[Show abstract][Hide abstract] ABSTRACT: OBJECTIVE
To examine the evolution of the dysregulated glucagon responses to mixed-meal tolerance tests (MMTTs) in youth with recent-onset type 1 diabetes (T1D).RESEARCH DESIGN AND METHODSMMTTs were performed in 25 youth (9-18 years of age) with 1.5-12 months disease duration (year 1); 22 subjects were restudied 1 year later (year 2). Twenty nondiabetic (ND) control children were also studied.RESULTSIn T1D children, MMTT-stimulated increases in glucagon were significantly greater than that in ND children (median increments: year 1, 21 pg/mL [16-30]; year 2, 25 pg/mL [16-30]; ND, 9 pg/mL [5-16]; P = 0.001 and P < 0.001, respectively).CONCLUSIONS
In comparison with ND control children, exaggerated plasma glucagon responses to mixed-meal feedings are observed in youth with T1D within the first 2 years of diagnosis. Further studies to determine whether suppression of these abnormal responses may help to improve glycemic control are warranted.
[Show abstract][Hide abstract] ABSTRACT: Abstract Objective: This study was undertaken to investigate the effect of an insulin infusion site warming device, the InsuPatch40(™) (IP40) (InsuLine Medical Ltd., Petach-Tikvah, Israel), on insulin aspart pharmacodynamics (PD) and pharmacokinetics (PK) in adolescents with type 1 diabetes. Subjects and Methods: 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 IP40 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. Results: 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 IP40 than without the IP40, 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 IP40. 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). Conclusions: Our data demonstrate that skin warming around the infusion site to 40°C with the IP40 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.
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVE
To investigate whether type 1 diabetes affects white matter (WM) structure in a large sample of young children.RESEARCH DESIGN AND METHODS
Children (ages 4 to <10 years) with type 1 diabetes (n = 127) and age-matched nondiabetic control subjects (n = 67) had diffusion weighted magnetic resonance imaging scans in this multisite neuroimaging study. Participants with type 1 diabetes were assessed for HbA1c history and lifetime adverse events, and glucose levels were monitored using a continuous glucose monitor (CGM) device and standardized measures of cognition.RESULTSBetween-group analysis showed that children with type 1 diabetes had significantly reduced axial diffusivity (AD) in widespread brain regions compared with control subjects. Within the type 1 diabetes group, earlier onset of diabetes was associated with increased radial diffusivity (RD) and longer duration was associated with reduced AD, reduced RD, and increased fractional anisotropy (FA). In addition, HbA1c values were significantly negatively associated with FA values and were positively associated with RD values in widespread brain regions. Significant associations of AD, RD, and FA were found for CGM measures of hyperglycemia and glucose variability but not for hypoglycemia. Finally, we observed a significant association between WM structure and cognitive ability in children with type 1 diabetes but not in control subjects.CONCLUSIONS
These results suggest vulnerability of the developing brain in young children to effects of type 1 diabetes associated with chronic hyperglycemia and glucose variability.
[Show abstract][Hide abstract] ABSTRACT: Objective
An integrated sensor-augmented pump system has been introduced that interrupts basal insulin infusion for 2-hrs if patients fail to respond to low glucose alarms. It has been suggested that such interruptions of basal insulin due to falsely low sensor glucose levels could lead to diabetic ketoacidosis. We hypothesized that random suspension of basal insulin for 2-hrs in the overnight period would not lead to clinically important increases in blood β-hydroxybutyrate (BHB) levels despite widely varying glucose values prior to the suspension.Research Design and Methods
Subjects measured meter blood glucose (BG) and BHB levels each night at 9PM and fasting the next morning. On control nights, usual basal rates were continued; on experimental nights, the basal insulin infusion was re-programmed for a 2-hr zero basal rate at random times after 11:30PM.ResultsIn seventeen type 1 diabetes subjects (age 24±9yr, duration 14±11yr, A1c 7.3±0.5 [56mmol/mol]) BG and BHB levels were similar at 9PM on suspend (144±63mg/dL and 0.09±0.07mmol/L) and non-suspend (151±65mg/dL and 0.08±0.06mmol/L) nights (p=0.39 and p=0.47, respectively). Fasting morning BG increased following suspend nights compared to non-suspend nights (191±68mg/dL vs. 141±75mg/dL, p<0.0001) and the frequency of fasting hypoglycemia decreased the morning following suspend nights (p<0.0001). Morning BHB levels were slightly higher after suspension (0.13±0.14mmol/L vs. 0.09±0.11mmol/L, p=0.053) but the difference was not clinically important.Conclusions
Systems that suspend basal insulin for 2-hrs are safe and do not lead to clinically significant ketonemia even if BG is elevated at the time of the suspension.
