Closed-loop (CL) insulin delivery effectively maintains glucose overnight but struggles when challenged with meals. Use of single-day, 30-μg/meal pramlintide lowers meal excursions during CL. We ...sought to further elucidate the potential benefits of adjunctive agents after 3-4 weeks of outpatient dose titration.
Two CL studies were conducted: one evaluating adjunctive pramlintide and the other liraglutide. Ten subjects (age 16-23 years; A1C 7.2 ± 0.6% 55 ± 6.6 mmol/mol) completed two 24-h sessions: one on CL alone and one on CL plus 60-μg pramlintide (CL + P), after a 3-4-week outpatient dose escalation. Eleven subjects (age 18-27 years; A1C 7.5 ± 0.9% 58 ± 9.8 mmol/mol) were studied before and after treatment with 1.8 mg liraglutide (CL + L) after a similar 3-4-week dose escalation period. Timing and content of meals during CL were identical within experiments; meals were not announced.
Pramlintide delayed the time to peak plasma glucose (PG) excursion (CL 1.6 ± 0.5 h vs. CL + P 2.6 ± 0.9 h, P < 0.001) with concomitant blunting of peak postprandial increments in PG (P < 0.0001) and reductions in postmeal incremental PG area under the curve (AUC) (P = 0.0002). CL + L also led to reductions in PG excursions (P = 0.05) and incremental PG AUC (P = 0.004), with a 28% reduction in prandial insulin delivery. Outpatient liraglutide therapy led to a weight loss of 3.2 ± 1.8 kg, with a 26% reduction in total daily insulin dose.
Adjunctive pramlintide and liraglutide treatment mitigated postprandial hyperglycemia during CL control; liraglutide demonstrated the additional benefit of weight loss in an insulin-sparing manner. Further investigations of these and other adjunctive agents in long-term outpatient CL studies are needed.
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.
Objective: This randomized, controlled trial evaluated a monetary-based reinforcement intervention for increasing self-monitoring blood glucose (SMBG) among youth with poorly controlled type 1 ...diabetes. SMBG frequency was the primary outcome, A1c was the secondary outcome.
Methods: After a 2-week baseline, 60 youth age 12-19 years with <4 BG checks per day and A1c >7.5% but ≤13% were randomized to enhanced usual care (EUC) or Reinforcers. The Reinforcers group earned monetary rewards for SMBG and associated behaviors such as uploading glucose meters, completing pattern recognition forms, and reviewing results with clinicians. Reinforcers were withdrawn at 24 weeks. A follow-up evaluation occurred at 36 weeks.
Results: Randomization produced groups that did not differ on any demographic or clinical characteristics. Participants in the Reinforcers group increased the proportion of days they completed ≥4 SMBG from 14.6% at baseline to 64.4%, 47.5%, and 37.8% at 6, 12, and 24 weeks, respectively. In contrast EUC participants declined from 22.7% at baseline to 17.5%, 10.5%, and 11.1% (ps<0.01 versus EUC at all time points). Group differences were attenuated but remained significant after withdrawal of reinforcers. Effect sizes for SMBG were very large during reinforcement and large after withdrawal of reinforcers. In the Reinforcers group, mean A1c dropped from 9.5±1.2% at baseline to 9.0±1.3% at week 6 and 9.0±1.4% at week 12. For EUC, A1c was 9.2%±0.2 at baseline and ranged from 9.2±1.5% to 9.6±1.6% throughout the study (p<0.05 versus EUC). Group differences in A1c were no longer significant at weeks 24 and 36. Effect sizes for A1c were small during reinforcement and also after withdrawal of reinforcement.
Conclusions: Monetary-based reinforcement of adolescents with type 1 diabetes caused durable increases in SMBG. Modification of the reinforcement structure may be needed to sustain improved metabolic control in this challenging age group.
