Transforming type 1 diabetes: the next wave of innovation.

The discovery of insulin in 1921 enabled pharmaceutical production of animal insulins for the treatment of people with type 1 diabetes by 1922. The last several decades have witnessed enormous scientific progress in the therapy of type 1 diabetes, yet some developments have been incremental, and insulin is not a cure. Herein, I highlight key scientific advances potentially poised to improve the quality of life and treatment outcomes in type 1 diabetes. These innovations range from newer insulin analogues to the development of smart insulins, oral and weekly insulins, glucose sensors and closed-loop insulin-delivery devices, as well as strategies for durable human beta cell replacement coupled with selective immune manipulation to preserve beta cell function. Finally, progress in the prediction and prevention of type 1 diabetes highlights the ongoing challenges and potential for altering the natural history of the disease or eliminating type 1 diabetes altogether.

'Smart' insulin-delivery technologies and intrinsic glucose-responsive insulin analogues.

Insulin replacement therapy for diabetes mellitus seeks to minimise excursions in blood glucose concentration above or below the therapeutic range (hyper- or hypoglycaemia). To mitigate acute and chronic risks of such excursions, glucose-responsive insulin-delivery technologies have long been sought for clinical application in type 1 and long-standing type 2 diabetes mellitus. Such 'smart' systems or insulin analogues seek to provide hormonal activity proportional to blood glucose levels without external monitoring. This review highlights three broad strategies to co-optimise mean glycaemic control and time in range: (1) coupling of continuous glucose monitoring (CGM) to delivery devices (algorithm-based 'closed-loop' systems); (2) glucose-responsive polymer encapsulation of insulin; and (3) mechanism-based hormone modifications. Innovations span control algorithms for CGM-based insulin-delivery systems, glucose-responsive polymer matrices, bio-inspired design based on insulin's conformational switch mechanism upon insulin receptor engagement, and glucose-responsive modifications of new insulin analogues. In each case, innovations in insulin chemistry and formulation may enhance clinical outcomes. Prospects are discussed for intrinsic glucose-responsive insulin analogues containing a reversible switch (regulating bioavailability or conformation) that can be activated by glucose at high concentrations.

The promising future of insulin therapy in diabetes mellitus.

The first therapeutic use of insulin by Frederick Banting and Charles Best in 1921 revolutionized the management of type 1 diabetes and considerably changed the lives of many patients with other types of diabetes. In the past 100 years, significant pharmacological advances took place in the field of insulin therapy, bringing closer the goal of optimal glycemic control along with decreased diabetes-related complications. Despite these developments, several challenges remain, such as increasing treatment flexibility, reducing iatrogenic hypoglycemia, and optimizing patient quality of life. Ongoing innovations in insulin therapy (e.g., new insulin analogs, alternative routes of insulin administration, and closed-loop technology) endeavor to overcome these hurdles and change the landscape of diabetes mellitus management. This report highlights recent advances made in the field of insulin therapy and discusses future perspectives.

Psychosocial aspects of diabetes technology.

AIM: To identify key psychosocial research in the domain of diabetes technology. RESULTS: Four trajectories of psychosocial diabetes technology research are identified that characterize research over the past 25 years. Key evidence is reviewed on psychosocial outcomes of technology use as well as psychosocial barriers and facilitating conditions of diabetes technology uptake. Psychosocial interventions that address modifiable barriers and psychosocial factors have proven to be effective in improving glycaemic and self-reported outcomes in diabetes technology users. CONCLUSIONS: Psychosocial diabetes technology research is essential for designing interventions and education programmes targeting the person with diabetes to facilitate optimized outcomes associated with technology uptake. Psychosocial aspects of diabetes technology use and related research will be even more important in the future given the advent of systems for automated insulin delivery and the increasingly widespread digitalization of diabetes care.

Modern diabetes devices in the school setting: Perspectives from school nurses.

