Time in range: A best practice guide for UK diabetes healthcare professionals in the context of the COVID-19 global pandemic.

The emergence of continuous glucose monitoring has driven improvements in glycaemic control and quality of life for people with diabetes. Recent changes in access to continuous glucose monitoring systems within UK health services have increased the number of people able to benefit from these technologies. The COVID-19 pandemic has created an opportunity for diabetes healthcare professionals to use continuous glucose monitoring technology to remotely deliver diabetes services to support people with diabetes. This opportunity can be maximized with improved application and interpretation of continuous glucose monitoring-generated data. Amongst the diverse measures of glycaemic control, time in range is considered to be of high value in routine clinical care because it is actionable and is visibly responsive to changes in diabetes management. Importantly, it is also been linked to the risk of developing complications associated with diabetes and can be understood by people with diabetes and healthcare professionals alike. The 2019 International Consensus on Time in Range has established a series of target glucose ranges and recommendations for time spent within these ranges that is consistent with optimal glycaemic control. The recommendations cover people with type 1 or type 2 diabetes, with separate targets indicated for elderly people or those at higher risk from hypoglycaemia, as well as for women with type 1 diabetes during pregnancy. The aim of this best practice guide was to clarify the intent and purpose of these international consensus recommendations and to provide practical insights into their implementation in UK diabetes care.

The transCampus Metabolic Training Programme Explores the Link of SARS-CoV-2 Virus to Metabolic Disease.

Currently, we are experiencing a true pandemic of a communicable disease by the virus SARS-CoV-2 holding the whole world firmly in its grasp. Amazingly and unfortunately, this virus uses a metabolic and endocrine pathway via ACE2 to enter our cells causing damage and disease. Our international research training programme funded by the German Research Foundation has a clear mission to train the best students wherever they may come from to learn to tackle the enormous challenges of diabetes and its complications for our society. A modern training programme in diabetes and metabolism does not only involve a thorough understanding of classical physiology, biology and clinical diabetology but has to bring together an interdisciplinary team. With the arrival of the coronavirus pandemic, this prestigious and unique metabolic training programme is facing new challenges but also new opportunities. The consortium of the training programme has recognized early on the need for a guidance and for practical recommendations to cope with the COVID-19 pandemic for the community of patients with metabolic disease, obesity and diabetes. This involves the optimal management from surgical obesity programmes to medications and insulin replacement. We also established a global registry analyzing the dimension and role of metabolic disease including new onset diabetes potentially triggered by the virus. We have involved experts of infectious disease and virology to our faculty with this metabolic training programme to offer the full breadth and scope of expertise needed to meet these scientific challenges. We have all learned that this pandemic does not respect or heed any national borders and that we have to work together as a global community. We believe that this transCampus metabolic training programme provides a prime example how an international team of established experts in the field of metabolism can work together with students from all over the world to address a new pandemic.

Do-it-yourself closed-loop systems for people living with type 1 diabetes.

Growing numbers of people with type 1 diabetes are using do-it-yourself closed-loop systems. While these technologies are not approved by regulatory bodies and are not commercially available, users of the technology report improvements in HbA1c and time in range, and reduced burden of diabetes. Healthcare professionals have expressed their concern that legal or regulatory body actions could ensue if they support people who choose to use do-it-yourself closed-loop systems. Diabetes UK's position statements make recommendations that aim to provide guidance for both people with diabetes and healthcare professionals, based on the current professional and legal situation. They respect an individual's right to make their own informed decisions about their diabetes management, and recommend that they should have access to the technology they need for optimal diabetes management. People who wish to use do-it-yourself closed-loop systems should continue to receive support and care from their diabetes team. Healthcare professionals should engage in conversations around do-it-yourself closed-loop systems, if the issue is raised, to allow a balanced discussion of risks and benefits. However, healthcare professionals cannot recommend the use of do-it-yourself closed-loop systems because of a lack of regulatory body approval and robust, published research to support safety or effectiveness. People using this technology should be aware that they do so at their own risk. This position statement recognizes that the development of diabetes technology is a rapidly changing environment, and guidance around do-it-yourself systems is required from professional and regulatory bodies.

