Search

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.

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.

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

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

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.

AIM: To assess the associations between demographic and clinical characteristics and sensor glucose metrics in young children with type 1 diabetes, using masked, continuous glucose monitoring data from children aged 2 to < 8 years. RESEARCH DESIGN AND METHODS: The analysis included 143 children across 14 sites in the USA, enrolled in a separate clinical trial. Eligibility criteria were: age 2 to 10.0 mmol/l) and a median of ~1 h/day in hypoglycaemia (

Objective: The aim of these analyses was to characterize the effect of exercise and meals on glucose concentrations in healthy individuals without diabetes. Methods: Healthy individuals without diabetes (age ≥6 years) with nonobese body mass index were enrolled at 12 centers within the T1D Exchange Clinic Network. Participants wore a blinded Dexcom G6 for up to ten days. Throughout this sensor wear, participants completed a daily log indicating times and type of any exercise and start times of meals and snacks. Results: A total of 153 participants (age 7-80 years) were included in the analyses. Exercise induced a mean change of −15 ± 18 mg/dL from baseline to nadir sensor glucose level. Mean nadir glucose concentration during nights following exercise days was 82 ± 11 mg/dL compared with 85 ± 11 mg/dL during nights following nonexercise days ( P = .05). Mean change from baseline to nadir sensor glucose level during aerobic exercise was −15 ± 18 and −9 ± 12 mg/dL for resistance exercise ( P = .25). Overnight nadir glucose during nights following aerobic and resistance exercise was 83 ± 12 and 76 ± 14 mg/dL, respectively ( P = .25). Overall mean peak postprandial glucose per participant increased from 93 ± 10 mg/dL premeal to 130 ± 13 mg/dL with an average time to peak glucose per participant of 97 ± 31 minutes. Consumption of alcohol on the day prior did not impact overnight mean or nadir glucose. Conclusion: The present analysis provides important data characterizing the effect of exercise and meals on glucose in healthy individuals without diabetes. These data provide a repository to which future therapies, whether pharmacologic or technologic, can be compared.

Background Many CpGs become hyper or hypo-methylated with age. Multiple methods have been developed by Horvath et al. to estimate DNA methylation (DNAm) age including Pan-tissue, Skin & Blood, PhenoAge, and GrimAge. Pan-tissue and Skin & Blood try to estimate chronological age in the normal population whereas PhenoAge and GrimAge use surrogate markers associated with mortality to estimate biological age and its departure from chronological age. Here, we applied Horvath’s four methods to calculate and compare DNAm age in 499 subjects with type 1 diabetes (T1D) from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study using DNAm data measured by Illumina EPIC array in the whole blood. Association of the four DNAm ages with development of diabetic complications including cardiovascular diseases (CVD), nephropathy, retinopathy, and neuropathy, and their risk factors were investigated. Results Pan-tissue and GrimAge were higher whereas Skin & Blood and PhenoAge were lower than chronological age (p < 0.0001). DNAm age was not associated with the risk of CVD or retinopathy over 18–20 years after DNAm measurement. However, higher PhenoAge (β = 0.023, p = 0.007) and GrimAge (β = 0.029, p = 0.002) were associated with higher albumin excretion rate (AER), an indicator of diabetic renal disease, measured over time. GrimAge was also associated with development of both diabetic peripheral neuropathy (OR = 1.07, p = 9.24E−3) and cardiovascular autonomic neuropathy (OR = 1.06, p = 0.011). Both HbA1c (β = 0.38, p = 0.026) and T1D duration (β = 0.01, p = 0.043) were associated with higher PhenoAge. Employment (β = − 1.99, p = 0.045) and leisure time (β = − 0.81, p = 0.022) physical activity were associated with lower Pan-tissue and Skin & Blood, respectively. BMI (β = 0.09, p = 0.048) and current smoking (β = 7.13, p = 9.03E−50) were positively associated with Skin & Blood and GrimAge, respectively. Blood pressure, lipid levels, pulse rate, and alcohol consumption were not associated with DNAm age regardless of the method used. Conclusions Various methods of measuring DNAm age are sub-optimal in detecting people at higher risk of developing diabetic complications although some work better than the others.

