Peiyao Cheng

Home Use of an Artificial Beta Cell in Type 1 Diabetes

BACKGROUND The feasibility, safety, and efficacy of prolonged use of an artificial beta cell (closed-loop insulin-delivery system) in the home setting have not been established. METHODS In two multicenter, crossover, randomized, controlled studies conducted under free-living home conditions, we compared closed-loop insulin delivery with sensor-augmented pump therapy in 58 patients with type 1 diabetes. The closed-loop system was used day and night by 33 adults and overnight by 25 children and adolescents. Participants used the closed-loop system for a 12-week period and sensor-augmented pump therapy (control) for a similar period. The primary end point was the proportion of time that the glucose level was between 70 mg and 180 mg per deciliter for adults and between 70 mg and 145 mg per deciliter for children and adolescents. RESULTS Among adults, the proportion of time that the glucose level was in the target range was 11.0 percentage points (95% confidence interval [CI], 8.1 to 13.8) greater with the use of the closed-loop system day and night than with control therapy (P<0.001). The mean glucose level was lower during the closed-loop phase than during the control phase (difference, -11 mg per deciliter; 95% CI, -17 to -6; P<0.001), as were the area under the curve for the period when the glucose level was less than 63 mg per deciliter (39% lower; 95% CI, 24 to 51; P<0.001) and the mean glycated hemoglobin level (difference, -0.3%; 95% CI, -0.5 to -0.1; P=0.002). Among children and adolescents, the proportion of time with the nighttime glucose level in the target range was higher during the closed-loop phase than during the control phase (by 24.7 percentage points; 95% CI, 20.6 to 28.7; P<0.001), and the mean nighttime glucose level was lower (difference, -29 mg per deciliter; 95% CI, -39 to -20; P<0.001). The area under the curve for the period in which the day-and-night glucose levels were less than 63 mg per deciliter was lower by 42% (95% CI, 4 to 65; P=0.03). Three severe hypoglycemic episodes occurred during the closed-loop phase when the closed-loop system was not in use. CONCLUSIONS Among patients with type 1 diabetes, 12-week use of a closed-loop system, as compared with sensor-augmented pump therapy, improved glucose control, reduced hypoglycemia, and, in adults, resulted in a lower glycated hemoglobin level. (Funded by the JDRF and others; AP@home04 and APCam08 ClinicalTrials.gov numbers, NCT01961622 and NCT01778348.).

Closed-Loop Basal Insulin Delivery Over 36 Hours in Adolescents With Type 1 Diabetes: Randomized clinical trial

OBJECTIVE We evaluated the safety and efficacy of closed-loop basal insulin delivery during sleep and after regular meals and unannounced periods of exercise. RESEARCH DESIGN AND METHODS Twelve adolescents with type 1 diabetes (five males; mean age 15.0 [SD 1.4] years; HbA1c 7.9 [0.7]%; BMI 21.4 [2.6] kg/m2) were studied at a clinical research facility on two occasions and received, in random order, either closed-loop basal insulin delivery or conventional pump therapy for 36 h. During closed-loop insulin delivery, pump basal rates were adjusted every 15 min according to a model predictive control algorithm informed by subcutaneous sensor glucose levels. During control visits, subjects’ standard infusion rates were applied. Prandial insulin boluses were given before main meals (50–80 g carbohydrates) but not before snacks (15–30 g carbohydrates). Subjects undertook moderate-intensity exercise, not announced to the algorithm, on a stationary bicycle at a 140 bpm heart rate in the morning (40 min) and afternoon (20 min). Primary outcome was time when plasma glucose was in the target range (71–180 mg/dL). RESULTS Closed-loop basal insulin delivery increased percentage time when glucose was in the target range (median 84% [interquartile range 78–88%] vs. 49% [26–79%], P = 0.02) and reduced mean plasma glucose levels (128 [19] vs. 165 [55] mg/dL, P = 0.02). Plasma glucose levels were in the target range 100% of the time on 17 of 24 nights during closed-loop insulin delivery. Hypoglycemia occurred on 10 occasions during control visits and 9 occasions during closed-loop delivery (5 episodes were exercise related, and 4 occurred within 2.5 h of prandial bolus). CONCLUSIONS Day-and-night closed-loop basal insulin delivery can improve glucose control in adolescents. However, unannounced moderate-intensity exercise and excessive prandial boluses pose challenges to hypoglycemia-free closed-loop basal insulin delivery.

