HOMA-IR and the Matsuda Index as predictors of progression to type 1 diabetes in autoantibody-positive relatives.

AIM/HYPOTHESIS: We assessed whether HOMA-IR and the Matsuda Index are associated with transitions through stages of type 1 diabetes. METHODS: Autoantibody (AAb)-positive relatives of individuals with type 1 diabetes (n=6256) from the TrialNet Pathway to Prevention were studied. Associations of indicators of insulin resistance (HOMA-IR) and insulin sensitivity (Matsuda Index) with BMI percentile (BMIp) and age were assessed with adjustments for measures of insulin secretion, Index60 and insulinogenic index (IGI). Cox regression was used to determine if tertiles of HOMA-IR and Matsuda Index predicted transitions from Not Staged (<2 AAbs) to Stage 1 (≥2 AAbs and normoglycaemia), from Stage 1 to Stage 2 (≥2 AAbs with dysglycaemia), and progression to Stage 3 (diabetes as defined by WHO/ADA criteria). RESULTS: There were strong associations of HOMA-IR (positive) and Matsuda Index (inverse) with baseline age and BMIp (p<0.0001). After adjustments for Index60, transitioning from Stage 1 to Stage 2 was associated with higher HOMA-IR and lower Matsuda Index (HOMA-IR: HR=1.71, p<0.0001; Matsuda Index, HR=0.40, p<0.0001), as with progressing from Stages 1 or 2 to Stage 3 (HOMA-IR: HR=1.98, p<0.0001; Matsuda Index: HR=0.46, p<0.0001). Without adjustments, associations of progression to Stage 3 were inverse for HOMA-IR and positive for Matsuda Index, opposite in directionality with adjustments. When IGI was used in place of Index60, the findings were similar. CONCLUSIONS/INTERPRETATION: Progression to Stages 2 and 3 of type 1 diabetes increases with HOMA-IR and decreases with the Matsuda Index after adjustments for insulin secretion. Indicators of insulin secretion appear helpful for interpreting associations of progression to type 1 diabetes with HOMA-IR or the Matsuda Index in AAb-positive relatives.

Comparisons of school-day glycemia in different settings for children with type 1 diabetes using continuous glucose monitoring.

Objective: Using continuous glucose monitoring (CGM), we examined patterns in glycemia during school hours for children with type 1 diabetes, exploring differences between school and non-school time. Methods: We conducted a retrospective analysis of CGM metrics in children 7-12 years (n=217, diabetes duration 3.5±2.5 years, hemoglobin A1c 7.5±0.8%). Metrics were obtained for weekday school hours (8 AM to 3 PM) during four weeks in fall 2019. Two comparison settings included weekend (fall 2019) and weekday (spring 2020) data when children had transitioned to virtual school due to COVID-19. We used multilevel mixed models to examine factors associated with time in range (TIR) and compare glycemia between in-school, weekends, and virtual school. Results: Though CGM metrics were clinically similar across settings, TIR was statistically higher, and time above range (TAR), mean glucose, and standard deviation (SD) lower, for weekends and virtual school (p<0.001). Hour and setting exhibited a significant interaction for several metrics (p<0.001). TIR in-school improved from a mean of 40.9% at the start of the school day to 58.0% later in school, with a corresponding decrease in TAR. TIR decreased on weekends (60.8 to 50.7%) and virtual school (62.2 to 47.8%) during the same interval. Mean glucose exhibited a similar pattern, though there was little change in SD. Younger age (p=0.006), lower hemoglobin A1c (p<0.001), and insulin pump use (p=0.02) were associated with higher TIR in-school. Conclusion: Although TIR was higher for weekends and virtual school, glycemic metrics improve while in-school, possibly related to beneficial school day routines.

Abatacept for Delay of Type 1 Diabetes Progression in Stage 1 Relatives at Risk: A Randomized, Double-Masked, Controlled Trial.

