Ultra-rapid-acting insulin analogs (URAA) are a further development and refinement of rapid-acting insulin analogs. Because of their adapted formulation, URAA provide an even faster pharmacokinetics and thus an accelerated onset of insulin action than conventional rapid-acting insulin analogs, allowing for a more physiologic delivery of exogenously applied insulin. Clinical trials have confirmed the superiority of URAA in controlling postprandial glucose excursions, with a safety profile that is comparable to the rapid-acting insulins. Consequently, many individuals with diabetes mellitus may benefit from URAA in terms of prandial glycemic control. Unfortunately, there are only few available recommendations from authoritative sources for use of URAA in clinical practice. Therefore, this expert consensus report aims to define populations of people with diabetes mellitus for whom URAA may be beneficial and to provide health care professionals with concrete, practical recommendations on how best to use URAA in this context.

The International Society for Pediatric and Adolescent Diabetes (ISPAD) guidelines represent a rich repository that serves as the only comprehensive set of clinical recommendations for children, adolescents, and young adults living with diabetes worldwide. This chapter builds on the 2022 ISPAD guidelines, and updates recommendations on the principles of intensive insulin regimens, including more intensive forms of multiple daily injections with new-generation faster-acting and ultra-long-acting insulins; a summary of adjunctive medications used alongside insulin treatment that includes details on pramlintide, metformin, glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RA) and sodium-glucose cotransporter inhibitors; and key considerations with regard to access to insulin and affordability to ensure that all persons with diabetes who need insulin can obtain it without financial hardship.

While most research has focused on the association between intracytoplasmic sperm injection (ICSI) and neurodevelopmental disorders in children, relatively little attention has been given to its metabolic effects. Previous studies have reported that low serum lipid levels are associated with mental health problems. Our objective was to analyze the impact of ICSI on metabolic alterations compared to their in vitro fertilization (IVF) counterparts in male offspring, as well as its interaction with paternal overweight/obesity.

We recruited families between January 2006 and December 2017 at the Center for Reproductive Medicine, Shandong University, China. Prospective data of offspring were obtained for body mass index (BMI), blood pressure, glucose, and lipid profile in their 0-11 years old. Linear mixed models were utilized to compute the mean difference and 95% confidence intervals (CI).

A total of 14,196 offspring visits were identified. In offspring aged 4-11 years, ICSI-conceived offspring exhibited significantly lower fasting glucose z-scores, total cholesterol z-scores, and low-density lipoprotein cholesterol (LDL-C) z-scores compared with their IVF counterparts (fasting glucose z-score: adjusted mean difference: - 0.13, 95% CI: - 0.23 to - 0.03; total cholesterol z-score: adjusted mean difference: - 0.13, 95% CI: - 0.23 to - 0.02; LDL-C z-score: adjusted mean difference: - 0.12, 95% CI: - 0.22 to - 0.01). Paternal overweight/obesity significantly influenced the relationship between ICSI and metabolic changes in offspring. In offspring born from fathers with overweight/obesity, ICSI-conceived offspring displayed significantly lower fasting glucose and total cholesterol z-scores than their IVF controls (fasting glucose z-score: adjusted mean difference: - 0.20, 95% CI: - 0.32 to - 0.08; total cholesterol z-score: adjusted mean difference: - 0.15, 95% CI: - 0.27 to - 0.02). In offspring born to fathers with normal weight, ICSI-conceived offspring showed significantly lower systolic blood pressure z-scores compared to those conceived via the IVF procedures (adjusted mean difference: - 0.21, 95% CI: - 0.37 to - 0.05).

The findings of this study suggested that ICSI was associated with altered glucose and lipid profiles compared to their IVF controls, characterized by lower fasting glucose z-scores, total cholesterol z-scores, and LDL-C z-scores. Encouraging fathers to reduce their body weight could potentially improve the metabolic health of their ICSI-conceived children.

Neonatal encephalopathy (NE) is a serious condition with various neurological dysfunctions in newborns. Disruptions in glucose metabolism, including both hypoglycemia and hyperglycemia, are common in NE and can significantly impact outcomes. Hypoglycemia, defined as blood glucose below 45 mg/dL, is associated with increased mortality, neurodevelopmental disabilities, and brain lesions on MRI. Conversely, hyperglycemia, above 120 to 150 mg/dL, has also been linked to heightened mortality, hearing impairment, and multiorgan dysfunction. Both aberrant glucose states appear to worsen prognosis compared to normoglycemic infants. Therapeutic hypothermia is the standard of care for NE that provides neuroprotection by reducing metabolic demands and inflammation. Adjunct therapies like glucagon and continuous glucose monitoring show promise in managing dysglycemia and improving outcomes. Glucagon can enhance cerebral blood flow and glucose supply, while continuous glucose monitoring enables real-time monitoring and personalized interventions. Maintaining balanced blood sugar levels is critical in managing NE. Early detection and intervention of dysglycemia are crucial to improve outcomes in neonates with encephalopathy. Further research is needed to optimize glycemic management strategies and explore the potential benefits of interventions like glucagon therapy.

After birth, healthy neonates undergo a period of altered glucose metabolism, known as "transitional hypoglycemia." During the first 0 to 4 hours of life, the mean plasma glucose concentration decreases to 57 mg/dL, then by 72 to 96 hours of life increases to 82 mg/dL, well within the normal adult range. Recent data suggest that transitional hypoglycemia is due to persistence of the fetal beta cell's lower threshold for insulin release, resulting in a transient hyperinsulinemic state. While hypoglycemia is an expected part of the transition to postnatal life, it makes the identification of infants with persistent hypoglycemia disorders challenging. Given the risk of neurologic injury from hypoglycemia, identifying these infants is critical. Hyperinsulinism is the most common cause of persistent hypoglycemia in neonates and infants and carries a high risk of neurocognitive dysfunction given the severity of the hypoglycemia and the inability to generate ketones, a critical alternative cerebral fuel. Screening neonates at risk for persistent hypoglycemia disorders and completing evaluations prior to hospital discharge is essential to prevent delayed diagnoses and neurologic damage.