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVE
To assess effectiveness of inpatient hybrid closed-loop control (HCLC) followed by outpatient sensor-augmented pump (SAP) therapy initiated within 7 days of diagnosis of type 1 diabetes on the preservation of β-cell function at 1 year.RESEARCH DESIGN AND METHODS
Sixty-eight individuals (mean age 13.3 ± 5.7 years; 35% female, 92% Caucasian) were randomized to HCLC followed by SAP therapy (intensive group; N = 48) or to the usual-care group treated with multiple daily injections or insulin pump therapy (N = 20). Primary outcome was C-peptide concentrations during mixed-meal tolerance tests at 12 months.RESULTSIntensive-group participants initiated HCLC a median of 6 days after diagnosis for a median duration of 71.3 h, during which median participant mean glucose concentration was 140 mg/dL (interquartile range 134-153 mg/dL). During outpatient SAP, continuous glucose monitor (CGM) use decreased over time, and at 12 months, only 33% of intensive participants averaged sensor use ≥6 days/week. In the usual-care group, insulin pump and CGM use were initiated prior to 12 months by 15 and 5 participants, respectively. Mean HbA1c levels were similar in both groups throughout the study. At 12 months, the geometric mean (95% CI) of C-peptide area under the curve was 0.43 (0.34-0.52) pmol/mL in the intensive group and 0.52 (0.32-0.75) pmol/mL in the usual-care group (P = 0.49). Thirty-seven (79%) intensive and 16 (80%) usual-care participants had a peak C-peptide concentration ≥0.2 pmol/mL (P = 0.30).CONCLUSIONS
In new-onset type 1 diabetes, HCLC followed by SAP therapy did not provide benefit in preserving β-cell function compared with current standards of care.
[Show abstract][Hide abstract] ABSTRACT: The ability to lie still in an MRI scanner is essential for obtaining usable image data. To reduce motion, young children are often sedated, adding significant cost and risk.
We assessed the feasibility of using a simple and affordable behavioral desensitization program to yield high-quality brain MRI scans in sedation-free children.
222 children (4-9.9 years), 147 with type 1 diabetes and 75 age-matched non-diabetic controls, participated in a multi-site study focused on effects of type 1 diabetes on the developing brain. T1-weighted and diffusion-weighted imaging (DWI) MRI scans were performed. All children underwent behavioral training and practice MRI sessions using either a commercial MRI simulator or an inexpensive mock scanner consisting of a toy tunnel, vibrating mat, and video player to simulate the sounds and feel of the MRI scanner.
205 children (92.3%), mean age 7 ± 1.7 years had high-quality T1-W scans and 174 (78.4%) had high-quality diffusion-weighted scans after the first scan session. With a second scan session, success rates were 100% and 92.5% for T1-and diffusion-weighted scans, respectively. Success rates did not differ between children with type 1 diabetes and children without diabetes, or between centers using a commercial MRI scan simulator and those using the inexpensive mock scanner.
Behavioral training can lead to a high success rate for obtaining high-quality T1-and diffusion-weighted brain images from a young population without sedation.