OBJECTIVE: Previous studies showed that inhibiting lymphocyte costimulation reduces declining ß-cell function in individuals newly diagnosed with type 1 diabetes. We tested whether abatacept would delay or prevent progression of type 1 diabetes from normal glucose tolerance (NGT) to abnormal glucose tolerance (AGT) or to diabetes and the effects of treatment on immune and metabolic responses. RESEARCH DESIGN AND METHODS: We conducted a phase 2, randomized, placebo-controlled, double-masked trial of abatacept in antibody-positive participants with NGT who received monthly abatacept/placebo infusions for 12 months. The end point was AGT or diabetes, assessed by oral glucose tolerance tests. RESULTS: A total of 101 participants received abatacept and 111 placebo. Of these, 81 (35 abatacept and 46 placebo) met the end point of AGT or type 1 diabetes diagnosis (hazard ratio 0.702; 95% CI 0.452, 1.09; P = 0.11) The C-peptide responses to oral glucose tolerance tests were higher in the abatacept arm (P < 0.03). Abatacept reduced the frequency of inducible T-cell costimulatory (ICOS)+ PD1+ T-follicular helper (Tfh) cells during treatment (P < 0.0001), increased naive CD4+ T cells, and also reduced the frequency of CD4+ regulatory T cells (Tregs) from the baseline (P = 0.0067). Twelve months after treatment, the frequency of ICOS+ Tfh, naive CD4+ T cells, and Tregs returned to baseline. CONCLUSIONS: Although abatacept treatment for 1 year did not significantly delay progression to glucose intolerance in at-risk individuals, it impacted immune cell subsets and preserved insulin secretion, suggesting that costimulation blockade may modify progression of type 1 diabetes.

From Antiquity to Modern Times: A History of Diabetes Mellitus and Its Treatments.

The past 200 years have brought an understanding of diabetes and its pathogenesis, as well as the development of treatments that could not have been predicted when the disorder was first clinically described 2000 years ago. Beginning in the late 19th century, the initial descriptions of the microscopic anatomy of the pancreatic islets by Langerhans led to recognition of pancreatic endocrine function. Many investigators attempted to isolate the hypoglycemic factor produced by the pancreas, but Banting, Best, Macleod, and Collip were able to extract and purify "isletin" to treat human diabetes in 1921. Rapid scientific progress over the next 100 years led to an understanding of insulin synthesis, structure and function, production of modified synthetic insulins, and the physiopathology that permitted classification of diabetes subtypes. Improvements in control of diabetes have reduced the risks of complications. In less than two hundred years, we have gone from being unable to measure glucose in blood to being able to offer people with diabetes continuous blood glucose monitoring, linked to continuous subcutaneous insulin infusion. We come ever closer with new drugs and treatments to repair the biochemical defects in type 2 diabetes and to biologically replace islets and their function in type 1 diabetes. This review addresses the history of continuing progress in diabetes care.

Implications of the School Day on Health Behaviors for Children With Type 1 Diabetes: A Survey of Parent Perspectives During the COVID-19 Pandemic.

PURPOSE: The purpose of this study is to survey parents of youth with type 1 diabetes during the COVID-19 pandemic with school closures to better understand the implications of the school day on health care behaviors. METHODS: A cross-sectional, online survey was distributed to parents of youth with type 1 diabetes ≤19 years of age in a large, academic diabetes center. Questions encompassed perceived changes in management behaviors and plans for return to school. Subgroup analysis compared parent responses by child's age, reported stressors, and socioeconomic markers. RESULTS: Parents reported a worsening in their child's diabetes health behaviors during school closures compared to what they perceived during a regular school day before the pandemic. More than half of parents reported feeling that their child was unable to maintain a normal routine, with particular implications for snacking between meals, daily physical activity, and sleep habits. Families with adolescents or those experiencing multiple pandemic-related stressors reported greater challenges. In open-ended responses, families highlighted difficulty in balancing school, work, and diabetes care and expressed concerns about the mental health repercussions of school closures for their children. Nearly half of parents reported being at least moderately worried about return to school, whereas only a minority reported seeking guidance from their diabetes provider. CONCLUSIONS: Parent-reported disruptions of school-day routines frequently had adverse consequences for diabetes management in this population. These findings highlight the importance of a school-day routine for children with type 1 diabetes; during closures, families may benefit from mitigating strategies to maintain effective habits.