The American Diabetes Association (ADA) "Standards of Care in Diabetes" includes the ADA's current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, an interprofessional expert committee, are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA's clinical practice recommendations and a full list of Professional Practice Committee members, please refer to Introduction and Methodology. Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.

Type 1 diabetes mellitus (T1DM) is a chronic childhood disease with potentially persistent CNS disruptions. In this study, we aimed to systematically review diffusion tensor imaging studies in patients with T1DM to understand the microstructural effects of this entity on individuals' brains METHODS: We performed a systematic search and reviewed the studies to include the DTI studies in individuals with T1DM. The data for the relevant studies were extracted and a qualitative synthesis was performed.

A total of 19 studies were included, most of which showed reduced FA widespread in optic radiation, corona radiate, and corpus callosum, as well as other frontal, parietal, and temporal regions in the adult population, while most of the studies in the juvenile patients showed non-significant differences or a non-persistent pattern of changes. Also, reduced AD and MD in individuals with T1DM compared to controls and non-significant differences in RD were noted in the majority of studies. Microstructural alterations were associated with clinical profile, including age, hyperglycemia, diabetic ketoacidosis and cognitive performance.

T1DM is associated with microstructural brain alterations including reduced FA, MD, and AD in widespread brain regions, especially in association with glycemic fluctuations and in adult age.

Dementia is a permanent illness characterized by mental instability, memory loss, and cognitive decline. Many studies have demonstrated an association between diabetes and cognitive dysfunction that proceeds in three steps, namely, diabetes-associated cognitive decrements, mild cognitive impairment (MCI; both non-amnesic MCI and amnesic MCI), and dementia [both vascular dementia and Alzheimer's disease (AD)]. Based on this association, this disease has been designated as type 3 diabetes mellitus. The underlying mechanisms comprise insulin resistance, inflammation, lipid abnormalities, oxidative stress, mitochondrial dysfunction, glycated end-products and autophagy. Moreover, insulin and insulin-like growth factor-1 (IGF-1) have been demonstrated to be involved. Insulin in the brain has a neuroprotective role that alters cognitive skills and alteration of insulin signaling determines beta-amyloid (Aβ) accumulation, in turn promoting brain insulin resistance. In this complex mechanism, other triggers include hyperglycemia-induced overproduction of reactive oxygen species (ROS) and inflammatory cytokines, which result in neuroinflammation, suggesting that antidiabetic drugs may be potential treatments to protect against AD. Among these, glucagon-like peptide-1 receptor agonists (GLP-1RAs) are the most attractive antidiabetic drugs due to their actions on synaptic plasticity, cognition and cell survival. The present review summarizes the significant data concerning the underlying pathophysiological and pharmacological mechanisms between diabetes and dementia.

The notion that pediatric type 1 diabetes impacts brain function and structure early in life is of great concern. Neurological manifestations, including neurocognitive and behavioral symptoms, may be present from childhood, initially mild and undetectable in daily life. Despite intensive management and technological therapeutic interventions, most pediatric patients do not achieve glycemic control targets for HbA1c. One of the most common causes of such poor control and frequent transient hyperglycemic episodes may be lifestyle factors, including missed meal boluses.

The aim of this study was to assess the association between specific neurocognitive accomplishments-learning and memory, inhibition ability learning, and verbal and semantic memory-during meals with and without bolusing, correlated to diffusion tensor imaging measurements of major related tracts, and glycemic control in adolescents with type 1 diabetes compared with their healthy siblings of similar age.

This is a case-control study of 12- to 18-year-old patients with type 1 diabetes (N = 17, 8 male patients, diabetes duration of 6.53 ± 4.1 years) and their healthy siblings (N = 13). All were hospitalized for 30 h for continuous glucose monitoring and repeated neurocognitive tests as a function of a missed or appropriate pre-meal bolus. This situation was mimicked by controlled, patient blinded manipulation of lunch pre-meal bolus administration to enable capillary glucose level of <180 mg/dl and to >240 mg/d 2 hours after similar meals, at a similar time. The diabetes team randomly and blindly manipulated post-lunch glucose levels by subcutaneous injection of either rapid-acting insulin or 0.9% NaCl solution before lunch. A specific neurocognitive test battery was performed twice, after each manipulation, and its results were compared, along with additional neurocognitive tasks administered during hospitalization without insulin manipulation. Participants underwent brain imaging, including diffusion tensor imaging and tractography.

A significant association was demonstrated between glycemic control and performance in the domains of executive functions, inhibition ability, learning and verbal memory, and semantic memory. Inhibition ability was specifically related to food management. Poorer glycemic control (>8.3%) was associated with a slower reaction time.

These findings highlight the potential impairment of brain networks responsible for learning, memory, and controlled reactivity to food in adolescents with type 1 diabetes whose glycemic control is poor.

The American Diabetes Association (ADA) "Standards of Care in Diabetes" includes the ADA's current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee, are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA's clinical practice recommendations and a full list of Professional Practice Committee members, please refer to Introduction and Methodology. Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.

Analysis of the impact on severe hypoglycaemia and direct costs of the introduction of the FreeStyle Libre sensor in paediatric population with type 1 Diabetes Mellitus.

Ambispective single-centre study to assess the impact on severe hypoglycaemia and direct costs, focusing on consumption of materials, in paediatric population with type 1 Diabetes Mellitus before and after introduction of the FreeStyle Libre 1 sensor.