AIM To compare the characteristics of children and adolescents with type 1 vs. type 2 diabetes in the Pediatric Diabetes Consortium (PDC) registries. METHODS Participants were 10 to

Treatment of type 2 diabetes (T2D) in children and adolescents is particularly challenging. Metformin monotherapy is the standard initial treatment for youth with T2D, once metabolic control is restored with insulin in patients who present with ketosis and/or marked hyperglycemia. Insulin, the only other drug approved for use in youth with T2D, is also used as add-on therapy when patients fail metformin mono-therapy.In this paper, we will summarize the current use of both metformin and insulin in the treatment of pediatric type 2 diabetes, as well as comment on their limitations. Given the rapid progression of T2D in youth, there is also considerable interest in treating youth with new oral and injectable agents that have been approved for use in adults with T2D. The potential for improving clinical outcomes of each of the main classes of new drugs for the treatment of pediatric T2D will be summerized.We will conclude by reviewing why phase 3 randomized clinical trials examining the safety and efficacy of these medications in the pediatric population have been difficult to complete and discuss a potential pathway to overcome these obstacles to regulatory approval for these drugs for adolescents with T2D.

Objective Canagliflozin, a sodium glucose cotransporter 2 inhibitor approved for the treatment of adults with type 2 diabetes (T2D), increases urinary glucose excretion (UGE) and lowers plasma glucose (PG) levels by reducing the renal threshold for glucose (RTG ). This study assessed the pharmacokinetics (PK) and pharmacodynamics (PD) of canagliflozin in pediatric T2D patients. Methods Patients, aged 10 to 17 years with mean weight 107.2 kg and body mass index 38.2 kg/m2 , underwent PK and PD assessments after receiving a single daily dose of canagliflozin 100 mg (n = 8) or 300 mg (n = 9) for 14 days. Data are presented as mean (SD). Results There were dose-dependent increases in the PK of canagliflozin 100 and 300 mg, with maximum plasma concentrations and areas under plasma concentration curves that were similar to the corresponding values in adults. Mean 24-hour RTG fell to 84.6 (13.8) mg/dL with canagliflozin 100 mg and to 69.1 (9.6) mg/dL with canagliflozin 300 mg; also consistent with reductions in RTG in adults. Mean 24-hour UGE increased from 5.3 (10.5) g at baseline to 74.1 (37.4) g with canagliflozin 100 mg and from 0.1 (0.04) g to 68.6 (26.5) g with canagliflozin 300 mg. Both doses were well tolerated and the tablets had acceptable taste, smell, and swallowability. Conclusions In pediatric T2D patients, canagliflozin 100 and 300 mg had PK and PD characteristics similar to those in adults with T2D, which is likely due to the relative maturity and increased body weight of youth affected with this disorder.

Objective To identify the dose of the dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin in pediatric patients with type 2 diabetes (T2D). Methods Double-blind, randomized, controlled parallel group study comparing linagliptin 1 and 5 mg once daily, with placebo in 39 patients with T2D aged 10 to below 18 years. The primary efficacy endpoint was the change from baseline in glycated hemoglobin (HbA1c) after 12 weeks of treatment. The key pharmacodynamic endpoint was DPP-4 inhibition during steady-state. Results Compared to placebo, there was a dose-dependent reduction in mean HbA1c of 0.48% and 0.63% with linagliptin 1 and 5 mg, respectively, associated with corresponding declines in mean fasting plasma glucose (FPG) of 5.6 and 34.2 mg/dL. Median DPP-4 inhibition was 38% with linagliptin 1 mg and 79% with linagliptin 5 mg. Geometric mean trough levels of linagliptin were 3.80 and 7.42 nmol/L in the 1 and 5 mg groups, respectively; levels that were slightly higher than in adult patients with T2D that were most likely caused by higher plasma DPP-4 concentrations in the study population. There were no drug-related adverse events during treatment with either dose of linagliptin. Conclusions Linagliptin was well tolerated and induced dose-dependent DPP-4 inhibition that was accompanied by corresponding reductions in HbA1c and FPG levels in young people with T2D. The results are consistent with the clinical efficacy and safety profile that have been reported for linagliptin in adult patients with T2D, favoring linagliptin 5 mg over 1 mg.