Distal technology interventions in people with diabetes: an umbrella review of multiple health outcomes.

AIM: To summarize and evaluate the existing evidence on the effectiveness of distal technology with regard to multiple health outcomes in people with diabetes. METHODS: We searched PubMed, EMBASE and the Cochrane Database of Systematic Reviews from database inception to 31 August 2018 for systematic reviews and/or meta-analyses of studies that examined the impact of distal technology and reported any clinical or patient-related outcomes among people with type 1 or type 2 diabetes. RESULTS: The umbrella review identified 95 reviews, including 162 meta-analyses with 46 unique outcomes. Evidence from meta-analyses of randomized controlled studies supports the use of distal technology, especially telehealth and mHealth (healthcare delivered by mobile technology), in people with diabetes for improving HbA1c values by 2-4 mmol/mol (0.2-0.4%). For other health outcomes, such as changes in fasting plasma glucose levels, risk of diabetic ketoacidosis or frequency of severe hypoglycaemia, the evidence was weaker. No evidence was reported for most patient-reported outcomes including quality of life, self-efficacy and medication-taking. The evidence base was poor, with most studies rated as low to very low quality. CONCLUSION: Distal technologies were associated with a modest improvement in glycaemic control, but it was unclear if they improved major clinical outcomes or were cost-effective in people with diabetes. More robust research to improve wider outcomes in people with diabetes is needed before such technologies can be recommended as part of routine care for any patient group.

Reducing the burden of hypoglycaemia in people with diabetes through increased understanding: design of the Hypoglycaemia REdefining SOLutions for better liVEs (Hypo-RESOLVE) project.

BACKGROUND: Hypoglycaemia is the most frequent complication of treatment with insulin or insulin secretagogues in people with diabetes. Severe hypoglycaemia, i.e. an event requiring external help because of cognitive dysfunction, is associated with a higher risk of adverse cardiovascular outcomes and all-cause mortality, but underlying mechanism(s) are poorly understood. There is also a gap in the understanding of the clinical, psychological and health economic impact of 'non-severe' hypoglycaemia and the glucose level below which hypoglycaemia causes harm. AIM: To increase understanding of hypoglycaemia by addressing the above issues over a 4-year period. METHODS: Hypo-RESOLVE is structured across eight work packages, each with a distinct focus. We will construct a large, sustainable database including hypoglycaemia data from >100 clinical trials to examine predictors of hypoglycaemia and establish glucose threshold(s) below which hypoglycaemia constitutes a risk for adverse biomedical and psychological outcomes, and increases healthcare costs. We will also investigate the mechanism(s) underlying the antecedents and consequences of hypoglycaemia, the significance of glucose sensor-detected hypoglycaemia, the impact of hypoglycaemia in families, and the costs of hypoglycaemia for healthcare systems. RESULTS: The outcomes of Hypo-RESOLVE will inform evidence-based definitions regarding the classification of hypoglycaemia in diabetes for use in daily clinical practice, future clinical trials and as a benchmark for comparing glucose-lowering interventions and strategies across trials. Stakeholders will be engaged to achieve broadly adopted agreement. CONCLUSION: Hypo-RESOLVE will advance our understanding and refine the classification of hypoglycaemia, with the ultimate aim being to alleviate the burden and consequences of hypoglycaemia in people with diabetes.

A Type 1 diabetes technology pathway: consensus statement for the use of technology in Type 1 diabetes.

