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Objective The primary objective of this trial was to evaluate the feasibility, safety, and efficacy of a predictive hyperglycemia and hypoglycemia minimization (PHHM) system vs predictive low glucose suspension (PLGS) alone in optimizing overnight glucose control in children 6 to 14 years old. Research Design and Methods Twenty‐eight participants 6 to 14 years old with T1D duration ≥1 year with daily insulin therapy ≥12 months and on insulin pump therapy for ≥6 months were randomized per night into PHHM mode or PLGS‐only mode for 42 nights. The primary outcome was percentage of time in sensor‐measured range 70 to 180 mg/dL in the overnight period. Results The addition of automated insulin delivery with PHHM increased time in target range (70‐180 mg/dL) from 66 ± 11% during PLGS nights to 76 ± 9% during PHHM nights (P<.001), without increasing hypoglycemia as measured by time below various thresholds. Average morning blood glucose improved from 176 ± 28 mg/dL following PLGS nights to 154 ± 19 mg/dL following PHHM nights (P<.001). Conclusions The PHHM system was effective in optimizing overnight glycemic control, significantly increasing time in range, lowering mean glucose, and decreasing glycemic variability compared to PLGS alone in children 6 to 14 years old.

OBJECTIVE: Upon diagnosis of type 1 diabetes, patients are usually symptomatic, and many have ketoacidosis. Screening for islet autoantibodies (IAs) has been shown to decrease A1C level and rate of hospitalization at diabetes onset. Metabolic tests and the presence of symptoms were described at diabetes onset during the Diabetes Prevention Trial-Type 1 (DPT-1). RESEARCH DESIGN AND METHODS: The DPT-1 screened relatives of patients with type 1 diabetes for islet cell autoantiobodies (ICAs). Those with positive ICAs had intravenous and oral glucose tolerance tests (IVGTTs and OGTTs) and were randomized into one of two prevention trials. Throughout the DPT-1 parenteral and oral insulin study, 246 people were diagnosed with type 1 diabetes. RESULTS: Of the 246 subjects diagnosed with diabetes, 218 had data regarding the presence of symptoms, and 138 (63.3%) reported no symptoms suggestive of diabetes. Eight subjects (3.67%) presented with ketosis. Subjects presented with a mean ± SD A1C of 6.41 ± 1.15%. At diagnosis, 90 subjects (50.8%) had A1C in the normal range (<6.2%). OGTT data at the time of diagnosis indicate that 35.4% had a glucose result of <100 mg/dl at 0 min. CONCLUSIONS: The majority of subjects diagnosed with type 1 diabetes through the DPT-1 were asymptomatic at onset and had normal fasting glucose and A1C levels. This suggests that intermittent screening (IA followed by OGTT) may allow diagnosis of diabetes before severe metabolic decompensation. Screening with A1C will miss identifying many of the subjects with newly diagnosed type 1 diabetes in this cohort.

OBJECTIVE:--There is little information regarding the pattern of metabolic deterioration before the onset of type 1 diabetes. The goal of this study was to utilize data from the Diabetes Prevention Trial-Type 1 (DPT-1) to obtain a picture of the metabolic progression to type 1 diabetes over a period of approximately 2.5 years before its diagnosis. RESEARCH DESIGN AND METHODS--Fifty-four DPT-1 participants (22 in the parenteral trial and 32 in the oral trial) were studied. All had oral glucose tolerance tests (OGTTs) at 6-month intervals from approximately 30 to 6 months before diagnosis. The vast majority also had OGTTs at diagnosis. Changes in OGTT glucose and C-peptide indexes from 30 to 6 months before diagnosis were examined by calculating slopes of the indexes for each individual over that time period. Changes from 6 months before diagnosis to diagnosis were examined by paired comparisons of the OGTT metabolic indexes between the time points. RESULTS:--Glucose levels increased gradually from 30 to 6 months before diagnosis in both the parenteral and oral groups (P < 0.001 for all indexes). Area under the curve (AUC) C-peptide (P < 0.05) and AUC C-peptide-to-AUC glucose ratio (P < 0.001) values decreased in the oral group; peak C-peptide-to-2-h glucose ratio values decreased in both groups (P < 0.001). In participants who also had OGTTs at diagnosis, AUC C-peptide (parenteral group, P < 0.05) and peak C-peptide (oral group, P < 0.05) values decreased from the last 6 months before diagnosis; stimulated C-peptide-to-glucose ratio values decreased in both groups (P < 0.001). Conversely, fasting C-peptide levels increased in both groups (oral group, P < 0.01). Fasting C-peptide-to-fasting glucose ratio values remained constant throughout the 30-month follow-up. CONCLUSIONS:--These data indicate that over a period of at least 2 years, glucose tolerance gradually deteriorates as stimulated C-peptide levels slowly decline in a substantial number of individuals who develop type 1 diabetes. However, fasting C-peptide levels are maintained, even at diagnosis.

