Re-analysis and meta-analysis of summary statistics from gene-environment interaction studies.

MOTIVATION: statistics from genome-wide association studies enable many valuable downstream analyses that are more efficient than individual-level data analysis while also reducing privacy concerns. As growing sample sizes enable better-powered analysis of gene-environment interactions, there is a need for gene-environment interaction-specific methods that manipulate and use summary statistics. RESULTS: We introduce two tools to facilitate such analysis, with a focus on statistical models containing multiple gene-exposure and/or gene-covariate interaction terms. REGEM (RE-analysis of GEM summary statistics) uses summary statistics from a single, multi-exposure genome-wide interaction study to derive analogous sets of summary statistics with arbitrary sets of exposures and interaction covariate adjustments. METAGEM (META-analysis of GEM summary statistics) extends current fixed-effects meta-analysis models to incorporate multiple exposures from multiple studies. We demonstrate the value and efficiency of these tools by exploring alternative methods of accounting for ancestry-related population stratification in genome-wide interaction study in the UK Biobank as well as by conducting a multi-exposure genome-wide interaction study meta-analysis in cohorts from the diabetes-focused ProDiGY consortium. These programs help to maximize the value of summary statistics from diverse and complex gene-environment interaction studies. AVAILABILITY AND IMPLEMENTATION: REGEM and METAGEM are open-source projects freely available at https://github.com/large-scale-gxe-methods/REGEM and https://github.com/large-scale-gxe-methods/METAGEM.

A comparison of two hybrid closed-loop systems in adolescents and young adults with type 1 diabetes (FLAIR): a multicentre, randomised, crossover trial.

BACKGROUND: Management of type 1 diabetes is challenging. We compared outcomes using a commercially available hybrid closed-loop system versus a new investigational system with features potentially useful for adolescents and young adults with type 1 diabetes. METHODS: In this multinational, randomised, crossover trial (Fuzzy Logic Automated Insulin Regulation [FLAIR]), individuals aged 14-29 years old, with a clinical diagnosis of type 1 diabetes with a duration of at least 1 year, using either an insulin pump or multiple daily insulin injections, and glycated haemoglobin (HbA1c) levels of 7·0-11·0% (53-97 mmol/mol) were recruited from seven academic-based endocrinology practices, four in the USA, and one each in Germany, Israel, and Slovenia. After a run-in period to teach participants how to use the study pump and continuous glucose monitor, participants were randomly assigned (1:1) using a computer-generated sequence, with a permuted block design (block sizes of two and four), stratified by baseline HbA1c and use of a personal MiniMed 670G system (Medtronic) at enrolment, to either use of a MiniMed 670G hybrid closed-loop system (670G) or the investigational advanced hybrid closed-loop system (Medtronic) for the first 12-week period, and then participants were crossed over with no washout period, to the other group for use for another 12 weeks. Masking was not possible due to the nature of the systems used. The coprimary outcomes, measured with continuous glucose monitoring, were proportion of time that glucose levels were above 180 mg/dL (>10·0 mmol/L) during 0600 h to 2359 h (ie, daytime), tested for superiority, and proportion of time that glucose levels were below 54 mg/dL (<3·0 mmol/L) calculated over a full 24-h period, tested for non-inferiority (non-inferiority margin 2%). Analysis was by intention to treat. Safety was assessed in all participants randomly assigned to treatment. This trial is registered with ClinicalTrials.gov, NCT03040414, and is now complete. FINDINGS: Between June 3 and Aug 22, 2019, 113 individuals were enrolled into the trial. Mean age was 19 years (SD 4) and 70 (62%) of 113 participants were female. Mean proportion of time with daytime glucose levels above 180 mg/dL (>10·0 mmol/L) was 42% (SD 13) at baseline, 37% (9) during use of the 670G system, and 34% (9) during use of the advanced hybrid closed-loop system (mean difference [advanced hybrid closed-loop system minus 670G system] -3·00% [95% CI -3·97 to -2·04]; p<0·0001). Mean 24-h proportion of time with glucose levels below 54 mg/dL (<3·0 mmol/L) was 0·46% (SD 0·42) at baseline, 0·50% (0·35) during use of the 670G system, and 0·46% (0·33) during use of the advanced hybrid closed-loop system (mean difference [advanced hybrid closed-loop system minus 670G system] -0·06% [95% CI -0·11 to -0·02]; p<0·0001 for non-inferiority). One severe hypoglycaemic event occurred in the advanced hybrid closed-loop system group, determined to be unrelated to study treatment, and none occurred in the 670G group. INTERPRETATION: Hyperglycaemia was reduced without increasing hypoglycaemia in adolescents and young adults with type 1 diabetes using the investigational advanced hybrid closed-loop system compared with the commercially available MiniMed 670G system. Testing an advanced hybrid closed-loop system in populations that are underserved due to socioeconomic factors and testing during pregnancy and in individuals with impaired awareness of hypoglycaemia would advance the effective use of this technology FUNDING: National Institute of Diabetes and Digestive and Kidney Diseases.