Disclosure
J. Wagner: None. K. Weyman: None. E.M. Tichy: None. E. Cengiz: Advisory Panel; Self; Abvance, ADOCIA, MannKind Corporation, Novo Nordisk Inc. Speaker's Bureau; Self; Novo Nordisk Inc. K. Zajac: None. W.V. Tamborlane: Consultant; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Medtronic MiniMed, Inc., Novo Nordisk Inc., Sanofi, Takeda Pharmaceutical Company Limited.
Background: Members of our group previously reported that monetary reinforcement of SMBG related behaviors shows robust increases in frequency of SMBG and modest decreases in A1c among youth with ...type 1 diabetes (T1D). In these secondary data analyses, we explored effects on psychosocial functioning.
Methods: Sixty youth ages 12-21 (Mage=15.58, SD=2.31) with T1D, A1c 7.5-13%, and <4 BG checks per day were randomized to either a 24-week reinforce intervention or enhanced usual care (EUC). The intervention consisted of monetary incentives for completing blood glucose checks, texts with provider, glucose data uploads, and glucose pattern recognition forms. Validated psychosocial questionnaires were administered at baseline, 6, 12, 24, and 36 weeks. Measures included youth reported diabetes distress, family conflict, and negative affective responses to out-of-range glucose results.
Results: Generalized linear models showed no significant time x condition effects. In t-tests at discrete follow-ups, compared to the control group, the reinforce group had significantly lower youth-reported diabetes related family conflict at 12 weeks (22.39 vs. 25.11, p=.043) and significantly higher negative affective responses to out-of-range glucose results at 24 weeks (13.62 vs. 11.71, p=.047).
Conclusion: Monetary reinforcers targeting SMBG behaviors may produce transitory decreases in youth perceptions of family conflict and transitory iatrogenic increases in youth’s negative affective responses to out-of-range glucose results. The timing of changes in family conflict, negative affect, and previously reported changes in A1c suggest that psychosocial changes may reflect youth responses to A1c as well as to reinforcers per se. For broader effects, the intervention could include psychosocial components that seek to directly maintain decreased family conflict and mitigate negative affect related to increased awareness of glucose control.
Disclosure
J.J. Wong: None. A. Addala: None. K.K. Hood: Consultant; Self; Lilly Diabetes. Research Support; Self; Dexcom, Inc. Speaker's Bureau; Self; Johnson & Johnson Diabetes Institute. J. Wagner: None. E. Cengiz: Advisory Panel; Self; Abvance, ADOCIA, MannKind Corporation, Novo Nordisk Inc. Speaker's Bureau; Self; Novo Nordisk Inc. E.M. Tichy: None. K. Weyman: None. D. Naranjo: Advisory Panel; Spouse/Partner; Eli Lilly and Company. Speaker's Bureau; Spouse/Partner; Johnson & Johnson Diabetes Institute. Other Relationship; Self; Abbott.
Funding
National Institutes of Health
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.
Youth with type 1 diabetes (T1D) who have A1c levels ≥ 9% have a 13-fold higher rate of diabetic ketoacidosis (DKA) than youth with A1c <7.5% and the rate of DKA is 2-fold higher with multiple daily ...injections (MDI) than with pump therapy. However, the frequency of mild to moderate ketosis (the gateway to DKA in these high-risk patients) is largely unknown and such knowledge is essential to evaluate strategies aimed at DKA prevention.
Methods: Youth ages 8-18 years with uncontrolled T1D (A1c> 8.5%) on MDI treatment were enrolled in the study. Blood glucose (BG) and blood β-hydroxybutyrate (BHB) levels were measured by school personnel in the AM on arrival to school.
Results: 14 patients (age 15 ± 2.3 years) enrolled in the study had A1c 10.7 ± 1.5% (range 8.8 - 14.0%). BHB or urine ketones were measured on 125 school days; ketone levels were small (0.6-0.9 mmol/L) on 6.4% of days (mean BHB 0.7+0.1 mmol/L) and moderate/large (>0.9 mmol/L) on 10.4% of days (mean BHB 2.1+1.4 mmol/L) (Figure). BG ranged between 147 to >600 mg/dL on days with elevated BHB levels; all were without other signs or symptoms of DKA.
