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OBJECTIVE: The objective of this clinical practice guideline is to provide updated and new evidence-based recommendations for the comprehensive care of persons with diabetes mellitus to clinicians, diabetes-care teams, other health care professionals and stakeholders, and individuals with diabetes and their caregivers. METHODS: The American Association of Clinical Endocrinology selected a task force of medical experts and staff who updated and assessed clinical questions and recommendations from the prior 2015 version of this guideline and conducted literature searches for relevant scientific papers published from January 1, 2015, through May 15, 2022. Selected studies from results of literature searches composed the evidence base to update 2015 recommendations as well as to develop new recommendations based on review of clinical evidence, current practice, expertise, and consensus, according to established American Association of Clinical Endocrinology protocol for guideline development. RESULTS: This guideline includes 170 updated and new evidence-based clinical practice recommendations for the comprehensive care of persons with diabetes. Recommendations are divided into four sections: (1) screening, diagnosis, glycemic targets, and glycemic monitoring; (2) comorbidities and complications, including obesity and management with lifestyle, nutrition, and bariatric surgery, hypertension, dyslipidemia, retinopathy, neuropathy, diabetic kidney disease, and cardiovascular disease; (3) management of prediabetes, type 2 diabetes with antihyperglycemic pharmacotherapy and glycemic targets, type 1 diabetes with insulin therapy, hypoglycemia, hospitalized persons, and women with diabetes in pregnancy; (4) education and new topics regarding diabetes and infertility, nutritional supplements, secondary diabetes, social determinants of health, and virtual care, as well as updated recommendations on cancer risk, nonpharmacologic components of pediatric care plans, depression, education and team approach, occupational risk, role of sleep medicine, and vaccinations in persons with diabetes. CONCLUSIONS: This updated clinical practice guideline provides evidence-based recommendations to assist with person-centered, team-based clinical decision-making to improve the care of persons with diabetes mellitus.

Purpose To determine the relationship between refractive error and diabetic retinopathy (DR). Design Clinical trial. Participants Type I diabetes individuals with serial refractive error and DR stage measurements over 30 years in the Diabetes Control and Complications Trial (DCCT) and Epidemiology of Diabetes Interventions and Complications (EDIC) follow-up study. Methods Stage of DR was measured every 6 months from standard fundus photographs, and refractive error was measured annually during the 6.5 years of DCCT; then, both were staggered every fourth year during EDIC with the full cohort measured at EDIC years 4 and 10. Outcomes of DR were 2- or 3-step progression, presence of proliferative DR (PDR), clinically significant macular edema (CSME), diabetic macular edema (DME), or ocular surgery. Myopia, emmetropia, and hyperopia were defined as a spherical equivalent of ≤−0.5, >−0.5 and Main Outcome Measures For each outcome separately, Cox proportional hazard (PH) models assessed the association between the refractive error status and the subsequent risk of that outcome, both without and with adjustment for potential risk factors. Results Hyperopia was associated with a higher risk of 2-step progression (hazard ratio [HR], 1.29; 95% confidence interval [CI], 1.05–1.59), 3-step progression (HR, 1.35; 95% CI, 1.05–1.73), and PDR (HR, 1.40; 95% CI, 1.02–1.92) compared with emmetropia in unadjusted models. These associations remained significant after adjustment for DCCT treatment group, cohort, age, sex, smoking, duration of diabetes, systolic and diastolic blood pressures, pulse, low-density lipoprotein, high-density lipoprotein, triglycerides, albumin excretion rate, and DCCT/EDIC mean updated hemoglobin A1c (HbA1c) (2-step progression: HR, 1.28; 95% CI, 1.03–1.58; 3-step progression: HR, 1.30; 95% CI, 1.00–1.68; PDR: HR, 1.38; 95% CI, 1.00–1.90). Myopia was not associated with any of the 5 DR outcomes in the unadjusted models and only marginally associated with 2-step progression (HR, 1.11; 95% CI, 1.00–1.24) in the adjusted models. Conclusions Myopia is not associated with DR progression risk. Hyperopia is an independent risk factor for 2-step and 3-step DR progression and PDR.

OBJECTIVE To assess whether previously observed brain and cognitive differences between children with type 1 diabetes and control subjects without diabetes persist, worsen, or improve as children grow into puberty and whether differences are associated with hyperglycemia. RESEARCH DESIGN AND METHODS One hundred forty-four children with type 1 diabetes and 72 age-matched control subjects without diabetes (mean ± SD age at baseline 7.0 ± 1.7 years, 46% female) had unsedated MRI and cognitive testing up to four times over 6.4 ± 0.4 (range 5.3–7.8) years; HbA1c and continuous glucose monitoring were done quarterly. FreeSurfer-derived brain volumes and cognitive metrics assessed longitudinally were compared between groups using mixed-effects models at 6, 8, 10, and 12 years. Correlations with glycemia were performed. RESULTS Total brain, gray, and white matter volumes and full-scale and verbal intelligence quotients (IQs) were lower in the diabetes group at 6, 8, 10, and 12 years, with estimated group differences in full-scale IQ of −4.15, −3.81, −3.46, and −3.11, respectively (P < 0.05), and total brain volume differences of −15,410, −21,159, −25,548, and −28,577 mm3 at 6, 8, 10, and 12 years, respectively (P < 0.05). Differences at baseline persisted or increased over time, and brain volumes and cognitive scores negatively correlated with a life-long HbA1c index and higher sensor glucose in diabetes. CONCLUSIONS Detectable changes in brain volumes and cognitive scores persist over time in children with early-onset type 1 diabetes followed longitudinally; these differences are associated with metrics of hyperglycemia. Whether these changes can be reversed with scrupulous diabetes control requires further study. These longitudinal data support the hypothesis that the brain is a target of diabetes complications in young children.