In Utero Dietary Exposures and Risk of Islet Autoimmunity in Children Carolyn M. Fronczak , MSPH 1 , Anna E. Barón , PHD 1 , H. Peter Chase , MD 2 , Colleen Ross , MS 1 , Heather L. Brady , RD, MS 1 , Michelle Hoffman , RN 1 , George S. Eisenbarth , MD, PHD 2 , Marian Rewers , MD, PHD 2 and Jill M. Norris , MPH, PHD 1 1 Department of Preventive Medicine and Biometrics, University of Colorado Health Sciences Center, Denver, Colorado 2 The Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center, Denver, Colorado Address correspondence and reprint requests to Jill M. Norris, MPH, PhD, Department of Preventive Medicine and Biometrics, University of Colorado Health Sciences Center, 4200 East Ninth Ave., Box B119, Denver, CO 80262. E-mail: jill.norris{at}uchsc.edu Abstract OBJECTIVE —The goal of this study was to examine whether maternal dietary intake of vitamin D, ω-3 fatty acids, and ω-6 fatty acids during pregnancy is associated with the appearance of islet autoimmunity (IA) in offspring. RESEARCH DESIGN AND METHODS —The Diabetes Autoimmunity Study in the Young (DAISY) is recruiting at birth and following children at increased risk for type 1 diabetes, as determined by HLA-DR genotype or by family history of type 1 diabetes. A total of 233 mothers of newly recruited DAISY subjects were asked to recall their intake of food and nutritional supplements during the third trimester of pregnancy using the Willett food frequency questionnaire. Children were followed for an average of 4 years (range 0.8–7.3 years) for the appearance of insulin, GAD 65 , and IA-2 autoantibodies. Sixteen children developed at least one autoantibody during this period. Unadjusted and adjusted hazard ratios (HRs) for the development of IA were estimated with survival analysis using a Weibull distribution. RESULTS —Maternal intake of vitamin D via food was significantly associated with a decreased risk of IA appearance in offspring, independent of HLA genotype, family history of type 1 diabetes, presence of gestational diabetes mellitus, and ethnicity (adjusted HR = 0.37; 95% CI 0.17–0.78). Vitamin D intake via supplements, ω-3 fatty acids, and ω-6 fatty acids intake during pregnancy were not associated with appearance of IA in offspring. CONCLUSIONS —Our findings suggest that maternal intake of vitamin D through food during pregnancy may have a protective effect on the appearance of IA in offspring. DAISY, Diabetes Autoimmunity Study in the Young DHA, docosahexaenoic acid EPA, eicosapentaenoic acid FFQ, food frequency questionnaire GDM, gestational diabetes mellitus IA, islet autoimmunity IAA, insulin autoantibody Footnotes A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances. Accepted September 4, 2003. Received May 21, 2002. DIABETES CARE