In both adults and children with diabetes, technologies such as continuous subcutaneous insulin infusion using insulin pumps and continuous glucose monitoring can help improve diabetes control, reduce hypoglycaemia and improve quality of life. Access to these technologies in the UK is very variable. Some technologies are recommended by the National Institute for Health and Care Excellence, while others have not been appraised, and new technologies are emerging all the time. Additionally, different guidelines for adults and children further complicate access to diabetes technology in the transition from paediatric to adult care. Against this background, Diabetes UK and NHS England have brought together a multidisciplinary group of experts, including clinicians and people with diabetes, to develop this consensus guideline, combining the different technologies into a common pathway to aid clinical and policy decision-making. We created a pathway that supports the incremental addition of technology as monotherapy and then dual therapy in the same way that we incrementally add in therapeutic agents to support people with Type 2 diabetes to achieve their personalized glycaemic targets. The pathway emphasizes the importance of structured education, specialist support and appropriate access to psychological therapies, as essential pillars for optimized use of diabetes-related technology, and recommends the re-evaluation of its use when the individual is unable either to use the technology appropriately or to achieve the intended outcomes. This pathway is endorsed by UK-wide clinical and patient associations and we recommend that providers and commissioners use it to ensure the right individual with diabetes has access to the right technology in a timely way to help achieve better outcomes.

Recurrent diabetic ketoacidosis and a brief history of brittle diabetes research: contemporary and past evidence in diabetic ketoacidosis research including mortality, mental health and prevention.

Pharmacological, technological and educational approaches have advanced the treatment of Type 1 diabetes in the last four decades and yet diabetic ketoacidosis (DKA) continues to be a leading cause of admission in Type 1 diabetes. This article begins by reviewing the contemporary epidemiological evidence in DKA. It highlights a rise in DKA episodes in the last two decades, with DKA continuing to be the leading cause of death in young people with Type 1 diabetes, and that DKA episodes are a marker for subsequent all-cause mortality. It also summarizes the limited evidence base for DKA prevention and associations with psychopathology. To emphasize the importance of this group with high-risk Type 1 diabetes and the degree to which they have been overlooked in the past two decades, the article summarizes the research literature of recurrent DKA during 1976-1991 when it was extensively investigated as part of the phenomenon of 'brittle diabetes'. This period saw numerous basic science studies investigating the pathophysiology of recurrent DKA. Subsequently, research centres published their experiences of brittle diabetes research participants manipulating their treatment under research conditions. Unfortunately, the driver for this behaviour and whether it was indicative of other people with ketoacidosis was not pursued. In summary, we suggest there has been a stasis in the approach to recurrent DKA prevention, which is likely linked to historical cases of mass sabotage of brittle diabetes research. Further investigation is required to clarify possible psychological characteristics that increase the risk of DKA and thereby targets for DKA prevention.

A modelling study of the budget impact of improved glycaemic control in adults with Type 1 diabetes in the UK.

AIMS: To develop a novel interactive budget impact model that assesses affordability of diabetes treatments in specific populations, and to test the model in a hypothetical scenario by estimating cost savings resulting from reduction in HbA1c from ≥69 mmol/mol (8.5%) to a target of 53 mmol/mol (7.0%) in adults with Type 1 diabetes in the UK. METHODS: A dynamic, interactive model was created using the projected incidence and progression over a 5-year horizon of diabetes-related complications (micro- and macrovascular disease, severe hypoglycaemia and diabetic ketoacidosis) for different HbA1c levels, with flexible input of population size, complications and therapy costs, HbA1c distribution and other variables. The model took a National Health Service and societal perspective. RESULTS: The model was developed, and in the proposed hypothetical situation, reductions in complications and expected costs evaluated. Achievement of target HbA1c in individuals with HbA1c ≥69 mmol/mol (8.5%) would reduce expected chronic complications from 6.8 to 1.2 events per 100 person-years, and diabetic ketoacidosis from 14.5 to 1.0 events per 100 person-years. Potential cumulative direct cost savings achievable in the modelled population were estimated at £687 m over 5 years (£5,585/person), with total (direct and indirect) savings of £1,034 m (£8,400/person). CONCLUSIONS: Implementation of strategies aimed at achieving target glucose levels in people with Type 1 diabetes in the UK has the potential to drive a significant reduction in complication costs. This estimate may provide insights into the potential for investment in achieving savings through improved diabetes care in the UK.