OBJECTIVE Approved treatments for type 2 diabetes in pediatric patients include metformin, liraglutide, and insulin. However, approximately one-half of the youth fail metformin monotherapy within 1 year, insulin therapy is associated with challenges, and liraglutide requires daily injections. Consequently, the efficacy and safety of once-weekly injections of exenatide for the treatment of youth with type 2 diabetes was evaluated. RESEARCH DESIGN AND METHODS Participants (aged 10 to RESULTS A total of 83 participants were randomized (exenatide, 59; placebo, 24) and 72 completed 24-week treatment (exenatide, 49; placebo, 23). At 24 weeks, the least squares mean change in glycated hemoglobin was −0.36% for the exenatide and +0.49% for the placebo groups (between-group difference, −0.85%; 95% CI −1.51, −0.19; P = 0.012). Nonsignificant least squares mean differences from baseline to 24 weeks favoring exenatide were observed: fasting glucose −21.6 mg/dL (−49.0, 5.7; P = 0.119), systolic blood pressure −2.8 mmHg (−8.0, 2.4; P = 0.284), and body weight −1.22 kg (−3.59, 1.15; P = 0.307). AEs occurred in 36 (61.0%) and 17 (73.9%) participants in the exenatide and placebo groups, respectively. CONCLUSIONS In youth with type 2 diabetes suboptimally controlled with current treatments, once-weekly exenatide reduced glycated hemoglobin at 24 weeks and was well tolerated.

T2D in youth remains challenging to manage and there is need for an expanded treatment armamentarium. The DINAMO study was designed to overcome recruitment difficulties that plagued previous T2D studies in youth. Within 3 years, DINAMO enrolled 158 patients aged to Disclosure L.M. Laffel: Advisory Panel; Medtronic, Roche Diabetes Care. Consultant; Boehringer Ingelheim International GmbH, Dexcom, Inc., Dompé, Insulet Corporation, Janssen Pharmaceuticals, Inc., Lilly Diabetes, Novo Nordisk, Provention Bio, Inc. T. Danne: Consultant; Abbott, AstraZeneca, Boehringer Ingelheim International GmbH, Dexcom, Inc., Lilly, Medtronic, Novo Nordisk, Roche Pharmaceuticals, Sanofi, Ypsomed AG. Research Support; Abbott, AstraZeneca, Boehringer Ingelheim International GmbH, Dexcom, Inc., Lilly, Medtronic, Novo Nordisk, Roche Pharmaceuticals, Sanofi, Ypsomed AG. Stock/Shareholder; DreaMed Diabetes, Ltd. W.V. Tamborlane: Consultant; AstraZeneca, Boehringer Ingelheim International GmbH, Medtronic, Novo Nordisk, Sanofi, Takeda Pharmaceutical Company Limited. G.J. Klingensmith: Research Support; AstraZeneca, Novo Nordisk, Takeda Pharmaceutical Company Limited. Stock/Shareholder; Dexcom, Inc., Insulet Corporation, Tandem Diabetes Care, Inc. C. Schroeder: Employee; Boehringer Ingelheim Inc. D. Neubacher: Employee; Boehringer Ingelheim International GmbH. N. Soleymanlou: Employee; Boehringer Ingelheim Pharmaceuticals Inc., Boehringer Ingelheim Pharmaceuticals Inc. J. Marquard: Employee; Boehringer Ingelheim Inc. P. Zeitler: Consultant; Boehringer Ingelheim International GmbH, Daiichi Sankyo, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk, Takeda Pharmaceutical Company Limited. S.M. Willi: Advisory Panel; Boehringer Ingelheim International GmbH, Medtronic. Research Support; Jaeb Center for Health Research, Provention Bio, Inc. Other Relationship; National Institute of Diabetes and Digestive and Kidney Diseases. Funding Boehringer Ingelheim

While the Type 1 Diabetes Exchange data noted that diabetic ketoacidosis (DKA) is more common in those utilizing injection regimens than insulin pumps, DKA remains a risk for pump users, as it can precipitously develop if insulin infusion is interrupted. We sought to obtain more recent DKA admission data in T1D youth using insulin pumps and the impact of CGM on DKA rates. Methods: We characterized DKA data in insulin pump users from episodes between 12/20 and 6/2021 in an academic pediatric endocrine practice in which 68% were pump users. Results: Among 591 pump patients aged Conclusions: DKA events were relatively uncommon; most episodes occurred in adolescents in poor diabetes control. Notably, most events could have been avoided if users followed standard trouble shooting guidelines. Thus, education on DKA prevention should be reinforced at each visit, particularly for teens on pumps with higher A1c levels. Moreover, while CGM wearers had higher admission bicarbonate values, over 50% of those hospitalized for DKA wore a CGM, suggesting even pump users using CGM require frequent reinforcement of DKA prevention education. Disclosure E.Doyle: None. S.A.Weinzimer: Consultant; Dompé, Research Support; Abbott Diabetes, Speaker's Bureau; Abbott Diabetes, Dexcom, Inc. W.V.Tamborlane: Consultant; AstraZeneca, Boehringer Ingelheim International GmbH, Medtronic, Novo Nordisk, Sanofi, Takeda Pharmaceutical Company Limited.

There are multiple information sources available to assist families in learning about rapidly advancing diabetes technologies as care options for their children. This study explored where and from whom families of young children with type 1 diabetes get information about diabetes technologies and the valence (positive vs. negative) of that information. Semi-structured interviews were conducted with parents (86% mothers) of 79 youth

