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Recommendations: Regular self-monitoring of glucose (using accurate fingerstick blood glucose [BG] measurements, with or without continuous glucose monitoring [CGM] or intermittently scanned CGM [isCGM]), is essential for diabetes management for all children and adolescents with diabetes (A). ○ Each child should have access to technology and materials for self-monitoring of glucose measurements to test enough to optimize diabetes care (B). ○ Diabetes center personnel should advocate to nations, states, and health care funders to ensure that children and adolescents with diabetes have adequate glucose monitoring supplies (E). ○ When fingerstick BGs are used, testing may need to be performed 6 to 10 times per day to optimize intensive control. For children, adolescents, and young adults aged ≤25 years we recommend individualized targets, aiming for the lowest achievable HbA1c without undue exposure to severe hypoglycemia balanced with quality of life and burden of care (E). For children, adolescents, and young adults ≤25 years who have access to comprehensive care a target of HbA1c of <53 mmol/mol (7.0%) is recommended (E). ○ A higher HbA1c goal (in most cases <58 mmol/mol [7.5%]) is appropriate in the following contexts: inability to articulate symptoms of hypoglycemia, hypoglycemia unawareness/history of severe hypoglycemia, lack of access to analog insulins, advanced insulin delivery technology, ability to regularly check BG, and CGM (E), and individuals who are “high glycators,” in whom an at-target HbA1c would reflect a significantly lower mean glucose than 8.6 mmoL/L (155 mg/dL) (E). ○ A lower goal (6.5%) or 47.5 mmol/mol may be appropriate if achievable without excessive hypoglycemia, impairment of quality of life, and undue burden of care (E). ○ A lower goal may be appropriate during the honeymoon phase of type 1 diabetes (E). ○ For patients who have elevated HbA1c, a step-wise approach to improve glycemic control is advised including individualized attention to: dose adjustments (E), personal factors limiting achievement of the target (E), assessment of the psychological effect of goal setting on the individual (E), and incorporation of available technology to improve glucose monitoring and insulin delivery modalities (E). Importantly, recent data suggest that lowering HbA1c targets is associated with a decreased mean HbA1c on a population and individual level without an increased frequency of severe hypoglycemia, even in children who achieve HbA1c levels <53 mmol/mol (7.0%).

Since the 2018 ISPAD guidelines on this topic, follow‐up of large cohorts from around the globe have continued informing the current incidence and prevalence of co‐morbidities and complications in young adults with youth‐onset type 2 diabetes (T2D). This chapter focuses on the risk factors, diagnosis and presentation of youth‐onset T2D, the initial and subsequent management of youth‐onset T2D, and management of co‐morbidities and complications. We include key updates from the observational phase of the multi‐center Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) clinical trial, the SEARCH for Diabetes in Youth (SEARCH) study and new data from the Restoring Insulin Secretion (RISE) study, a head‐to‐head comparison of youth onset vs adult‐onset T2D. We also include an expanded section on risk factors associated with T2D, algorithms and tables for treatment, management, and assessment of co‐morbidities and complications, and sections on recently approved pharmacologic therapies for the treatment of youth‐onset T2D, social determinants of health, and settings of care given COVID‐19 pandemic.

The possibility of other types of diabetes should be considered in the child who has negative diabetes-associated autoantibodies and (B): an autosomal dominant family history of diabetes (maturity-onset diabetes of the young [MODY]) age less than 12 months and especially in first 6 months of life (NDM [neonatal diabetes mellitus]) mild-fasting hyperglycemia (5.5-8.5 mmol [100-150 mg/dL]), especially if young, non-obese, and asymptomatic a prolonged honeymoon period over 1 year or an unusually low requirement for insulin of ≤0.5 U/kg/day after 1 year of diabetes associated conditions such as deafness, optic atrophy, or syndromic features (mitochondrial disease) a history of exposure to drugs known to be toxic to β-cells or cause insulin resistance (eg, immunosuppressive drugs such as tacrolimus or cyclosporin; gluocorticoids or some antidepressants). While type 1 diabetes remains the most common form of diabetes in young people in many populations, especially those of European background, type 2 diabetes has become an increasingly important public health concern globally among children in high risk ethnic populations as well as in those with severe obesity, see ISPAD guideline on type 2 diabetes . Diabetes in young people usually presents with characteristic symptoms such as polyuria, polydipsia, nocturia, enuresis, weight loss—which may be accompanied by polyphagia, behavioral disturbance including reduced school performance, and blurred vision. Glycated hemoglobin (HbA1c) can be used as a diagnostic test for diabetes providing that stringent quality assurance tests are in place and assays are standardized to criteria aligned to the international reference values, and there are no conditions present which preclude its accurate measurement. [...]the validity of HbA1c as a measure of average glucose is complicated in the context of hemoglobinopathies, certain forms of anemia, or any other condition that affects normal red blood cell turnover.