Measurement of glycated hemoglobin (HbA1c) has been the traditional method for assessing glycemic control. However, it does not reflect intra- and interday glycemic excursions that may lead to acute events (such as hypoglycemia) or postprandial hyperglycemia, which have been linked to both microvascular and macrovascular complications. Continuous glucose monitoring (CGM), either from real-time use (rtCGM) or intermittently viewed (iCGM), addresses many of the limitations inherent in HbA1c testing and self-monitoring of blood glucose. Although both provide themeans to move beyond the HbA1c measurement as the sole marker of glycemic control, standardized metrics for analyzing CGM data are lacking. Moreover, clear criteria for matching people with diabetes to themost appropriate glucose monitoring methodologies, as well as standardized advice about howbest to use the new information they provide, have yet to be established. In February 2017, the Advanced Technologies & Treatments for Diabetes (ATTD) Congress convened an international panel of physicians, researchers, and individuals with diabetes who are expert in CGM technologies to address these issues. This article summarizes the ATTD consensus recommendations and represents the current understanding of how CGM results can affect outcomes.

Enthusiasm for the benefits of sodium-glucose cotransporter 2 inhibitors (SGLT2i) as an adjunctive treatment in type 1 diabetes (T1D) has been offset by the possible increased risk of diabetic ketoacidosis (DKA). Since pump-treated T1D patients are susceptible to DKA due to infusion site problems, this study was undertaken to assess how treatment with SGLT2i affects patterns of early metabolic decompensation following suspension of basal insulin.Ten T1D participants (age 19-35 years, duration 10 ± 8 years, A1c 7.4% ± 0.8%) underwent overnight pump suspension studies before and after treatment with canagliflozin (CANA). On both nights, basal insulin was suspended at 3 AM and plasma glucose (PG), β-hydroxybutyrate (BHB), free fatty acids (FFA), plasma insulin (PI), and glucagon were measured. Studies were terminated 6 h after suspension or if PG rose to350 mg/dL or BHB2.5 mmol/L.PI levels at the start of suspension were reduced by 30% after CANA treatment (44 ± 11 uU/mL vs. 31 ± 10 uU/mL, P 0.01), but baseline PG, BHB, FFA, and glucagon levels were not significantly different. During the suspension, PG rose from 104 ± 10 to 301 ± 21 mg/dL before treatment, but only from 109 ± 8 to 195 ± 14 mg/dL after treatment (P = 0.002 vs. pretreatment values). On the other hand, CANA treatment did not significantly affect the magnitude of increases in FFA, BHB, and glucagon levels during the suspension study.These data indicate that SGLT2i do not accelerate the rate of ketogenesis following the interruption of basal insulin infusion in T1D. Rather, the failure of patients to promptly recognize early metabolic decompensation relates to the much more gradual rise in PG levels.

Background/Aims: Many adolescents with type 2 diabetes (T2D) have rapid deterioration of glycemic control on metformin monotherapy within 2 years of diagnosis. Methods: Enrollment data from the Pediatric Diabetes Consortium T2D Registry were used to categorize 276 youth with a T2D duration ≥2 years into two groups: (1) participants with HbA1c n = 75) and (2) participants treated with insulin ± metformin (group 2, n = 201). The characteristics of the groups were compared. Results: At enrollment, groups 1 and 2 did not differ in age (16.2 vs. 16.8 years) or BMI percentile (99 vs. 98%); group 2 had higher HbA1c (9.9% [85 mmol/mol] vs. 5.9% [41 mmol/mol], p < 0.001). Lower HbA1c and metformin monotherapy at diagnosis were associated with a greater likelihood of adequate control with metformin alone (p < 0.001). In multivariable analysis, HbA1c at diagnosis (p = 0.001) and diabetes duration (p = 0.009) were associated with adequate control on metformin. The HbA1c trajectory after diagnosis was worse in group 2. Conclusion: Durable metabolic control of T2D with metformin monotherapy is most likely in youth presenting with lower HbA1c and with shorter diabetes duration, independent of age, race-ethnicity, and BMI. Elevated HbA1c levels in those on insulin therapy highlight the importance of early diagnosis and a better understanding of glycemic control barriers.