Six-Month Randomized, Multicenter Trial of Closed-Loop Control in Type 1 Diabetes.

BACKGROUND: Closed-loop systems that automate insulin delivery may improve glycemic outcomes in patients with type 1 diabetes. METHODS: In this 6-month randomized, multicenter trial, patients with type 1 diabetes were assigned in a 2:1 ratio to receive treatment with a closed-loop system (closed-loop group) or a sensor-augmented pump (control group). The primary outcome was the percentage of time that the blood glucose level was within the target range of 70 to 180 mg per deciliter (3.9 to 10.0 mmol per liter), as measured by continuous glucose monitoring. RESULTS: A total of 168 patients underwent randomization; 112 were assigned to the closed-loop group, and 56 were assigned to the control group. The age range of the patients was 14 to 71 years, and the glycated hemoglobin level ranged from 5.4 to 10.6%. All 168 patients completed the trial. The mean (±SD) percentage of time that the glucose level was within the target range increased in the closed-loop group from 61±17% at baseline to 71±12% during the 6 months and remained unchanged at 59±14% in the control group (mean adjusted difference, 11 percentage points; 95% confidence interval [CI], 9 to 14; P<0.001). The results with regard to the main secondary outcomes (percentage of time that the glucose level was >180 mg per deciliter, mean glucose level, glycated hemoglobin level, and percentage of time that the glucose level was <70 mg per deciliter or <54 mg per deciliter [3.0 mmol per liter]) all met the prespecified hierarchical criterion for significance, favoring the closed-loop system. The mean difference (closed loop minus control) in the percentage of time that the blood glucose level was lower than 70 mg per deciliter was -0.88 percentage points (95% CI, -1.19 to -0.57; P<0.001). The mean adjusted difference in glycated hemoglobin level after 6 months was -0.33 percentage points (95% CI, -0.53 to -0.13; P = 0.001). In the closed-loop group, the median percentage of time that the system was in closed-loop mode was 90% over 6 months. No serious hypoglycemic events occurred in either group; one episode of diabetic ketoacidosis occurred in the closed-loop group. CONCLUSIONS: In this 6-month trial involving patients with type 1 diabetes, the use of a closed-loop system was associated with a greater percentage of time spent in a target glycemic range than the use of a sensor-augmented insulin pump. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases; iDCL ClinicalTrials.gov number, NCT03563313.).

Youth with type 2 diabetes have a high rate of treatment failure after discontinuation of insulin: A Pediatric Diabetes Consortium study.