Alterations in White Matter Structure in Young Children With Type 1 Diabetes

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. RESULTS Between-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.

Neuroanatomical Correlates of Dysglycemia in Young Children With Type 1 Diabetes

Studies of brain structure in type 1 diabetes (T1D) describe widespread neuroanatomical differences related to exposure to glycemic dysregulation in adults and adolescents. In this study, we investigate the neuroanatomical correlates of dysglycemia in very young children with early-onset T1D. Structural magnetic resonance images of the brain were acquired in 142 children with T1D and 68 age-matched control subjects (mean age 7.0 ± 1.7 years) on six identical scanners. Whole-brain volumetric analyses were conducted using voxel-based morphometry to detect regional differences between groups and to investigate correlations between regional brain volumes and measures of glycemic exposure (including data from continuous glucose monitoring). Relative to control subjects, the T1D group displayed decreased gray matter volume (GMV) in bilateral occipital and cerebellar regions (P < 0.001) and increased GMV in the left inferior prefrontal, insula, and temporal pole regions (P = 0.002). Within the T1D group, hyperglycemic exposure was associated with decreased GMV in medial frontal and temporal-occipital regions and increased GMV in lateral prefrontal regions. Cognitive correlations of intelligence quotient to GMV were found in cerebellar-occipital regions and medial prefrontal cortex for control subjects, as expected, but not for the T1D group. Thus, early-onset T1D affects regions of the brain that are associated with typical cognitive development.

Day-and-Night Hybrid Closed-Loop Insulin Delivery in Adolescents With Type 1 Diabetes: A Free-Living, Randomized Clinical Trial

OBJECTIVE To evaluate feasibility, safety, and efficacy of day-and-night hybrid closed-loop insulin delivery in adolescents with type 1 diabetes under free-living conditions without remote monitoring or supervision. RESEARCH DESIGN AND METHODS In an open-label, randomized, free-living, crossover study design, 12 adolescents receiving insulin pump therapy (mean [±SD] age 15.4 ± 2.6 years; HbA1c 8.3 ± 0.9%; duration of diabetes 8.2 ± 3.4 years) underwent two 7-day periods of sensor-augmented insulin pump therapy or hybrid closed-loop insulin delivery without supervision or remote monitoring. During the closed-loop insulin delivery, a model predictive algorithm automatically directed insulin delivery between meals and overnight; prandial boluses were administered by participants using a bolus calculator. RESULTS The proportion of time when the sensor glucose level was in the target range (3.9–10 mmol/L) was increased during closed-loop insulin delivery compared with sensor-augmented pump therapy (72 vs. 53%, P < 0.001; primary end point), the mean glucose concentration was lowered (8.7 vs. 10.1 mmol/L, P = 0.028), and the time spent above the target level was reduced (P = 0.005) without changing the total daily insulin amount (P = 0.55). The time spent in the hypoglycemic range was low and comparable between interventions. CONCLUSIONS Unsupervised day-and-night hybrid closed-loop insulin delivery at home is feasible and safe in young people with type 1 diabetes. Compared with sensor-augmented insulin pump therapy, closed-loop insulin delivery may improve glucose control without increasing the risk of hypoglycemia in adolescents with suboptimally controlled type 1 diabetes.

Longitudinal Assessment of Neuroanatomical and Cognitive Differences in Young Children with Type 1 Diabetes: Association with Hyperglycemia

Significant regional differences in gray and white matter volume and subtle cognitive differences between young diabetic and nondiabetic children have been observed. Here, we assessed whether these differences change over time and the relation with dysglycemia. Children ages 4 to <10 years with (n = 144) and without (n = 72) type 1 diabetes (T1D) had high-resolution structural MRI and comprehensive neurocognitive tests at baseline and 18 months and continuous glucose monitoring and HbA1c performed quarterly for 18 months. There were no differences in cognitive and executive function scores between groups at 18 months. However, children with diabetes had slower total gray and white matter growth than control subjects. Gray matter regions (left precuneus, right temporal, frontal, and parietal lobes and right medial-frontal cortex) showed lesser growth in diabetes, as did white matter areas (splenium of the corpus callosum, bilateral superior-parietal lobe, bilateral anterior forceps, and inferior-frontal fasciculus). These changes were associated with higher cumulative hyperglycemia and glucose variability but not with hypoglycemia. Young children with T1D have significant differences in total and regional gray and white matter growth in brain regions involved in complex sensorimotor processing and cognition compared with age-matched control subjects over 18 months, suggesting that chronic hyperglycemia may be detrimental to the developing brain.