OBJECTIVE:--To compare the glucose variability associated with insulin glargine and NPH/Lente insulin used as the basal insulin component of a multiple daily injection (MDI) regimen in pediatric patients with type 1 diabetes. RESEARCH DESIGN AND METHODS--Continuous glucose monitoring data were collected from a subset of patients (n = 90) who agreed to use a continuous glucose monitoring system during an active-controlled, randomized, open-label study evaluating the safety and efficacy of insulin glargine and NPH/Lente insulin used with insulin lispro as part of an MDI regimen. RESULTS:--Treatment with insulin glargine resulted in significant reductions in glucose variability as measured by the SD of glucose values (adjusted mean change from baseline to week 24: -13.4 mg/dl [-0.74 mmol/l]; P [less-than or equal to] 0.05), mean amplitude of glycemic excursion (-34.4 mg/dl [-1.91 mmol/l]; P [less-than or equal to] 0.0001), and M value (-9.6 mg/dl [-0.53 mmol/l]; P [less-than or equal to] 0.03). The corresponding reductions in glucose variability for NPH/Lente were not significant. CONCLUSIONS:--Insulin glargine is associated with greater reductions in glucose variability than NPH/Lente insulin in pediatric patients with type 1 diabetes.

Modem Transmission of Glucose Values Reduces the Costs and Need for Clinic Visits H. Peter Chase , MD 1 , Jerusha A. Pearson , BA 1 , Clare Wightman , BA 1 , Mary D. Roberts , MD 1 , Adam D. Oderberg , BA 1 and Satish K. Garg , MD 1 2 1 Department of Pediatrics, Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center, Denver, Colorado 2 Department of Medicine, Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center, Denver, Colorado Abstract OBJECTIVE —To determine whether modem technology allows for effective management of type 1 diabetes when used in lieu of a clinic visit. RESEARCH DESIGN AND METHODS —A total of 70 adolescent patients with diabetes were prospectively randomized to either a control group or a modem group. Control group patients continued the standard of care of quarterly clinic visits, and modem group patients were instructed to transmit blood glucose data every 2 weeks for 6 months instead of a usual quarterly clinic visit. Health care providers analyzed the data received by modem and contacted patients to discuss diabetes treatment changes. GHbA 1c levels were determined at 0 and 6 months, and the number of high and low blood glucose levels and adverse events were tracked. Clinic visit costs, patient expenses, and health care provider times were tracked for cost analysis for both groups. RESULTS —A total of 63 patients (33 control, 30 modem) completed the 6-month study. The GHbA 1c values significantly decreased in both groups, with no statistically significant difference between groups ( P = 0.96). The occurrence of mild-to-moderate hypoglycemic events were similar in the two groups, and there were no severe hypoglycemic events. The average cost of care for a clinic visit was $305.00, whereas the cost for 6 months of modem transmission was $163.00. CONCLUSIONS —This study shows that electronic transmission of blood glucose levels and other diabetes data every 2 weeks—in lieu of a clinic visit—results in a similar level of glucose control and incidence of acute diabetes complications when compared with current standard care. DCCT, Diabetes Control and Complications Trial Footnotes Address correspondence and reprint requests to H. Peter Chase, MD, 4200 E. 9th Ave., B140, Denver, CO 80262. E-mail: peter.chase{at}uchsc.edu . Received for publication 23 July 2002 and accepted in revised form 12 December 2002. A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances. See accompanying editorial, p. 1626. DIABETES CARE