OBJECTIVE: To explore the experiences, practices, and attitudes of school nurses related to modern diabetes devices (insulin pumps, continuous glucose monitors, and hybrid-closed loop systems). RESEARCH DESIGN AND METHODS: Semistructured interviews were conducted with 40 public school nurses caring for children in elementary and middle schools. Developed with stakeholder input, the interview questions explored experiences working with devices and communicating with the health care system. Deidentified transcripts were analyzed through an iterative process of coding to identify major themes. RESULTS: School nurses reported a range of educational backgrounds (58% undergraduate, 42% graduate), geographic settings (20% urban, 55% suburban, 25% rural), and years of experience (20% <5 years, 38%, 5-15 years, 42% >15 years). Four major themes emerged: (a) As devices become more common, school nurses must quickly develop new knowledge and skills yet have inconsistent training opportunities; (b) Enthusiasm for devices is tempered by concerns about implementation due to poor planning prior to the school year and potential disruptions by remote monitors; (c) Barriers exist to integrating devices into schools, including school/classroom policies, liability/privacy concerns, and variable staff engagement; and (d) Collaboration between school nurses and providers is limited; better communication may benefit children with diabetes. CONCLUSIONS: Devices are increasingly used by school-aged children. School nurses appreciate device potential but share structural and individual-level challenges. Guiding policy is needed as the technology progressively becomes standard of care. Enhanced training and collaboration with diabetes providers may help to optimize school-based management for children in the modern era.

Changing costs of type 1 diabetes care among US children and adolescents.

BACKGROUND: Modern therapy for type 1 diabetes (T1D) increasingly utilizes technology such as insulin pumps and continuous glucose monitors (CGMs). Prior analyses suggest that T1D costs are driven by preventable hospitalizations, but recent escalations in insulin prices and use of technology may have changed the cost landscape. METHODS: We conducted a retrospective analysis of T1D medical costs from 2012 to 2016 using the OptumLabs Data Warehouse, a comprehensive database of deidentified administrative claims for commercial insurance enrollees. Our study population included 9445 individuals aged ≤18 years with T1D and ≥13 months of continuous enrollment. Costs were categorized into ambulatory care, hospital care, insulin, diabetes technology, and diabetes supplies. Mean costs for each category in each year were adjusted for inflation, as well as patient-level covariates including age, sex, race, census region, and mental health comorbidity. RESULTS: Mean annual cost of T1D care increased from $11 178 in 2012 to $17 060 in 2016, driven primarily by growth in the cost of insulin ($3285 to $6255) and cost of diabetes technology ($1747 to $4581). CONCLUSIONS: Our findings suggest that the cost of T1D care is now driven by mounting insulin prices and growing utilization and cost of diabetes technology. Given the positive effects of pumps and CGMs on T1D health outcomes, it is possible that short-term costs are offset by future savings. Long-term cost-effectiveness analyses should be undertaken to inform providers, payers, and policy-makers about how to support optimal T1D care in an era of increasing reliance on therapeutic technology.

Characteristics of young adults with multiple episodes of diabetic ketoacidosis.

Transition from paediatric to adult diabetes care can be associated with a deterioration in metabolic control and hospitalisation. This was a retrospective review (2012-2016) of medical records of all patients attending a transition diabetes clinic in a teaching hospital with paediatric and adult diabetes on the same site. Among the 91/102 (89.2%) patients with type 1 diabetes, mean age at first visit was 19 ± 2 years, last body mass index was 25.2 ± 4.7 kg/m2 , diabetes duration was 11 ± 6 years and 22 (24%) used continuous subcutaneous insulin infusions. Loss to follow-up was 15 (14.7%). Mental health issues were common (59%), as were prior pregnancies (23%) and diabetic ketoacidosis since diagnosis (39%). Those with diabetic ketoacidosis had a higher mean glycated haemoglobin (70 ± 19 vs 86 ± 25 mmol/mol or 8.6 ± 1.7 vs 10.0 ± 2.3%; P = 0.001), fewer clinic attendances (8 ± 5 vs 5 ± 4; P = 0.008) and fewer years in clinic (1.8 ± 1.7 vs 2.3 ± 1.4; P = 0.114). Our data suggest that investment in joint approaches with mental health services should be considered.

Diabetes technology: improving care, improving patient-reported outcomes and preventing complications in young people with Type 1 diabetes.

With the evolution of diabetes technology, those living with Type 1 diabetes are given a wider arsenal of tools with which to achieve glycaemic control and improve patient-reported outcomes. Furthermore, the use of these technologies may help reduce the risk of acute complications, such as severe hypoglycaemia and diabetic ketoacidosis, as well as long-term macro- and microvascular complications. In addition, diabetes technology can have a beneficial impact on psychosocial health by reducing the burden of diabetes. Unfortunately, diabetes goals are often unmet and people with Type 1 diabetes too frequently experience acute and long-term complications of this condition, in addition to often having less than ideal psychosocial outcomes. Increasing realization of the importance of patient-reported outcomes is leading to diabetes care delivery becoming more patient-centred. Diabetes technology in the form of medical devices, digital health and big data analytics have the potential to improve clinical care and psychosocial support, resulting in lower rates of acute and chronic complications, decreased burden of diabetes care, and improved quality of life.