OBJECTIVE To compare efficacy and safety of insulin glargine 300 units/mL (Gla-300) and 100 units/mL (Gla-100) in children and adolescents (6–17 years old) with type 1 diabetes. RESEARCH DESIGN AND METHODS EDITION JUNIOR was a noninferiority, international, open-label, two-arm, parallel-group, phase 3b trial. Participants were randomized 1:1 to Gla-300 or Gla-100, titrated to achieve fasting self-monitored plasma glucose levels of 90–130 mg/dL (5.0–7.2 mmol/L), with continuation of prior prandial insulin. The primary end point was change in HbA1c from baseline to week 26. Other assessments included change in fasting plasma glucose (FPG), hypoglycemia, hyperglycemia with ketosis, and adverse events. RESULTS In 463 randomized participants (Gla-300, n = 233; Gla-100, n = 230), comparable least squares (LS) mean (SE) reductions in HbA1c were observed from baseline to week 26 (−0.40% [0.06%] for both groups), with LS mean between-group difference of 0.004% (95% CI −0.17 to 0.18), confirming noninferiority at the prespecified 0.3% (3.3 mmol/mol) margin. Mean FPG change from baseline to week 26 was also similar between groups. During the 6-month treatment period, incidence and event rates of severe or documented (≤70 mg/dL [≤3.9 mmol/L]) hypoglycemia were similar between groups. Incidence of severe hypoglycemia was 6.0% with Gla-300 and 8.8% with Gla-100 (relative risk 0.68 [95% CI 0.35–1.30]). Incidence of any hyperglycemia with ketosis was 6.4% with Gla-300 and 11.8% with Gla-100. CONCLUSIONS Gla-300 provided similar glycemic control and safety profiles to Gla-100 in children and adolescents with type 1 diabetes, indicating that Gla-300 is a suitable therapeutic option in this population.

Objective: We evaluated blinded continuous glucose monitoring (CGM) profiles in a subset of adults with type 1 diabetes from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study to characterize the frequency of glycemic excursions and contributing factors. Research Design and Methods: CGM-derived metrics were compared for daytime and nighttime periods using blinded CGM for a minimum of 6.5 days (average 11.9 days) and correlated with HbA1c levels, routine use of diabetes devices, and other characteristics in 765 participants. Results: Participants were 58.9±6.5 years of age with diabetes duration 36.8±4.9 years and HbA1c 7.8±1.2%; 58% used insulin pumps and 27% used personal, unblinded CGM. Compared to daytime, nighttime mean sensor glucose was lower, % time in range 70-180 mg/dL (TIR) was similar and hypoglycemia more common. Over the entire recording period, only 9% of the 765 participants achieved >70% TIR and only 28% achieved Conclusions: In adults with long-standing type 1 diabetes, short-term blinded CGM profiles revealed frequent clinically-significant hypoglycemia (

OBJECTIVE We evaluated blinded continuous glucose monitoring (CGM) profiles in a subset of adults with type 1 diabetes from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study to characterize the frequency of glycemic excursions and contributing factors. RESEARCH DESIGN AND METHODS CGM-derived metrics were compared for daytime and nighttime periods using blinded CGM for a minimum of 6.5 days (average 11.9 days) and correlated with HbA1c levels, routine use of diabetes devices, and other characteristics in 765 participants. RESULTS Participants were 58.9 ± 6.5 years of age with diabetes duration 36.8 ± 4.9 years and HbA1c 7.8 ± 1.2%; 58% used insulin pumps, and 27% used personal, unblinded CGM. Compared with daytime, nighttime mean sensor glucose was lower, percent time in range 70–180 mg/dL (TIR) was similar, and hypoglycemia was more common. Over the entire recording period, only 9% of the 765 participants achieved >70% TIR and only 28% achieved CONCLUSIONS In adults with long-standing type 1 diabetes, short-term blinded CGM profiles revealed frequent clinically significant hypoglycemia (

BACKGROUND: Across all age groups, management of type 1 diabetes (T1D) places substantial responsibility and emotional burden upon families. This study explored parent perceptions of the burdens of caring for very young children with T1D. METHODS: Semi-structured qualitative interviews were conducted with parents (85% mothers) of 79 children with T1D, aged 1 to

Context Use of continuous glucose monitoring (CGM) is increasing for insulin-requiring patients with diabetes. Although data on glycemic profiles of healthy, nondiabetic individuals exist for older sensors, assessment of glycemic metrics with new-generation CGM devices is lacking. Objective To establish reference sensor glucose ranges in healthy, nondiabetic individuals across different age groups using a current generation CGM sensor. Design Multicenter, prospective study. Setting Twelve centers within the T1D Exchange Clinic Network. Patients or Participants Nonpregnant, healthy, nondiabetic children and adults (age ≥6 years) with nonobese body mass index. Intervention Each participant wore a blinded Dexcom G6 CGM, with once-daily calibration, for up to 10 days. Main Outcome Measures CGM metrics of mean glucose, hyperglycemia, hypoglycemia, and glycemic variability. Results A total of 153 participants (age 7 to 80 years) were included in the analyses. Mean average glucose was 98 to 99 mg/dL (5.4 to 5.5 mmol/L) for all age groups except those over 60 years, in whom mean average glucose was 104 mg/dL (5.8 mmol/L). The median time between 70 to 140 mg/dL (3.9 to 7.8 mmol/L) was 96% (interquartile range, 93 to 98). Mean within-individual coefficient of variation was 17 ± 3%. Median time spent with glucose levels >140 mg/dL was 2.1% (30 min/d), and median time spent with glucose levels Conclusion By assessing across age groups in a healthy, nondiabetic population, normative sensor glucose data have been derived and will be useful as a benchmark for future research studies.

INTRODUCTION: The expanding variety of insulins, including biosynthetic human insulin and rapid and long-acting insulin analogs, have dramatically transformed the management of type 1 diabetes (T1D) over the past 25 years. Moreover, increasing interest in the use of novel drugs developed for the treatment of type 2 diabetes (T2D) as adjunctive therapies for T1D remains a work in progress. AREAS COVERED: We reviewed articles published up to December 2018 in PubMed and ClinicalTrials.gov for recent developments in the pharmacologic treatment of T1D, including inhaled insulin, ultrafast and ultralong-acting insulins and adjunctive therapies including pramlintide, metformin, GLP-1 receptor agonists, DPP-4 inhibitors, SGLT-2, and SGLT1/2 inhibitors. EXPERT OPINION: With the creation of ultrafast-acting insulin analogs and very prolonged duration of action of basal insulins, it is possible to more closely mimic physiologic insulin secretion. Adjunctive therapies, likewise, may also overcome some of the abnormal physiology that is a hallmark of T1D. Therefore, individualized consideration of the efficacy of these agents must be measured alongside the potential adverse effects when choosing an adjunctive therapy.