Cognitive functioning in young children with type 1 diabetes

The aim of this study was to assess cognitive functioning in children with type 1 diabetes (T1D) and examine whether glycemic history influences cognitive function. Neuropsychological evaluation of 216 children (healthy controls, n = 72; T1D, n = 144) ages 4-10 years across five DirecNet sites. Cognitive domains included IQ, Executive Functions, Learning and Memory, and Processing Speed. Behavioral, mood, parental IQ data, and T1D glycemic history since diagnosis were collected. The cohorts did not differ in age, gender or parent IQ. Median T1D duration was 2.5 years and average onset age was 4 years. After covarying age, gender, and parental IQ, the IQ and the Executive Functions domain scores trended lower (both p = .02, not statistically significant adjusting for multiple comparisons) with T1D relative to controls. Children with T1D were rated by parents as having more depressive and somatic symptoms (p < .001). Learning and memory (p = .46) and processing speed (p = .25) were similar. Trends in the data supported that the degree of hyperglycemia was associated with Executive Functions, and to a lesser extent, Child IQ and Learning and Memory. Differences in cognition are subtle in young children with T1D within 2 years of onset. Longitudinal evaluations will help determine whether these findings change or become more pronounced with time.

Depressive Symptoms in Youth With Type 1 or Type 2 Diabetes: Results of the Pediatric Diabetes Consortium Screening Assessment of Depression in Diabetes Study

OBJECTIVE To evaluate the frequency of depressive symptoms and the diagnosis and management of depression in youth with type 1 diabetes (T1D) and type 2 diabetes (T2D) enrolled in the Pediatric Diabetes Consortium T1D and T2D registries. RESEARCH DESIGN AND METHODS The Children’s Depression Inventory (CDI) 2 Self-Report (Short) version was completed by 261 T1D and 339 T2D youth aged 10–17 years. RESULTS Symptoms of depression were identified in 13% of T1D and 22% of T2D (P = 0.007) participants; of these, only 4% of T1D and 9% of T2D youth were treated by a therapist within the prior 12 months. Depressive symptoms were associated with lower family income (P = 0.006) and obesity (P = 0.002) in T1D but not T2D youth. CONCLUSIONS Depressive symptoms are more frequent than diagnosed depression in youth with T1D or T2D. These results underscore the need for regular depression screening and appropriate referral for youth with diabetes.

The effects of inpatient hybrid closed-loop therapy initiated within 1 week of type 1 diabetes diagnosis.

BACKGROUND This article describes our experience with inpatient hybrid closed-loop control (HCLC) initiated shortly after the diagnosis of type 1 diabetes in a randomized trial designed to assess the effectiveness of inpatient HCLC followed by outpatient sensor-augmented pump (SAP) therapy on the preservation of β-cell function. SUBJECTS AND METHODS Forty-eight individuals with newly diagnosed type 1 diabetes and positive pancreatic autoantibodies (7.8-37.7 years old) received inpatient HCLC therapy for up to 93 h, initiated within 7 days of diagnosis. RESULTS On initiation of HCLC, mean glucose concentration was 240±100 mg/dL. During the first day of HCLC, median of the participants mean glucose concentrations fell rapidly to 146 mg/dL, a level of control that was sustained on Days 2 and 3 (138 mg/dL and 139 mg/dL, respectively). By Day 3, the median percentage of glucose values >250 and <60 mg/dL was <1%. During the first 2 weeks of SAP treatment at home, the median participant mean glucose level was 126 mg/dL (interquartile range, 117, 137 mg/dL), and the median percentage of values between 71 and 180 mg/dL was 85% (interquartile range, 80%, 90%). CONCLUSIONS Inpatient HCLC followed by outpatient SAP therapy can provide a safe and effective means to rapidly reverse glucose toxicity and establish near-normal glycemic control in patients with newly diagnosed type 1 diabetes.

A cross-sectional view of the current state of treatment of youth with type 2 diabetes in the USA: enrollment data from the Pediatric Diabetes Consortium Type 2 Diabetes Registry.

To describe the clinical characteristics, treatment approaches, clinical outcomes, and co‐morbidities of youth with type 2 diabetes (T2D) enrolled in the Pediatric Diabetes Consortium (PDC) T2D Registry.