[Show abstract][Hide abstract] ABSTRACT: Objective: A pilot study was undertaken to determine whether establishment of a Spanish Language Diabetes Clinic (SLDC) for Spanish speaking families conducted by a team of Spanish speaking, Hispanic and non-Hispanic clinicians provides a means to improve control of type 1 diabetes.Methods: The first 21 Hispanic pediatric patients with T1D who enrolled in the SLDC were matched to 21 Hispanic patients treated in the English Language Diabetes Clinic (ELDC) based on age and duration of diabetes. The two groups did not differ significantly with respect to gender, BMI, or A1c. Patients in both groups were followed for 12 months.Results: The mean (±SD) baseline A1c in the SLDC group (8.4±1.0%) was similar to that in the ELDC group (8.6±1.4%, p=0.83). A1c levels fell by 0.5±1.0% (p=0.01) during the year following enrollment in the SLDC but did not change significantly from baseline during the year of follow-up in the ELDC group (decrease of 0.2±0.9%, p=0.1). At the start of the study, only 5 patients (23%) in the SLDC group and only 7 patients (33%) in the ELDC group met the ≤7.5% target A1c level. After one year, 10 of the SLDC patients (48%) compared to only 4 of ELDC patients (19%) had A1C levels ≤7.5% (p=0.01).Conclusions: Our preliminary findings support the hypothesis that overcoming language barriers by the establishment of a SLDC can be an effective means of improving metabolic control in youth with T1D in Hispanic families with limited English language skills.
Endocrine Practice 06/2013; 19(5):1-19. · 2.49 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVE
Afternoon exercise increases the risk of nocturnal hypoglycemia (NH) in subjects with type 1 diabetes. We hypothesized that automated feedback-controlled closed-loop (CL) insulin delivery would be superior to open-loop (OL) control in preventing NH and maintaining a higher proportion of blood glucose levels within the target blood glucose range on nights with and without antecedent afternoon exercise.RESEARCH DESIGN AND METHODS
Subjects completed two 48-h inpatient study periods in random order: usual OL control and CL control using a proportional-integrative-derivative plus insulin feedback algorithm. Each admission included a sedentary day and an exercise day, with a standardized protocol of 60 min of brisk treadmill walking to 65-70% maximum heart rate at 3:00 p.m.RESULTSAmong 12 subjects (age 12-26 years, A1C 7.4 ± 0.6%), antecedent exercise increased the frequency of NH (reference blood glucose <60 mg/dL) during OL control from six to eight events. In contrast, there was only one NH event each on nights with and without antecedent exercise during CL control (P = 0.04 vs. OL nights). Overnight, the percentage of glucose values in target range was increased with CL control (P < 0.0001). Insulin delivery was lower between 10:00 p.m. and 2:00 a.m. on nights after exercise on CL versus OL, P = 0.008.CONCLUSIONSCL insulin delivery provides an effective means to reduce the risk of NH while increasing the percentage of time spent in target range, regardless of activity level in the mid-afternoon. These data suggest that CL control could be of benefit to patients with type 1 diabetes even if it is limited to the overnight period.
[Show abstract][Hide abstract] ABSTRACT: When a person consumes ethanol, the body quickly begins to convert it to acetic acid, which circulates in the blood and can serve as a source of energy for the brain and other organs. This study used 13C magnetic resonance spectroscopy to test whether chronic heavy drinking is associated with greater brain uptake and oxidation of acetic acid, providing a potential metabolic reward or adenosinergic effect as a consequence of drinking. Seven heavy drinkers, who regularly consumed at least 8 drinks per week and at least 4 drinks per day at least once per week, and 7 light drinkers, who consumed fewer than 2 drinks per week were recruited. The subjects were administered [2-13C]acetate for 2 hours and scanned throughout that time with magnetic resonance spectroscopy of the brain to observe natural 13C abundance of N-acetylaspartate (NAA) and the appearance of 13C-labeled glutamate, glutamine, and acetate. Heavy drinkers had approximately 2-fold more brain acetate relative to blood and twice as much labeled glutamate and glutamine. The results show that acetate transport and oxidation are faster in heavy drinkers compared with that in light drinkers. Our finding suggests that a new therapeutic approach to supply acetate during alcohol detoxification may be beneficial.