Insulin is commonly used to reverse gluco-toxicity in youth with newly diagnosed type 2 diabetes (T2D), but many are subsequently weaned off insulin. We analyzed Pediatric Diabetes Consortium (PDC) data to determine how long glycemic control is maintained after termination of initial insulin treatment. Youth with T2D who had previously been on insulin but were on either an intensive lifestyle intervention alone or metformin alone upon enrollment in the PDC T2D Registry were studied (N = 183). The primary outcome was time to treatment failure, defined by need to restart insulin or metformin or another diabetes medication. Data were analyzed using logistic regression to assess risk factors for treatment failure. Of the 183 participants studied (mean age 15 years, diabetes duration 1.7 years), 54% experienced treatment failure (median follow-up time 1.7 years). In the subgroup on metformin monotherapy (N = 140), 45% subsequently required restart of insulin. Moreover, of participants in the subgroup treated with an intensive lifestyle intervention alone (N = 43), 81% restarted insulin or were treated with metformin or other diabetes medication. In both groups, median time to treatment failure was 1.2 years. Higher HbA1c at enrollment was significantly associated with treatment failure (p < 0.001). Youth with T2D who are initially treated with insulin have a high rate of treatment failure when switched to intensive lifestyle alone or metformin alone. Our data highlight the severe and progressive nature of youth onset T2D, hence patients should be monitored closely for deteriorating glycemic control after being weaned off insulin.

Evaluation of the longitudinal change in health behavior profiles across treatment groups in the TODAY clinical trial.

BACKGROUND: Individual health behaviors (ie, eating habits and sedentary lifestyle) are associated with type 2 diabetes (T2D). Health behavior profiles specific to adolescents with T2D have not been described. OBJECTIVE: To identify health behavior profiles in adolescents with T2D and examine how these profiles change over time. METHODS: Diet (via food frequency questionnaire) and activity behaviors (via 3-day physical activity recall) examined at baseline, 6 months, and 24 months from participants in the the Treatment Options for T2D in Adolescents and Youth (TODAY) study were used for this analysis. Latent profile analysis identified profiles of health behaviors within three time points, and latent transition probabilities were estimated to examine the change from baseline to 6 months (n = 450) and baseline to 24 months (n = 415). Multinomial logistic regressions were used to examine if the assigned TODAY treatment group (Metformin [Met], Met + Rosiglitazone [Rosi], or Met + Lifestyle) predicted change in health behavior profiles. RESULTS: Three profiles emerged: "most sedentary," "healthy eaters," and "active and eat most." At 6 months, 50% of males and 29% of females in the Met + Lifestyle treatment group improved in their health behavior profile. Among males only, the Met + Lifestyle treatment group were more likely to improve their profiles from baseline to 6 months (P = .01). CONCLUSIONS: Three health behavior profiles emerged and shifted over time. A high quality, lifestyle intervention had little effect on improving health behavior profiles. Optimizing outcomes in youth with T2D might require more robust and multifaceted interventions beyond family-level lifestyle, including more extensive psychosocial intervention, novel medication regimen, or bariatric surgery.

Developmental Programming of Body Composition: Update on Evidence and Mechanisms.

PURPOSE OF REVIEW: A growing body of epidemiological and experimental data indicate that nutritional or environmental stressors during early development can induce long-term adaptations that increase risk of obesity, diabetes, cardiovascular disease, and other chronic conditions-a phenomenon termed "developmental programming." A common phenotype in humans and animal models is altered body composition, with reduced muscle and bone mass, and increased fat mass. In this review, we summarize the recent literature linking prenatal factors to future body composition and explore contributing mechanisms. RECENT FINDINGS: Many prenatal exposures, including intrauterine growth restriction, extremes of birth weight, maternal obesity, and maternal diabetes, are associated with increased fat mass, reduced muscle mass, and decreased bone density, with effects reported throughout infancy and childhood, and persisting into middle age. Mechanisms and mediators include maternal diet, breastmilk composition, metabolites, appetite regulation, genetic and epigenetic influences, stem cell commitment and function, and mitochondrial metabolism. Differences in body composition are a common phenotype following disruptions to the prenatal environment, and may contribute to developmental programming of obesity and diabetes risk.

