Comparison of Shoulder Motion Measurements by Visual Estimate, Goniometer and Motion Capture.

BACKGROUND: Brachial plexus birth injuries (BPBI) can result in lasting impairments of external rotation and cross-body adduction (CBA) that disrupt functional activities such as dressing, grooming, or throwing a ball. The purpose of this study was to compare the quantification of shoulder humerothoracic (HT) external rotation (ER), and glenohumeral (GH) CBA by 3 methods - physician visual estimate, goniometer measurement by an occupational therapist, and motion capture. METHODS: Twenty-six patients with BPBI (average age of 9.9±3.2 y) participated in this study. Mallet scores and visual estimates of passive HT ER and GH CBA were recorded by a physician. The passive measures were repeated by an occupational therapist using a goniometer while motion capture measures were simultaneously collected. Active HT ER was also measured by motion capture. The passive measures were compared with analyses of variance with repeated measures, intraclass correlations, and Bland-Altman plots. External rotation Mallet scores determined by motion capture and by the physician were compared. RESULTS: The measures of GH CBA were not statistically different and demonstrated good agreement, but substantial variation. For HT ER, all measures were significantly different and demonstrated poor agreement and substantial variation. When the joint angles measured by motion capture were used to determine the Mallet score, 79% of external rotation Mallet scores assigned by the physician were incorrectly categorized, with the physician always scoring the participant higher than predicted motion capture Mallet score. CONCLUSIONS: Both GH CBA and HT ER measures demonstrated substantial variability between measurement types, but only HT ER joint angles were significantly different. In addition, more than three-quarters of external rotation Mallet scores were misclassified by the physician. Motion capture measurements offer the benefit of less susceptibility to patients' compensatory and/or out-of-plane movements and should be considered for clinical assessment of shoulder range of motion in children with BPBI. If motion capture is unavailable, the use of a goniometer provides more accurate clinical measures of shoulder motion than visual estimates and care should be taken to minimize and account for compensatory movement strategies. LEVEL OF EVIDENCE: Level IV Case series.

Scapular Stabilization Limits Glenohumeral Stretching in Children With Brachial Plexus Injuries.

PURPOSE: To quantify the effects of scapular stabilization on scapulothoracic and glenohumeral (GH) stretching. METHODS: Motion capture data during external rotation and abduction with and without scapular stabilization were collected and analyzed for 26 children with brachial plexus birth palsy. These positions were performed by an experienced occupational therapist and by the child's caretaker. Scapulothoracic and GH joint angular displacements were compared between stretches with no stabilization, stabilization performed by the therapist, and stabilization performed by the caretaker. The relationship between the age and ability of the therapist and caretaker to perform the stretches with scapular stabilization was also assessed. RESULTS: During external rotation there were no significant differences in either the scapulothoracic or GH joint during stabilization by either the therapist or the caretaker. During abduction, both scapulothoracic and GH joint angular displacements were statistically different. Scapulothoracic upward rotation angular displacement significantly decreased with scapular stabilization by the therapist and caretaker. Glenohumeral elevation angular displacement significantly decreased with scapular stabilization performed by the therapist and caretaker. There were only weak correlations between age and the differences in scapulothoracic and GH joint angular displacement performed by both the therapist and the caretaker. CONCLUSIONS: The findings of this study indicate that scapular stabilization may be detrimental to passive stretching of the GH joint in children, as demonstrated by a reduced stretch. Based on the findings of this study, we have changed our practice to recommend passive stretches without scapular stabilization for children aged 5 years and older with brachial plexus birth palsy. In infants and children aged less than 5 years, we now recommend stretching with and without scapular stabilization until the effect of scapular stabilization is objectively assessed in these age groups. LEVEL OF EVIDENCE/TYPE OF STUDY: Therapeutic IV.

Efficacy of 3 therapeutic taping configurations for children with brachial plexus birth palsy.