Elevated C-Reactive Protein Levels in the Development of Type 1 Diabetes H. Peter Chase 1 , Sonia Cooper 1 , Iris Osberg 2 , Lars C. Stene 1 , Katherine Barriga 3 , Jill Norris 3 , George S. Eisenbarth 1 and Marian Rewers 1 3 1 Department of Pediatrics, The Barbara Davis Center for Childhood Diabetes, Denver, Colorado 2 General Clinical Research Center Laboratory, University of Colorado Health Sciences Center, Denver, Colorado 3 Department of Preventive Medicine and Biometrics, University of Colorado Health Sciences Center, Denver, Colorado Address correspondence and reprint requests to H. Peter Chase, MD, 4200 E. 9th Ave., B140, Denver, CO 80262. E-mail: peter.chase{at}uchsc.edu Abstract Elevated C-reactive protein (CRP) levels have previously been described before the onset of type 2 diabetes and gestational diabetes. We hypothesized that inflammation, as reflected by elevated CRP levels, can help predict development of islet autoimmunity or type 1 diabetes. Children at risk for type 1 diabetes and followed in the Diabetes Autoimmunity Study of the Young (DAISY) had blood samples drawn and frozen serum saved at various intervals after birth. CRP was measured using a high-sensitivity sandwich enzyme immunoassay. Islet autoantibodies (IAs) were measured using biochemical immunoassays. Elevations in CRP concentrations were significantly more frequent ( P < 0.01) in children who later developed type 1 diabetes (8 of 16 children) than in children negative for IAs at their last testing (3 of 26). Children with one or more positive IA were more likely to have elevated CRP concentrations (15 of 36) than IA-negative children (3 of 26; P < 0.01). The finding of elevated CRP levels in infants and young children before the onset of type 1 diabetes adds to the evidence that the disease is an immunoinflammatory disorder. The elevated CRP levels may provide an additional marker for risk of progression to type 1 diabetes. COX2, cyclooxygenase 2 CRP, C-reactive protein DAISY, Diabetes Autoimmunity Study of the Young IA, islet autoantibody IL, interleukin Footnotes L.C.S. is currently affiliated with the Norwegian Institute of Public Health, Division of Epidemiology, Oslo, Norway. Accepted July 13, 2004. Received October 22, 2003. DIABETES

Factors Predictive of Use and of Benefit From Continuous Glucose Monitoring in Type 1 Diabetes Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group * Corresponding author: Roy W. Beck, jdrfapp{at}jaeb.org . Abstract OBJECTIVE To evaluate factors associated with successful use of continuous glucose monitoring (CGM) among participants with intensively treated type 1 diabetes in the Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Randomized Clinical Trial. RESEARCH DESIGN AND METHODS The 232 participants randomly assigned to the CGM group (165 with baseline A1C ≥7.0% and 67 with A1C <7.0%) were asked to use CGM on a daily basis. The associations of baseline factors and early CGM use with CGM use ≥6 days/week in the 6th month and with change in A1C from baseline to 6 months were evaluated in regression models. RESULTS The only baseline factors found to be associated with greater CGM use in month 6 were age ≥25 years ( P < 0.001) and more frequent self-reported prestudy blood glucose meter measurements per day ( P < 0.001). CGM use and the percentage of CGM glucose values between 71 and 180 mg/dl during the 1st month were predictive of CGM use in month 6 ( P < 0.001 and P = 0.002, respectively). More frequent CGM use was associated with a greater reduction in A1C from baseline to 6 months ( P < 0.001), a finding present in all age-groups. CONCLUSIONS After 6 months, near-daily CGM use is more frequent in intensively treated adults with type 1 diabetes than in children and adolescents, although in all age-groups near-daily CGM use is associated with a similar reduction in A1C. Frequency of blood glucose meter monitoring and initial CGM use may help predict the likelihood of long-term CGM benefit in intensively treated patients with type 1 diabetes of all ages. Footnotes ↵ *The list of members of the Writing Committee can be found in the appendix , and a complete list of the members of the Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group is available in an online appendix at http://care.diabetesjournals.org/cgi/content/full/dc09-0889/DC1 . Clinical trial reg. no. NCT00406133, clinicaltrials.gov . The study was designed and conducted by the investigators who collectively wrote the manuscript and vouch for the data. The investigators had complete autonomy to analyze and report the trial results. There were no agreements concerning confidentiality of the data between the Juvenile Diabetes Research Foundation and the authors or their institutions. The Jaeb Center for Health Research had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Received May 14, 2009. Accepted July 21, 2009. © 2009 by the American Diabetes Association.

