Second international consensus report on gaps and opportunities for the clinical translation of precision diabetes medicine.

Precision medicine is part of the logical evolution of contemporary evidence-based medicine that seeks to reduce errors and optimize outcomes when making medical decisions and health recommendations. Diabetes affects hundreds of millions of people worldwide, many of whom will develop life-threatening complications and die prematurely. Precision medicine can potentially address this enormous problem by accounting for heterogeneity in the etiology, clinical presentation and pathogenesis of common forms of diabetes and risks of complications. This second international consensus report on precision diabetes medicine summarizes the findings from a systematic evidence review across the key pillars of precision medicine (prevention, diagnosis, treatment, prognosis) in four recognized forms of diabetes (monogenic, gestational, type 1, type 2). These reviews address key questions about the translation of precision medicine research into practice. Although not complete, owing to the vast literature on this topic, they revealed opportunities for the immediate or near-term clinical implementation of precision diabetes medicine; furthermore, we expose important gaps in knowledge, focusing on the need to obtain new clinically relevant evidence. Gaps include the need for common standards for clinical readiness, including consideration of cost-effectiveness, health equity, predictive accuracy, liability and accessibility. Key milestones are outlined for the broad clinical implementation of precision diabetes medicine.

Precision gestational diabetes treatment: a systematic review and meta-analyses.

BACKGROUND: Gestational Diabetes Mellitus (GDM) affects approximately 1 in 7 pregnancies globally. It is associated with short- and long-term risks for both mother and baby. Therefore, optimizing treatment to effectively treat the condition has wide-ranging beneficial effects. However, despite the known heterogeneity in GDM, treatment guidelines and approaches are generally standardized. We hypothesized that a precision medicine approach could be a tool for risk-stratification of women to streamline successful GDM management. With the relatively short timeframe available to treat GDM, commencing effective therapy earlier, with more rapid normalization of hyperglycaemia, could have benefits for both mother and fetus. METHODS: We conducted two systematic reviews, to identify precision markers that may predict effective lifestyle and pharmacological interventions. RESULTS: There was a paucity of studies examining precision lifestyle-based interventions for GDM highlighting the pressing need for further research in this area. We found a number of precision markers identified from routine clinical measures that may enable earlier identification of those requiring escalation of pharmacological therapy (to metformin, sulphonylureas or insulin). This included previous history of GDM, Body Mass Index and blood glucose concentrations at diagnosis. CONCLUSIONS: Clinical measurements at diagnosis could potentially be used as precision markers in the treatment of GDM. Whether there are other sensitive markers that could be identified using more complex individual-level data, such as omics, and if these can feasibly be implemented in clinical practice remains unknown. These will be important to consider in future studies.

Gestational diabetes (GDM) is high blood sugar first detected during pregnancy. Normalizing blood sugar levels quickly is important to avoid pregnancy complications. Many women achieve this with lifestyle changes, such as to diet, but some need to inject insulin or take tablets. We did two thorough reviews of existing research to see if we could predict which women need medication. Firstly we looked for ways to identify the characteristics of women who benefit most from changing their lifestyles to treat GDM, but found very limited research on this topic. We secondly searched for characteristics that help identify women who need medication to treat GDM. We found some useful characteristics that are obtained during routine pregnancy care. Further studies are needed to test if additional information could provide even better information about how we could make GDM treatment more tailored for individuals during pregnancy.

Non-severe hypoglycemia in type 1 diabetes: a randomized crossover trial comparing two quantities of oral carbohydrates at different insulin-induced hypoglycemia ranges.