A significant decrease was found in episodes of severe hypoglycaemia, with 4.2 episodes of severe hypoglycaemia per 100 patients under follow-up versus 0.25 episodes per 100 patients a year after introduction of the system. This represents a cost difference for severe hypoglycaemia, estimated at €6559.52 before introduction and €409.97 after introduction of the FreeStyle Libre sensor. We found a decrease in the daily consumption of capillary blood glucose strips, which translates as a decrease in the cost of materials and helps mitigate the cost of the sensor. The cost in materials for the patient with FreeStyle Libre was €185.13 per patient and year higher than conventional control with capillary blood glucose strips.

Type 1 diabetes mellitus (T1DM) affects the development of cognitive function in children, which may be due to deficits in brain structures or functions. It is unclear whether children with T1DM experience alterations in the gray matter (GM) structure at the initial stages of the disease. This study investigated GM structure alterations in children with newly diagnosed T1DM.

Based on 3D T1-weighted MR images, we investigated the gray matter volume (GMV) of 35 newly diagnosed T1DM children and 35 age- and sex-matched healthy controls using voxel-based morphometry. The brain regions with significant differences in GMV between the newly diagnosed T1DM children and the controls were extracted and the correlation with clinical data was assessed.

Compared with the control group, children with newly diagnosed T1DM had a lower GMV in the right inferior and middle temporal gyri, right lingual gyrus, and left superior frontal gyrus. In T1DM subjects, the GMV of the right middle temporal gyrus was positively correlated with IQ but was negatively correlated with HbA1c.

Our findings provide compelling evidence that GM abnormalities occur during early disease stages in T1DM children, which may be a potential neurobiological mechanism underlying cognitive deficits.

Using an efficient method to analyze gray matter changes in T1DM is very important. The anterior, posterior, and temporal brain regions are susceptible to T1DM in children. Recent glucose variability may affect regional gray matter volume in children with newly diagnosed T1DM. Structural changes were documented in the gray matter of the brain even at the early stages of the disease in children with T1DM.

Wolfram Syndrome (WS) is a very rare genetic disorder characterized by several symptoms that occur from childhood to adulthood. Usually, the first clinical sign is non-autoimmune diabetes even if other clinical features (optic subatrophy, neurosensorial deafness, diabetes insipidus) may be present in an early state and may be diagnosed after diabetes' onset. Prognosis is poor, and the death occurs at the median age of 39 years as a consequence of progressive respiratory impairment, secondary to brain atrophy and neurological failure. The aim of this paper is the description of the metabolic treatment of the WS. We reported the experience of long treatment in patients with this syndrome diagnosed in pediatric age and followed also in adult age. It is known that there is a correlation between metabolic control of diabetes, the onset of other associated symptoms, and the progression of the neurodegenerative alterations. Therefore, a multidisciplinary approach is necessary in order to prevent, treat and carefully monitor all the comorbidities that may occur. An extensive understanding of WS from pathophysiology to novel possible therapy is fundamental and further studies are needed to better manage this devastating disease and to guarantee to patients a better quality of life and a longer life expectancy.

Glucose is the most important substrate for proper brain functioning and development, with an increased glucose consumption in relation to the need of creating new brain structures and connections. Therefore, alterations in glucose homeostasis will inevitably be associated with changes in the development of the Nervous System. Several studies demonstrated how the alteration of glucose homeostasis - both hyper and hypoglycemia- may interfere with the development of brain structures and cognitivity, including deficits in intelligence quotient, anomalies in learning and memory, as well as differences in the executive functions. Importantly, differences in brain structure and functionality were found after a single episode of diabetic ketoacidosis suggesting the importance of glycemic control and stressing the need of screening programs for type 1 diabetes to protect children from this dramatic condition. The exciting progresses of the neuroimaging techniques such as diffusion tensor imaging, has helped to improve the understanding of the effects, outcomes and mechanisms underlying brain changes following dysglycemia, and will lead to more insights on the physio-pathological mechanisms and related neurological consequences about hyper and hypoglycemia.

The American Diabetes Association (ADA) "Standards of Medical Care in Diabetes" includes the ADA's current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee (https://doi.org/10.2337/dc22-SPPC), are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA's clinical practice recommendations, please refer to the Standards of Care Introduction (https://doi.org/10.2337/dc22-SINT). Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.

The American Diabetes Association (ADA) "Standards of Medical Care in Diabetes" includes the ADA's current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee (https://doi.org/10.2337/dc21-SPPC), are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA's clinical practice recommendations, please refer to the Standards of Care Introduction (https://doi.org/10.2337/dc21-SINT). Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.

A considerable endeavor had taken place in order to understand the associated challenges for children and adolescents with Specific Learning Disorder (SLD) and Type 1 Diabetes Mellitus (T1DM) but also in order to describe the necessary skills and approaches that the care givers have to develop to assist both children and parents. (1) Aim: The aim of this review is twofold. Firstly, to highlight the T1DM's potential impact on psychological well-being, on cognitive functioning and on school performance in children and adolescents who confront SLD. Secondly, to discuss the necessity of a multidiscipline approach of poor school performance in students with SLD and T1DM, presenting the serious contribution of care providers: (a) parents/carers in the family setting, (b) teachers and psychologists in the school setting and (c) health specialists (pediatricians, nutricians, nurses, child psychiatrists and psychologists) in the medical setting. (2) Methods: In this narrative literature review of 12 selected articles, each one studies a special aspect of approach, during the diagnosis and the treatment of individuals with T1DM and SLD. The review concerns the arising problems and difficulties in the adherence to diagnosis, the management of insulin, the mental and physical wellbeing, the school performance, the cognitive functioning and learning difficulties of patients. We tried to synthesize an interdisciplinary approach that involves collaboration between family, school and medical frame; facilitating children's and adolescents' difficulties management, as well as parent and teacher involvement during the intervention implementation. (3) Results: The main issues of concern were examined through the available literature, as different factors had to be re-examined in the previous studies, regarding the potential impact of T1DM in cognitive and psychological functioning, as well as the effects of the intervention/approach/treatment of children and adolescents with SLD and T1DM. (4) Conclusions: Although T1DM diagnosis and demanding treatment are a heavy burden for children and their families, T1DM may or may not be associated with a variety of academic and psychological outcomes. Despite the variability of the reviewed research design quality, it was clearly defined that the impact of T1DM is not uniform across educational and mental variables. Strengthening the children's physical, psychological and social wellbeing is an especially important factor, as it facilitates the insulin's management as well as the learning difficulties. This is possible by supporting the parental and teacher involvement in the intervention process. This review highlights the need to reduce the distance between theory/research and practice, in some of the proposed areas in this field of knowledge.

