Hypoglycemia In Youth Research Articles

Pharmacodynamics, pharmacokinetics, safety, and tolerability of a ready-to-use, room temperature, liquid stable glucagon administered via an autoinjector pen to youth with type 1 diabetes.

Prompt and reliable management of hypoglycemia in youth with diabetes is important to prevent serious medical complications. To determine efficacy, pharmacodynamics (PD), pharmacokinetics (PK), safety, and tolerability of a ready-to-use, liquid stable glucagon formulation administered subcutaneously via an autoinjector pen to youth with type 1 diabetes (T1D). After plasma glucose concentration was < 80 mg/dL (< 4.4 mmol/L) after insulin, participants aged 2 to < 12 years with T1D were administered 0.5mg of glucagon; participants aged 12 to < 18 years instead received 1mg of glucagon. Then, adolescents were challenged with 0.5mg after a 7- to 28-day washout period. Primary endpoint was mean plasma glucose concentration at 30min after glucagon. Plasma glucose concentrations significantly (p< 0.001) increased from baseline to 30min after glucagon, with mean change in plasma glucose concentration between baseline and 30min for each age cohort as follows: 2 to < 6 years (n= 7; 81.4mg/dL [4.5 mmol/L]); 6 to < 12 years (13; 84.2mg/dL [4.7 mmol/L]); 12 to < 18 years (11; dose, 1mg; 54.0mg/dL [3.0 mmol/L]); and 12 to < 18 years (11; 0.5mg; 52.4mg/dL [2.9 mmol/L]). Among age cohorts, no clinically relevant differences were observed for PD and PK parameters. Common adverse events were nausea, vomiting, and hypoglycemia. Age-appropriate dosing of this glucagon formulation was effective at 30min in reversing plasma glucose concentrations from < 80 mg/dL in youth with T1D.

Dietary intake on days with and without hypoglycemia in youth with type 1 diabetes: The Flexible Lifestyle Empowering Change trial.

To address a common perception that hypoglycemia is associated with increased dietary intake, we examined calorie and carbohydrate consumption on days with and without hypoglycemia among adolescents with type 1 diabetes (T1D). Days (N = 274) with 24-hour dietary recalls and continuous glucose monitoring were available for 122 adolescents with T1D in the Flexible Lifestyle Empowering Change trial (age 13-16 years, diabetes duration >1 year, hemoglobin A1c 8%-13%). Days with no hypoglycemia, clinical hypoglycemia (54-69 mg/dL) or clinically serious hypoglycemia (<54 mg/dL) were further split into night (12-5:59 am) and day (6 am-11:59 pm). Mixed models tested whether intake of calories or carbohydrates was greater on days with than without hypoglycemia. Fifty-nine percent, 23% and 18% of days had no hypoglycemia, clinical hypoglycemia and clinically serious hypoglycemia, respectively. Intake of calories and carbohydrates was not statistically significantly different on days with clinical hypoglycemia (57.2 kcal [95% CI -126.7, 241.5]; 12.6 g carbohydrate [95% CI -12.7, 38.0]) or clinically serious hypoglycemia (-74.0 kcal [95% CI -285.9, 137.9]; (-7.8 g carbohydrate [95% CI -36.8, 21.1]), compared to days without hypoglycemia. Differences by day and night were not statistically significant. Among adolescents with T1D, daily intake of calories and carbohydrates did not differ on days with and without hypoglycemia. It is possible that hypoglycemic episodes caused by undereating relative to insulin dosing, followed by overeating, leading to a net neutral difference. Given the post-hoc nature of these analyses, larger studies should be designed to prospectively test the hypoglycemia-diet relationship.