STUDY DESIGN: Cross-sectional clinical measurement study. INTRODUCTION: Scapular winging is a frequent complaint among children with brachial plexus birth palsy (BPBP). Therapeutic taping for scapular stabilization has been reported to decrease scapular winging. PURPOSE OF THE STUDY: This study aimed to determine which therapeutic taping construct was most effective for children with BPBP. METHODS: Twenty-eight children with BPBP participated in motion capture assessment with 4 taping conditions: (1) no tape, (2) facilitation of rhomboid major and rhomboid minor, (3) facilitation of middle and lower trapezius, and (4) facilitation of rhomboid major, rhomboid minor, and middle and lower trapezius (combination of both 2 and 3, referred to as combined taping). The participants held their arms in 4 positions: (1) neutral with arms by their sides, (2) hand to mouth, (3) hand to belly, and (4) maximum crossbody adduction (CBA). The scapulothoracic, glenohumeral and humerothoracic (HT) joint angles and joint angular displacements were compared using multivariate analyses of variance with Bonferroni corrections. RESULTS: Scapular winging was significantly decreased in both the trapezius and combined taping conditions in all positions compared with no tape. Rhomboids taping had no effect. Combined taping reduced HT CBA in the CBA position. CONCLUSIONS: Rhomboid taping cannot be recommended for treatment of children with BPBP. Both trapezius and combined taping approaches reduced scapular winging, but HT CBA was limited with combined taping. Therefore, therapeutic taping of middle and lower trapezius was the most effective configuration for scapular stabilization in children with BPBP. Resting posture improved, but performance of the positions was not significantly improved. LEVEL OF EVIDENCE: Level II.

Therapeutic Taping for Scapular Stabilization in Children With Brachial Plexus Birth Palsy.

OBJECTIVE: In this study, we aimed to assess whether therapeutic taping for scapular stabilization affected scapulothoracic, glenohumeral, and humerothoracic joint function in children with brachial plexus birth palsy and scapular winging. METHOD: Motion capture data were collected with and without therapeutic taping to assist the middle and lower trapezius in seven positions for 26 children. Data were compared with one-way multivariate analyses of variance. RESULTS: With therapeutic taping, scapular winging decreased considerably in all positions except abduction. Additionally, there were increased glenohumeral cross-body adduction and internal rotation angles in four positions. The only change in humerothoracic function was an increase of 3° of external rotation in the external rotation position. CONCLUSION: Therapeutic taping for scapular stabilization resulted in a small but statistically significant decrease in scapular winging. Overall performance of positions was largely unchanged. The increased glenohumeral joint angles with therapeutic taping may be beneficial for joint development; however, the long-term impact remains unknown.

Increased gluconeogenesis in youth with newly diagnosed type 2 diabetes.

AIMS/HYPOTHESIS: The role of increased gluconeogenesis as an important contributor to fasting hyperglycaemia at diabetes onset is not known. We evaluated the contribution of gluconeogenesis and glycogenolysis to fasting hyperglycaemia in newly diagnosed youths with type 2 diabetes following an overnight fast. METHODS: Basal rates (µmol kg(FFM) (-1) min(-1)) of gluconeogenesis ((2)H2O), glycogenolysis and glycerol production ([(2)H5] glycerol) were measured in 18 adolescents (nine treatment naive diabetic and nine normal-glucose-tolerant obese adolescents). RESULTS: Type 2 diabetes was associated with higher gluconeogenesis (9.2 ± 0.6 vs 7.0 ± 0.3 µmol kg(FFM) (-1) min(-1), p < 0.01), plasma fasting glucose (7.0 ± 0.6 vs 5.0 ± 0.2 mmol/l, p = 0.004) and insulin (300 ± 30 vs 126 ± 31 pmol/l, p = 0.001). Glucose production and glycogenolysis were similar between the groups (15.4 ± 0.3 vs 12.4 ± 1.4 µmol kg(FFM) (-1) min(-1), p = 0.06; and 6.2 ± 0.8 vs 5.3 ± 0.7 µmol kg(FFM) (-1) min(-1), p = 0.5, respectively). After controlling for differences in adiposity, gluconeogenesis, glycogenolysis and glucose production were higher in diabetic youth (p ≤ 0.02). Glycerol concentration (84 ± 6 vs 57 ± 6 µmol/l, p = 0.01) and glycerol production (5.0 ± 0.3 vs 3.6 ± 0.5 µmol kg(FFM) (-1) min(-1), p = 0.03) were 40% higher in youth with diabetes. The increased glycerol production could account for only ~1/3 of substrate needed for the increased gluconeogenesis in diabetic youth. CONCLUSION/INTERPRETATIONS: Increased gluconeogenesis was a major contributor to fasting hyperglycaemia and hepatic insulin resistance in newly diagnosed untreated adolescents and was an early pathological feature of type 2 diabetes. Increased glycerol availability may represent a significant source of new carbon substrates for increased gluconeogenesis but would not account for all the carbons required to sustain the increased rates.