This study aimed to clarify whether brain-derived neurotrophic factor (BDNF) is a biomarker for cognitive dysfunction in children with type 1 diabetes.

We conducted a cross-sectional case-control study of children aged between 6 and 18 years with type 1 diabetes and healthy volunteers. Serum BDNF level was measured in all of the studied children, and they all underwent intelligence tests with the Wechsler Intelligence Scale for Children, Fourth Edition (WISC-IV). We further compared the cognitive function and BDNF levels in the diabetic children with positive glutamic acid decarboxylase 65 antibody (GAD65-Ab) and those with negative GAD65-Ab.

Forty-five children with type 1 diabetes (mean age 14.0 ± 2.6 years, 42% male) and 50 normal controls (mean age 13.2 ± 2.3 years, 54% male) were recruited. The serum BDNF level was significantly lower in the diabetes group than in the controls (15.92 ± 7.2 vs. 18.5 ± 5.1 ng/mL, respectively, t = -2.03, p = 0.045) and much lower in the subgroup with GAD65-Ab positive type 1 diabetes. The average Full-Scale IQ, verbal comprehension, perceptual reasoning and working memory scores in the diabetes group were significantly lower than in the controls (all p < 0.05). Among the children with type 1 diabetes, poor glycemic control was related to lower general cognitive abilities (r = -0.34, p < 0.02), lower verbal comprehension (r = -0.305, p < 0.05), and lower perceptual reasoning scores (r = -0.346, p = 0.02).

The children with type 1 diabetes had a lower serum BDNF level and poorer neurocognitive function than normal healthy children, especially those with GAD65-Ab positive diabetes. Poor glycemic control was correlated with worse cognitive performance.

Evidence suggests that obesity adversely affects brain function. High body mass index, hypertension, dyslipidemia, insulin resistance, and diabetes are risk factors for increasing cognitive decline. Tart cherries (PrunusCerasus L.) are rich in anthocyanins and components that modify lipid metabolism. This study evaluated the effects of tart cherries on the brain in diet-induced obese (DIO) rats. DIO rats were fed with a high-fat diet alone or in association with a tart cherry seeds powder (DS) and juice (DJS). DIO rats were compared to rats fed with a standard diet (CHOW). Food intake, body weight, fasting glycemia, insulin, cholesterol, and triglycerides were measured. Immunochemical and immunohistochemical techniques were performed. Results showed that body weight did not differ among the groups. Blood pressure and glycemia were decreased in both DS and DJS groups when compared to DIO rats. Immunochemical and immunohistochemical techniques demonstrated that in supplemented DIO rats, the glial fibrillary acid protein expression and microglial activation were reduced in both the hippocampus and in the frontal cortex, while the neurofilament was increased. Tart cherry intake modified aquaporin 4 and endothelial inflammatory markers. These findings indicate the potential role of this nutritional supplement in preventing obesity-related risk factors, especially neuroinflammation.

The American Diabetes Association (ADA) "Standards of Medical Care in Diabetes" includes the ADA's current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee (https://doi.org/10.2337/dc20-SPPC), are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA's clinical practice recommendations, please refer to the Standards of Care Introduction (https://doi.org/10.2337/dc20-SINT). Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.

Follow-up observation is needed for type 1 diabetes mellitus (T1DM) children due to the potential injury to the brain. However, the effect of short-term T1DM on gray matter in school-aged children is still unclear. This study aimed to evaluate gray matter volume (GMV) changes and their relationships with clinical variables in school-aged children with short-term T1DM. Twenty-one school-aged T1DM children were compared with 21 control patients, matched for sex and age. T1-weighted gradient echo three-dimensional MRI was performed using a 3.0-Tesla scanner and the resulting images were processed with FSL software to assess the difference in GMV between the two groups. The children with T1DM presented with decreased GMV in the left middle temporal gyrus (LMTG), the right postcentral gyrus, and the left triangular part of the frontal inferior gyrus (LTP-FIG). No significant changes in intelligence quotient (IQ) were found between the T1DM and control groups. In T1DM patients, there was a significant positive correlation between the GMV of LMTG and full-scale IQ or linguistic IQ. In addition, an increased glycosylated hemoglobin level was negatively correlated with reduced GMV in the LMTG and LTP-FIG in the T1DM group. These findings suggest that short-term T1DM could lead to regional structural brain deficits in school-aged children. The GMV of the LMTG may affect IQ, and poor recent glycemic control may have an adverse effect on GMV in the LMTG and LTP-FIG in T1DM children.Video abstract: http://links.lww.com/WNR/A506.

Historically, data on the rate of hyperglycemia and ketosis have not been collected in clinical trials. However, it is clinically important to assess the rate of these events in children with type 1 diabetes (T1D). This question was addressed in two pediatric trials using insulin degludec (degludec).

To assess the rate of hyperglycemia and ketosis in two-phase 3b trials investigating degludec (Study 1) and degludec with insulin aspart (IDegAsp [Study 2]) vs insulin detemir (IDet).