390-P: Household Food Security and Fear of Hypoglycemia in Youth and Young Adults with Diabetes and Parents of Youth with Diabetes

Hypoglycemia is a common acute complication in diabetes that is often treated with carbohydrate-rich snacks or drinks. For individuals with diabetes and household food insecurity (HFI), uncertain availability of food may increase fear of hypoglycemia (FOH). FOH may prevent individuals from optimal diabetes management. We analyzed data from 1,603 adult (≥18 years, mean 23.7 years, 80% type 1 diabetes [T1D], 20% type 2 diabetes [T2D]) and 592 youth (10.0-17.9 years, mean 15.2 years, 100% T1D) participants in the SEARCH for Diabetes in Youth Study. Adult participants and parents of youth participants completed the U.S. Household Food Security Survey, where ≥3 food insecure conditions or behaviors indicate HFI. Adults, youth, and parents of youth completed the Hypoglycemia Fear Survey that provides a behavior subscale (scores 0-60), worry subscale (scores 0-72), and total score (sum of subscales). We examined the association of HFI with FOH with general linear models, adjusting for socioeconomic, demographic, and clinical covariates. Approximately 20% of adults and 17% of youth had HFI. Adults with T1D reporting HFI (vs. no HFI) had increased FOH (+3 units for behavior, +11 units for worry, +14 units for total), after adjustment for covariates (all p&amp;lt;0.0001). Parents of youth with T1D reporting HFI had a 3 unit increase in worry FOH (p=0.03). Adults with T2D reporting HFI had increased FOH (+8.9 units for total, +6 units for worry; all p&amp;lt;0.01). Youth with T1D reporting HFI did not differ in FOH than those not reporting HFI. This research suggests that among adults with diabetes and parents of youth with T1D, those with HFI are more likely to experience FOH than those without HFI. Implementation of common approaches to ameliorate risk of hypoglycemia such as carrying snacks is problematic for people who are food insecure. Providers could consider HFI when discussing hypoglycemia and fear thereof with their patients. Disclosure L.A. Reid: None. S. Zheng: None. J.A. Mendoza: None. B.A. Reboussin: None. K.A. Sauder: None. S. Saydah: None. J.M. Lawrence: None. E.T. Jensen: None. L. Henkin: None. K. Flory: None. L.M. Knight: None. C. Pihoker: None. L.M. Dolan: None. A.D. Liese: None. Funding National Institutes of Health (1UC4DK108173, 1R01DK117461-01)

1281-P: Pilot Study on the Feasibility of Weekly CGM Data Review in Youth with New-Onset Type 1 Diabetes

Despite advances in diabetes technology and treatment, many youth with type 1 diabetes (T1D) continue to have hemoglobin A1c (HbA1c) above target. Consistent use of continuous glucose monitors (CGM) improves HbA1c and time in range (TIR 70-180 mg/dl) glucose, while minimizing hypoglycemia in youth with T1D. A previous study suggested that long-term HbA1c outcomes may be determined early in the course of T1D. Thus, increased awareness of glucose trends and frequent insulin dose adjustments early in the course of T1D is hypothesized to improve long-term HbA1c and health outcomes. We have initiated CGM in the first month of T1D diagnosis. In March 2019, we added weekly remote review of CGM data by a pediatric endocrinologist or certified diabetes educator to provide dose adjustments. Data sharing is facilitated by using a custom platform including Apple HealthKit to transmit data from the Dexcom G6 mobile app to Epic MyChart. Inclusion criteria were diagnosis of T1D within the past 30 days and intention to follow in our clinic. During the initial 8 months of this study, we enrolled 43 youth (age at diagnosis 9.2±4.2 years, 57% male, 78% on private insurance, 42.5% non-Hispanic White, initial HbA1c 12.0±2.0%). Twenty-eight youth had at least 1 documented data review with an average of 15.8±8.1 reviews/patient and 5.4 dose adjustments/youth (∼1 dose adjustment every 3 weeks) via phone calls or secure MyChart messages. Based on CGM downloads, users had a high percentage of time of CGM wear (88±11% of time over 2-week periods), high percentage of TIR glucose (72.2±18.4%), and low incidence of hypoglycemia (32±54 min/day, 2.2±3.8%). This pilot study demonstrates that implementing routine data review as part of a new onset program increases the frequency of insulin dose adjustments. Tools should be developed to allow for efficient data review for population health management. Further follow up is needed to determine long-term outcomes, scalability, and sustainability of this new onset program. Disclosure M. Lee: None. J. Leverenz: None. B. Leverenz: None. N.M. Pageler: None. D. Scheinker: None. D.M. Maahs: Advisory Panel; Self; Eli Lilly and Company, Insulet Corporation, Medtronic, Novo Nordisk A/S. Consultant; Self; Abbott, Sanofi. Research Support; Self; Bigfoot Biomedical, Dexcom, Inc., Roche Diabetes Care, Tandem Diabetes Care. P. Prahalad: None. Funding Stanford Diabetes Research Center (P30DK116074)