Conclusions: Unrecognized mild to moderate ketosis during regular school attendance is common in youth with uncontrolled T1D on MDI therapy. Novel strategies, such as having school personnel supervise injections of long-acting basal insulin, are needed to support reliable insulin dosing to prevent ketosis in youth with uncontrolled T1D at risk for DKA
Disclosure
L.M. Nally: None. S. Elahi: None. M.A. Van Name: Research Support; Self; Novo Nordisk Inc. A. Steffen: None. E.M. Tichy: None. A.D. Urban: None. K. Weyman: None. W.V. Tamborlane: Consultant; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Medtronic MiniMed, Inc., Novo Nordisk Inc., Sanofi, Takeda Pharmaceutical Company Limited.
Funding
Novo Nordisk
To assess whether snacking could be used with closed-loop (CL) insulin delivery to avoid exercise-induced reductions in plasma glucose (PG), as well as elevations in PG at the end of exercise.
Twelve ...type 1 diabetes (T1D) subjects (age 13-36 years, duration 10.7 ± 8.4 years, A1c 7.4% ± 0.8% 57 ± 8.7 mmol/mol) underwent two 105-min exercise studies while under CL control: CL alone and CL+snack. Exercise, commenced at 3 PM, consisted of four 15-min periods of brisk treadmill walking to 65%-70% HR
(separated by three 5-min rest periods), followed by a 30-min recovery period. Fifteen to 30 g carbohydrate (Gatorade) was provided on snacking visits just before and midway through the exercise period. PG and insulin were measured every 15-20 min during the exercise studies.
Baseline PG levels were similar for CL alone (164 ± 16 mg/dL) versus CL+snack (172 ± 11 mg/dL). During exercise, PG levels fell by 53 ± 10 mg/dL without snacking versus a modest 10 ± 13 mg/dL increase in PG with snacking (P = 0.0005); similar differences in the change in PG levels were observed at the end of recovery period. Hypoglycemia requiring rescue treatment (PG ≤60 mg/dL) during exercise occurred in three nonsnacking visits versus none with snacking. During the 75-min exercise period, insulin delivered was 1.8 ± 0.4 U for the CL+snack admission compared to 0.7 ± 0.1 U during CL alone (P = 0.002).
These results support the use of a simple snacking strategy to avoid exercise-induced lowering of PG while on CL insulin delivery. Persistent insulin infusion during exercise with snacking also appears to be effective in limiting increases in PG at the end of exercise.
An integrated sensor-augmented pump system has been introduced that interrupts basal insulin infusion for 2 h if patients fail to respond to low-glucose alarms. It has been suggested that such ...interruptions of basal insulin due to falsely low glucose levels detected by sensor could lead to diabetic ketoacidosis. We hypothesized that random suspension of basal insulin for 2 h in the overnight period would not lead to clinically important increases in blood β-hydroxybutyrate levels despite widely varying glucose values prior to the suspension.
Subjects measured blood glucose and blood β-hydroxybutyrate levels using a meter each night at 9:00 p.m., then fasted until the next morning. On control nights, the usual basal rates were continued; on experimental nights, the basal insulin infusion was reprogrammed for a 2-h zero basal rate at random times after 11:30 p.m.
In 17 type 1 diabetic subjects (mean age 24 ± 9 years, diabetes duration 14 ± 11 years, A1C level 7.3 ± 0.5% 56 mmol/mol), blood glucose and blood β-hydroxybutyrate levels were similar at 9:00 p.m. on suspend nights (144 ± 63 mg/dL and 0.09 ± 0.07 mmol/L) and nonsuspend nights (151 ± 65 mg/dL and 0.08 ± 0.06 mmol/L) (P = 0.39 and P = 0.47, respectively). Fasting morning blood glucose levels increased after suspend nights compared with nonsuspend nights (191 ± 68 vs. 141 ± 75 mg/dL, P < 0.0001), and the frequency of fasting hypoglycemia decreased the morning following suspend nights (P < 0.0001). Morning blood β-hydroxybutyrate levels were slightly higher after suspension (0.13 ± 0.14 vs. 0.09 ± 0.11 mmol/L, P = 0.053), but the difference was not clinically important.