Continuous subcutaneous insulin infusion in diabetes: patient populations, safety, efficacy, and pharmacoeconomics.

The level of glycaemic control necessary to achieve optimal short-term and long-term outcomes in subjects with type 1 diabetes mellitus (T1DM) typically requires intensified insulin therapy using multiple daily injections or continuous subcutaneous insulin infusion. For continuous subcutaneous insulin infusion, the insulins of choice are the rapid-acting insulin analogues, insulin aspart, insulin lispro and insulin glulisine. The advantages of continuous subcutaneous insulin infusion over multiple daily injections in adult and paediatric populations with T1DM include superior glycaemic control, lower insulin requirements and better health-related quality of life/patient satisfaction. An association between continuous subcutaneous insulin infusion and reduced hypoglycaemic risk is more consistent in children/adolescents than in adults. The use of continuous subcutaneous insulin infusion is widely recommended in both adult and paediatric T1DM populations but is limited in pregnant patients and those with type 2 diabetes mellitus. All available rapid-acting insulin analogues are approved for use in adult, paediatric and pregnant populations. However, minimum patient age varies (insulin lispro: no minimum; insulin aspart: ≥2 years; insulin glulisine: ≥6 years) and experience in pregnancy ranges from extensive (insulin aspart, insulin lispro) to limited (insulin glulisine). Although more expensive than multiple daily injections, continuous subcutaneous insulin infusion is cost-effective in selected patient groups. This comprehensive review focuses on the European situation and summarises evidence for the efficacy and safety of continuous subcutaneous insulin infusion, particularly when used with rapid-acting insulin analogues, in adult, paediatric and pregnant populations. The review also discusses relevant European guidelines; reviews issues that surround use of this technology; summarises the effects of continuous subcutaneous insulin infusion on patients' health-related quality of life; reviews relevant pharmacoeconomic data; and discusses recent advances in pump technology, including the development of closed-loop 'artificial pancreas' systems. © 2015 The Authors. Diabetes/Metabolism Research and Reviews Published by John Wiley & Sons Ltd.

The rise of technology in diabetes care. Not all that is new is necessarily better.

Health-care technologies have brought many benefits to the medical profession and to patients. The introduction of the continuous subcutaneous insulin infusion (CSII) pump and continuous glucose monitoring (CGM) devices offers patients with type 1 diabetes (T1D) the opportunity to optimize their blood glucose control and are increasingly being championed as a routine treatment approach for young people. However, the current evidence base does not convincingly support arguments for the generalized application of CSII and CGM into routine clinical practice. The 'patient-medical device interface' is clearly a complex paradigm, and central to its success is the degree of adherence, understanding, and engagement demonstrated by the patient with the technology. The introduction CSII/CGM technologies into the daily routine care of the patient imposes both psychological and 'time-effort' burdens that many patients and families with T1D will find demanding. The current application of these devices cannot therefore be considered a panacea for the self-management of T1D, and raises a number of challenging problems, including those of a practical, health-economic, and ethical nature that need to be fully resolved before it and other emerging technologies can be considered to have achieved this status.

Banting Memorial Lecture 2014* Technology and diabetes care: appropriate and personalized.

Continuous subcutaneous insulin infusion was initially developed as a research procedure in the 1970s but quickly became a routine treatment for selected people with Type 1 diabetes. Continuous subcutaneous insulin infusion and other diabetes technologies, such as continuous glucose monitoring, are now an established and evidence-based part of diabetes care, but there has been some confusion about effectiveness and best use, particularly because of conflicting results from meta-analyses. This is because literature summary meta-analyses (including all trials) are inappropriate for therapeutic and economic decision-making; such meta-analyses should only include trials representative of groups likely to benefit. For example, for continuous subcutaneous insulin infusion, this would be those with continued disabling hypoglycaemia or elevated HbA1c levels. Alternatively, individual patient data meta-analysis allows modelling of covariates that determine effect size, e.g. in the case of continuous glucose monitoring, baseline HbA1c and frequency of sensor usage. Diabetes technology is therefore an example of personalized medicine, where evaluation and use should be both appropriate and targeted. This will also apply to future technologies such as new 'patch' pumps for Type 2 diabetes, closed-loop insulin delivery systems and nanomedicine applications in diabetes that we are currently researching. These include fluorescence lifetime-based non-invasive glucose monitoring and nanoencapsulation of islets for improved post-transplant survival.