Association of TCF7L2 variation with single islet autoantibody expression in children with type 1 diabetes.

BACKGROUND: The transcription factor 7-like 2 (TCF7L2) gene has the strongest genetic association with type 2 diabetes. TCF7L2 also associates with latent autoimmune diabetes in adults, which often presents with a single islet autoantibody, but not with classical type 1 diabetes. METHODS: We aimed to test if TCF7L2 is associated with single islet autoantibody expression in pediatric type 1 diabetes. We studied 71 prospectively recruited children who had newly diagnosed type 1 diabetes and evidence of islet autoimmunity, that is, expressed ≥1 islet autoantibody to insulin, glutamic acid decarboxylase 65, islet cell autoantigen 512, or zinc transporter 8. TCF7L2 rs7903146 alleles were identified. Data at diagnosis were cross-sectionally analyzed. RESULTS: We found that 21.1% of the children with autoimmune type 1 diabetes expressed a single islet autoantibody. The distribution of TCF7L2 rs7903146 genotypes in children with a single autoantibody (n=15) was 40% CC, 26.7% CT and 33.3% TT, compared with children with ≥2 islet autoantibodies (50% CC, 42.9% CT and 7.1% TT, p=0.024). Furthermore, compared with children with ≥2 autoantibodies, single-autoantibody children had characteristics reflecting milder autoimmune destruction of ß-cells. Restricting to lean children (body mass index<85th centile; n=36), 45.5% of those expressing a single autoantibody were rs7903146 TT homozygotes, compared with 0% of those with ≥2 autoantibodies (p<0.0001). CONCLUSION: These results suggest that, in children with only mild islet autoimmunity, mechanisms associated with TCF7L2 genetic variation contribute to diabetogenesis, and this contribution is larger in the absence of obesity.

Challenging recruitment of youth with type 2 diabetes into clinical trials.

PURPOSE: To better understand and overcome difficulties with recruitment of adolescents with type 2 diabetes into clinical trials at three United States institutions, we reviewed recruitment and retention strategies in clinical trials of youth with various chronic conditions. We explored whether similar strategies might be applicable to pediatric patients with type 2 diabetes. METHODS: We compiled data on recruitment and retention of adolescents with type 2 diabetes at three centers (National Institutes of Health, Bethesda, Maryland; Baylor College of Medicine, Houston, Texas; and Children's National Medical Center, Washington, DC) from January 2009 to December 2011. We also conducted a thorough literature review on recruitment and retention in adolescents with chronic health conditions. RESULTS: The number of recruited patients was inadequate for timely completion of ongoing trials. Our review of recruitment strategies in adolescents included monetary and material incentives, technology-based advertising, word-of-mouth referral, and continuous patient-research team contact. Cellular or Internet technology appeared promising in improving participation among youths in studies of various chronic conditions and social behaviors. CONCLUSIONS: Adolescents with type 2 diabetes are particularly difficult to engage in clinical trials. Monetary incentives and use of technology do not represent "magic bullets," but may presently be the most effective tools. Future studies should be conducted to explore motivation in this population. We speculate that (1) recruitment into interventional trials that address the main concerns of the affected youth (e.g., weight loss, body image, and stress management) combined with less tangible outcomes (e.g., blood glucose control) may be more successful; and (2) study participation and retention may be improved by accommodating patients' and caregivers' schedules, by scheduling study visits before and after working hours, and in more convenient locations than in medical facilities.