Use of sensor-integrated pump therapy to reduce hypoglycaemia in people with Type 1 diabetes: a real-world study in the UK.

AIMS: To assess the efficacy of insulin pumps with automated insulin suspension systems in a real-world setting. METHODS: We analysed anonymized data uploaded to CareLink™ by people (n=920) with Type 1 diabetes using the MiniMed Paradigm Veo system and the MiniMed 640G system (Medtronic International Trading Sàrl, Tolochanez, Switzerland) with SmartGuard technology, with or without automated insulin suspension enabled, between February 2016 and June 2018. Users with ≥15 days of sensor data and ≥70% sensor-wear time were classified as sensor-augmented pump alone, sensor-integrated pump with low glucose suspend enabled or sensor-integrated pump with predictive low glucose management enabled. RESULTS: The median (25th -75th percentile) system use was 161 (58-348) days. The median time spent with sensor glucose values ≤3 mmol/l was 0.8 (0.3-1.7)% in the sensor-augmented pump group, 0.3 (0.1-0.7)% in the sensor-integrated pump with low glucose suspend group, and 0.3 (0.1-0.5)% in the sensor-integrated pump with predictive low glucose management group. In individuals switching from sensor-augmented pump to sensor-integrated pump with low glucose suspend (n=31), there were significant reductions in the monthly rate of hypoglycaemic events <3 mmol/l (rate ratio 0.63, 95% CI 0.45-0.89; P=0.009) and in the percentage of time with glucose values ≤3 mmol/l [sensor-augmented pump: 0.63% (95% CI 0.34-1.29), sensor-integrated pump with low glucose suspend: 0.33% (95% CI 0.16-0.64); P=0.001]. The monthly rate of hypoglycaemic events decreased further in individuals (n=139) switching from sensor-integrated pump with low glucose suspend to sensor-integrated pump with predictive low glucose management [rate ratio 0.82 (95% CI 0.69-0.98); P<0.0274]. Similar results were seen for events <3.9 mmol/l. There was no difference in median time spent in target glucose range. CONCLUSION: Real-world UK data show that increasing automation of insulin suspension reduces hypoglycaemia exposure in people with Type 1 diabetes.

Optimal prandial timing of bolus insulin in diabetes management: a review.

The inability to achieve optimal diabetes glucose control in people with diabetes is multifactorial, but one contributor may be inadequate control of postprandial glucose. In patients treated with multiple daily injections of insulin, both the dose and timing of meal-related rapid-acting insulin are key factors in this. There are conflicting opinions and evidence on the optimal time to administer mealtime insulin. We performed a comprehensive literature search to review the published data, focusing on the use of rapid-acting insulin analogues in patients with Type 1 diabetes. Pharmacokinetic and pharmacodynamic studies of rapid-acting insulin analogues, together with postprandial glucose excursion data, suggest that administering these 15-20 min before food would provide optimal postprandial glucose control. Data from clinical studies involving people with Type 1 diabetes receiving structured meals and rapid-acting insulin analogues support this, showing a reduction in post-meal glucose levels of ~30% and less hypoglycaemia when meal insulin was taken 15-20 min before a meal compared with immediately before the meal. Importantly, there was also a greater risk of postprandial hypoglycaemia when patients took rapid-acting analogues after eating compared with before eating.

Proportion of daily capillary blood glucose readings required in the target range for target glycaemic control: shift of focus from target range to proportion in range.