Automated insulin pump suspension for hypoglycaemia mitigation: development, implementation and implications.

In type 1 diabetes (T1D), insulin replacement therapy should ideally replicate endogenous insulin secretion, but achieving this goal requires frequent adjustments to insulin delivery based on glucose levels and trends, carbohydrate intake and physical activity. An overriding concern for people taking insulin is hypoglycaemia, which remains the most feared consequence of insulin therapy and limits therapy intensification options. Although fully automated systems that achieve consistent euglycaemia in T1D remain an elusive goal, improvements in continuous glucose monitoring (CGM) sensors and control algorithms have enabled semi-automated systems that lower the risk of hypoglycaemia, especially nocturnal hypoglycaemia. The present review focuses on an important advance in insulin delivery systems: the use of CGM data to stop insulin delivery in the presence of hypoglycaemia. Although conceptually simple, this strategy represents a critical step in the journey toward a fully closed-loop artificial pancreas; the next steps in this journey are also discussed.

Current management of diabetes mellitus and future directions in care.

The last 90 years have seen considerable advances in the management of type 1 and type 2 diabetes. Prof MacLean of Guy's Hospital wrote in the Postgraduate Medical Journal in 1926 about the numerous challenges that faced patients and their healthcare professionals in delivering safe and effective diabetes care at that time. The discovery of insulin in 1922 heralded a new age in enabling long-term glycaemic control, which reduced morbidity and mortality. Thirty years later, the first oral agents for diabetes, the biguanides and sulfonylureas, appeared and freed type 2 patients from having to inject insulin following diagnosis. Improvements in insulin formulations over the decades, including rapid-acting and long-acting insulin analogues that more closely mimic physiological insulin secretion, have increased the flexibility and efficacy of type 1 diabetes management. The last two decades have seen major advances in technology, which has manifested in more accurate glucose monitoring systems and insulin delivery devices ('insulin pump'). Increased understanding of the pathophysiological deficits underlying type 2 diabetes has led to the development of targeted therapeutic approaches such as on the small intestine (glucagon-like peptide-1 receptor analogues and dipeptidyl-peptidase IV inhibitors) and kidneys (sodium-glucose cotransporter-2 inhibitors). A patient-centred approach delivered by a multidisciplinary team is now advocated. Glycaemic targets are set according to individual circumstances, taking into account factors such as weight, hypoglycaemia risk and patient preference. Stepwise treatment guidelines devised by international diabetes organisations standardise and rationalise management. Structured education programmes and psychological support are now well-established as essential for improving patient motivation and self-empowerment. Large multicentre randomised trials have confirmed the effectiveness of intensive glycaemic control on microvascular outcomes, but macrovascular outcomes and cardiovascular safety remain controversial with several glucose-lowering agents. Future directions in diabetes care include strategies such as the 'bionic pancreas', stem cell therapy and targeting the intestinal microbiome. All of these treatments are still being refined, and it may be several decades before they are clinically useful. Prevention and cure of diabetes is the Holy Grail but remain elusive due to lack of detailed understanding of the metabolic, genetic and immunological causes that underpin diabetes. Much progress has been made since the time of Prof MacLean 90 years ago, but there are still great strides to be taken before the life of the patient with diabetes improves even more significantly.

Use of insulin in diabetes: a century of treatment.

Insulin is a key player in the control of hyperglycaemia for patients with type 1 diabetes mellitus and selected patients with type 2 diabetes mellitus. There have been many advances in insulin drug delivery from its first administration as a crude pancreatic extract till today. The traditional and most predictable method for administration of insulin is by subcutaneous injection. Currently available insulin delivery systems include insulin syringes, infusion pumps, jet injectors, and pens. The major drawback of insulin therapy is its invasive nature. Non-invasive delivery of insulin has long been a major goal for the treatment of diabetes mellitus. Although there have been improvements in insulin therapy since it was first conceived, it is still far from mimicking the physiological secretion of pancreatic ß-cells, and research to find new insulin formulations and new routes of administration continues. This article reviews the emerging technologies, including insulin inhalers, insulin buccal spray, insulin pill, islet cell transplant, and stem cell therapy, as treatment options for diabetes mellitus.

