in type 2 diabetes after the event. Our aim was to examine acute and downstream effects of hypoglycemia on markers of thrombosis risk and inflammation in type 2 diabetes. RESEARCH DESIGN AND METHODS Twelve individuals with type 2 diabetes with no history of CV disease and 11 age-and BMI-matched volunteers without diabetes underwent paired hyperinsulinemiceuglycemic (glucose 6 mmol/L for two 60-min periods) and hypoglycemic (glucose 2.5 mmol/L for two 60-min periods) clamps on separate occasions on day 0. Fibrin clot properties, platelet reactivity, and inflammatory markers were measured at baseline, end of and after recovery from the initial clamp, day 1, and day 7 using validated assays and electron microscopy. RESULTS Euglycemic hyperinsulinemia reduced platelet reactivity, decreased fibrin clot density, and improved fibrinolytic efficiency in both groups. Platelet reactivity and aggregation increased during acute hypoglycemia in both groups, resolving at recovery. In type 2 diabetes, clot lysis times and clot maximum absorbance increased up to day 7 (P = 0.002 and 0.001 vs. euglycemia, respectively), but clots from control subjects without diabetes showed limited changes. Fibrin network density increased D 1.15 6 0.28 fibers/mm 2 at day 7 after the hypoglycemic clamp (P < 0.01 for glycemic arm), whereas fibrinogen and complement C3 increased after hypoglycemia up to day 7 in type 2 diabetes only. CONCLUSIONS Antecedent hypoglycemia has acute and persistent prothrombotic effects, lasting at least 7 days, that were enhanced in individuals with type 2 diabetes. These findings identify mechanisms by which hypoglycemia might increase short-and medium-term risk of CV mortality. Cardiovascular (CV) disease is the leading cause of death in type 2 diabetes. A number of large clinical trials have attempted to address the role of intensive glucose control on vascular events and have shown either no reduction (1,2) or an increase in mortality (3). Hypoglycemia is associated with increased CV mortality (2,4), but evidence establishing cause and effect is lacking. In interventional trials, the increased mortality associated with hypoglycemia extended well beyond the acute event, with elevated risk months later (2). Mechanisms by which hypoglycemia might lead to increased CV mortality in the short to medium term are unclear.

Hypoglycaemia remains an over-riding factor limiting optimal glycaemic control in type 1 diabetes. Severe hypoglycaemia is prevalent in almost half of those with long-duration diabetes and is one of the most feared diabetes-related complications. In this review, we present an overview of the increasing body of literature seeking to elucidate the underlying pathophysiology of severe hypoglycaemia and the limited evidence behind the strategies employed to prevent episodes. Drivers of severe hypoglycaemia including impaired counter-regulation, hypoglycaemia-associated autonomic failure, psychosocial and behavioural factors and neuroimaging correlates are discussed. Treatment strategies encompassing structured education, insulin analogue regimens, continuous subcutaneous insulin infusion pumps, continuous glucose sensing and beta-cell replacement therapies have been employed, yet there is little randomized controlled trial evidence demonstrating effectiveness of new technologies in reducing severe hypoglycaemia. Optimally designed interventional trials evaluating these existing technologies and using modern methods of teaching patients flexible insulin use within structured education programmes with the specific goal of preventing severe hypoglycaemia are required. Individuals at high risk need to be monitored with meticulous collection of data on awareness, as well as frequency and severity of all hypoglycaemic episodes.

OBJECTIVEImpaired awareness of hypoglycemia (IAH) and defective counterregulation significantly increase severe hypoglycemia risk in type 1 diabetes (T1D). We evaluated restoration of IAH/defective counterregulation by a treatment strategy targeted at hypoglycemia avoidance in adults with T1D with IAH (Gold score ≥4) participating in the U.K.-based multicenter HypoCOMPaSS randomized controlled trial.RESEARCH DESIGN AND METHODSEighteen subjects with T1D and IAH (mean ± SD age 50 ± 9 years, T1D duration 35 ± 10 years, HbA1c 8.1 ± 1.0% [65 ± 10.9 mmol/mol]) underwent stepped hyperinsulinemic-hypoglycemic clamp studies before and after a 6-month intervention. The intervention comprised the HypoCOMPaSS education tool in all and randomized allocation, in a 2 × 2 factorial study design, to multiple daily insulin analog injections or continuous subcutaneous insulin infusion therapy and conventional glucose monitoring or real-time continuous glucose monitoring. Symptoms, cognitive function, and counterregulatory hormones were measured at each glucose plateau (5.0, 3.8, 3.4, 2.8, and 2.4 mmol/L), with each step lasting 40 min with subjects kept blinded to their actual glucose value throughout clamp studies.RESULTSAfter intervention, glucose concentrations at which subjects first felt hypoglycemic increased (mean ± SE from 2.6 ± 0.1 to 3.1 ± 0.2 mmol/L, P = 0.02), and symptom and plasma metanephrine responses to hypoglycemia were higher (median area under curve for symptoms, 580 [interquartile range {IQR} 420–780] vs. 710 [460–1,260], P = 0.02; metanephrine, 2,412 [−3,026 to 7,279] vs. 5,180 [−771 to 11,513], P = 0.01). Glycemic threshold for deterioration of cognitive function measured by four-choice reaction time was unchanged, while the color-word Stroop test showed a degree of adaptation.CONCLUSIONSEven in long-standing T1D, IAH and defective counterregulation may be improved by a clinical strategy aimed at hypoglycemia avoidance.

BackgroundSevere hypoglycaemia (SH) is one of the most feared complications of type 1 diabetes (T1DM) with a reported prevalence of nearly 40%. In randomized trials of Multiple Daily Injections (MDI) and Continuous Subcutaneous Insulin Infusion (CSII) therapy there is a possible benefit of CSII in reducing SH. However few trials have used basal insulin analogues as the basal insulin in the MDI group and individuals with established SH have often been excluded from prospective studies. In published studies investigating the effect of Real Time Continuous Glucose Monitoring (RT-CGM) benefit in terms of reduced SH has not yet been demonstrated. The primary objective of this study is to elucidate whether in people with T1DM complicated by impaired awareness of hypoglycaemia (IAH), rigorous prevention of biochemical hypoglycaemia using optimized existing self-management technology and educational support will restore awareness and reduce risk of recurrent SH.Methods/designThis is a multicentre prospective RCT comparing hypoglycaemia avoidance with optimized MDI and CSII with or without RT-CGM in a 2×2 factorial design in people with type 1 diabetes who have IAH. The primary outcome measure for this study is the difference in IAH (Gold score) at 24 weeks. Secondary outcomes include biomedical measures such as HbA1c, SH incidence, blinded CGM analysis, self monitored blood glucose (SMBG) and response to hypoglycaemia in gold standard clamp studies. Psychosocial measures including well-being and quality of life will also be assessed using several validated and novel measures. Analysis will be on an intention-to-treat basis.DiscussionMost existing RCTs using this study’s interventions have been powered for change in HbA1c rather than IAH or SH. This trial will demonstrate whether IAH can be reversed and SH prevented in people with T1DM in even those at highest risk by using optimized conventional management and existing technology.Trial RegistrationISRCTN52164803 Eudract No: 2009-015396-27