1289-P: The Association between Time-in-Range, Mean Glucose, and Incidence of Hypoglycemia in Youth with Newly Diagnosed T1D

New hypoglycemia guidelines define &amp;lt;70 mg/dl as a clinical alert for hypoglycemia and &amp;lt;54 mg/dl as clinically significant hypoglycemia. Fear of hypoglycemia is a significant barrier to increased time in range (TIR, 70-180 mg/dl). We examined the association between incidence of hypoglycemia and TIR and mean glucose (MG). CGM data were collected from youth starting CGM within 1 month of a T1D diagnosis. For each patient, for each two-week period, TIR, MG, and percent time in hypoglycemia (Hyp) (&amp;lt;70) and clinically significant hypoglycemia (csHyp) (&amp;lt;54) were calculated. The associations between each of TIR, MG and each of Hyp and csHyp in each two-week period were modelled with multivariate linear regression, controlling for age, race, sex, insurance type, CGM wear time, and partial clinical remission status (Table 1). In total, 1049 two-week periods from 51 patients were reviewed; 41% of these patients were female, the mean age was 9.4 years, and patients wore their CGMs an average of 89% within each two-week period. For csHyp, there was a non-significant negative association with TIR and a significant negative association with MG (p&amp;lt;0.001). For Hyp, there was a significant association with TIR and MG (Table 1). We found no association between csHyp and TIR. These findings suggest that high TIR may be maintained without increasing csHyp. Further study should examine the use of CGM to improve TIR. Disclosure A. Gu: None. P. Prahalad: None. D.M. Maahs: Advisory Panel; Self; Eli Lilly and Company, Insulet Corporation, Medtronic, Novo Nordisk A/S. Consultant; Self; Abbott, Sanofi. Research Support; Self; Bigfoot Biomedical, Dexcom, Inc., Roche Diabetes Care, Tandem Diabetes Care. A. Addala: None. D. Scheinker: None.

The relationship of glycemic control, insulin dose, and race with hypoglycemia in youth with type 1 diabetes

IntroductionBlack youth with T1D have been reported to experience more episodes of hypoglycemia than white patients, despite blacks having higher levels of HbA1c. We hypothesized that black patients may be prescribed higher daily doses of insulin putting them at greater higher risk for hypoglycemia. MethodsWe performed a retrospective analysis of data from a study of social and environmental factors influencing HbA1c in a biracial pediatric population with T1DM. Changes in patient insulin dose were made at clinic visit based on their self-monitored glucose (SMG) data. Insulin dose (units/kg/d) was compared with HbA1c, reported hypoglycemic episodes and occurrence of low blood glucose from SMG data. ResultsAge, duration of diabetes and BMI-z were similar for black and white patients. Black patients had higher levels of HbA1c and mean blood glucose (MBG). HbA1c was higher in blacks even after adjustment for MBG. Reported insulin dose increased with increasing HbA1c (ρ = 0.30, p = 0.0052) or MBG (ρ = 0.36, p < 0.0008). There was no difference in insulin dose between blacks and whites. Reported hypoglycemia was inversely associated with HbA1c and MBG, but there was no racial difference. Occurrence of low glucoses from meter data was slightly higher in whites (p = 0.047). ConclusionInsulin dose increased with increasing HbA1c or MBG for both groups. Occurrence of hypoglycemia was inversely related to glycemic control. There was slightly higher occurrence low glucose meter readings in white patients. Reported racial disparities in occurrence of hypoglycemia and insulin dosing may be due to clinic specific factors.

Risk of hypoglycemia in youth with type 2 diabetes on insulin.