Serum cortisol and early postoperative outcome after stage-1 palliation for hypoplastic left heart syndrome.

OBJECTIVES: The postoperative cortisol profile and its association with early outcomes are poorly understood in neonates undergoing surgery for complex congenital heart disease. We investigated the postoperative profile of cortisol and its relationship with the clinical course in a cohort of newborns after stage-1 palliation for hypoplastic left heart syndrome. DESIGN: Prospective observational study. SETTING: Pediatric cardiovascular ICU at a tertiary children's hospital. SUBJECTS: Twenty-three neonates after stage-1 palliation for hypoplastic left heart syndrome between 2009 and 2011. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Three serial measurements of total serum cortisol after surgery. The first measurement was taken immediately after surgery and the second and third-on the first and second postoperative mornings. The median weight of the infants was 3.0 kg (2.7-3.4 kg), and the age at surgery was 7 days (6-9 d). The median (25th-75th percentile) cortisol levels at admission, day 1, and day 2 were 96.2 µg/dL (51.1-112 µg/dL), 17.3 µg/dL (9.7-25.1 µg/dL), and 10 µg/dL (6.5-17 µg/dL), respectively (p < 0.0001 between admission and day 1). Higher cortisol was associated with greater morbidity, including the need for preoperative ventilation, increased total duration of ventilation, duration of inotropic support, and hospital length of stay. CONCLUSIONS: Cortisol levels fell significantly over the first 24 hours after stage-1 palliation for hypoplastic left heart syndrome. A higher postoperative cortisol was associated with increased postoperative morbidity, which warrants further investigation.

Types of pediatric diabetes mellitus defined by anti-islet autoimmunity and random C-peptide at diagnosis.

OBJECTIVE: To test the hypothesis that anti-islet autoantibody expression and random serum C-peptide obtained at diagnosis define phenotypes of pediatric diabetes with distinct clinical features. SUBJECTS: We analyzed 607 children aged <19 yr consecutively diagnosed with diabetes after exclusion of 13% of cases with secondary diabetes (e.g., cystic fibrosis related, steroid induced) and 7.3% of cases lacking measurement of C-peptide and/or autoantibodies. METHODS: Autoantibody positivity (A+) was defined as ≥ 1 positive out of GAD65, insulin, and ICA512 antibodies. Preserved beta-cell function (ß+) was defined as random serum C-peptide at diagnosis ≥ 0.6 ng/mL. Body mass index (BMI) was measured at median 1.2 months after diagnosis. Characteristics at diagnosis and 2 yr (range 18-30 months) after diagnosis were compared among groups. RESULTS: Autoantibody expression and C-peptide at diagnosis defined the following groups: A+ß- (52.1% of the children), A+ß+ (32.8%), A-ß+ (12.5%), and A-ß- (2.6%). These four groups differed in gender, race/ethnicity, and clinical characteristics at diagnosis [i.e., age, pubertal development, obesity/overweight, diabetic ketoacidosis, glycemia, and hemoglobin A1c (HbA1c)] and at 2 yr (i.e., clinical diagnosis, treatment, and HbA1c) (all p < 0.0001). Among all ß+ children, C-peptide >2 ng/mL was associated with lower HbA1c at onset (p = 0.0001) and, in the A+ß+ subgroup, with higher frequency of achieving HbA1c < 7% at 2 yr (p = 0.03). All three patients (0.7% of total) with monogenic diabetes (maturity onset diabetes of the young, MODY) were A-ß+ with C-peptide between 0.6 and 2 ng/mL. CONCLUSIONS: Anti-islet autoantibodies status and serum random C-peptide at diagnosis define four distinct phenotypes of pediatric diabetes with prognostic value.