OBJECTIVE In type 1 diabetes (T1D), the course of microalbuminuria is unpredictable and timing of glomerular filtration rate (GFR) loss is uncertain. Thus, there is a need to identify the risk factors associated with the development of more advanced stages of kidney disease through large, long-term systematic analysis. RESEARCH DESIGN AND METHODS Multivariable Cox proportional hazards models assessed the association of baseline and time-dependent glycemic and nonglycemic risk factors for incident macroalbuminuria and reduced estimated GFR (eGFR; defined as RESULTS Higher mean HbA1c (hazard ratio [HR] 1.969 per 1% higher level [95% CI 1.671–2.319]) and male sex (HR 2.767 [95% CI 1.951–3.923]) were the most significant factors independently associated with incident macroalbuminuria, whereas higher mean triglycerides, higher pulse, higher systolic blood pressure (BP), longer diabetes duration, higher current HbA1c, and lower mean weight had lower magnitude associations. For incident reduced eGFR, higher mean HbA1c (HR 1.952 per 1% higher level [95% CI 1.714–2.223]) followed by higher mean triglycerides, older age, and higher systolic BP were the most significant factors. CONCLUSIONS Although several risk factors associated with macroalbuminuria and reduced eGFR were identified, higher mean glycemic exposure was the strongest determinant of kidney disease among the modifiable risk factors. These findings may inform targeted clinical strategies for the frequency of screening, prevention, and treatment of kidney disease in T1D.

Many youth with diabetes struggle to meet glycemic targets. The new ultralong duration of action of insulin degludec (iDeg) holds potential to ameliorate missed doses of basal insulin and improve glycemic control in youth with diabetes.A retrospective chart review was undertaken of youth age 13 to24 years in our practice with type 1 diabetes (T1D) or type 2 diabetes (T2D) who had been switched from glargine or detemir to iDeg to evaluate the impact of this transition on glycemic control.Glycated hemoglobin A1c (HbA1c) in youth with T1D (n = 82) remained stable during 6 months of treatment with iDeg (10.1 ± 2.11% [87 ± 23 mmol/mol] at start of iDeg compared to 10.1 ± 2.12% [87 ± 23 mmol/mol] at 6 months of treatment), whereas in youth with T2D (n = 16), HbA1c significantly declined from 10.6 ± 2.3% (92 ± 25 mmol/mol) to 8.3 ± 2.2% (67 ± 24 mmol/mol) ( P = .0024).In youth switched to iDeg, which in our practice is commonly due to ineffectiveness of the patient's current regimen, the outcome differences we saw may be due to preserved beta-cell function in youth with T2D. It remains to be seen whether there are benefits of transition to iDeg in youth with T1D beyond glycemic outcomes, such as reduction in ketosis and episodes of diabetic ketoacidosis.DKA = diabetic ketoacidosis; DPV = Diabetes-Patienten-Verlaufsdokumentation (German/Austrian Prospective Diabetes Follow-Up Registry); HbA1c = glycated hemoglobin A1c; iDeg = insulin degludec; T1D = type 1 diabetes; T2D = type 2 diabetes.

Objective: To provide a snapshot of the profile of adults and youth with type 1 diabetes (T1D) in the United States and assessment of longitudinal changes in T1D management and clinical outcomes in the T1D Exchange registry. Research Design and Methods: Data on diabetes management and outcomes from 22,697 registry participants (age 1–93 years) were collected between 2016 and 2018 and compared with data collected in 2010–2012 for 25,529 registry participants. Results: Mean HbA1c in 2016–2018 increased from 65 mmol/mol at the age of 5 years to 78 mmol/mol between ages 15 and 18, with a decrease to 64 mmol/mol by age 28 and 58–63 mmol/mol beyond age 30. The American Diabetes Association (ADA) HbA1c goal of 10-fold in children

Aim: To evaluate the efficacy and safety of once‑weekly exenatide (EQW) in youth with T2D. Methods: Participants (aged 10 to Results: Overall, 83 participants were randomized (exenatide: 59; placebo: 24); 72 completed 24-week treatment. Baseline characteristics were mostly balanced between groups. At 24 weeks, EQW was superior to placebo in lowering HbA1c; the least squares mean (LSM) change in HbA1c was −0.36% for EQW and +0.49% for placebo (between-group difference: −0.85%; P=0.012). Nonsignificant LSM differences from baseline to 24 weeks favoring EQW were observed for FG (−21.6 mg/dL; 95% CI: −49.0, 5.7; P=0.119), SBP (−2.8 mmHg; 95% CI: −8.0, 2.4; P=0.284), and body weight (−1.22 kg; 95% CI: −3.59, 1.15; P=0.307). EQW was well tolerated; AEs occurred in 61.0% and 73.9% and serious AEs in 3.4% and 4.3% of participants in the EQW and placebo groups, respectively. Conclusion: In youth with T2D sub-optimally controlled with current treatments, EQW was effective in improving metabolic control. EQW was well-tolerated and no AEs led to treatment discontinuation by the investigator. Disclosure W. V. Tamborlane: Consultant; Self; Medtronic, Sanofi, Other Relationship; Self; Tolerion, Inc. C. Sjostrom: Employee; Self; AstraZeneca, Stock/Shareholder; Self; AstraZeneca. R. Bishai: Employee; Self; AstraZeneca. D. Geller: None. N. Shehadeh: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk, Sanofi, Research Support; Self; Novo Nordisk, Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk, Sanofi. D. Al-abdulrazzaq: None. E. Karoly: None. O. Doehring: Employee; Self; AstraZeneca. D. Carter: Employee; Self; AstraZeneca. J. Monyak: Employee; Self; AstraZeneca.