Patients (aged 1-17 years inclusive) with T1D treated with insulin for ≥3 months.

Study 1: patients were randomized to degludec once daily (OD) or IDet OD/twice daily (BID) for 26 weeks, followed by a 26-week extension phase. Study 2: patients were randomized to IDegAsp OD or IDet OD/BID for 16 weeks. Bolus mealtime IAsp was included in both studies. In Study 1, hyperglycemia was recorded if plasma glucose (PG) was >11.1 mmol/L, with ketone measurement required with significant hyperglycemia (>14.0 mmol/L). In Study 2, hyperglycemia was recorded with PG >14.0 mmol/L where the subject looked/felt ill, with ketone measurement also required in these hyperglycemic patients. In this post hoc analysis, the hyperglycemia threshold was 14.0 mmol/L for uniformity.

Despite similar rates of hyperglycemia with degludec/IDegAsp compared with IDet, the rates of ketosis were lower with degludec/IDegAsp.

These trials, the first to systematically collect data on ketosis in pediatric patients with T1D, demonstrate the potential of degludec/IDegAsp to reduce rates of metabolic decompensation, compared with IDet.

The effect of type 1 diabetes on the developing brain is a topic of primary research interest. A variety of potential dysglycaemic insults to the brain can cause cellular and structural injury and lead to altered neuropsychological outcomes. These outcomes might be subtle in terms of cognition but appear to persist into adult life. Age and circumstance at diagnosis appear to play a substantial role in potential CNS injury. A history of diabetic ketoacidosis and chronic hyperglycaemia appear to be more injurious than previously suspected, whereas a history of severe hypoglycaemia is perhaps less injurious. Neurocognitive deficits manifest across multiple cognitive domains, including executive function and speed of information processing. Some evidence suggests that subtle brain injury might directly contribute to psychological and mental health outcomes. Impaired executive function and mental health, in turn, could affect patients' adherence and the ability to make adaptive lifestyle choices. Impaired executive functioning creates a potential feedback loop of diabetic dysglycaemia leading to brain injury, further impaired executive function and mental health, which results in suboptimal adherence, and further dysglycaemia. Clinicians dealing with patients with suboptimal glycaemic outcomes should be aware of these potential issues.

The risk of developing long-term complications of type 1 diabetes (T1D) is related to glycaemic control and is reduced by the use of intensive insulin treatment regimens: multiple daily injections (MDI) (≥ 4) and continuous subcutaneous insulin infusion (CSII). Despite a lack of evidence that the more expensive treatment with CSII is superior to MDI, both treatments are used widely within the NHS.

(1) To compare glycaemic control during treatment with CSII and MDI and (2) to determine safety and cost-effectiveness of the treatment, and quality of life (QoL) of the patients.

A pragmatic, open-label randomised controlled trial with an internal pilot and 12-month follow-up with 1 : 1 web-based block randomisation stratified by age and centre.

Fifteen diabetes clinics in hospitals in England and Wales.

Patients aged 7 months to 15 years.

Continuous subsutaneous insulin infusion or MDI initiated within 14 days of diagnosis of T1D.

Data were collected at baseline and at 3, 6, 9 and 12 months using paper forms and were entered centrally. Data from glucometers and CSII were downloaded. The Health Utilities Index Mark 2 was completed at each visit and the Pediatric Quality of Life Inventory (PedsQL, diabetes module) was completed at 6 and 12 months. Costs were estimated from hospital patient administration system data.

The primary outcome was glycosylated haemoglobin (HbA_1c) concentration at 12 months. The secondary outcomes were (1) HbA_1c concentrations of < 48 mmol/mol, (2) severe hypoglycaemia, (3) diabetic ketoacidosis (DKA), (4) T1D- or treatment-related adverse events (AEs), (5) change in body mass index and height standard deviation score, (6) insulin requirements, (7) QoL and (8) partial remission rate. The economic outcome was the incremental cost per quality-adjusted life-year (QALY) gained.

A total of 293 participants, with a median age of 9.8 years (minimum 0.7 years, maximum 16 years), were randomised (CSII, n = 149; MDI, n = 144) between May 2011 and January 2015. Primary outcome data were available for 97% of participants (CSII, n = 143; MDI, n = 142). At 12 months, age-adjusted least mean squares HbA_1c concentrations were comparable between groups: CSII, 60.9 mmol/mol [95% confidence interval (CI) 58.5 to 63.3 mmol/mol]; MDI, 58.5 mmol/mol (95% CI 56.1 to 60.9 mmol/mol); and the difference of CSII - MDI, 2.4 mmol/mol (95% CI -0.4 to 5.3 mmol/mol). For HbA_1c concentrations of < 48 mmol/mol (CSII, 22/143 participants; MDI, 29/142 participants), the relative risk was 0.75 (95% CI 0.46 to 1.25), and for partial remission rates (CSII, 21/86 participants; MDI, 21/64), the relative risk was 0.74 (95% CI 0.45 to 1.24). The incidences of severe hypoglycaemia (CSII, 6/144; MDI, 2/149 participants) and DKA (CSII, 2/144 participants; MDI, 0/149 participants) were low. In total, 68 AEs (14 serious) were reported during CSII treatment and 25 AEs (eight serious) were reported during MDI treatment. Growth outcomes did not differ. The reported insulin use was higher with CSII (mean difference 0.1 unit/kg/day, 95% CI 0.0 to 0.2 unit/kg/day; p = 0.01). QoL was slightly higher for those randomised to CSII. From a NHS perspective, CSII was more expensive than MDI mean total cost (£1863, 95% CI £1620 to £2137) with no additional QALY gains (-0.006 QALYs, 95% CI -0.031 to 0.018 QALYs).