The Relationship between Self-Management and Glycemic Control in a Cohort of Children with Type 1 and Type 2 Diabetes.

AIM: Self-management of diabetes improves glycemic control. The development of a quick, objective questionnaire in the clinic setting may provide data to the clinician caring for the patient in overall evaluation. OBJECTIVE: We developed a 23 question tool (clinic preparedness score) and administered it to type 1 and 2 (T1DM & T2DM) diabetes patients. Clinicians of patients were surveyed to determine their perception of adherence by patients. A total of 350 T1DM patients and families and 137 T2DM families were administered the questionnaire. Additionally, HbA1C was correlated to the various parameters that are related to improved glycemic control such as having a meter, carrying glucose tablets for hypoglycemia, and downloading/ writing blood sugars in log book in T1DM and T2DM. RESULTS: T1DM subjects had a lower HbA1C with better clinic preparedness (8.2 ± 1.3 vs. 9.4 ± 1.9%) However, this did not hold true for T2DM (p NS). If T1DM subjects adjusted their insulin dose and reported that their parent was involved they had better HbA1C than those that did not change insulin dose and if parent was uninvolved in the care. Clinicians of patients were able to accurately predict that appropriate dose adjustments resulted in good glycemic control. CONCLUSIONS: Pediatric T2DM adherence measures do not mirror similar characteristics of T1DM in childhood. The variability in glucose monitoring, medication and insulin administration may affect T2DM differently than T1DM.

Beta cell function and BMI in ethnically diverse children with newly diagnosed autoimmune type 1 diabetes.

OBJECTIVE: To examine the relationship between BMI and beta-cell function at diagnosis of autoimmune type 1 diabetes (T1D) in a large group of ethnically diverse children. METHODS: Cross-sectional analysis of 524 children (60.8% White, 19.5% Hispanic, 14.5% African-American, 5.2% other non-Hispanic; mean age = 9.8 yr [SD = 2.5]) with newly diagnosed autoimmune T1D. RESULTS: As much as 22.2% of children were overweight or obese. Median random serum C-peptide was 0.40 ng/mL (25th-75th percentiles = 0.3-0.8), with median glycemia of 366 mg/dL (25th-75th percentiles = 271-505). Median C-peptide was 0.3, 0.5, 0.7, and 0.85 ng/mL, respectively, in underweight, normal weight, overweight, and obese children (p < 0.0001, Kruskal-Wallis). In the final model (p < 0.0001), the odds of having preserved C-peptide (≥0.6 ng/mL) were increased by 2.4-fold (95% CI = 1.2-4.9, p < 0.015) and 4.1-fold (1.9-8.5, p < 0.0001), respectively, in overweight and obese compared to lean children; 1.3-fold per each year of age; 2.5-fold in girls compared to boys; 4-fold in children who presented without, compared to with, diabetes ketoacidosis (DKA); and decreased by 21% for each point increase in HbA1c. Tanner stage, race/ethnicity, glycemia, and number of anti-islet antibodies expressed were not independently associated with preserved C-peptide. The association between BMI and C-peptide levels was significant in children with and without preserved C-peptide. Excluding patients who presented with DKA and/or using BMI obtained 5 wk after diagnosis did not alter the results. CONCLUSION: Obese and overweight children compared to lean children have greater beta-cell function at the onset of autoimmune T1D. Prospective studies on the relationships among BMI, beta-cell function, and progression to clinical T1D are warranted.

Clinical trials in youth with type 2 diabetes.