Puberty is a known stage of insulin resistance in lean adolescents with or without T1D. Moreover, 25% of adolescents with T1D in clinical practice are overweight, which may further contribute to insulin resistance. The present study examines whether higher body fat aggravates insulin resistance in the liver, muscle, and adipose tissue in pubertal adolescents with T1D by performing a 2-step, 8 and 80 mU/m2/min hyperinsulinemic euglycemic clamp. Body Composition was measured by DEXA, abdominal fat by MRI and hepatic fat by MRI-proton density fat fraction (PDFF). Endogenous glucose production and glycerol turnover were traced with [6,6-2H2] glucose and [2H5]-glycerol (Figure). Participants (mean age 14.4±1.2 years, A1c 7.6±0.5%) with lower (22.9) and higher (36.7) mean % body fat had mean weights of 61.6 and 68.1 kg, BMI% 68.3 and 84.8, and PDFF 1.4 and 1.7%, respectively. Endogenous glucose production was partially suppressed across the body fat spectrum during the low dose insulin infusion. In contrast, those with higher body fat tended to have diminished suppression of glucose production during the high dose insulin infusion. Rates of lipolysis appear to be unaffected. Hence our preliminary findings suggest that on the spectrum of increasing body fat in pubertal adolescents with T1D, we start to see metabolic inflexibility in youth with a moderate degree of adiposity. Disclosure M. A. Van name: None. S. Siebel: None. E. M. Tichy: None. S. Caprio: None. W. V. Tamborlane: Consultant; Self; Medtronic, Sanofi, Other Relationship; Self; Tolerion, Inc. N. Santoro: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (1K23DK115894-01A1)

Youth with T1D and high HbA1c are at higher risk of DKA. This study examined whether daily school-supervised basal insulin injections reduced the risk of morning ketosis in youth with high HbA1c. We hypothesized that glargine and degludec would reduce the risk of ketosis, and explored whether the prolonged action of degludec protects from ketosis after 2-4 days unsupervised injections. After a 2-4 week run-in, youth (10-18y) on injections with A1c ≥ 8.5% were randomized to supervised administration of either degludec or glargine for 4 months. School nurses observed daily fasting blood β-hydroxybutyrate (βHB) and glucose checks and basal insulin doses. During COVID closures, our research team is supervising procedures remotely. Twenty-four youth (mean age 14.4 ± 2.4 y, 67% F, HbA1c 11.6% ± 1.9%) were analyzed. Supervised injections of both basal insulins for 1-4 days progressively lowered the % participants with elevated βHB (Figure). The % of participants with elevated βHB after 2 days of unsupervised basal insulin tended to be greater in the glargine group. HbA1c did not change. None had DKA. In high risk youth with T1D, daily supervised insulin administration decreased the probability of elevated ketone levels the following school day, regardless of insulin type. A larger sample is needed to determine if degludec’s longer action profile offers additional protection from ketosis during days off from school. Disclosure L. M. Nally: None. M. A. Van name: None. O. K. Sosnoski: None. J. Sherr: Advisory Panel; Self; Cecelia Health, Insulet Corporation, Medtronic, Consultant; Self; Insulet Corporation, Lexicon Pharmaceuticals, Inc., Lilly Diabetes, Medtronic, Research Support; Self; Dexcom, Inc., Insulet Corporation, Medtronic, Speaker’s Bureau; Self; Lilly Diabetes. E. M. Tichy: None. K. Weyman: None. A. Steffen: None. S. Mccollum: None. V. Shabanova: None. W. V. Tamborlane: Consultant; Self; Medtronic, Sanofi, Other Relationship; Self; Tolerion, Inc. Funding National Institutes of Health (K12DK094714); Novo Nordisk

OBJECTIVE We examined whether the presence of microvascular complications was associated with increased subsequent risk of cardiovascular disease (CVD) among participants with type 1 diabetes in the Diabetes Control and Complications Trial and Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study followed for >35 years. RESEARCH DESIGN AND METHODS Standardized longitudinal data collection included: 1) stereoscopic seven-field retinal fundus photography centrally graded for retinopathy stage and clinically significant macular edema; 2) urinary albumin excretion rate (AER) and estimated glomerular filtration rate (eGFR); 3) cardiovascular autonomic neuropathy (CAN) reflex testing; and 4) adjudicated CVD events, including death from CVD, nonfatal myocardial infarction, stroke, subclinical myocardial infarction on electrocardiogram, confirmed angina, or coronary artery revascularization. Cox proportional hazards models assessed the association of microvascular complications with subsequent risk of CVD. RESULTS A total of 239 participants developed CVD, including 120 participants who suffered major adverse cardiovascular events (MACE) defined as nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. The presence of microvascular disease (diabetic retinopathy, kidney disease, or CAN) was associated with increased risk of subsequent CVD and MACE (hazard ratios 1.86 to 3.18 and 2.09 to 3.63, respectively), associations that remained significant after adjusting for age and HbA1c. After adjustment for traditional CVD risk factors, however, only sustained AER ≥30 mg/24 h occurring alone and/or with eGFR CONCLUSIONS Advanced microvascular disease, especially moderate to severe albuminuria or eGFR

This corrigendum has been withdrawn due to a publisher error that caused it to be duplicated. The definitive version of this corrigendum is published under DOI https://doi.org/10.1210/clinem/dgab250

OBJECTIVE Type 2 diabetes in the U.S. is more prevalent in youth of minority racial-ethnic background, but disparities in health outcomes have not been examined in this population. RESEARCH DESIGN AND METHODS We examined racial-ethnic differences in the initial presentation and subsequent comorbidities in 1,217 youth with type 2 diabetes (63% girls) enrolled in the Pediatric Diabetes Consortium (PDC) Registry from February 2012 to June 2018. Demographic and clinical data were collected from medical records and participant self-report. RESULTS Overall, the mean age at presentation was 13.4 ± 2.4 years, and BMI was 35.0 ± 9.4 kg/m2. HbA1c was higher and C-peptide was lower in non-Hispanic Black (NHB) and Hispanic (H) youth compared with non-Hispanic White (NHW) youth. NHB were three times as likely to present in diabetic ketoacidosis (19%) versus NHW (6.3%) and H (7.5%), and NHB and H both had a worse HbA1c trajectory compared with NHW peers. Microalbuminuria was documented in 11%, hypertension in 34%, and dyslipidemia in 42% of Registry participants, with no significant difference among racial-ethnic groups. Nonalcoholic fatty liver disease (NAFLD) was diagnosed in 9% and 11% of H and NHW, respectively, versus 2% in NHB. CONCLUSIONS NHB and H youth with type 2 diabetes presented with worse metabolic control and had persistently worse HbA1c trajectories compared with NHW. Comorbidities exist in a large percentage of these youth independent of race-ethnicity, except for NAFLD being less prevalent in NHB. Greater efforts are needed to mitigate racial-ethnic disparities at diagnosis and in the management of youth with type 2 diabetes.