Evaluating the Impact of Stakeholder Engagement in a School-Based Type 1 Diabetes Study.

OBJECTIVE: Although the importance of stakeholder engagement (SE) for patient-centered research is recognized, few studies document SE processes and influence on research outcomes in the diabetes field. We applied a research-informed framework to evaluate the impact of SE on a pediatric diabetes study exploring school nurse perspectives on modern diabetes devices. METHODS: We recruited parents of children with type 1 diabetes, school nurses, and diabetes providers. Stakeholders convened virtually every 2 months for 12 months. Goals for SE included input on research materials, interpretation of findings, and future research directions. Processes were assessed using a validated survey. Immediate outcomes included changes to research materials and satisfaction. Secondary outcomes included research efficiency and value (acceptance by community partners). RESULTS: Each role was represented at every meeting. The majority of stakeholders (>70%) completed the survey at study midpoint and end points. All surveyed indicated that they had received all desired information, shared feedback, and felt valued. Stakeholders were satisfied with the meeting frequency. Participants appreciated learning from each other and expressed enthusiasm for continued research participation. They described their role as one of consultant rather than research team members. SE resulted in five additional interview questions. Nearly 70 comments added to the interpretation of qualitative themes. Findings were published within 12 months and recognized by the state school nursing organization. CONCLUSION: SE was well received and led to meaningful changes in content and dissemination of a diabetes study. A systematic approach to evaluating SE can increase scientific rigor and reproducibility and contribute to best practices for SE in diabetes research.

TCF7L2 Genetic Variants Do Not Influence Insulin Sensitivity or Secretion Indices in Autoantibody-Positive Individuals at Risk for Type 1 Diabetes.

OBJECTIVE: We aimed to test whether type 2 diabetes (T2D)-associated TCF7L2 genetic variants affect insulin sensitivity or secretion in autoantibody-positive relatives at risk for type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS: We studied autoantibody-positive TrialNet Pathway to Prevention study participants (N = 1,061) (mean age 16.3 years) with TCF7L2 single nucleotide polymorphism (SNP) information and baseline oral glucose tolerance test (OGTT) to calculate indices of insulin sensitivity and secretion. With Bonferroni correction for multiple comparisons, P values < 0.0086 were considered statistically significant. RESULTS: None, one, and two T2D-linked TCF7L2 alleles were present in 48.1%, 43.9%, and 8.0% of the participants, respectively. Insulin sensitivity (as reflected by 1/fasting insulin [1/IF]) decreased with increasing BMI z score and was lower in Hispanics. Insulin secretion (as measured by 30-min C-peptide index) positively correlated with age and BMI z score. Oral disposition index was negatively correlated with age, BMI z score, and Hispanic ethnicity. None of the indices were associated with TCF7L2 SNPs. In multivariable analysis models with age, BMI z score, ethnicity, sex, and TCF7L2 alleles as independent variables, C-peptide index increased with age, while BMI z score was associated with higher insulin secretion (C-peptide index), lower insulin sensitivity (1/IF), and lower disposition index; there was no significant effect of TCF7L2 SNPs on any of these indices. When restricting the analyses to participants with a normal OGTT (n = 743; 70%), the results were similar. CONCLUSIONS: In nondiabetic autoantibody-positive individuals, TCF7L2 SNPs were not related to insulin sensitivity or secretion indices after accounting for BMI z score, age, sex, and ethnicity.

Nutrition and Obesity in the Pathogenesis of Youth-Onset Type 1 Diabetes and Its Complications.