AIM: Most guidelines provide people with Type 1 diabetes with pre- and post-meal capillary blood glucose (CBG) targets to achieve optimal glycaemic control. We evaluated the proportion of daily CBG readings between 4 and 10 mmol/l in people achieving different HbA1c levels. METHOD: We analysed CBG data from routine pump/meter downloads from 201 adults treated with continuous subcutaneous insulin infusion (CSII) at a single hospital clinic. Exclusion criteria were CSII < 6 months, < 3 CBG/day, pregnancy, haemoglobinopathy and continuous sensor use. People were categorized into three groups based on HbA1c : < 58 mmol/mol, < 7.5% (n = 58); 58-74 mmol/mol, 7.5-8.9% (n = 107); and ≥ 75 mmol/mol, ≥ 9.0% (n = 36). RESULTS: Participants had a mean age of 43 ± 13 years and mean HBA1c of 64 mmol/mol (8.0 ± 1.1%). 47% of people started CSII for raised HbA1c , 25% due to hypoglycaemia and the rest during pregnancy. Downloads contained a mean of 22 ± 6.8 days of data per participant. CBG frequency was similar between the three groups (5.6 ± 2.0, 5.6 ± 1.9 and 5.4 ± 1.2 CBG/day; P = 0.468). The proportion of CBG readings between 4 and 10 mmol/l (72-180 mg/dl) was 57.3 ± 25.4%, 50.6 ± 11.1% and 39.9 ± 16.5% (P < 0.0001); < 4 mmol was 13.8%, 8.8% and 4.4% (P < 0.0001) and > 10 mmol/l was 28.9 ± 16.5%, 40.6 ± 12.1% and 55.6 ± 17.9% (P < 0.0001) in the three groups respectively. CONCLUSIONS: Participants achieving HBA1c < 58 mmol/mol (< 7.5%) had ~ 60% of CBG readings in range (4-10 mmol/l), with up to 30% of readings > 10 mmol/l. This target of achieving 60% or more readings within target, and being permissive with up to 30% readings > 10 mmol/l may be a novel target for people with diabetes, and may reduce anxiety associated with readings out of range.

Zooanthroponotic transmission of rotavirus in Haryana State of Northern India.

Rotaviruses are the major cause of severe gastroenteritis and mortality in young children and animals. Due to segmented nature of dsRNA genome and wide host range, vast genetic and antigenic diversity exists amongst different isolates of rotaviruses. A total of 230 fecal ovine and caprine samples collected from organized farms and villages in Haryana were screened for rotavirus detection. Samples were screened by latex agglutination test and RNA-PAGE followed by RT-PCR and nucleic acid sequencing. The latex agglutination test showed 25 newborn lamb and 4 kid fecal samples positive for rotavirus. However, RNA-PAGE showed only 9 lamb fecal samples positive for rotavirus. All the samples were subjected to RT-PCR employing vp4 and vp7 gene specific primers of group A rotavirus of ovine, bovine and human origin. Only two samples from lamb (Sheep18/Hisar/2013 and Sheep22/Hisar/2013) showed vp4 and vp7 gene specific amplification with human group A rotavirus (GAR) specific primer. However, they did not show any amplification with ovine and bovine rotavirus specific primers. The nucleotide as well as deduced amino acid sequence analysis of vp4 gene of these isolates showed >98/97% and vp7 gene >95/94% nt/aa identity with human GAR from different regions of the world. Based on nucleotide similarity search, Sheep18/Hisar/2013 and Sheep22/Hisar/2013 isolates were genotyped as G1P[8] and G1P[4]. Phylogenetic analysis also confirmed that these isolates were clustered closely with human rotaviruses from different regions of the world. Earlier, higher prevalence of human rotaviruses was reported from the sample collecting area. The amplification of ovine samples with human rotavirus gene specific primers, sequence identity and phylogenetic analysis strongly suggests the zoonotic transmission of human GAR to sheep.

Sustained benefit of continuous subcutaneous insulin infusion on glycaemic control and hypoglycaemia in adults with Type 1 diabetes.