In this chapter, the benefits of exercise and physical activity for children and adolescents with T1D are discussed. However, there are challenges that T1D presents to youth with T1D involved with intermittent exercise, especially the increased risk of nocturnal hypoglycemia following antecedent exercise in the afternoon. Finally, our study of the efficacy of snacking to prevent hypoglycemia in patients with T1D using a closed-loop insulin delivery system is presented.

Youth with type 1 diabetes are at risk of other autoimmune disorders, including autoimmune thyroid disease, celiac disease, and rarely adrenal insufficiency. Monitoring of blood pressure and lipid screening are recommended given the risk for cardiovascular disease in individuals with diabetes. Retinopathy is relatively uncommon in youth, and recommendations regarding screening have recently been updated. Psychosocial disorders including disordered eating, depression, and anxiety are common and should be considered in youth with T1D.

Treatment of pediatric type 2 diabetes (T2D) is extremely challenging for many reasons. Chief among these are the fact that metformin had been the only drug approved for use in adolescents with T2D for more than 20 years based on the results of a randomized clinical trial. Insulin was approved for use in pediatric T2D, but this was extrapolated from its effectiveness in youth with T1D and in adults with T2D. During the past year, liraglutide (a GLP1 agonist) was also approved for use in youth with T2D. However, the liraglutide study required more than 4 years to complete, and similar challenges are being faced by other randomized clinical trials of new drugs that have been approved for use in adults with T2D. In addition to reviewing the benefits and limitations of currently approved drugs in youth with T2D, we explain some of the challenges faced in trying to complete these trials.

The increase in the prevalence of type 2 diabetes (T2D) in youth mirrors the rise in the prevalence of obesity in children. Overweight and obese children with T2D have a dual goal of achieving loss of at least 7% of body weight, as well as developing healthy eating patterns for the future. Both goals work together to improve glycemia by decreasing the overproduction of insulin and improving insulin sensitivity. Consequently, an intensive lifestyle intervention program is one of the cornerstones of treatment of children and adolescents with T2D. Specifically, programs that are family-based and foster parental and caregiver support are essential components of an effective pediatric lifestyle intervention. This chapter summarizes the components of the Yale Bright Bodies Lifestyle Intervention developed by one of our dietitians, Mary Savoy, RD, CDCES, which has been shown to be very effective in several clinical studies.

The Yale T1D Treatment Program has utilized traditional, twice a day injections of insulin as initial treatment of youth with type 1 diabetes (T1D). Moreover, almost all of our newly diagnosed patients are admitted to the hospital when first diagnosed with T1D. While the limitations of twice a day insulin injections become more apparent over time, it is very effective during the initial treatment of T1D, since most youngsters go through a honeymoon period of increased endogenous insulin secretion during the first 6 months of diabetes. We refer to this approach as “The Bridge to Pump Treatment,” since most of our patients transition to pump therapy when metabolic control of diabetes because more difficult during the second half of the first year of treatment.

In this chapter, we review attempts to improve clinical outcomes in youth with T1D with adjunctive treatments not related to insulin. While none of these adjunctive therapies have been approved for use in patients with T1D, SGLT2 and SGLT1/2 inhibitors have been used “off-label” in adults with type 1 diabetes. The experience with these agents to date indicates that patients need to carefully monitor β-hydroxybutyrate levels to avoid the development of diabetic ketoacidosis.

It can be argued that little has changed in treatment of type 1 diabetes in children and adolescents for more than 80 years: there have been new ways to produce insulin, better ways to monitor insulin, and new devices to administer insulin. However, the treatment of type 1 diabetes in pediatrics is still solely based on administration of insulin. In this chapter, we will review the limitations of insulin extracted from animal pancreases and the impact of the ability to produce biosynthetic human insulin. This has led to the production of rapid- and long-acting insulin analogs and the further development of ultra-rapid and long-acting insulin preparations. Adjunctive therapies for type 1 diabetes are discussed in Chap. 13.

OBJECTIVE This study evaluated the effects of continuous glucose monitoring (CGM) combined with family behavioral intervention (CGM+FBI) and CGM alone (Standard-CGM) on glycemic outcomes and parental quality of life compared with blood glucose monitoring (BGM) in children ages 2 to RESEARCH DESIGN AND METHODS This was a multicenter (N = 14), 6-month, randomized controlled trial including 143 youth 2 to RESULTS Approximately 90% of participants in the CGM groups used CGM ≥6 days/week at 6 months. Between-group TIR comparisons showed no significant changes: CGM+FBI vs. BGM 3.2% (95% CI −0.5, 7.0), Standard-CGM vs. BGM 0.5% (−2.6 to 3.6), CGM+FBI vs. Standard-CGM 2.7% (−0.6, 6.1). Mean time with glucose level CONCLUSIONS CGM used consistently over a 6-month period in young children with type 1 diabetes did not improve TIR but did significantly reduce time in hypoglycemia. The FBI benefited parental well-being.