The Journal of clinical investigation 03/2013; · 15.39 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVE
To 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 METHODS
Twenty-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 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.CONCLUSIONS
Impaired 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.
[Show abstract][Hide abstract] ABSTRACT: Hyperglycemia is a significant problem for critically ill children. Treatment for hyperglycemia remains contro-versial. This study explores the effect of controlling blood glucose (BG) in hyperglycemic critically ill children.
A retrospective cohort of nondiabetic critically ill children (defined as requiring mechanical ventilation and/or vasopressors) with BG persistently ≥150 mg/dl and treated with insulin (treatment group) were compared with a historical cohort of similar children who did not receive interventions to control hyperglycemia (baseline group).
There were 130 children in the treatment group and 137 children in the baseline group. Mean BG in the treatment group was 140 ± 24 mg/dl compared with 179 ± 47 mg/dl in the baseline group (p < .001). After adjusting for patient characteristics, cointerventions, and glucose metrics, patients in the treatment group had 2.5 fewer intensive care unit (ICU)-free days (i.e., number of days alive and discharged from ICU within 28 days after inclusion) than the baseline group (p = .023). Glucose control was not independently associated with duration of ICU stay, ventilator-free days, vasopressor-free days, or mortality.
Blood glucose control appears associated with worse outcomes in critically ill children. Our data combined with conflicting results in adults leads us to strongly advocate for the conduct of randomized trials on glucose control in critically ill children.
Journal of diabetes science and technology 01/2013; 7(5):1220-1228.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND AND OBJECTIVE: Subcutaneously injected rapid-acting insulin analogs do not replicate physiologic insulin action due to delays in their onset and peak action resulting in postprandial glucose excursions. The InsuPatch (IP) is a novel insulin infusion site warming device developed to accelerate insulin action by increasing blood flow to the area of insulin absorption. Thirteen adolescents with type 1 diabetes (T1D, mean age 14 ± 4 yr) were enrolled in this study to investigate the effect of the IP on the pharmacodynamics and pharmacokinetics of a 0.2 unit/kg bolus dose of aspart insulin using the euglycemic clamp technique. RESEARCH DESIGN AND METHODS: Each subject underwent two euglycemic clamp procedures on separate occasions: one with IP and one without IP activation in random order. RESULTS: When the insulin bolus was given with IP activation as compared to without IP activation, time to reach maximum insulin action (T(GIRmax) ) and to reach 50% maximum action (T(50%GIRmax) ) were 35 and 18 min earlier (125 ± 8 min vs. 90 ± 6 min, p = 0.002 and 58 ± 5 min. vs. 40 ± 3 min, p = 0.01, respectively), and the area under curve, AUC(GIR) (0-90 min) , reflecting early glucodynamic action, was significantly greater (p = 0.001). IP activation also accelerated the rise in plasma insulin levels after the bolus (p = 0.03) and resulted in a higher peak (p = 0.04) and greater overall increase (p = 0.02) in plasma insulin levels. CONCLUSIONS: Our results show that insulin infusion site warming with IP activation accelerates the time action profile of aspart insulin which may be of benefit to current open-loop and future closed-loop insulin delivery in patients with T1D.