To compare rates of microvascular complications in adolescents with type 1 diabetes treated with continuous subcutaneous insulin infusion (CSII) versus multiple daily injections (MDI). Prospective cohort of 989 patients (aged 12-20 years; diabetes duration >5 years) treated with CSII or MDI for >12 months. Microvascular complications were assessed from 2000-14: early retinopathy (seven-field fundal photography), peripheral nerve function (thermal and vibration threshold testing), autonomic nerve abnormality (heart rate variability analysis of electrocardiogram recordings) and albuminuria (albumin creatinine ratio/timed overnight albumin excretion). Generalized estimating equations (GEE) were used to examine the relationship between treatment and complications rates, adjusting for socio-economic status (SES) and known risk factors including HbA1c and diabetes duration. Comparing CSII with MDI: HbA1C was 8.6% [70mmol/mol] vs. 8.7% [72 mmol/mol]) (p = 0.7), retinopathy 17% vs. 22% (p = 0.06); microalbuminuria 1% vs. 4% (p = 0.07), peripheral nerve abnormality 27% vs. 33% (p = 0.108) and autonomic nerve abnormality 24% vs. 28% (p = 0.401). In multivariable GEE, CSII use was associated with lower rates of retinopathy (OR 0.66, 95% CI 0.45-0.95, p = 0.029) and peripheral nerve abnormality (OR 0.63, 95% CI 0.42-0.95, p = 0.026), but not albuminuria (OR 0.46, 95% CI 0.10-2.17, p = 0.33). SES was not associated with any of the complication outcomes. In adolescents, CSII use is associated with lower rates of retinopathy and peripheral nerve abnormality, suggesting an apparent benefit of CSII over MDI independent of glycemic control or SES.

The incidence of type 1 diabetes has increased since the mid-twentieth century at a rate that is too rapid to be attributed to genetic predisposition alone. While the disease can occur at any age, mounting evidence from longitudinal cohort studies of at-risk children indicate that type 1 diabetes associated autoantibodies can be present from the first year of life, and that those who develop type 1 diabetes at a young age have a more aggressive form of the disease. This corroborates the hypothesis that environmental exposures in early life contribute to type 1 diabetes risk, whether related to maternal influences on the fetus during pregnancy, neonatal factors or later effects during infancy and early childhood. Studies to date show a range of environmental triggers acting at different time points, suggesting a multifactorial model of genetic and environmental factors in the pathogenesis of type 1 diabetes, which integrally involves a dialogue between the immune system and pancreatic beta cells. For example, breastfeeding may have a weak protective effect on type 1 diabetes risk, while use of an extensively hydrolysed formula does not. Additionally, exposure to being overweight pre-conception, both in utero and postnatally, is associated with increased risk of type 1 diabetes. Epidemiological, clinical and pathological studies in humans support a role for viral infections, particularly enteroviruses, in type 1 diabetes, but definitive proof is lacking. The role of the early microbiome and its perturbations in islet autoimmunity and type 1 diabetes is the subject of investigation in ongoing cohort studies. Understanding the interactions between environmental exposures and the human genome and metagenome, particularly across ethnically diverse populations, will be critical for the development of future strategies for primary prevention of type 1 diabetes.