Since the 1980s, there has been a dramatic rise in the prevalence of overweight and obesity in pediatric populations, in large part driven by sedentary lifestyles and changing dietary patterns with more processed foods. In parallel with the rise in pediatric obesity in the general population, the prevalence of overweight and obesity has increased among children and adolescents with type 1 diabetes. Adiposity has been implicated in a variety of mechanisms both potentiating the risk for type 1 diabetes as well as exacerbating long-term complications, particularly cardiovascular disease. Treatment options targeting the unique needs of obese pediatric patients, both before and after diagnosis of type 1 diabetes, are limited. In this review, we discuss the history of the epidemiology of the obesity epidemic in the context of pediatric type 1 diabetes, highlight the possible role of obesity in type 1 diabetes pathogenesis and review the concept of "double diabetes". The impact of obesity at and after diagnosis will be discussed, including noted differences in clinical and biochemical markers, lipid abnormalities, and long-term cardiovascular complications. Finally, we will review the existing literature on pharmacologic and nutritional interventions as potential treatment strategies for youth with coexisting type 1 diabetes and obesity.

Cyber School Is a Marker of Youth with High-Risk Diabetes.

OBJECTIVE: To explore the health characteristics of youth with diabetes in cyber school compared with peers with diabetes in traditional brick-and-mortar schools. STUDY DESIGN: This was a single-center cross-sectional study of youth with type 1 or type 2 diabetes in K-12 education during academic year 2017-2018. Youth enrolled in cyber school were matched with traditional school peers by age, sex, race, diagnosis, and diabetes duration. Comparisons included insurance status, hemoglobin A1c, treatment, coexisting conditions, screening, and healthcare use. RESULTS: Of 1694 participants, 5% (n = 87) were enrolled in cyber school. Youth enrolled in cyber school were predominantly white (89%), female (60%), adolescents (median 15.2 years) with type 1 diabetes (91%). Youth with type 2 diabetes were excluded from analyses owing to the small sample (n = 7). Public insurance was more common among youth enrolled in cyber school (P = .005). Youth in cyber school had higher mean hemoglobin A1c, 9.1 ± 1.8% (76 ± 20 mmol/mol) vs 8.3 ± 1.2% (67 ± 13 mmol/mol) (P = .003), lower insulin pump use (OR, 0.36; 95% CI, 0.18-0.73), and more mental health conditions (OR, 4.48; 95% CI, 1.94-10.35) compared with peers in traditional schools. Youth in cyber school were less likely to have recommended vision (OR, 0.34; 95% CI, 0.15-0.75) and dental (OR, 0.33; 95% CI, 0.15-0.75) evaluations. The relationship between hemoglobin A1c and cyber school persisted after adjusting for insurance status, pump use, and mental health conditions (P = .02). Similar trends were observed for participants with type 2 diabetes. CONCLUSIONS: Youth with diabetes in cyber school may be a high-risk population. Understanding the potential impact of cyber school-related factors on health may encourage additional provider/system/school supports for these patients.

The Pathological Evolution of Glucose Response Curves During the Progression to Type 1 Diabetes in the TrialNet Pathway to Prevention Study.

OBJECTIVE: Glucose response curves (GRCs) during oral glucose tolerance tests (OGTTs) are predictive of type 1 diabetes. We performed a longitudinal analysis in pancreatic autoantibody-positive individuals to assess 1) characteristic GRC changes during progression to type 1 diabetes and 2) GRC changes in relation to ß-cell function changes and to combined glucose and C-peptide response curve (GCRC) changes. RESEARCH DESIGN AND METHODS: Among antibody-positive individuals with serial OGTTs in the TrialNet Pathway to Prevention study, GRC changes from first to last OGTTs were compared between progressors (n = 298) to type 1 diabetes and nonprogressors (n = 2,216). GRC changes from last OGTT before diagnosis to diagnostic OGTTs were studied in progressors. RESULTS: GRCs changed more frequently from biphasic (two peaks) to monophasic (one peak) GRCs between first and last OGTTs in progressors than in nonprogressors (75.4% vs. 51.0%, respectively; P < 0.001). In contrast, GRCs of progressors changed less frequently from monophasic to biphasic than those of nonprogressors (12.6% vs. 30.6%; P < 0.001). Monotonic (continuous increase) GRCs were present in 47.7% of progressors at diagnosis. The early (30-0 min) C-peptide response decreased in progressors with GRCs changing from biphasic to monophasic between first and last OGTTs (P < 0.001) and from monophasic to monotonic between last and diagnostic OGTTs (P < 0.001). Conversely, the early C-peptide response increased among nonprogressors with GRCs changing from monophasic to biphasic (P < 0.001). Changes in GRCs were related to changes in GCRCs. CONCLUSIONS: Characteristic GRC changes, biphasic to monophasic to monotonic, occur during the progression to type 1 diabetes. These GRC changes correspond to decreasing ß-cell function.