Generalisability beyond 12 months is uncertain.

No clinical benefit of CSII over MDI was identified. CSII is not a cost-effective treatment in patients representative of the study population.

Longer-term follow-up is required to determine if clinical outcomes diverge after 1 year. A qualitative exploration of patient and professional experiences of MDI and CSII should be considered.

Current Controlled Trials ISRCTN29255275 and EudraCT 2010-023792-25.

This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 42. See the NIHR Journals Library website for further project information. The cost of insulin pumps and consumables supplied by F. Hoffman-La Roche AG (Basel, Switzerland) for the purpose of the study were subject to a 25% discount on standard NHS costs.

To compare the efficacy, safety, and cost utility of continuous subcutaneous insulin infusion (CSII) with multiple daily injection (MDI) regimens during the first year following diagnosis of type 1 diabetes in children and young people.

Pragmatic, multicentre, open label, parallel group, randomised controlled trial and economic evaluation.

15 paediatric National Health Service (NHS) diabetes services in England and Wales. The study opened to recruitment in May 2011 and closed in January 2017.

Patients aged between 7 months and 15 years, with a new diagnosis of type 1 diabetes were eligible to participate. Patients who had a sibling with the disease, and those who took drug treatments or had additional diagnoses that could have affected glycaemic control were ineligible.

Participants were randomised, stratified by age and treating centre, to start treatment with CSII or MDI within 14 days of diagnosis. Starting doses of aspart (CSII and MDI) and glargine or detemir (MDI) were calculated according to weight and age, and titrated according to blood glucose measurements and according to local clinical practice.

Primary outcome was glycaemic control (as measured by glycated haemoglobin; HbA1c) at 12 months. Secondary outcomes were percentage of patients in each treatment arm with HbA1c within the national target range, incidence of severe hypoglycaemia and diabetic ketoacidosis, change in height and body mass index (as measured by standard deviation scores), insulin requirements (units/kg/day), partial remission rate (insulin dose adjusted HbA1c <9), paediatric quality of life inventory score, and cost utility based on the incremental cost per quality adjusted life year (QALY) gained from an NHS costing perspective.

294 participants were randomised and 293 included in intention to treat analyses (CSI, n=144; MDI, n=149). At 12 months, mean HbA1c was comparable with clinically unimportant differences between CSII and MDI participants (60.9 mmol/mol v 58.5 mmol/mol, mean difference 2.4 mmol/mol (95% confidence interval -0.4 to 5.3), P=0.09). Achievement of HbA1c lower than 58 mmol/mol was low among the two groups (66/143 (46%) CSII participants v 78/142 (55%) MDI participants; relative risk 0.84 (95% confidence interval 0.67 to 1.06)). Incidence of severe hypoglycaemia and diabetic ketoacidosis were low in both groups. Fifty four non-serious and 14 serious adverse events were reported during CSII treatment, and 17 non-serious and eight serious adverse events during MDI treatment. Parents (but not children) reported superior PedsQL scores for those patients treated with CSII compared to those treated with MDI. CSII was more expensive than MDI by £1863 (€2179; $2474; 95% confidence interval £1620 to £2137) per patient, with no additional QALY gains (difference -0.006 (95% confidence interval -0.031 to 0.018)).

During the first year following type 1 diabetes diagnosis, no clinical benefit of CSII over MDI was identified in children and young people in the UK setting, and treatment with either regimen was suboptimal in achieving HbA1c thresholds. CSII was not cost effective.

Current Controlled Trials ISRCTN29255275; European Clinical Trials Database 2010-023792-25.

Type 1 diabetes mellitus (T1DM) is considered a risk factor for the development of cognitive difficulties. The present study examined whether the cognitive performance of Chinese children with T1DM differs from that of healthy control (HC) children, and whether cognitive dysfunction is related to glycemic control.

Using a cross-sectional design, cognitive tests were administered, including general intelligence tests, to pediatric T1DM patients (n = 105) and HCs (n = 90). The effects of specific diabetes-related variables, including an earlier diabetes onset (<7 years of age), severe hypoglycemia, chronic hyperglycemia, and diabetic ketoacidosis (DKA), on cognitive outcomes were examined.

The T1DM group had lower IQ (P = 0.001) and attention (P = 0.018) scores than the HC group. Among T1DM patients, a younger age of diabetes onset was related to poorer performance on the visuospatial perception test (P = 0.017) and delayed logical memory (P = 0.012). Greater exposure to hyperglycemia over time was associated with lower visuospatial perception (P = 0.029), and DKA had a negative effect on the IQ score (P = 0.024). Compared with the late severe hypoglycemia subgroup, the early severe hypoglycemia subgroup (<7 years old) performed worse on both immediate (P = 0.001) and delayed (P = 0.049) visual memory tests.

Chinese children with T1DM showed deficits in IQ and attention. Earlier age of diabetes onset, chronic hyperglycemia, and DKA affected particular cognitive domains. Early exposure to severe hypoglycemia had negative effects on visual memory.

Type 1 diabetes mellitus (T1D), one of the most frequent chronic diseases in children, is associated with glucose dysregulation that contributes to an increased risk for neurocognitive deficits. While there is a bulk of evidence regarding neurocognitive deficits in adults with T1D, little is known about how early-onset T1D affects neural networks in young children. Recent data demonstrated widespread alterations in regional gray matter and white matter associated with T1D in young children. These widespread neuroanatomical changes might impact the organization of large-scale brain networks. In the present study, we applied graph-theoretical analysis to test whether the organization of structural covariance networks in the brain for a cohort of young children with T1D (N = 141) is altered compared to healthy controls (HC; N = 69). While the networks in both groups followed a small world organization-an architecture that is simultaneously highly segregated and integrated-the T1D network showed significantly longer path length compared with HC, suggesting reduced global integration of brain networks in young children with T1D. In addition, network robustness analysis revealed that the T1D network model showed more vulnerability to neural insult compared with HC. These results suggest that early-onset T1D negatively impacts the global organization of structural covariance networks and influences the trajectory of brain development in childhood. This is the first study to examine structural covariance networks in young children with T1D. Improving glycemic control for young children with T1D might help prevent alterations in brain networks in this population. Hum Brain Mapp 37:4034-4046, 2016. © 2016 Wiley Periodicals, Inc.