Recommendations Commence screening for microvascular complications at age 11 years (formerly 10 years) Screening for microvascular disease should be performed preconception and during each trimester of pregnancy Screen for lipid abnormalities in the non-fasting state Screen for renal disease by first morning albumin creatinine ratio as the preferred method Recommendations—Screening for and prevention of complications Prevention Intensive education and treatment should be used in children and adolescents to prevent or delay the onset and progression of vascular complications. E Because of potential worsening of retinopathy for patients with longstanding poor glycemic control when control is rapidly improved, ophthalmological monitoring is recommended before initiation of intensive treatment and at three monthly intervals for 6 to 12 months thereafter, particularly if retinopathy is moderate non-proliferative stage or worse at the time of intensification. Screening methods Risk factors Nephropathy 11 years with 2-5 years diabetes duration Urinary albumin/creatinine ratio Hyperglycaemia High BP Lipid abnormalities Smoking Retinopathy 11 years with 2-5 years diabetes duration Fundal photography or mydriatic ophthalmoscopy Hyperglycemia High BP Lipid abnormalities Higher BMI Neuropathy 11 years with 2-5 years diabetes duration History Physical examination Clinical tests Hyperglycemia Higher BMI Age Diabetes duration Genetics Macrovascular disease 11 years with 2-5 years diabetes duration Lipid profile every 2 years, BP annually Hyperglycemia High BP Lipid abnormalities Higher BMI Smoking Other ocular conditions A comprehensive initial eye examination should also be considered to detect cataracts, major refractive errors, or other ocular disorders. B Recommended threshold values for different parameters for intervention and primary prevention of microvascular and CVD in children and adolescents with type 1 diabetes Threshold value Type of intervention BP >90th percentile for age, gender and height Lifestyle intervention: exercise, less screen time and diet BP >90th percentile despite lifestyle intervention ACE inhibitor or other BP lowering agent If microalbuminuria is present: ACE inhibitor or ARB BP >95th percentile for age, gender and height Lifestyle intervention and ACE inhibitor or other BP lowering agent If microalbuminuria is present: ACE inhibitor or ARB LDL cholesterol >2.6 mmol/L (100 mg/dL) Dietary and lifestyle intervention LDL cholesterol >3.4 mmol/L (130 mg/dL) Statins Lipids Screening for dyslipidemia should be performed soon after diagnosis (when diabetes stabilized) in all children with type 1 diabetes from age 11 years E. If normal results are obtained, this should be repeated every 5 years.

Preeclampsia is a hypertensive disorder of pregnancy with serious health implications for mother and their offspring. The uteroplacental vascular insufficiency caused by preeclampsia is associated with epigenetic and pathological changes in the mother and fetus. However, the impact of preeclampsia in infancy (birth to 2 years), a time of rapid development influenced by pre- and postnatal factors that can predict future health outcomes, remains inconclusive. This narrative review of 23 epidemiological and basic science studies assessed the measurement and impact of preeclampsia exposure on infant growth and psychomotor developmental outcomes from birth to 2 years. Studies assessing infant growth report that preeclampsia-exposed infants have lower weight, length and BMI at 2 years than their normotensive controls, or that they instead experience accelerated weight gain to catch up in growth by 2 years, which may have long-term implications for their cardiometabolic health. In contrast, clear discrepancies remain as to whether preeclampsia exposure impairs infant motor and cognitive development, or instead has no impact. It is additionally unknown whether any impacts of preeclampsia are independent of confounders including shared genetic factors that predispose to both preeclampsia and childhood morbidity, perinatal factors including small for gestational age or preterm birth and their sequelae, and postnatal environmental factors such childhood nutrition. Further research is required to account for these variables in larger cohorts born at term, to help elucidate the independent pathophysiological impact of this clinically heterogenous and dangerous disease.

T follicular regulatory (Tfr) cells control the magnitude and specificity of the germinal centre reaction, but how regulation is contained to ensure generation of high-affinity antibody is unknown. Here we show that this balance is maintained by the reciprocal influence of interleukin (IL)-2 and IL-21. The number of IL-2-dependent FoxP3 + regulatory T cells is increased in the peripheral blood of human patients with loss-of-function mutations in the IL-21 receptor (IL-21R). In mice, IL-21:IL-21R interactions influence the phenotype of T follicular cells, reducing the expression of CXCR4 and inhibiting the expansion of Tfr cells after T-cell-dependent immunization. The negative effect of IL-21 on Tfr cells in mice is cell intrinsic and associated with decreased expression of the high affinity IL-2 receptor (CD25). Bcl-6, expressed in abundance in Tfr cells, inhibits CD25 expression and IL-21-mediated inhibition of CD25 is Bcl-6 dependent. These findings identify a mechanism by which IL-21 reinforces humoral immunity by restricting Tfr cell proliferation. IL-21 is central to follicular helper T cell function and germinal centre responses. Here the authors show that IL-21 signalling directly inhibits T follicular regulatory cells by limiting Bcl-6-dependent IL-2 receptor expression.