OBJECTIVE: The aim of this study was to develop a partial closed-loop system to safely prevent nocturnal hypoglycemia by suspending insulin delivery when hypoglycemia is predicted in type 1 diabetes. RESEARCH DESIGN AND METHODS: Forty subjects with type 1 diabetes (age range 12-39 years) were studied overnight in the hospital. For the first 14 subjects, hypoglycemia (<60 mg/dl) was induced by gradually increasing the basal insulin infusion rate (without the use of pump shutoff algorithms). During the subsequent 26 patient studies, pump shutoff occurred when either three of five (n = 10) or two of five (n = 16) algorithms predicted hypoglycemia based on the glucose levels measured with the FreeStyle Navigator (Abbott Diabetes Care). RESULTS: The standardized protocol induced hypoglycemia on 13 (93%) of the 14 nights. With use of a voting scheme that required three algorithms to trigger insulin pump suspension, nocturnal hypoglycemia was prevented during 6 (60%) of 10 nights. When the voting scheme was changed to require only two algorithms to predict hypoglycemia to trigger pump suspension, hypoglycemia was prevented during 12 (75%) of 16 nights. In the latter study, there were 25 predictions of hypoglycemia because some subjects had multiple hypoglycemic events during a night, and hypoglycemia was prevented for 84% of these events. CONCLUSIONS: Using algorithms to shut off the insulin pump when hypoglycemia is predicted, it is possible to prevent hypoglycemia on 75% of nights (84% of events) when it would otherwise be predicted to occur.

The Impact of the Diabetes Control and Complications Trial and Humalog Insulin on Glycohemoglobin Levels and Severe Hypoglycemia in Type 1 Diabetes H. Peter Chase , MD 1 , Tai Lockspeiser , BA 1 , Ben Peery , BA 1 , Mark Shepherd , BA 1 , Todd MacKenzie , PHD 1 , James Anderson , MD 2 and Satish K. Garg , MD 1 1 Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center, Denver, Colorado 2 Eli Lilly and Company, Indianapolis, Indiana Abstract OBJECTIVE —This study was performed to determine the effects of the Diabetes Control and Complications Trial (DCCT) report in 1993 and the introduction of Lispro (Humalog) insulin in 1996 on glycemic control and on the number of severe hypoglycemic episodes in type 1 diabetic patients of various ages. RESEARCH DESIGN AND METHODS —Diabetes care parameters and HbA 1c data from 884 subjects with type 1 diabetes were entered into our database at the time of clinic visits from 1993 through 1998. In addition, a questionnaire was sent to all patients to validate the number of insulin injections per day, the incidence of severe hypoglycemic episodes (as defined by the DCCT), and the use of Humalog insulin. Data were divided into four age-groups: <5, 5–12, 13–18, and >18 years of age. RESULTS —Longitudinal HbA 1c levels declined significantly after the DCCT report in 1993–1996 ( P < 0.001), but the number of severe hypoglycemic events increased ( P < 0.001). A second decline in HbA 1c levels was observed after the introduction of Humalog insulin in 1996 ( P < 0.001). However, severe hypoglycemic episodes did not change ( P = 0.26). CONCLUSIONS —Administration of Humalog resulted in an additional reduction in HbA 1c levels beyond the reduction in HbA 1c values after the DCCT report. In contrast to the increase in severe hypoglycemic events after the DCCT results, the number of severe hypoglycemic episodes did not increase after the introduction of Humalog, despite a further decrease in HbA 1c values. DCCT, Diabetes Control and Complications Trial Footnotes Address correspondence and reprint requests to H. Peter Chase, MD, 4200 E. 9th Ave., B140, Denver, CO 80262. E-mail: peter.chase{at}uchsc.edu . Received for publication 8 May 2000 and accepted in final form 10 November 2000. A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.