AIM: To evaluate the sustainability of the benefits of continuous subcutaneous insulin infusion therapy in routine practice in a cohort of adults with diabetes. METHODS: The clinical records of all adults starting continuous subcutaneous insulin infusion over 12 years at our centre were included in this study. Baseline and mean annual HbA(1c) levels were recorded. The frequency of mild-to-moderate and severe hypoglycaemia and hypoglycaemia awareness were analysed in a subgroup. RESULTS: Adequate data were available from 327 patients, of whom 71% were female. The patients' mean ± sd age was 41 ± 14 years, the mean ± sd (range) follow-up for continuous subcutaneous insulin infusion was 4.3 ± 2.7 (1-12) years. The mean ± sd HbA(1c) concentration fell by 8 ± 5 mmol/mol (0.7 ± 0.5%) at year 1 [to 63 ± 12 mmol/mol from 70 ± 18 mmol/mol (7.9 ± 1.1% from 8.6 ± 1.6%); P < 0.0005], sustained to year 5. In patients with initial poor control, HbA(1c) dropped by 12 ± 11 mmol/mol (1.1 ± 1.0%; P < 0.0005) at year 1, sustained to year 6. The percentage of patients with ≥ 5 mild to moderate hypoglycaemic episodes per week fell from 29 to 12% (n = 163; P = 0.006). In the subgroup (n = 87; follow-up 2.5 ± mean ± sd 1.1 years), the frequency of severe hypoglycaemia fell from 0.6 ± 1.7 episodes per patient per year to 0.3 ± 0.9 (P = 0.047). Of 24 patients with impaired awareness of hypoglycaemia (Gold score ≥ 4), the mean ± sd Gold score improved from 4.9 ± 0.9 to 3.8 ± 1.7 (P = 0.011). Nine people regained awareness. No deterioration in HbA(1c) was seen in the hypoglycaemia-prone groups. CONCLUSIONS: The benefits of continuous subcutaneous insulin infusion with regard to improving glycaemic control and reducing hypoglycaemia frequency, along with improvement in hypoglycaemia awareness without deterioration in glycaemic control, can be sustained over several years in clinical practice.

Outcomes for adults with type 1 diabetes referred with severe hypoglycaemia and/or referred for islet transplantation to a specialist hypoglycaemia service.

Islet transplantation alone (ITA) is indicated for patients with type 1 diabetes (T1D) with disabling severe hypoglycaemia (SH) despite optimised medical therapy. We examined outcomes for patients referred to an islet transplant unit with recurrent SH. Retrospective case note audit of 45 patients with ≥1 SH per year who were referred to our ITA unit between 2009-2012; 36 patients attended follow-up appointments. The cohort was 52.8% male, mean (± SD) age 43.9 (± 11.4) years, and duration of diabetes 26.5 (± 12.9) years. Baseline HbA1c was 8.3% (± 1.7) (67.2 mmol/mol), median (IQR) frequency of SH was 6.0 (2.0-24.0) per/patient/year and 83.3% had impaired awareness of hypoglycaemia (IAH). 80.6% of patients were referred from other secondary diabetes services, 22.2% had completed structured education, and 30.6% were using continuous subcutaneous insulin infusion (CSII). Seventeen patients were optimised with conventional therapy; SH reduced from 2.0 (1.5-9.0) to 0.0 (0.0-0.5) episodes/patient/year; p<0.001, and there was concurrent improvement in HbA1c (8.1-7.7%; 65.0 vs. 60.7 mmol/mol; p=0.072). Ten patients were listed for transplantation as they were not optimised despite structured education, CSII, and continuous glucose monitoring (CGM). The remaining 9 had a reduction in SH [7.0 (4.8-40.5) to 4.0 (2.5-6.3) episodes/patient/year; p=0.058] and either left the service (n=5) or are still being optimised (n=4). In conclusion, 47.2% of patients presenting with problematic hypoglycaemia resolved with optimal medical therapy, with a further 25% achieving clinically relevant improvement, however 27.8% required transplantation despite access to all therapies. Provision of expertise in hypoglycaemia management is essential to focus limited transplant resources on those who need it most.