Modern diabetes devices in the school setting: Perspectives from school nurses.

OBJECTIVE: To explore the experiences, practices, and attitudes of school nurses related to modern diabetes devices (insulin pumps, continuous glucose monitors, and hybrid-closed loop systems). RESEARCH DESIGN AND METHODS: Semistructured interviews were conducted with 40 public school nurses caring for children in elementary and middle schools. Developed with stakeholder input, the interview questions explored experiences working with devices and communicating with the health care system. Deidentified transcripts were analyzed through an iterative process of coding to identify major themes. RESULTS: School nurses reported a range of educational backgrounds (58% undergraduate, 42% graduate), geographic settings (20% urban, 55% suburban, 25% rural), and years of experience (20% <5 years, 38%, 5-15 years, 42% >15 years). Four major themes emerged: (a) As devices become more common, school nurses must quickly develop new knowledge and skills yet have inconsistent training opportunities; (b) Enthusiasm for devices is tempered by concerns about implementation due to poor planning prior to the school year and potential disruptions by remote monitors; (c) Barriers exist to integrating devices into schools, including school/classroom policies, liability/privacy concerns, and variable staff engagement; and (d) Collaboration between school nurses and providers is limited; better communication may benefit children with diabetes. CONCLUSIONS: Devices are increasingly used by school-aged children. School nurses appreciate device potential but share structural and individual-level challenges. Guiding policy is needed as the technology progressively becomes standard of care. Enhanced training and collaboration with diabetes providers may help to optimize school-based management for children in the modern era.

Excess BMI Accelerates Islet Autoimmunity in Older Children and Adolescents.

OBJECTIVE: Sustained excess BMI increases the risk of type 1 diabetes (T1D) in autoantibody-positive relatives without diabetes of patients. We tested whether elevated BMI also accelerates the progression of islet autoimmunity before T1D diagnosis. RESEARCH DESIGN AND METHODS: We studied 706 single autoantibody-positive pediatric TrialNet participants (ages 1.6-18.6 years at baseline). Cumulative excess BMI (ceBMI) was calculated for each participant based on longitudinally accumulated BMI ≥85th age- and sex-adjusted percentile. Recursive partitioning analysis and multivariable modeling defined the age cut point differentiating the risk for progression to multiple positive autoantibodies. RESULTS: At baseline, 175 children (25%) had a BMI ≥85th percentile. ceBMI range was -9.2 to 15.6 kg/m2 (median -1.91), with ceBMI ≥0 kg/m2 corresponding to persistently elevated BMI ≥85th percentile. Younger age increased the progression to multiple autoantibodies, with age cutoff of 9 years defined by recursive partitioning analysis. Although ceBMI was not significantly associated with progression from single to multiple autoantibodies overall, there was an interaction with ceBMI ≥0 kg/m2, age, and HLA (P = 0.009). Among children ≥9 years old without HLA DR3-DQ2 and DR4-DQ8, ceBMI ≥0 kg/m2 increased the rate of progression from single to multiple positive autoantibodies (hazard ratio 7.32, P = 0.004) and conferred a risk similar to that in those with T1D-associated HLA haplotypes. In participants <9 years old, the effect of ceBMI on progression to multiple autoantibodies was not significant regardless of HLA type. CONCLUSIONS: These data support that elevated BMI may exacerbate islet autoimmunity prior to clinical T1D, particularly in children with lower risk based on age and HLA. Interventions to maintain normal BMI may prevent or delay the progression of islet autoimmunity.

Characteristics of slow progression to diabetes in multiple islet autoantibody-positive individuals from five longitudinal cohorts: the SNAIL study.