Factitious hypoglycemia in children and adolescents with diabetes.

BACKGROUND: Factitious hypoglycemia is a condition of self-induced hypoglycemia due to surreptitious administration of insulin or oral hypoglycemic agents. In adults, it is an uncommon, but well known clinical entity observed in individuals with and without diabetes. OBJECTIVES: To report a case of factitious hypoglycemia highlighting diagnostic pitfalls, to identify common characteristics of children and adolescents with factitious hypoglycemia, and to examine whether the information on long-term outcome exists. METHODS: We present a case of an adolescent with type 1 diabetes who had self-induced hypoglycemia of several years' duration; and we conducted a systematic literature review on factitious hypoglycemia in pediatric patients with diabetes. RESULTS: We identified a total of 83 articles of which 14 met the inclusion criteria (describing 39 cases). All but 1 individual had type 1 diabetes and the majority was female (63%). Average age was 13.5 ± 2.0 years with the youngest patient presenting at the age 9.5 years. Blood glucose control was poor (hemoglobin A1c: 12.1 ± 4.0%). In 35%, psychiatric disorders were mentioned as contributing factors. Only 3 reports provided follow-up beyond 6 months. CONCLUSIONS: Factitious hypoglycemia typically occurs in adolescents with type 1 diabetes who use insulin to induce hypoglycemia. Awareness of this differential diagnosis and knowledge of potentially misleading laboratory results may facilitate earlier recognition and intervention. Little information exists on effective treatments and long-term outcome.

What Have Metabolomics Approaches Taught Us About Type 2 Diabetes?

Type 2 diabetes (T2D) is increasing worldwide, making identification of biomarkers for detection, staging, and effective prevention strategies an especially critical scientific and medical goal. Fortunately, advances in metabolomics techniques, together with improvements in bioinformatics and mathematical modeling approaches, have provided the scientific community with new tools to describe the T2D metabolome. The metabolomics signatures associated with T2D and obesity include increased levels of lactate, glycolytic intermediates, branched-chain and aromatic amino acids, and long-chain fatty acids. Conversely, tricarboxylic acid cycle intermediates, betaine, and other metabolites decrease. Future studies will be required to fully integrate these and other findings into our understanding of diabetes pathophysiology and to identify biomarkers of disease risk, stage, and responsiveness to specific treatments.

An unbiased assessment of the role of imprinted genes in an intergenerational model of developmental programming.

Environmental factors during early life are critical for the later metabolic health of the individual and of future progeny. In our obesogenic environment, it is of great socioeconomic importance to investigate the mechanisms that contribute to the risk of metabolic ill health. Imprinted genes, a class of functionally mono-allelic genes critical for early growth and metabolic axis development, have been proposed to be uniquely susceptible to environmental change. Furthermore, it has also been suggested that perturbation of the epigenetic reprogramming of imprinting control regions (ICRs) may play a role in phenotypic heritability following early life insults. Alternatively, the presence of multiple layers of epigenetic regulation may in fact protect imprinted genes from such perturbation. Unbiased investigation of these alternative hypotheses requires assessment of imprinted gene expression in the context of the response of the whole transcriptome to environmental assault. We therefore analyse the role of imprinted genes in multiple tissues in two affected generations of an established murine model of the developmental origins of health and disease using microarrays and quantitative RT-PCR. We demonstrate that, despite the functional mono-allelicism of imprinted genes and their unique mechanisms of epigenetic dosage control, imprinted genes as a class are neither more susceptible nor protected from expression perturbation induced by maternal undernutrition in either the F1 or the F2 generation compared to other genes. Nor do we find any evidence that the epigenetic reprogramming of ICRs in the germline is susceptible to nutritional restriction. However, we propose that those imprinted genes that are affected may play important roles in the foetal response to undernutrition and potentially its long-term sequelae. We suggest that recently described instances of dosage regulation by relaxation of imprinting are rare and likely to be highly regulated.