The objective of this study was to ascertain the risk of hypoglycemia among youth with type 2 diabetes (T2D) on insulin therapy. Twenty-two youth with T2D on insulin therapy (M=12, F=10, age=14.4±4.0 years) were enrolled from a single pediatric endocrine practice. They were followed-up for 3 months with weekly phone calls and monthly in-person visits to review blood glucose logs and document any signs or symptoms of hypoglycemia (defined as finger stick glucose of ≤70 mg/dL). Episodes of hypoglycemia were categorized into five categories: severe, documented symptomatic, asymptomatic, probable symptomatic and relative hypoglycemia. In addition to examining the risk of hypoglycemia, the degree to which hypoglycemia was associated with patient demographics (e.g. age, gender and body mass index [BMI]) or clinical factors (i.e. duration of diabetes, duration of insulin treatment, glycemic control or insulin dose and regimen) was determined. Nine hypoglycemic events occurred during the study period in five patients with an incidence rate of nine events per 5.3 patient-years. Of the hypoglycemic events, five were symptomatic and four were asymptomatic. No severe hypoglycemic events occurred. Hypoglycemia was not associated with age, ethnicity, duration of insulin treatment, insulin dose or initial hemoglobin (HbA1c). However, a significant difference in BMI was noted, with T2D youth who experienced hypoglycemia having a lower BMI than those who did not experience hypoglycemia. The results of this study suggest that the risk of hypoglycemia in youth with T2D on insulin therapy is low.

Glucagon Nasal Powder: A Promising Alternative to Intramuscular Glucagon in Youth With Type 1 Diabetes.

OBJECTIVETreatment of severe hypoglycemia outside of the hospital setting is limited to intramuscular glucagon requiring reconstitution prior to injection. The current study examined the safety and dose-response relationships of a needle-free intranasal glucagon preparation in youth aged 4 to <17 years.RESEARCH DESIGN AND METHODSA total of 48 youth with type 1 diabetes completed the study at seven clinical centers. Participants in the two youngest cohorts (4 to <8 and 8 to <12 years old) were randomly assigned to receive either 2 or 3 mg intranasal glucagon in two separate sessions or to receive a single, weight-based dose of intramuscular glucagon. Participants aged 12 to <17 years received 1 mg intramuscular glucagon in one session and 3 mg intranasal glucagon in the other session. Glucagon was given after glucose was lowered to <80 mg/dL (mean nadir ranged between 67 and 75 mg/dL).RESULTSAll 24 intramuscular and 58 of the 59 intranasal doses produced a ≥25 mg/dL rise in glucose from nadir within 20 min of dosing. Times to peak plasma glucose and glucagon levels were similar under both intramuscular and intranasal conditions. Transient nausea occurred in 67% of intramuscular sessions versus 42% of intranasal sessions (P = 0.05); the efficacy and safety of the 2- and 3-mg intranasal doses were similar in the youngest cohorts.CONCLUSIONSResults of this phase 1, pharmacokinetic, and pharmacodynamic study support the potential efficacy of a needle-free glucagon nasal powder delivery system for treatment of hypoglycemia in youth with type 1 diabetes. Given the similar frequency and transient nature of adverse effects of the 2- and 3-mg intranasal doses in the two youngest cohorts, a single 3-mg intranasal dose appears to be appropriate for use across the entire 4- to <17-year age range.

Obesity in Youth with Type 1 Diabetes in Germany, Austria, and the United States

To examine the current extent of the obesity problem in 2 large pediatric clinical registries in the US and Europe and to examine the hypotheses that increased body mass index (BMI) z-scores (BMIz) are associated with greater hemoglobin A1c (HbA1c) and increased frequency of severe hypoglycemia in youth with type 1 diabetes (T1D). International (World Health Organization) and national (Centers for Disease Control and Prevention/German Health Interview and Examination Survey for Children and Adolescents) BMI references were used to calculate BMIz in participants (age 2-<18 years and ≥ 1 year duration of T1D) enrolled in the T1D Exchange (n = 11,435) and the Diabetes Prospective Follow-up (n = 21,501). Associations between BMIz and HbA1c and severe hypoglycemia were assessed. Participants in both registries had median BMI values that were greater than international and their respective national reference values. BMIz was significantly greater in the T1D Exchange vs the Diabetes Prospective Follow-up (P < .001). After stratification by age-group, no differences in BMI between registries existed for children 2-5 years, but differences were confirmed for 6- to 9-, 10- to 13-, and 14- to 17-year age groups (all P < .001). Greater BMIz were significantly related to greater HbA1c levels and more frequent occurrence of severe hypoglycemia across the registries, although these associations may not be clinically relevant. Excessive weight is a common problem in children with T1D in Germany and Austria and, especially, in the US. Our data suggest that obesity contributes to the challenges in achieving optimal glycemic control in children and adolescents with T1D.