Type 2 diabetes in youth was almost unheard of only two decades ago. However, tracking the recent dramatic rise in childhood obesity, type 2 diabetes has become increasingly prevalent. Thus, there is an urgent need for high-quality clinical trials to increase in-depth knowledge about pathophysiology, optimal treatment, and prevention. We therefore systematically reviewed published and ongoing clinical trials of type 2 diabetes in children and adolescents. The results demonstrate that (i) few randomized clinical trials have been completed and published in children with type 2 diabetes; (ii) ongoing trials in type 1 diabetes clearly outnumber trials in type 2 diabetes; and (iii) recruitment and enrollment into the latter trials are challenging, however once achieved, drop-out rates are not excessively high. We conclude that type 2 diabetes in youth is an important but difficult new field of clinical research, and we discuss the existing barriers to successful recruitment, conduct, and support of these clinical trials.

Continuous glucose monitoring in subjects after simultaneous pancreas-kidney and kidney-alone transplantation.

BACKGROUND: Simultaneous pancreas-kidney (SPK) transplantation is an important replacement therapy for individuals with diabetes and end-stage renal disease. Kidney-alone (KA) transplantation is associated with a high incidence of post-transplant diabetes. METHODS: This was a cross-sectional study. We studied 48-h glucose concentrations in eight subjects with type 1 diabetes mellitus after SPK transplantation, six subjects post-KA transplantation, and nine healthy controls using the CGMS (Medtronic Minimed, Northridge, CA) continuous glucose monitoring system. RESULTS: The 48-h mean glucose concentration was 101 +/- 7 mg/dL in the SPK subjects, 105 +/- 12 mg/dL in the KA subjects, and 99 +/- 7 mg/dL in the healthy controls. The glycemic excursions were higher in the KA group compared to the SPK cohort and healthy controls (P < 0.0001). No differences in the incidence of hypoglycemia were detected among the three groups. Significant postprandial hyperglycemia was uncovered in four of the six KA subjects. CONCLUSIONS: SPK transplantation is very effective at normalizing glycemic excursions. Unsuspected hyperglycemia was identified in the KA group. The CGMS was a useful ambulatory tool to study glucose profiles in the post-transplant period and may help uncover hyperglycemia undetected by routine laboratory testing.

The role of adjunctive exenatide therapy in pediatric type 1 diabetes.

OBJECTIVE: Exenatide improves postprandial glycemic excursions in type 2 diabetes. Exenatide could benefit type 1 diabetes as well. We aimed to determine an effective and safe glucose-lowering adjuvant exenatide dose in adolescents with type 1 diabetes. RESEARCH DESIGN AND METHODS: Eight subjects completed a three-part double-blinded randomized controlled study of premeal exenatide. Two doses of exenatide (1.25 and 2.5 microg) were compared with insulin monotherapy. Prandial insulin dose was reduced by 20%. Gastric emptying and hormones were analyzed for 300 min postmeal. RESULTS: Treatment with both doses of exenatide versus insulin monotherapy significantly reduced glucose excursions over 300 min (P < 0.0001). Exenatide administration failed to suppress glucagon but delayed gastric emptying (P < 0.004). CONCLUSIONS: Adjunctive exenatide therapy reduces postprandial hyperglycemia in adolescents with type 1 diabetes. This reduction in glucose excursion occurs despite reduction in insulin dose. We suggest that exenatide has therapeutic potential as adjunctive therapy in type 1 diabetes.

A 12-week aerobic exercise program reduces hepatic fat accumulation and insulin resistance in obese, Hispanic adolescents.