AIMS/HYPOTHESIS: Multiple islet autoimmunity increases risk of diabetes, but not all individuals positive for two or more islet autoantibodies progress to disease within a decade. Major islet autoantibodies recognise insulin (IAA), GAD (GADA), islet antigen-2 (IA-2A) and zinc transporter 8 (ZnT8A). Here we describe the baseline characteristics of a unique cohort of 'slow progressors' (n = 132) who were positive for multiple islet autoantibodies (IAA, GADA, IA-2A or ZnT8A) but did not progress to diabetes within 10 years. METHODS: Individuals were identified from five studies (BABYDIAB, Germany; Diabetes Autoimmunity Study in the Young [DAISY], USA; All Babies in Southeast Sweden [ABIS], Sweden; Bart's Oxford Family Study [BOX], UK and the Pittsburgh Family Study, USA). Multiple islet autoantibody characteristics were determined using harmonised assays where possible. HLA class II risk was compared between slow progressors and rapid progressors (n = 348 diagnosed <5 years old from BOX) using the χ2 test. RESULTS: In the first available samples with detectable multiple antibodies, the most frequent autoantibodies were GADA (92%), followed by ZnT8A (62%), IAA (59%) and IA-2A (41%). High risk HLA class II genotypes were less frequent in slow (28%) than rapid progressors (42%, p = 0.011), but only two slow progressors carried the protective HLA DQ6 allele. CONCLUSION: No distinguishing characteristics of slow progressors at first detection of multiple antibodies have yet been identified. Continued investigation of these individuals may provide insights into slow progression that will inform future efforts to slow or prevent progression to clinical diabetes.

The influence of body mass index and age on C-peptide at the diagnosis of type 1 diabetes in children who participated in the diabetes prevention trial-type 1.

BACKGROUND/OBJECTIVE: The extent of influence of BMI and age on C-peptide at the diagnosis of type 1 diabetes (T1D) is unknown. We thus studied the impact of body mass index Z-scores (BMIZ) and age on C-peptide measures at and soon after the diagnosis of T1D. METHODS: Data from Diabetes Prevention Trial-Type 1 (DPT-1) participants <18.0 years at diagnosis was analyzed. Analyses examined associations of C-peptide measures with BMIZ and age in 2 cohorts: oral glucose tolerance tests (OGTTs) at diagnosis (n = 99) and mixed meal tolerance tests (MMTTs) <6 months after diagnosis (n = 80). Multivariable linear regression was utilized. RESULTS: Fasting and area under the curve (AUC) C-peptide from OGTTs (n = 99) at diagnosis and MMTTs (n = 80) after diagnosis were positively associated with BMIZ and age (P < .001 for all). Associations persisted when BMIZ and age were included as independent variables in regression models (P < .001 for all). BMIZ and age explained 31%-47% of the variance of C-peptide measures. In an example, 2 individuals with identical AUC C-peptide values had an approximate 5-fold difference in values after adjustments for BMIZ and age. The association between fasting glucose and C-peptide decreased markedly when fasting C-peptide values were adjusted (r = 0.30, P < .01 to r = 0.07, n.s.). CONCLUSIONS: C-peptide measures are strongly and independently related to BMIZ and age at and soon after the diagnosis of T1D. Adjustments for BMIZ and age cause substantial changes in C-peptide values, and impact the association between glycemia and C-peptide. Such adjustments can improve assessments of ß-cell impairment at diagnosis.

Insulin Sensitivity and Diabetic Kidney Disease in Children and Adolescents With Type 2 Diabetes: An Observational Analysis of Data From the TODAY Clinical Trial.