Differences in cognition and brain structure have been found in youth with type 1 diabetes compared with controls, even after relatively short disease duration. To determine whether severity of clinical presentation contributes to these differences, we obtained structural magnetic resonance imaging (MRI) scans in youth ages 7-17 who were either newly diagnosed with type 1 diabetes (<3.5 months from diagnosis, n  = 46) or a sibling without diabetes (n = 28).

Severity of presentation was measured by the presence of diabetic ketoacidosis (DKA) and degree of hyperglycemia exposure [hemoglobin A1c (HbA1c)] at diagnosis. MRI were obtained using T1-weighted, T2-weighted, and diffusion-weighted sequences.

Within the group with type 1 diabetes, 12 subjects presented in DKA and 34 did not. After controlling for age, sex, and multiple comparisons, the type 1 diabetes group had lower volume in the left temporal-parietal-occipital cortex compared with controls. Within the type 1 diabetes group, DKA at presentation was associated with lower radial, axial, and mean diffusivity (MD) throughout major white matter tracts and higher HbA1c was associated with lower hippocampal, thalamic, and cerebellar white matter volumes, lower right posterior parietal cortical thickness, and greater right occipital cortical thickness.

These data suggest that severity of clinical presentation is an important factor in predicting brain structural differences in youth with type 1 diabetes approximately 3 months after diagnosis.

To examine the relationship between diabetes distress and gender, and the association with glycemic control, social support, health behaviors, and socio-economic status.

All adolescents, aged 15 to 18 years, in the national, pediatric diabetes registry SWEDIABKIDS with type 1 diabetes were invited to complete an online questionnaire. A total of 2112 teenagers were identified.

453 complete responses were valid for analyses. Young women scored significantly higher on the distress-screening instrument DDS-2. Almost half of the female respondents exhibited moderate to severe diabetes distress-more than twice the proportion than among male respondents (44% vs 19%). Females reported twice as high scores on the fear of hypoglycemia scale (P < 0.0001) and had a higher HbA1c value than males (P < 0.0001). Gender was highly correlated with distress level even when controlling for multiple factors that may affect distress (parameter_female  = 0.4, P = 0.0003). Particular social problems were highly significant, that is, those who trust that their parents can handle their diabetes when necessary were significantly less distressed than others (P = 0.018). Higher HbA1c levels were associated with higher distress scores (P = 0.0005 [female], P = 0.0487 [male]).

Diabetes-related distress is a great burden for adolescents living with diabetes. Actively involved family and friends may reduce diabetes distress, but female adolescents appear to be particularly vulnerable and may need extra focus and support. Our findings indicate that pediatric diabetes teams working with teenagers must intensify the care during this vulnerable period of life in order to reduce the risk of both psychological and vascular complications in young adults.

Insulin lispro, the first rapid-acting insulin analog, was developed 20 years ago and has been studied in multiple situations and various populations.

To review the literature on the use of insulin lispro in children, adolescents, and young adults.

Children, adolescents, and young adults with type-1-diabetes.

One hundred and twenty-two relevant publications, identified by a systematic (MEDLINE) and manual literature search, were reviewed.

Multiple daily injection (MDI) treatment with insulin lispro or other rapid-acting insulins, mainly using neutral protamine Hagedorn (NPH) insulin as the basal component, was associated with reduced postprandial glucose excursions, similar or improved HbA1c levels, and similar or reduced risks of severe hypoglycemia when compared with regular human insulin across all age-groups. Continuous subcutaneous insulin infusion (CSII)-treatment with insulin lispro also showed similar or improved glycemic control vs. MDI- or other CSII-regimens across all age-groups, without increasing the rate of severe hypoglycemia. The other two more recently developed rapid-acting insulins (aspart, glulisine) demonstrated non-inferiority to lispro on HbA1c. Long-term observational studies and real-life experience indicate that the increasing use of optimized MDI- and CSII-regimens with insulin lispro was associated with improvements in overall glycemic control.

For almost 20 years, rapid-acting insulins, in particular insulin lispro as the first-in-class, have contributed to broadening the treatment options for the unique needs of pediatric patients with type-1-diabetes across all age-groups, and have enabled more physiological insulin administration. Now widely used, they have allowed pediatric patients to safely reach better glycemic control, with more flexibility in their daily lives.

Hypoglycemia and fear of hypoglycemia limit appropriate glycemic control in many children and adolescents with type 1 diabetes. Traditional approaches to the prevention of hypoglycemia including patient education about modifiable risk factors for hypoglycemia (changes in insulin, diet, and exercise) and frequency of self glucose monitoring remain important for hypoglycemia prevention. Continuous glucose monitoring systems with or without a partial closed-loop control of insulin infusion have been very useful in the prevention of hypoglycemia. Oral carbohydrate and parenteral glucagon continue to be the mainstays of hypoglycemia treatment. In the future, we can look forward to regulatory approval of closed-loop insulin delivery and glucose monitoring systems to facilitate euglycemia, as well as glucagon administered by the intranasal route to treat hypoglycemia.

To determine if children and young people aged < 23 years with Type 1 diabetes differ in academic ability from age-matched control subjects without Type 1 diabetes and whether academic scores are related to glycaemic control.