Exercise in Youth with Type 1 Diabetes.

Exercise is important in the management of type 1 diabetes mellitus (T1DM). Modern diabetes care includes the goal that all youth meet guidelines for regular physical activity. Evidence suggests regular physical activity improves cardiovascular health, lipid profiles, psychosocial wellbeing and, possibly, glycemic control in youth with T1DM. However, exercise is especially problematic for children and adolescents because wide glycemic excursions commonly occur during and after exercise and may increase the risk of severe hypoglycemia. In addition, youth with T1DM have abnormal counterregulatory hormone responses, further increasing the risk of exercise-associated hypoglycemia. Recent studies have demonstrated that this risk is present during, and many hours after exercise, and have tested strategies to prevent exercise-induced hypoglycemia in youth. Despite these recent studies, the fear of hypoglycemia remains a major impediment to achieving target glycemic control in youth, targets that have recently been tightened. Equally, data suggests fear of hypoglycemia is the major impediment to participation in regular daily exercise in T1DM. Recent advances in insulin delivery systems and in real time continuous glucose monitoring have improved care for youth with T1DM, allowing safer participation in exercise programs. The impending development and approval of "closed loop" insulin delivery systems (the artificial pancreas) holds great promise for the safe participation in exercise for all youth with T1DM.

Lack of association between residual insulin production and glucagon response to hypoglycemia in youth with short duration of type 1 diabetes.

OBJECTIVETo examine the loss of glucagon response to hypoglycemia and its relationship with residual β-cell function early in the course of type 1 diabetes (T1D) in youth.RESEARCH DESIGN AND METHODSTwenty-one youth with T1D duration <1 year (ages 8–18 years, T1D duration 6–52 weeks) underwent mixed-meal tolerance tests (MMTTs) to assess residual β-cell function and hypoglycemic clamps to assess glucagon responses to hypoglycemia. Glucagon responses to hypoglycemia in T1D subjects were compared with those in 12 nondiabetic young adults (ages 19–25 years).RESULTSPeak MMTT-stimulated C-peptide levels (range 0.12–1.43) were ≥0.2 nmol/L in all but one T1D subject. As expected, the median of glucagon responses to hypoglycemia in the T1D subjects (18 pg/mL [interquartile range 7–32]) was significantly reduced compared with the responses in nondiabetic control subjects (38 pg/mL [19–66], P = 0.02). However, there was no correlation between the incremental increase in plasma glucagon during the hypoglycemic clamp and the incremental increase and peak plasma C-peptide level during the MMTT. Similarly, the seven T1D subjects who failed to achieve an increase in glucagon ≥12 pg/mL (i.e., 3 SD above baseline values) had C-peptide response ≥0.2 nmol/L (0.54–1.12), and the one T1D subject with peak stimulated <0.2 nmol/L had a 14 pg/mL increase in plasma glucagon in response to hypoglycemia.CONCLUSIONSImpaired plasma glucagon responses to hypoglycemia are evident in youth with T1D during the first year of the disease. Moreover, defective and absent glucagon responses to hypoglycemia were observed in patients who retained clinically important residual endogenous β-cell function.

Severe hypoglycemia in youth with T1DM: going, going … but not yet gone

Severe hypoglycemia in youth with T1DM: going, going … but not yet gone

Is an automatic pump suspension feature safe for children with type 1 diabetes? An exploratory analysis with a closed-loop system.