OBJECTIVE: Many youth do not use the hybrid closed-loop system for type 1 diabetes effectively. This study evaluated the impact of financial incentives for diabetes-related tasks on use of the 670G hybrid closed-loop system and on glycemia. METHODS: At auto mode initiation and for 16 weeks thereafter, participants received a flat rate for wearing and calibrating the sensor ($1/day), administering at least 3 mealtime insulin boluses per day ($1/day), and uploading ($5/week). Weekly bonuses were given for maintaining at least 70% of the time in auto mode, which were increased for persistent auto mode use from $3/week to a maximum of $13/week. If a participant failed to maintain auto mode for a week, the rewards were reset to baseline. Data from 17 participants aged 15.9 years ± 2.5 years (baseline hemoglobin A1c [HbA1c] 8.6% ± 1.1%) were collected at 6, 12, and 16 weeks. The reinforcers were withdrawn at 16 weeks, with a follow-up assessment at 24 weeks. RESULTS: With reinforcers, the participants administered an average of at least 3 mealtime insulin boluses per day and wore the sensor over 70% of the time. However, auto mode use waned. HbA1c levels decreased by 0.5% after 6 weeks, and this improvement was maintained at 12 and 16 weeks (P < .05). Upon withdrawal of reinforcers, HbA1c levels increased back to baseline at 24 weeks. CONCLUSION: Compensation for diabetes-related tasks was associated with lower HbA1c levels, consistent administration of mealtime insulin boluses, and sustained sensor use. These results support the potential of financial rewards for improving outcomes in youth with type 1 diabetes.

OBJECTIVE During the Diabetes Control and Complications Trial (DCCT), intensive diabetes therapy achieving a mean HbA1c of ∼7% was associated with a threefold increase in the rate of severe hypoglycemia (defined as requiring assistance) compared with conventional diabetes therapy with a mean HbA1c of 9% (61.2 vs. 18.7 per 100 patient-years). After ∼30 years of follow-up, we investigated the rates of severe hypoglycemia in the DCCT/Epidemiology of Diabetes Inverventions and Complications (EDIC) cohort. RESEARCH DESIGN AND METHODS Rates of severe hypoglycemia were reported quarterly during DCCT and annually during EDIC (i.e., patient recall of episodes in the preceding 3 months). Risk factors influencing the rate of severe hypoglycemia over time were investigated. RESULTS One-half of the DCCT/EDIC cohort reported episodes of severe hypoglycemia. During EDIC, rates of severe hypoglycemia fell in the former DCCT intensive treatment group but rose in the former conventional treatment group, resulting in similar rates (36.6 vs. 40.8 episodes per 100 patient-years, respectively) with a relative risk of 1.12 (95% CI 0.91–1.37). A preceding episode of severe hypoglycemia was the most powerful predictor of subsequent episodes. Entry into the DCCT study as an adolescent was associated with an increased risk of severe hypoglycemia, whereas insulin pump use was associated with a lower risk. Severe hypoglycemia rates increased with lower HbA1c similarly among participants in both treatment groups. CONCLUSIONS Rates of severe hypoglycemia have equilibrated over time between the two DCCT/EDIC treatment groups in association with advancing duration of diabetes and similar HbA1c levels. Severe hypoglycemia persists and remains a challenge for patients with type 1 diabetes across their life span.

Background: Given the paucity of treatment options for youth with type 2 diabetes (T2D), insulin is commonly used to rapidly reverse gluco-toxicity. Subsequently, some youth with short duration T2D can be weaned off insulin soon after diagnosis. We analyzed data from the Pediatric Diabetes Consortium (PDC) Registry to determine how long glycemic control is maintained off insulin. Methods: Youth with T2D in the PDC Registry on metformin alone or lifestyle therapy alone upon registry enrollment but had previously been on insulin were included in this study (N=183). The primary outcome was time to treatment failure, defined by need to restart insulin or other diabetes medication (including metformin). Clinical data at enrollment and follow-up were analyzed using logistic regression to assess risk factors for treatment failure. Results: Of participants who had previously been on insulin therapy (58% female, 53% Hispanic, mean age 15 ± 2 years, median diabetes duration 1.7 years), 54% (98/183) experienced treatment failure. In the subgroup on metformin alone at enrollment (N=140), 45% restarted insulin, while in the lifestyle alone subgroup (N=43), 81% restarted insulin or other diabetes medication. Time to treatment failure was a median of 1.2 years. High HbA1c (mean 7.7% vs. 6.1% in the treatment failure group vs. non-failure group; p Conclusion: Youth with T2D previously treated with insulin have a high treatment failure rate on lifestyle or metformin therapy alone and are likely to restart insulin therapy. Youth with T2D should be monitored closely for worsening glycemic control. Disclosure R. Wolf: None. P. Cheng: None. R.L. Gal: None. L.C. Beaulieu: None. C. Kollman: Other Relationship; Self; Dexcom, Inc., Tandem Diabetes Care. E.M. Isganaitis: None. S.N. Magge: None. L.D. Mastrandrea: Board Member; Self; American Academy of Pediatrics. Research Support; Self; AstraZeneca, JDRF, Novo Nordisk Inc., Sanofi-Aventis. G.J. Klingensmith: Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk Inc., Takeda Pharmaceutical Company Limited. W.V. Tamborlane: Consultant; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Medtronic, Novo Nordisk Inc., Sanofi US. Other Relationship; Self; Eisai Inc., MannKind Corporation. M.A. Van Name: None. Funding Boehringer Ingelheim; Novo Nordisk; Takeda Pharmaceutical Company Limited

GLP-1 analogues (GLP-1a) may change sweet food preferences but the neural mechanisms are not fully understood. We studied the effect of GLP-1a on neural responses to drinking high fructose corn syrup (HFCS) using fMRI in 5 lean (LN, BMI 21kg/m2, mean age 21, A1c 5.3%) and 7 obese (OB, BMI 38, age 26, A1c 5.5%) subjects. The OB group had a second fMRI after 3-mos treatment with liraglutide 3.0 mg daily. Food intake was evaluated by dietary recall. At baseline, OB group had increased cerebral blood flow (CBF) in regions implicated in reward/motivation (putamen) and taste perception (insula) vs. LN (p=.05). However, the OB group’s responses to HFCS changed markedly after 3-mos GLP-1a treatment. As shown in the Figure, CBF in OB group increased in regions related to impulse control (anterior cingulate cortex/ventromedial prefrontal cortex), taste perception (insula), and thalamus. It is also noteworthy that CBF did not increase in the reward/motivation region (putamen) during liraglutide treatment. Changes in neural responses to HFCS intake during GLP-1a treatment were accompanied by a 1080 kcal/d decrease in food intake (p50% decrease in daily sugar intake. These preliminary data suggest decreased food and sugar intake induced by GLP-1a may be related to neural mechanisms that promote impulse control while simultaneously suppressing dysregulated reward responses following sugar intake. Disclosure K. Joseph: None. J. Leventhal: None. S. Hwang: None. M. Knight: None. D. Seo: None. C. Lacadie: None. M.A. Van Name: None. S. Caprio: None. J. Sherr: Advisory Panel; Self; Bigfoot Biomedical, Cecelia Health. Consultant; Self; Eli Lilly and Company, Lexicon Pharmaceuticals, Inc., Medtronic, Sanofi, T1D Exchange. W.V. Tamborlane: Consultant; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Medtronic, Novo Nordisk Inc., Sanofi US. Other Relationship; Self; Eisai Inc., MannKind Corporation. R. Sinha: None. A.M. Jastreboff: Consultant; Self; Novo Nordisk Inc., Rhythm Pharmaceuticals. Funding American Diabetes Association (1-18-JDF-003 to A.M.J.)