Background: Managing type 1 diabetes (T1D) in young children presents challenges to families and caregivers. Pump therapy may reduce challenges and benefit glycemic control. However, pump use is not universal; parent-reported reasons for lack of uptake are not well described. Methods: Parents of children

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 (40.8 vs. 36.6 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.

Emerging adults (EA) with disordered eating behaviors (DEBs) and Type 1 diabetes (T1D) are at increased risk for severe complications of T1D, and these behaviors have been reported in EA women with T1D. Few studies, though, have included men. This study assessed the prevalence of DEB in both EA men and women with T1D.DEB was measured with the diabetes-specific Diabetes Eating Problem Survey-Revised (DEPS-R); scores of 20 or greater indicate need for further evaluation for DEB.A total of 27 women and 33 men (age range = 21 ± 2.5 years) completed the DEPS-R; 27% of women and 18% of men had scores of 20 or greater (p = .23). Hemoglobin A1c level was significantly higher in subjects with elevated DEPS-R scores (10.4 ± 2.1% vs. 7.8 ± 1.3%; p .001), and DEPS-R scores correlated with increased body mass index values (r = 0.27, p .05).Clinicians should assess for DEB in both male and female emerging adults with T1D, especially overweight patients with poor glycemic control.

Background Fear of hypoglycemia is common in parents of young children with type 1 diabetes (T1D), but little is known about the specific fears that parents most often experience. Hypoglycemia fear has been associated with poorer glycemic control in older children, though not yet studied in a large cohort of very young children. Materials and Methods Parents of 549 children

Background Despite significant advances in type 1 diabetes (T1D) management, achieving targeted glycemic control in pediatric patients remains a struggle. Continuous glucose monitoring (CGM) with remote access holds the promise to address this challenge by allowing caregivers to monitor glucose, even when the child is not directly under their supervision. Objective To explore real-time and remote CGM practices in homes and schools, including caregiver expectations regarding this technology. Subjects Parents and daytime caregivers. Methods Respondents answered an anonymous survey assessing characteristics of CGM use. Cross-sectional data were collected and analyzed using quantitative and qualitative methods. Results Thirty-three parents and 17 daytime caregivers responded. Threshold alerts (alerts when patients reached certain pre-set high or low limits) were used most frequently, followed by rate of change alerts. Most parents and daytime caregivers responded to low- and high-threshold CGM alerts by confirming with a glucose meter prior to treatment; while about one-third endorsed treating lows without a confirmatory test. Most parents expected their child's daytime caregiver to respond to CGM alerts and daytime caregivers felt the parent's expectations of them were reasonable. All parents and most caregivers reported decreased overall worry/stress. Parents felt positive about CGM use and daytime caregivers felt comfortable with CGM. Conclusion The positive and collaborative management reported by parents and daytime caregivers sets the stage for CGM to play an important role in the management of children with T1D both in the home and in the school settings.

Despite the increased popularity of newer, fast-acting bolus insulin treatment options that allow for more flexibility in the timing of bolus insulin dosing in recent years, relatively little is known about people with diabetes who administer bolus insulin at differing times in relation to their meals. The purpose of this study was to investigate bolus insulin dose timing in relation to meals among people with type 1 (T1D) and type 2 (T2D) diabetes, as well as to better understand the characteristics and experiences of people who bolus dose at differing times.A web-based survey of adults with T1D and T2D treated with bolus insulin therapy in Germany, the UK, and USA was conducted.A total of 906 respondents completed the survey (39% T1D; 61% T2D). A majority of respondents reported bolus dosing before meals in the previous week (57.0%), followed by after meals (18.9%), with meals (12.7%), and at varying times (11.5%). Compared to respondents who dosed with or after meals, those who dosed before meals were significantly less likely to experience hypoglycemia (before, 55.7%; with, 72.8%; after, 68.7%; p .001) in the previous week. Respondents who bolus dosed before meals were significantly more likely to perceive bolus dose timing as flexible (45.5%) compared to those who dosed with (27.8%) or after (35.7%) meals (p .001).Results show that many people with T1D and T2D dose their bolus insulin with or after meals. Key limitations of all self-report surveys include potential bias in responses and generalizability of findings. However, the study was designed to help mitigate these limitations. The findings have implications for clinicians and suggest opportunities for improving diabetes education and care.