[New technologies in diabetology. How far are we from a closed loop?]. / Neue Technologien in der Diabetologie. Wie weit ist es noch bis zum Closed-loop-System?

Today, assistive technologies are highly important in the treatment of diabetes, especially in the therapy of type 1 diabetes. The use of insulin pumps, for example, has become an established form of treatment. Modern insulin pumps offer various functions, such as different basal rate profiles, split delivery of the meal bolus, and integrated bolus calculators. Some pumps are additionally connected to a blood glucose meter or a continuous glucose-monitoring sensor. Several minimally invasive needle-type sensor systems for continuous tissue glucose monitoring are already available. Recent developments aim at increasing the functionality of insulin pumps and the improvements of sensors for continuous glucose monitoring. In addition, many research groups are working on closing the loop between these two components and thus developing an artificial pancreas, which automatically regulates insulin delivery. The first steps have already been taken and bolus calculators or sensor-augmented insulin pumps with suspension of insulin delivery are now available. Many experimental models show promising results. Prior to the implementation of a fully automated system for everyday use, however, partially automated systems that require user input are to be expected. This article aims at giving an overview of the current state of development in the field of diabetes technology.

Updates in the Management of Type 1 Diabetes in Pregnancy.

The care of pregnant individuals with type 1 diabetes mellitus has experienced significant advancements in recent years. Preconception counseling has re-emerged as a core dimension of management. Continuous glucose monitoring plays an increasingly useful and beneficial role in gestational glycemic monitoring, a practice informed by improved maternofetal outcomes. While studies have not shown that continuous subcutaneous insulin infusion is superior to multiple daily injections of insulin for glycemic control, recent work has signaled that hybrid closed-loop systems with pregnancy-specific targets could meaningfully improve glycemic control and potentially ameliorate maternofetal outcomes while reducing self-care burden.

Quality of life and technology: impact on children and families with diabetes.

Ensuring quality of life (QOL) while maintaining glycemic control within targets is an important challenge in type 1 and type 2 diabetes treatment. For children with diabetes, QOL includes enjoying meals, feeling safe in school, and perceiving positive, supportive relationships with parents, siblings, and friends. Yet many treatment-related and psychosocial barriers can interfere with a child's QOL and their ability to manage diabetes effectively. Diabetes management also imposes considerable lifestyle demands that are difficult and often frustrating for children to negotiate at a young age. Recent advances in diabetes medications and technologies have improved glycemic control in children with diabetes. Two widely used technologies are the insulin pump and continuous glucose monitoring (CGM) system. These technologies provide patients with more flexibility in their daily life and information about glucose fluctuations. Several studies report improvements in glycemic control in children with type 1 diabetes using the insulin pump or sensor-augmented pump therapy. Importantly, these technologies may impact QOL for children and families with diabetes, although they are rarely used or studied in the treatment of children with type 2 diabetes. Further, emerging closed loop and web- and phone-based technologies have great potential for supporting diabetes self-management and perhaps QOL. A deeper understanding and appreciation of the impact of diabetes technology on children's and parents' QOL is critical for both the medical and psychological care of diabetes. Thus, the purpose of this review is to discuss the impact of new diabetes technologies on QOL in children, adolescents and families with type 1 diabetes.

Pumpers, skypers, surfers and texters: technology to improve the management of diabetes in teenagers.

A variety of innovative technologies are available to assist with the management of diabetes in teenagers. Technologies include devices that assist with the direct day-to-day management of diabetes including insulin pumps and continuous glucose monitors. These devices are being used more and more with teenagers as a means of improving treatment adherence and glycaemic control. In addition, telehealth is being used to deliver care and support around diabetes management issues for teens with diabetes. Telehealth used in diabetes care for teens includes cell phones and video-conferencing. The goal of this telehealth technology is to support health behaviours and implement behavioural change strategies in a way that is more integrated into the everyday lives of patients and even in the context in which the behaviours occur in 'real time'. Finally, information and support via the Internet are gaining acceptance and use among teens with diabetes as an effective means of strategies for improved diabetes self-care. All three of these broad uses of technology in diabetes in teens represent flexible, innovative, and accessible approaches to improving both diabetes management and glycaemic control in this 'at risk' population.