The SENCE study in children < 8 yrs with T1D compared the efficacy of CGM combined with a family behavioral intervention (CGM + FBI) and CGM alone (Standard-CGM) with blood glucose monitoring (BGM) alone. Time in hypoglycemia fell in both CGM groups but was unaffected in the BGM group during the 26-week trial. After trial completion, both CGM groups extended their time on CGM for 26 weeks without additional education/behavioral intervention. This analysis assessed whether prolonged CGM use maintained durable reductions in time in hypoglycemia throughout the entire 52-week period. The extended study was completed by 45 of 50 in the CGM + FBI group and 42 of 44 in Standard-CGM. In these 87 kids, median age was 5.6 years and 31% were on insulin pumps. Differences in the two CGM groups were compared to masked baseline CGM data from run-in. Median time Conclusion: Sustained CGM use results in less hypoglycemia in young children with T1D. Disclosure M.A. Van Name: None. K. Miller: None. L. Kanapka: None. W.V. Tamborlane: Consultant; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Medtronic, Novo Nordisk Inc., Sanofi US. Other Relationship; Self; Eisai Inc., MannKind Corporation. L. DiMeglio: None. Funding The Leona M. and Harry B. Helmsley Charitable Trust

Objective: To compare efficacy and safety of insulin glargine 300 U/mL (Gla-300) and 100 U/mL (Gla-100) in children and adolescents (6–17 years) with type 1 diabetes. Study Design: EDITION JUNIOR was a non-inferiority, international, open-label, two-arm, parallel-group, phase 3b trial. Participants were randomized 1:1 to Gla-300 or Gla-100, titrated to achieve fasting self-monitored plasma glucose levels of 90–130 mg/dL (5.0–7.2 mmol/L), with continuation of prior prandial insulin. The primary endpoint was between-group difference in HbA1c change from baseline to Week 26. Other assessments included change in fasting plasma glucose (FPG), hypoglycemia, hyperglycemia with ketosis and adverse events. Results: In 463 randomized participants (Gla-300, n=233; Gla-100, n=230), comparable least squares (LS) mean (standard error) reductions in HbA1c were observed from baseline to Week 26 (−0.40 [0.06] % for both), with LS mean between-group difference of 0.004 % (95% CI: −0.17–0.18), confirming non-inferiority at the prespecified 0.3 % (3.3 mmol/mol) margin. Mean FPG change from baseline to Week 26 was also similar between groups. During the 6-month treatment period, incidence and event rates of severe or documented (≤70 mg/dL [≤3.9 mmol/L]) hypoglycemia were similar between groups. Incidence of severe hypoglycemia was 6.0% with Gla-300 and 8.8% with Gla-100 (relative risk 0.68 [95% CI: 0.35–1.30]). Incidence of any hyperglycemia with ketosis was 6.4% with Gla-300, 11.8% with Gla-100. Conclusions: Gla-300 provided similar glycemic control and safety profiles to Gla-100 in children and adolescents with type 1 diabetes, indicating that Gla-300 is a suitable therapeutic option in this population.

BACKGROUND: This a unique case of late-onset endocrinopathies after stem cell transplant in a girl with Griscelli syndrome. Griscelli syndrome is a rare disorder characterized by partial albinism, silver hair and immune failure with alteration in genes necessary for melanin transport, which is curative by stem cell transplant. Although late endocrinopathies are quite common in other disorders after stem cell transplant, these complications have not been reported in Griscelli syndrome. CLINICAL CASE: A 7-year old female who received a stem cell transplant as a toddler and subsequently developed graft-versus-host-disease (GvHD) at 2 years of age presented for evaluation of growth failure. Patient had severe short stature along with mild hyperthyroxinemia with subsequent diagnosis of Graves’ disease which was treated with methimazole. Although hypothyroidism is more commonly seen after stem cell transplant, rare cases of hyperthyroidism have been reported. Despite normal GH and IGF-1 levels, GH therapy was commenced due to persistent growth failure. She showed a robust increase in growth parameter from -6 to -2 SD below the mean. She started spontaneous puberty, however, biochemical evaluation showed hypergonadotropic hypogonadism with undetectable anti-mullerian hormone (AMH) which is consistent with low ovarian reserve most likely related to total body irradiation prior to stem cell transplant. CONCLUSION: Our patient demonstrates that growth failure, thyroid disease and ovarian dysfunction can be complications of stem cell transplants in young children with Griscelli syndrome. This can be a result of the underlying disease leading to transplant, conditioning regimen prior to transplant or complications thereafter. GvHD may also be a risk factor for future autoimmune endocrine complications in this syndrome and in other syndromes treated with stem cell transplant. REFERENCES: (1) Griscelli C, Prunieras M. Pigment dilution and immunodeficiency: a new syndrome. Int J Dermatol. 1978;10:788–91. (2) Sağ E, Gönç N, Alikaşifoğlu A, et al. Hyperthyroidism after allogeneic hematopoietic stem cell transplantation: A Report of Four Cases. J Clin Res Pediatr Endocrinol. 2015;4:349–54.