Modification of human islet preparation: an effective approach to improve graft outcome after islet transplantation?

Revascularisation of transplanted islets is an essential prerequisite for graft survival and function. However, current islet isolation procedures deprive the islets of endothelial tubulets. This may have a detrimental effect on the revascularisation process of islets following transplantation. We hypothesise that modification of the isolation procedure that preserves islet endothelial vessels may improve the islet revascularisation process following transplantation. Here, we present a modified islet isolation method by which a substantial amount of endothelial cells still attached to the islets could be preserved. The islets with preserved endothelial cells isolated by this method were revascularised within 3 days, not observed in islets isolated by standard methods. Further, we observed that grafts of islets isolated by standard methods had more patches of dead tissue than islet grafts obtained by the modified method, indicating that attached endothelial cells may play an important role in the islet revascularisation process and potentially help to improve the transplantation outcome.

Unsupervised home use of an overnight closed-loop system over 3-4 weeks: a pooled analysis of randomized controlled studies in adults and adolescents with type 1 diabetes.

AIMS: To compare overnight closed-loop and sensor-augmented pump therapy in patients with type 1 diabetes by combining data collected during free-living unsupervised randomized crossover home studies. METHODS: A total of 40 participants with type 1 diabetes, of whom 24 were adults [mean ± standard deviation (s.d.) age 43 ± 12 years and glycated haemoglobin (HbA1c) 8.0 ± 0.9%] and 16 were adolescents (mean ± s.d. age 15.6 ± 3.6 years and HbA1c 8.1 ± 0.8%), underwent two periods of sensor-augmented pump therapy in the home setting, in combination with or without an overnight closed-loop insulin delivery system that uses a model predictive control algorithm to direct insulin delivery. The order of the two interventions was random; each period lasted 4 weeks in adults and 3 weeks in adolescents. The primary outcome was time during which sensor glucose readings were in the target range of 3.9-8.0 mmol/l. RESULTS: The proportion of time when sensor glucose was in the target range (3.9-8.0 mmol/l) overnight (between 24:00 and 08:00 hours) was 18.5% greater during closed-loop insulin delivery than during sensor-augmented therapy (p < 0.001). Closed-loop therapy significantly reduced mean overnight glucose levels by 0.9 mmol/l (p < 0.001), with no difference in glycaemic variability, as measured by the standard deviation of sensor glucose. Time spent above the target range was reduced (p = 0.001), as was time spent in hypoglycaemia (<3.9 mmol/l; p = 0.014) during closed-loop therapy. Lower mean overnight glucose levels during closed-loop therapy were brought about by increased overnight insulin delivery (p < 0.001) without changes to the total daily delivery (p = 0.84). CONCLUSION: Overnight closed-loop insulin therapy at home in adults and adolescents with type 1 diabetes is feasible, showing improvements in glucose control and reducing the risk of nocturnal hypoglycaemia.

Severe hypoglycaemia in type 1 diabetes mellitus: underlying drivers and potential strategies for successful prevention.

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.

Attainment of metabolic goals in the integrated UK islet transplant program with locally isolated and transported preparations.