Using a cross-sectional study design, we administered cognitive and academic tests (Woodcock-Johnson III Spatial Relations, General Information, Letter-Word Recognition, Calculation and Spelling tests) to young people with Type 1 diabetes (n=61) and control subjects (n=26) aged 9-22 years. The groups did not differ in age or gender. Participants with Type 1 diabetes had a disease duration of 5-17.7 years. History of glycaemic control (HbA1c , diabetic ketoacidosis and severe hypoglycaemic episodes) was obtained via medical records and interviews.

The participants with Type 1 diabetes had a lower mean estimated verbal intelligence (IQ) level compared with those in the control group (P=0.04). Greater exposure to hyperglycaemia over time was associated with lower spelling abilities within the group with Type 1 diabetes (P=0.048), even after controlling for age, gender, socio-economic status, blood glucose level at time of testing and verbal IQ (P=0.01). History of severe hypoglycaemia or ketoacidosis was not associated with differences in academic abilities.

In children and young people, Type 1 diabetes was associated with a lower verbal IQ. Moreover, increased exposure to hyperglycaemia was associated with lower spelling performance. These results imply that hyperglycaemia can affect cognitive function and/or learning processes that may affect academic achievement.

Decrements in cognitive function may already be evident in young children with type 1 diabetes (T1D). Here we report prospectively acquired cognitive results over 18 months in a large cohort of young children with and without T1D.

A total of 144 children with T1D (mean HbA1c: 7.9%) and 70 age-matched healthy controls (mean age both groups 8.5 years; median diabetes duration 3.9 years; mean age of onset 4.1 years) underwent neuropsychological testing at baseline and after 18-months of follow-up. We hypothesized that group differences observed at baseline would be more pronounced after 18 months, particularly in those T1D patients with greatest exposure to glycemic extremes.

Cognitive domain scores did not differ between groups at the 18 month testing session and did not change differently between groups over the follow-up period. However, within the T1D group, a history of diabetic ketoacidosis (DKA) was correlated with lower Verbal IQ and greater hyperglycemia exposure (HbA1c area under the curve) was inversely correlated to executive functions test performance. In addition, those with a history of both types of exposure performed most poorly on measures of executive function.

The subtle cognitive differences between T1D children and nondiabetic controls observed at baseline were not observed 18 months later. Within the T1D group, as at baseline, relationships between cognition (Verbal IQ and executive functions) and glycemic variables (chronic hyperglycemia and DKA history) were evident. Continued longitudinal study of this T1D cohort and their carefully matched healthy comparison group is planned.

Massive insulin overdose may be associated with unpredictable and prolonged hypoglycemia. Concerns surrounding the potential provocation of insulin release from beta cells have previously prevented the use of intravenous glucagon as an adjunct to infusion of dextrose in this situation. We describe the case of a 15-yr-old boy with type 1 diabetes mellitus (T1DM) who presented with profound hypoglycemia following an overdose of an unknown quantity of premixed insulin. Owing to an increasing dextrose requirement and a dependence on hourly intramuscular glucagon injections, a continuous intravenous infusion of glucagon was commenced which successfully avoided the requirement for central venous access or concentrated dextrose infusion. Nausea was managed with anti-emetics. Intramuscular and subcutaneous glucagon is effective in the management of refractory and severe hypoglycemia in youth with both T1DM and hyperinsulinism. Concerns regarding the precipitation of rebound hypoglycemia with the use of intravenous glucagon do not relate to those with T1DM. This treatment option may be a useful adjunct in the management of insulin overdose in youth with T1DM and may avoid the requirement for invasive central venous access placement.

In this article, the author reviews the long-term outcomes and their precursors of type 1 diabetes starting in youth. The author also contrasts the changing incidence of these long-term complications as we have moved from the pre-Diabetes Control and Complications Trial (DCCT) to the post-DCCT standard of care and reviews the emerging data related to complications in youths with type 2 diabetes. Finally, the author reviews the recent understanding related to the effects of diabetes on the brain and cognition.

Both type 1 and type 2 diabetes have been associated with reduced performance on multiple domains of cognitive function and with structural abnormalities in the brain. With an aging population and a growing epidemic of diabetes, central nervous system-related complications of diabetes are expected to rise and could have challenging future public health implications. In this review, we will discuss the brain structural and functional changes that have been associated with type 1 and type 2 diabetes. Diabetes duration and glycemic control may play important roles in the development of cognitive impairment in diabetes, but the exact underlying pathophysiological mechanisms causing these changes in cognition and structure are not well understood. Future research is needed to better understand the natural history and the underlying mechanisms, as well as to identify risk factors that predict who is at greatest risk of developing cognitive impairment. This information will lead to the development of new strategies to minimize the impact of diabetes on cognitive function.

Glucose control in childhood type 1 diabetes is difficult and often characterized by significant glucose variability, including periods of prolonged hyperglycemia and intermittent episodes of hypoglycemia that can be severe. The brain of the developing child is thought to be more susceptible to metabolic insults because of its relatively high demand for glucose to fuel neuronal growth and differentiation. In this review we consider the impact of glucose variability, especially when associated with recurrent hypoglycemia, on long-term cognitive function in childhood type 1 diabetes. At present, this indicates a subtle effect of type 1 diabetes per se on a number of cognitive modalities. Within the population of children with type 1 diabetes, a history of severe hypoglycemia also appears to have an additional negative effect on cognitive function. However, interpretation of the literature is difficult in that the human studies draw largely from cross-sectional observational epidemiology while more basic work has used models that do not translate well into human disease. Moreover, it is likely to be many years before we will be able to clearly document the effects of recurrent hypoglycemia or chronic hyperglycemia on cognitive function. In the meantime, it seems appropriate to advocate that minimizing glucose variability when achieving glycemic targets should be the therapeutic goal of clinicians involved in the management of childhood type 1 diabetes.