Diabetes Care ’s editorial committee customarily presents a midyear report of activities and progress. At the midpoint of 2018 we can describe, in addition to a satisfying array of original scientific reports, important feature articles of current interest and a significant new initiative. In the first half of this year, the journal published several feature articles related to our core responsibility as a journal representing the American Diabetes Association (ADA). An update to the ADA’s “Standards of Medical Care in Diabetes” (Standards of Care [SOC]) appeared as a supplement to the January issue (1). The SOC is prepared by the Professional Practice Committee of the ADA and contains guidance on various aspects of care of those with or at risk for diabetes, together with summaries of published data supporting these statements. Because scientific information is accumulating faster than ever before, the ADA announced a new policy in the March 2018 issue (2). The yearly January supplement to Diabetes Care will continue as before, but the SOC will now be updated more frequently. The ADA now uses a web annotation tool to update and revise the online version throughout the year, whenever new evidence or regulatory changes merit immediate incorporation. Already in 2018 new information has been added regarding two medications recently approved by the U.S. Food and Drug Administration (semaglutide and ertugliflozin) and an update on the definitions of hypoglycemia. Changes of this kind will be communicated by the ADA through its print, online, and social media channels. Additional consensus statements and commentaries on new or controversial topics will continue to appear in Diabetes Care . Unlike the SOC, they are not official guidance statements but generally reflect the ADA’s thinking. For example, a joint statement by representatives of the ADA and the European Association for the Study of Diabetes …

Background: Completing phase 3 trials of new drugs for youth with type 2 diabetes is challenging. The Pediatric Diabetes Consortium (PDC) of U.S. pediatric treatment centers developed a Consortium model to improve the efficiency of successfully completing these trials. Aims and Innovations: An aim of the PDC model is to utilize the resources of the PDC Coordinating Center and Executive Committee to improve study protocols, centralize interactions with sponsors, and oversee the performance of PDC Clinical Centers. Key features include a Consulting Group to improve protocol design; Master Service Agreements between the Coordinating Center and Clinical Centers covering confidentiality agreements and contract language; negotiation of a standard Site Budget with Contract Research Organizations (CROs)/Sponsors that reflect actual Clinical Center costs; Weekly Conference Calls with CROs/sponsors to track progress of Clinical Center launches, Monthly Oversight Calls with investigators and study Coordinators to track Clinical Center performance, discuss enrollment strategies, and identify emerging problems. Successes and Challenges: The Consortium model played a key role in the completion of the pivotal trial of liraglutide for treatment of youth with type 2 diabetes. PDC centers also played a pivotal role in exceeding the projected number of randomized subjects needed by two ongoing studies that are nearing completion. Conclusions: While the Consortium model is still a work in progress, PDC has assisted in the successful launch of new type 2 diabetes studies, and negotiations are in underway for PDC participation in pediatric type 1 diabetes and other diabetes-related studies.