[Show abstract][Hide abstract] ABSTRACT: Background: Closed-loop (CL) insulin delivery systems utilizing proportional-integral-derivative (PID) controllers have demonstrated susceptibility to late postprandial hypoglycemia because of delays between insulin delivery and blood glucose (BG) response. An insulin feedback (IFB) modification to the PID algorithm has been introduced to mitigate this risk. We examined the effect of IFB on CL BG control. Methods: Using the Medtronic ePID CL system, four subjects were studied for 24 h on PID control and 24 h during a separate admission with the IFB modification (PID + IFB). Target glucose was 120 mg/dl; meals were served at 8:00 AM, 1:00 PM, and 6:00 PM and were identical for both admissions. No premeal manual boluses were given. Reference BG excursions, defined as incremental glucose rise from premeal to peak, and postprandial BG area under the curve (AUC; 0-5 h) were compared. Results are reported as mean ± standard deviation. Results: The PID + IFB control resulted in higher mean BG levels compared with PID alone (153 ± 54 versus 133 ± 56 mg/dl; p < .0001). Postmeal BG excursions (114 ± 28 versus 114 ± 47 mg/dl) and AUCs (285 ± 102 versus 255 ± 129 mg/dl/h) were similar under both conditions. Total insulin delivery averaged 57 ± 20 U with PID versus 45 ± 13 U with PID + IFB (p = .18). Notably, eight hypoglycemic events (BG < 60 mg/dl) occurred during PID control versus none during PID + IFB. Conclusions: Addition of IFB to the PID controller markedly reduced the occurrence of hypoglycemia without increasing meal-related glucose excursions. Higher average BG levels may be attributable to differences in the determination of system gain (Kp) in this study. The prevention of postprandial hypoglycemia suggests that the PID + IFB algorithm may allow for lower target glucose selection and improved overall glycemic control.
Journal of diabetes science and technology 09/2012; 6(5):1123-30.
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVE Even under closed-loop (CL) conditions, meal-related blood glucose (BG) excursions frequently exceed target levels as a result of delays in absorption of insulin from the subcutaneous site of infusion. We hypothesized that delaying gastric emptying with preprandial injections of pramlintide would improve postprandial glycemia by allowing a better match between carbohydrate and insulin absorptions. RESEARCH DESIGN AND METHODS Eight subjects (4 female; age, 15-28 years; A1C, 7.5 ± 0.7%) were studied for 48 h on a CL insulin-delivery system with a proportional integral derivative algorithm with insulin feedback: 24 h on CL control alone (CL) and 24 h on CL control plus 30-μg premeal injections of pramlintide (CLP). Target glucose was set at 120 mg/dL; timing and contents of meals were identical on both study days. No premeal manual boluses were given. Differences in reference BG excursions, defined as the incremental glucose rise from premeal to peak, were compared between conditions for each meal. RESULTS CLP was associated with overall delayed time to peak BG (2.5 ± 0.9 vs. 1.5 ± 0.5 h; P < 0.0001) and reduced magnitude of glycemic excursion (88 ± 42 vs. 113 ± 32 mg/dL; P = 0.006) compared with CL alone. Pramlintide effects on glycemic excursions were particularly evident at lunch and dinner, in association with higher premeal insulin concentrations at those mealtimes. CONCLUSIONS Pramlintide delayed the time to peak postprandial BG and reduced the magnitude of prandial BG excursions. Beneficial effects of pramlintide on CL may in part be related to higher premeal insulin levels at lunch and dinner compared with breakfast.
Diabetes care 07/2012; 35(10):1994-9. · 7.74 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The availability of glucose sensors and insulin pumps has enabled the development of devices and software to partially or completely automate insulin delivery. Over the last 2 years, the number of centers developing and evaluating such systems, as well as the number of reports of these studies in the literature, have expanded dramatically. The purpose of this review is to highlight the progress along multiple fronts to develop automated systems to improve control of type 1 diabetes.
Multiple approaches, including automated suspension for actual or impending hypoglycemia, automated augmentation for hyperglycemia, as well as hybrid and full closed-loop control, are in parallel development. So far, early hypoglycemia prevention studies and small inpatient feasibility studies have demonstrated the potential for reducing hypoglycemia and improving overall diabetes control.
Current sensors, pumps, and control algorithms show promise for use in a closed-loop system but have been limited to inpatient studies. The next phase of development should focus on their evaluation in controlled short-term outpatient safety and efficacy trials.
Current opinion in endocrinology, diabetes, and obesity 04/2012; 19(2):88-92. · 3.77 Impact Factor