The objective was to determine whether metabolic goals have been achieved with locally isolated and transported preparations over the first 3 years of the UK's nationally funded integrated islet transplant program. Twenty islet recipients with C-peptide negative type 1 diabetes and recurrent severe hypoglycemia consented to the study, including standardized meal tolerance tests. Participants received a total of 35 infusions (seven recipients: single graft; 11 recipients: two grafts: two recipients: three grafts). Graft function was maintained in 80% at [median (interquartile range)] 24 (13.5-36) months postfirst transplant. Severe hypoglycemia was reduced from 20 (7-50) episodes/patient-year pretransplant to 0.3 (0-1.6) episodes/patient-year posttransplant (p < 0.001). Resolution of impaired hypoglycemia awareness was confirmed [pretransplant: Gold score 6 (5-7); 24 (13.5-36) months: 3 (1.5-4.5); p < 0.03]. Target HbA1c of <7.0% was attained/maintained in 70% of recipients [pretransplant: 8.0 (7.0-9.6)%; 24 (13.5-36) months: 6.2 (5.7-8.4)%; p < 0.001], with 60% reduction in insulin dose [pretransplant: 0.51 (0.41-0.62) units/kg; 24 (13.5-36) months: 0.20 (0-0.37) units/kg; p < 0.001]. Metabolic outcomes were comparable 12 months posttransplant in those receiving transported versus only locally isolated islets [12 month stimulated C-peptide: transported 788 (114-1764) pmol/L (n = 9); locally isolated 407 (126-830) pmol/L (n = 11); p = 0.32]. Metabolic goals have been attained within the equitably available, fully integrated UK islet transplant program with both transported and locally isolated preparations.

Do high fasting glucose levels suggest nocturnal hypoglycaemia? The Somogyi effect-more fiction than fact?

AIMS: The Somogyi effect postulates that nocturnal hypoglycaemia causes fasting hyperglycaemia attributable to counter-regulatory hormone release. Although most published evidence has failed to support this hypothesis, this concept remains firmly embedded in clinical practice and often prevents patients and professionals from optimizing overnight insulin. Previous observational data found lower fasting glucose was associated with nocturnal hypoglycaemia, but did not assess the probability of infrequent individual episodes of rebound hypoglycaemia. We analysed continuous glucose monitoring data to explore its prevalence. METHODS: We analysed data from 89 patients with Type 1 diabetes who participated in the UK Hypoglycaemia study. We compared fasting capillary glucose following nights with and without nocturnal hypoglycaemia (sensor glucose < 3.5 mmol/l). RESULTS: Fasting capillary blood glucose was lower after nights with hypoglycaemia than without [5.5 (3.0) vs. 14.5 (4.5) mmol/l, P < 0.0001], and was lower on nights with more severe nocturnal hypoglycaemia [5.5 (3.0) vs. 8.2 (2.3) mmol/l; P = 0.018 on nights with nadir sensor glucose of < 2.2 mmol/l vs. 3.5 mmol/l]. There were only two instances of fasting capillary blood glucose > 10 mmol/l after nocturnal hypoglycaemia, both after likely treatment of the episode. When fasting capillary blood glucose is < 5 mmol/l, there was evidence of nocturnal hypoglycaemia on 94% of nights. CONCLUSION: Our data indicate that, in clinical practice, the Somogyi effect is rare. Fasting capillary blood glucose ≤ 5 mmol/l appears an important indicator of preceding silent nocturnal hypoglycaemia.

Genetic structure and diversity analysis of the primary gene pool of chickpea using SSR markers.

Members of the primary gene pool of the chickpea, including 38 accessions of Cicer arietinum, six of C. reticulatum and four of C. echinospermum grown in India were investigated using 100 SSR markers to analyze their genetic structure, diversity and relationships. We found considerable diversity, with a mean of 4.8 alleles per locus (ranging from 2 to 11); polymorphic information content ranged from 0.040 to 0.803, with a mean of 0.536. Most of the diversity was confined to the wild species, which had higher values of polymorphic information content, gene diversity and heterozygosity than the cultivated species, suggesting a narrow genetic base for cultivated chickpea. An unrooted neighbor-joining tree, principal coordinate analysis and population structure analysis revealed differentiation between the cultivated accessions and the wild species; three cultivated accessions were in an intermediate position, demonstrating introgression within the cultivated group. Better understanding of the structure, diversity and relationships within and among the members of this primary gene pool will contribute to more efficient identification, conservation and utilization of chickpea germplasm for allele mining, association genetics, mapping and cloning gene(s) and applied breeding to widen the genetic base of this cultivated species, for the development of elite lines with superior yield and improved adaptation to diverse environments.