BACKGROUND: Diabetic kidney disease is a major cause of premature mortality in type 2 diabetes mellitus (T2DM). Worsening insulin sensitivity independent of glycemic control may contribute to the development of diabetic kidney disease. We investigated the longitudinal association of insulin sensitivity with hyperfiltration and increased albumin excretion in adolescents with T2DM. STUDY DESIGN: Observational prospective cohort study. SETTING & PARTICIPANTS: 532 TODAY (Treatment Options for Type 2 Diabetes in Adolescents and Youth) participants aged 12 to 17 years with T2DM duration less than 2 years at baseline. The TODAY Study was a multicenter randomized clinical trial that examined the efficacy of 3 treatment regimens (metformin monotherapy, metformin plus rosiglitazone, or metformin plus an intensive lifestyle intervention program) to achieve durable glycemic control. PREDICTORS: Natural log-transformed estimated insulin sensitivity (reciprocal of fasting insulin), hemoglobin A1c concentration, age, race-ethnicity, treatment group, body mass index, loss of glycemic control, and hypertension. OUTCOMES: Hyperfiltration was defined as 99th percentile or higher of estimated glomerular filtration rate (≥140mL/min/1.73m2) when referenced to healthy adolescents (NHANES 1999-2002) and albumin-creatinine ratio ≥ 30µg/mg at 3 consecutive annual visits. RESULTS: Hyperfiltration was observed in 7.0% of participants at baseline and in 13.3% by 5 years, with a cumulative incidence of 5.0% over 5 years. The prevalence of increased albumin excretion was 6% at baseline and 18% by 5 years, with a cumulative incidence of 13.4%. There was an 8% increase in risk for hyperfiltration per 10% lower estimated insulin sensitivity in unadjusted and adjusted models (P=0.01). Increased albumin excretion was associated with hemoglobin A1c concentration, but not estimated insulin sensitivity. LIMITATIONS: Longer follow-up is needed to capture the transition from hyperfiltration to rapid glomerular filtration rate decline in youth-onset T2DM. CONCLUSIONS: Lower estimated insulin sensitivity was associated with risk for hyperfiltration over time, whereas increased albumin excretion was associated with hyperglycemia in youth-onset T2DM.

Adiposity and Asthma in a Nationwide Study of Children and Adults in the United States.

RATIONALE: Although obesity has been associated with asthma, body mass index is suboptimal to fully characterize adiposity. OBJECTIVES: We examined the relation between adiposity and asthma in a large sample of the U.S. population, using indices defined by dual-energy X-ray absorptiometry. METHODS: We analyzed data from 8,886 children (aged 8-19 yr) and 12,795 adults (aged 20-69 yr) from the 2001 to 2006 National Health and Nutrition Examination Survey. In addition to body mass index, percent body fat, waist circumference, and waist-to-height ratio, dual-energy X-ray absorptiometry was used to calculate whole-body and local adiposity indices: fat mass index; total, trunk, and legs percent fat; and trunk-to-total fat mass ratio, legs-to-total fat mass ratio, and trunk-to-legs fat mass ratios. Logistic regression was used for the analysis of adiposity measures and asthma. RESULTS: Among children, general adiposity was significantly associated with asthma, with no major differences by sex. Results were driven by nonatopic children, in whom trunk-predominant (central) adiposity (assessed by waist circumference, waist-to-height ratio, trunk-to-total fat mass ratio, and trunk-to-legs fat mass ratio) was also associated with asthma. There were no significant associations among atopic children. Among adults, all adiposity indices were associated with asthma, with central adiposity significant only among women. The results in adults were driven by atopy, especially in women. CONCLUSIONS: Adiposity measured by dual-energy X-ray absorptiometry provides similar information to that obtained by using anthropometric indices among children of both sexes and among adult men. However, dual-energy X-ray absorptiometry provides additional information in adult women, in whom dual-energy X-ray absorptiometry-measured central adiposity is significantly associated with asthma, particularly atopic asthma.

The shape of the glucose concentration curve during an oral glucose tolerance test predicts risk for type 1 diabetes.