Systems that suspend basal insulin for 2 h are safe and do not lead to clinically significant ketonemia even if the blood glucose level is elevated at the time of the suspension.
This study was undertaken to investigate the effect of an insulin infusion site warming device, the InsuPatch(40)(™) (IP(40)) (InsuLine Medical Ltd., Petach-Tikvah, Israel), on insulin aspart ...pharmacodynamics (PD) and pharmacokinetics (PK) in adolescents with type 1 diabetes.
Seventeen subjects with type 1 diabetes (age, 15±1 years; hemoglobin A1c, 7.5±0.2% 58±2.2 mmol/mol) underwent two euglycemic clamps performed on separate mornings with and without IP(40) activation with warming temperature at 40°C. On both days, the basal infusion was suspended, and glucose levels were maintained between 90 and 100 mg/dL by a variable rate dextrose infusion for up to 5 h after a 0.2 U/kg bolus of insulin aspart.
Time to peak insulin action and time to half-maximal action occurred earlier with a greater early glucodynamic effect (area under the curve AUC for glucose infusion rate from 0 to 30 min) with IP(40) than without the IP(40), whereas the AUC for the time-action profile and the peak action did not differ with and without infusion site warming. PK parameters were in agreement with PD parameters, namely, a significantly earlier time to reach the maximum increment in insulin concentrations and greater early bioavailability (AUC for the change in insulin concentration from 0 to 30 min) with the IP(40). The tail of the plasma insulin response curve was also shortened with infusion site warming, with the time to reach baseline insulin concentration occurring significantly earlier (P=0.04).
Our data demonstrate that skin warming around the infusion site to 40°C with the IP(40) is an effective means to accelerate absorption and action of rapid-acting insulin. These improvements in time-action responses have the potential to enhance the performance of open- and closed-loop insulin delivery systems.
Introduction & Objective: Young adults (YA) with T1D have the greatest deviation from targeted glycemia. The transition of care from pediatric to adult providers may be cumbersome and lead to delays ...in follow up (f/u). To identify methods to tailor the process and augment transition of care, a feasibility study is underway at our tertiary care center. Methods: In this prospective study, 15 YA (≥18y/o) with ≥1y T1D duration were recruited. The Readiness for Emerging Adults with Diabetes Diagnosed in Youth (READDY) tool was completed at baseline. Results guide education during f/u visits (initial, 3- and 6-mo after enrollment) and structured visits with social work and nutrition. Results: Fifteen YA (age: 22.9 ± 1.4y, duration: 15.3 ± 4.6y, HbA1c/GMI median: 6.9% (range 6.0-9.9), pump: 87%, male: 53%) enrolled, with 3-mo f/u completed by 46%. The figure shows average score for each participant for the 4 core domains. The knowledge domain was below average for 26% of the cohort, with specific deficits noted in complications, HbA1c, impact of substances on glucose, and reproductive health. Conclusion: Implementation of the READDY tool has identified individualized areas requiring focus in the pre-transition period in our feasibility study. Structured topics to be covered based on knowledge deficits and a multidisciplinary approach will be used to assess whether gaps can be mitigated by the 6-mo f/u when the READDY tool will be re-administered. Disclosure A.A. Dias: None. E.G. Considine: None. K. Weyman: None. D. Carr: None. E.M. Tichy: None. J.L. Sherr: Consultant; Medtronic. Advisory Panel; Medtronic, Insulet Corporation. Speaker's Bureau; Insulet Corporation. Advisory Panel; Vertex Pharmaceuticals Incorporated, MannKind Corporation, StartUp Health T1D Moonshot, Bigfoot Biomedical, Inc., Cecelia Health. Speaker's Bureau; Zealand Pharma A/S. Funding Friends of Yale New Haven Children's Hospital
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