It has been proposed that the first step towards a closed-loop artificial pancreas might be to use a continuous glucose sensor to automatically suspend the basal insulin delivery based on projected low sensor glucose values. We reviewed our recent experience with an artificial pancreas system, utilizing a proportional-integrative-derivative (PID) algorithm, in 17 adolescents with type 1 diabetes (T1D) to assess the safety and efficacy of this maneuver. During 34 h of closed-loop automated insulin delivery, 18 pump suspensions > or =60 min (90 +/- 18 min) occurred in eight subjects. Sensor glucose levels fell from 159 +/- 42 mg/dL to a nadir of 72 +/- 13 mg/dL. Corresponding plasma glucose levels fell from 168 +/- 51 to 72 +/- 16 mg/dL, with values <60 mg/dL recorded in only four of the 18 events. These data suggest that automatic pump suspension using the PID algorithm may be an effective means to prevent hypoglycemia in youth with T1D.

Predictors of fear of hypoglycemia in youth with type 1 diabetes and their parents

Predictors of fear of hypoglycemia in youth with type 1 diabetes and their parents

Hypoglycemia in childhood type 1 diabetes mellitus: Understanding and managing the dark side of intensive insulin therapy

Background: Despite the availability of advanced insulin delivery systems, blood glucose-monitoring equipment, and insulin analogue formulations, hypoglycemia remains a significant concern in the treatment of children and adolescents with type 1 diabetes mellitus (DM). Furthermore, patients who manage their blood glucose levels most effectively may also be the ones at greatest risk for hypoglycemia.Objective: The aim of this article was to review current issues surrounding the pathophysiology and frequency of hypoglycemia in children and adolescents with type 1 DM.Methods: Relevant articles for this review were identified through a search of MEDLINE (1992–2007; English-language articles only). The search terms used were children, adolescents, hypoglycemia, diabetes, insulin, and continuous subcutaneous insulin infusion.Results: The threat of severe hypoglycemia remains a major obstacle to the effective treatment of type 1 DM. Basalbolus therapy, using continuous subcutaneous insulin infusion or multiple daily injections, is the most effective and flexible method available for maintaining good glycemic control in children as well as in adults. Insulin analogues can be used effectively in these regimens and may be helpful toward addressing risks for hypoglycemia. Patient education should also be given a high priority in addressing the risk of hypoglycemia in children and adolescents with type 1 DM. The development of continuous glucose-monitoring systems offers the potential for an even brighter future for this group of patients.Conclusions: Recent advances in DM technology reduce but do not eliminate the risk of hypoglycemia in youth with type 1 DM. These observations underscore the need for a closed-loop insulin delivery system in which the rate of insulin infusion is regulated by real-time changes in glucose concentrations. (Insulin. 2007;2:157–165)Key words: type 1 diabetes mellitus; hypoglycemia; children; adolescents; insulin analogue; continuous subcutaneous insulin infusion; multiple daily injections; basal-bolus therapy.Accepted for publication 09052007

Regional Brain Volume Differences Associated With Hyperglycemia and Severe Hypoglycemia in Youth With Type 1 Diabetes

Despite interest in the effects of type 1 diabetes on the developing brain, structural brain volumes in youth with this disease have not previously been examined. This study is the first to quantify regional brain volume differences in a large sample of youth with diabetes. Magnetic resonance images (MRIs) were acquired from youth with diabetes (n = 108) and healthy sibling control subjects (n = 51) aged 7-17 years. History of severe hypoglycemia was assessed by parent interview and included seizure, loss of consciousness, or requiring assistance to treat. A1C values since diagnosis were obtained from medical records; median A1C was weighted by duration of disease. Voxel-based morphometry was used to determine the relationships of prior hypo- and hyperglycemia to regional grey and white matter volumes across the whole brain. No significant differences were found between diabetic and healthy control groups in grey or white matter. However, within the diabetic group, a history of severe hypoglycemia was associated with smaller grey matter volume in the left superior temporal region. Greater exposure to hyperglycemia was associated with smaller grey matter volume in the right cuneus and precuneus, smaller white matter volume in a right posterior parietal region, and larger grey matter volume in a right prefrontal region. Qualitatively different relationships were found between hypo- and hyperglycemia and regional brain volumes in youth with type 1 diabetes. Future studies should investigate whether these differences relate to cognitive function and how these regions are affected by further exposure.

Searching for glycemic control in pediatric type 1 diabetes: A long way to go

Searching for glycemic control in pediatric type 1 diabetes: A long way to go