AIMS/HYPOTHESIS: We aimed to examine: (1) whether specific glucose-response curve shapes during OGTTs are predictive of type 1 diabetes development; and (2) the extent to which the glucose-response curve is influenced by insulin secretion. METHODS: Autoantibody-positive relatives of people with type 1 diabetes whose baseline OGTT met the definition of a monophasic or biphasic glucose-response curve were followed for the development of type 1 diabetes (n = 2627). A monophasic curve was defined as an increase in OGTT glucose between 30 and 90 min followed by a decline of ≥ 0.25 mmol/l between 90 and 120 min. A biphasic response curve was defined as a decrease in glucose after an initial increase, followed by a second increase of ≥ 0.25 mmol/l. Associations of type 1 diabetes risk with glucose curve shapes were examined using cumulative incidence curve comparisons and proportional hazards regression. C-peptide responses were compared with and without adjustments for potential confounders. RESULTS: The majority of participants had a monophasic curve at baseline (n = 1732 [66%] vs n = 895 [34%]). The biphasic group had a lower cumulative incidence of type 1 diabetes (p < 0.001), which persisted after adjustments for age, sex, BMI z score and number of autoantibodies (p < 0.001). Among the monophasic group, the risk of type 1 diabetes was greater for those with a glucose peak at 90 min than for those with a peak at 30 min; the difference persisted after adjustments (p < 0.001). Compared with the biphasic group, the monophasic group had a lower early C-peptide (30-0 min) response, a lower C-peptide index (30-0 min C-peptide/30-0 min glucose), as well as a greater 2 h C-peptide level (p < 0.001 for all). CONCLUSIONS/INTERPRETATION: Those with biphasic glucose curves have a lower risk of progression to type 1 diabetes than those with monophasic curves, and the risk among the monophasic group is increased when the glucose peak occurs at 90 min than at 30 min. Differences in glucose curve shapes between the monophasic and biphasic groups appear to be related to C-peptide responses.

The Role of Age and Excess Body Mass Index in Progression to Type 1 Diabetes in At-Risk Adults.

Background: Given the global rise in both type 1 diabetes incidence and obesity, the role of body mass index (BMI) on type 1 diabetes pathophysiology has gained great interest. Sustained excess BMI in pediatric participants of the TrialNet Pathway to Prevention (PTP) cohort increased risk for progression to type 1 diabetes, but the effects of age and obesity in adults remain largely unknown. Objective: To determine the effect of age and sustained obesity on the risk for type 1 diabetes in adult participants in the TrialNet PTP cohort (i.e., nondiabetic autoantibody-positive relatives of patients with type 1 diabetes). Research Design and Methods: Longitudinally accumulated BMI >25 kg/m2 was calculated to generate a cumulative excess BMI (ceBMI) for each participant, with ceBMI values ≥0 kg/m2 and ≥5 kg/m2 representing sustained overweight or obese status, respectively. Recursive partitioning analysis yielded sex- and age-specific thresholds for ceBMI that confer the greatest risk for type 1 diabetes progression. Results: In this cohort of 665 adults (age 20 to 50 years; median follow-up, 3.9 years), 49 participants developed type 1 diabetes. Age was an independent protective factor for type 1 diabetes progression (hazard ratio, 0.95; P = 0.008), with a threshold of >35 years that reduced risk for type 1 diabetes. In men age >35 years and women age <35 years, sustained obesity (ceBMI ≥5 kg/m2) increased the risk for type 1 diabetes. Conclusions: Age is an important factor for type 1 diabetes progression in adults and influences the impact of elevated BMI, indicating an interplay of excess weight, age, and sex in adult type 1 diabetes pathophysiology.

Excess BMI in Childhood: A Modifiable Risk Factor for Type 1 Diabetes Development?

OBJECTIVE: We aimed to determine the effect of elevated BMI over time on the progression to type 1 diabetes in youth. RESEARCH DESIGN AND METHODS: We studied 1,117 children in the TrialNet Pathway to Prevention cohort (autoantibody-positive relatives of patients with type 1 diabetes). Longitudinally accumulated BMI above the 85th age- and sex-adjusted percentile generated a cumulative excess BMI (ceBMI) index. Recursive partitioning and multivariate analyses yielded sex- and age-specific ceBMI thresholds for greatest type 1 diabetes risk. RESULTS: Higher ceBMI conferred significantly greater risk of progressing to type 1 diabetes. The increased diabetes risk occurred at lower ceBMI values in children <12 years of age compared with older subjects and in females versus males. CONCLUSIONS: Elevated BMI is associated with increased risk of diabetes progression in pediatric autoantibody-positive relatives, but the effect varies by sex and age.