Background Optimal glycemic control is particularly difficult to achieve in children and adolescents with type 1 diabetes (T1D), yet the influence of dysglycemia on the developing brain remains poorly understood. Methods and findings Using a large multi-site study framework, we investigated activation patterns using functional magnetic resonance imaging (fMRI) in 93 children with T1D (mean age 11.5 ± 1.8 years; 45.2% female) and 57 non-diabetic (control) children (mean age 11.8 ± 1.5 years; 50.9% female) as they performed an executive function paradigm, the go/no-go task. Children underwent scanning and cognitive and clinical assessment at 1 of 5 different sites. Group differences in activation occurring during the contrast of “no-go > go” were examined while controlling for age, sex, and scan site. Results indicated that, despite equivalent task performance between the 2 groups, children with T1D exhibited increased activation in executive control regions (e.g., dorsolateral prefrontal and supramarginal gyri; p = 0.010) and reduced suppression of activation in the posterior node of the default mode network (DMN; p = 0.006). Secondary analyses indicated associations between activation patterns and behavior and clinical disease course. Greater hyperactivation in executive control regions in the T1D group was correlated with improved task performance (as indexed by shorter response times to correct “go” trials; r = −0.36, 95% CI −0.53 to −0.16, p < 0.001) and with better parent-reported measures of executive functioning (r values < −0.29, 95% CIs −0.47 to −0.08, p-values < 0.007). Increased deficits in deactivation of the posterior DMN in the T1D group were correlated with an earlier age of T1D onset (r = −0.22, 95% CI −0.41 to −0.02, p = 0.033). Finally, exploratory analyses indicated that among children with T1D (but not control children), more severe impairments in deactivation of the DMN were associated with greater increases in hyperactivation of executive control regions (T1D: r = 0.284, 95% CI 0.08 to 0.46, p = 0.006; control: r = 0.108, 95% CI −0.16 to 0.36, p = 0.423). A limitation to this study involves glycemic effects on brain function; because blood glucose was not clamped prior to or during scanning, future studies are needed to assess the influence of acute versus chronic dysglycemia on our reported findings. In addition, the mechanisms underlying T1D-associated alterations in activation are unknown. Conclusions These data indicate that increased recruitment of executive control areas in pediatric T1D may act to offset diabetes-related impairments in the DMN, ultimately facilitating cognitive and behavioral performance levels that are equivalent to that of non-diabetic controls. Future studies that examine whether these patterns change as a function of improved glycemic control are warranted., Lars C. Foland Ross and colleagues investigate executive brain function in children with Type 1 diabetes., Author summary Why was this study done? Maintaining optimal levels of blood glucose in children with type 1 diabetes (T1D) is difficult. Because childhood and adolescence are periods of major neurodevelopmental change, there has been growing interest in whether T1D is associated with variations in the brain. No studies to date, to our knowledge, have examined brain function in children with T1D as they engaged in a cognitively demanding task. What did the researchers do and find? Brain function was examined in 150 children with or without T1D as they performed an executive function paradigm, the go/no-go task. This task requires that participants respond as quickly and accurately as possible, using a button press, to a high number of “go” stimuli (e.g., when they see any letter except “X”), and suppress a prepotent response on a smaller subset of “no-go” stimuli (e.g., when they see the letter “X”). Despite equivalent performance on the go/no-go task, children with T1D exhibited increased activation in task-positive networks (e.g., in executive control regions), as well as reduced suppression of activation in the default mode network (DMN). Increased hyperactivation in task-positive networks was associated with better executive functioning, improved go/no-go task performance, and reduced suppression of the DMN in children with T1D. Reduced suppression of the DMN, in turn, was associated with an earlier age of onset of T1D. What do these findings mean? These data indicate that increased recruitment of executive control areas in pediatric T1D may act to offset diabetes-related impairments in the DMN and cognitive function. Future studies that examine whether these patterns change as a function of improved glycemic control are warranted.

Sodium-glucose cotransporter (SGLT) inhibitors are new oral antidiabetes medications shown to effectively reduce glycated hemoglobin (A1C) and glycemic variability, blood pressure, and body weight without intrinsic properties to cause hypoglycemia in people with type 1 diabetes. However, recent studies, particularly in individuals with type 1 diabetes, have demonstrated increases in the absolute risk of diabetic ketoacidosis (DKA). Some cases presented with near-normal blood glucose levels or mild hyperglycemia, complicating the recognition/diagnosis of DKA and potentially delaying treatment. Several SGLT inhibitors are currently under review by the U.S. Food and Drug Administration and European regulatory agencies as adjuncts to insulin therapy in people with type 1 diabetes. Strategies must be developed and disseminated to the medical community to mitigate the associated DKA risk. This Consensus Report reviews current data regarding SGLT inhibitor use and provides recommendations to enhance the safety of SGLT inhibitors in people with type 1 diabetes. ispartof: DIABETES CARE vol:42 issue:6 pages:1147-1154 ispartof: location:United States status: published