The rise in obesity-related morbidity in children and adolescents requires urgent prevention and treatment strategies. Currently, only limited data are available on the effects of exercise programs on insulin resistance, and visceral, hepatic, and intramyocellular fat accumulation. We hypothesized that a 12-week controlled aerobic exercise program without weight loss reduces visceral, hepatic, and intramyocellular fat content and decreases insulin resistance in sedentary Hispanic adolescents. Twenty-nine postpubertal (Tanner stage IV and V), Hispanic adolescents, 15 obese (7 boys, 8 girls; 15.6 +/- 0.4 years; 33.7 +/- 1.1 kg/m(2); 38.3 +/- 1.5% body fat) and 14 lean (10 boys, 4 girls; 15.1 +/- 0.3 years; 20.6 +/- 0.8 kg/m(2); 18.9 +/- 1.5% body fat), completed a 12-week aerobic exercise program (4 x 30 min/week at > or =70% of peak oxygen consumption (VO(2)peak)). Measurements of cardiovascular fitness, visceral, hepatic, and intramyocellular fat content (magnetic resonance imaging (MRI)/magnetic resonance spectroscopy (MRS)), and insulin resistance were obtained at baseline and postexercise. In both groups, fitness increased (obese: 13 +/- 2%, lean: 16 +/- 4%; both P < 0.01). In obese participants, intramyocellular fat remained unchanged, whereas hepatic fat content decreased from 8.9 +/- 3.2 to 5.6 +/- 1.8%; P < 0.05 and visceral fat content from 54.7 +/- 6.0 to 49.6 +/- 5.5 cm(2); P < 0.05. Insulin resistance decreased indicated by decreased fasting insulin (21.8 +/- 2.7 to 18.2 +/- 2.4 microU/ml; P < 0.01) and homeostasis model assessment of insulin resistance (HOMA(IR)) (4.9 +/- 0.7 to 4.1 +/- 0.6; P < 0.01). The decrease in visceral fat correlated with the decrease in fasting insulin (R(2) = 0.40; P < 0.05). No significant changes were observed in any parameter in lean participants except a small increase in lean body mass (LBM). Thus, a controlled aerobic exercise program, without weight loss, reduced hepatic and visceral fat accumulation, and decreased insulin resistance in obese adolescents.

Twenty-four-hour simultaneous subcutaneous Basal-bolus administration of insulin and amylin in adolescents with type 1 diabetes decreases postprandial hyperglycemia.

CONTEXT: The purpose of this study was to examine the effect of continuous sc replacement of amylin and insulin for a 24-h period on glucose homeostasis in adolescents with type 1diabetes. METHODS: Thirteen adolescents with type 1 diabetes on insulin pump therapy participated in a randomized, controlled, crossover design study comparing continuous sc insulin monotherapy (part A) vs. continuous sc insulin and pramlintide infusion (part B). In part A, basal and bolus insulin infusion was per prescribed home regimen. In part B, the basal insulin infusion was the same as part A, but prandial insulin boluses were reduced by 20%. Basal and prandial bolus pramlintide were administered simultaneously via another pump. All boluses were given as a dual wave. RESULTS: The study regimen resulted in a 26% reduction in postprandial hyperglycemia as compared to insulin monotherapy (area under the curve, 600 min, 2610 +/- 539 vs. 692 +/- 861 mg/liter . min) (P < 0.008). Glucagon concentrations were suppressed postprandially (P < 0.003) but not in the postabsorptive state, whereas plasma insulin concentrations were unchanged. CONCLUSIONS: Simultaneous continuous sc pramlintide and insulin infusion has the potential of improving glucose concentrations by way of physiological replacement.

Gastric emptying and postprandial glucose excursions in adolescents with type 1 diabetes.

Because amylin is co-secreted with insulin from beta cells, patients with type 1 diabetes (T1DM) are deficient in both insulin and amylin. Amylin delays gastric emptying and suppresses glucagon in the postprandial period. Hence, we hypothesized that children with complication-naive T1DM have accelerated gastric emptying in response to a mixed meal because of amylin deficiency. Amylin, glucagon, insulin, glucose, and gastric emptying were measured in seven T1DM and in eight control subjects without diabetes. Subjects with T1DM had markedly elevated glucose concentrations when compared with controls (p < 0.0001). Amylin concentrations as predicted were lower in T1DM compared with those in controls (p < 0.0001). Insulin did not peak in the immediate postprandial period in T1DM when compared with controls (p < 0.0001). Glucagon concentrations did not significantly differ between groups. Interestingly, gastric velocity was delayed in patients with T1DM compared with controls (p < 0.01). In conclusion, subjects with T1DM do have amylin deficiency but this is not associated with accelerated gastric emptying as we had hypothesized but rather with delayed gastric emptying. Factors other than amylin play a role in control of gastric motility in T1DM. Subcutaneous insulin delivery fails to reach adequate concentrations in the postprandial period to curtail peak glucose concentration in T1DM.

A randomized, controlled trial comparing twice-a-day insulin glargine mixed with rapid-acting insulin analogs versus standard neutral protamine Hagedorn (NPH) therapy in newly diagnosed type 1 diabetes.

OBJECTIVE: Insulin glargine is difficult to use for children due to the number of injections required because it is claimed to be immiscible with rapid-acting insulin analogs. For this study, we hypothesized that treating new-onset type 1 diabetes with twice-daily insulin glargine plus a rapid-acting insulin analog mixed in the same syringe would result in better glycosylated hemoglobin than twice-daily neutral protamine Hagedorn with a rapid-acting insulin analog (standard treatment). METHODS: Forty-two patients with new-onset type 1 diabetes were started on standard treatment. Three months after diagnosis, if patients were found compliant and had a glycosylated hemoglobin level of < or = 9%, then they were randomly assigned either to receive insulin glargine twice daily mixed with a rapid-acting insulin analog or to continue on standard treatment for 3 more months. Additional lunchtime rapid-acting insulin analog injections were given for the insulin glargine group as necessary. RESULTS: Nineteen patients in the insulin glargine group and 17 in the neutral protamine Hagedorn group completed the study. The glycosylated hemoglobin level at baseline was 6.8% +/- 1% vs 6.9% +/- 1% and at poststudy was 6.7% +/- 1.3% vs 7.6% +/- 1% in the insulin glargine versus neutral protamine Hagedorn group, respectively. Two patients in the insulin glargine group required lunch rapid-acting insulin analog in the last month of the study. Although both groups were encouraged to contact the principal investigator with all queries, more in the insulin glargine arm opted to do so. CONCLUSIONS: Glycemic control with insulin glargine mixed with a rapid-acting insulin analog given twice daily seems significantly more effective than the standard therapy in newly diagnosed type 1 diabetes. Furthermore, it decreases pain and burden of injections for children with diabetes by allowing patients to mix glargine with rapid-acting insulin analog.

The role of prandial pramlintide in the treatment of adolescents with type 1 diabetes.

Pramlintide, a synthetic analog of amylin, improves postprandial hyperglycemia. We compared subcutaneous (s.c.) pramlintide injection with square wave pramlintide infusion in adolescents with type 1 diabetes (T1DM). Eight subjects with T1DM underwent two randomized studies. Subcutaneous pramlintide (dose = 5 microg/unit of insulin) bolus, was given one time and another time, the same dose was given as a 120-min s.c. infusion. Insulin dose was constant between studies. Gastric emptying was assessed with oral acetaminophen and [l-13C]glucose in meal. Plasma glucagon, pramlintide, and insulin concentrations were measured. Insulin concentrations (p < 0.99) between pramlintide injection versus infusion were similar; however, glucose concentrations were different (p < 0.0001), with the absence of hypoglycemia during pramlintide infusion [AUC (0-120 min) -0.07 +/- 0.2 versus 1.05 +/- 0.24 mg * h/dL (p < 0.0088)]. Insulin-only administration resulted in postprandial hyperglycemia and late postprandial hypoglycemia (p < 0.0001). Two subjects experienced hypoglycemia with pramlintide injection. Pramlintide bolus caused pronounced glucagon suppression (p < 0.0003) and delayed gastric emptying as ([13CO2] p < 0.0003 and acetaminophen p < 0.01) compared with infusion. We conclude that pramlintide bolus may result in an increase in risk of immediate postprandial hypoglycemia. Further modifications in pramlintide delivery are indicated before it can be safely used in children.