Aims: Non-severe hypoglycemia (NS-H) is challenging for people living with type 1 diabetes (PWT1D) and often results from relative iatrogenic hyper-insulinemia. Current guidelines recommend a one-size-fits-all approach of 15-20 g of simple carbohydrates (CHO) every 15 min regardless of the triggering conditions of the NS-H event. We aimed to test different amounts of CHO to treat insulin-induced NS-H at various glucose ranges. Methods: This is a randomized, four-way, crossover study involving PWT1D, testing NS-H treatment outcomes with 16 g vs. 32 g CHO at two plasma glucose (PG) ranges: A: 3.0-3.5 mmol/L and B: <3.0 mmol/L. Across all study arms, participants consumed an additional 16 g of CHO if PG was still <3.0 mmol/L at 15 min and <4.0 mmol/L at 45 min post-initial treatment. Subcutaneous insulin was used in a fasting state to induce NS-H. Participants had frequent venous sampling of PG, insulin, and glucagon levels. Results: Participants (n = 32; 56% female participants) had a mean (SD) age of 46.1 (17.1) years, had HbA1c at 54.0 (6.8 mmol/mol) [7.1% (0.9%)], and had a diabetes duration of 27.5 (17.0) years; 56% were insulin pump users. We compared NS-H correction parameters between 16 g and 32 g of CHO for range A, 3.0-3.5 mmol/L (n = 32), and range B, <3.0 mmol/L (n = 29). Change in PG at 15 min for A: 0.1 (0.8) mmol/L vs. 0.6 (0.9) mmol/L, p = 0.02; and for B: 0.8 (0.9) mmol/L vs. 0.8 (1.0) mmol/L, p = 1.0. Percentage of participants with corrected episodes at 15 min: (A) 19% vs. 47%, p = 0.09; (B) 21% vs. 24%, p = 1.0. A second treatment was necessary in (A) 50% vs. 15% of participants, p = 0.001; (B) 45% vs. 34% of participants, p = 0.37. No statistically significant differences in insulin and glucagon parameters were observed. Conclusions: NS-H, in the context of hyper-insulinemia, is difficult to treat in PWT1D. Initial consumption of 32 g of CHO revealed some advantages at the 3.0-3.5 mmol/L range. This was not reproduced at lower PG ranges since participants needed additional CHO regardless of the amount of initial consumption. Clinical trial registration: ClinicalTrials.gov, identifier NCT03489967.

Are Complementary Feeding Practices Aligned with Current Recommendations? A Narrative Review.

The complementary feeding introduction period (introduction of solid foods alongside breastmilk or formula) is defining in children's health; however, it appears that many parents do not follow complementary feeding guidelines. Our aim was to describe current parental feeding practices during complementary feeding in relation to current recommendations and explore determinants of adherence to guidelines. We included any relevant studies published within the last decade in French or English and summarized findings by recommendation category. The timing of complementary food introduction varied widely across and within continents (earlier in North America and often delayed in Asia). The introduction of allergenic foods tended to be delayed globally. Although some parents now begin complementary feeding with solid foods (i.e., baby-led weaning), delayed introduction of lumpy textures was still prevalent in the United States and in Europe. The consumption of iron-rich foods was predominantly low in Africa. Added sugars were globally introduced early, especially in America. Evidence for the prevalence of responsive feeding practices among parents is unclear due to the small number of studies. Determinants of complementary feeding practices included parental characteristics, such as age, education, socio-economic status, and race/ethnicity. Interventions aiming to increase adherence to complementary feeding guidelines must account for parental characteristics.

Factors Associated with Eating in the Absence of Hunger among Children and Adolescents: A Systematic Review.

Eating in the absence of hunger (EAH) has been extensively studied over the past two decades and has been associated with excess body weight and the development of obesity. However, determinants of EAH remain uncertain. This systematic review aims to identify individual, familial, and environmental factors associated with EAH among children and adolescents. We included studies with a measure of EAH in participants aged 3-17 years old and including ≥1 factor associated with EAH. Our search identified 1494 articles. Of these, we included 81 studies: 53 cross-sectional, 19 longitudinal and nine intervention studies. In childhood (≤12 years old), EAH increases with age, it is greater in boys compared to girls, and it is positively associated with adiposity. Moreover, EAH development seems to be influenced by genetics. In adolescence, the number of studies is limited; yet, studies show that EAH slightly increases or remains stable with age, is not clearly different between sexes, and findings for overweight or obesity are less consistent across studies in adolescence. For familial factors, parental restrictive feeding practices are positively associated with EAH during childhood, mostly for girls. Studies assessing environmental factors are lacking and robust longitudinal studies spanning from early childhood to adolescence are needed.

Estimated causal effects of complementary feeding behaviors on early childhood diet quality in a US cohort.

BACKGROUND: Complementary feeding (CF) provides an opportunity to shape children's future dietary habits, setting the foundation for good nutrition and health. OBJECTIVES: We estimated effects of 3 CF behaviors on early childhood diet quality using inverse probability (IP) weighting of marginal structural models (MSMs). METHODS: Among 1041 children from the Boston-area Project Viva cohort, we estimated effects on the mean Youth Healthy Eating Index (YHEI) score in early childhood of 1) delayed (≥12 mo) compared with early (<12 mo) introduction of sweets and fruit juice; 2) continued compared with ceased offering of initially refused foods; and 3) early (<12 mo) compared with late (≥12 mo) introduction of flavor/texture variety. Mothers reported CF behaviors at 1 y and completed FFQs for children in early childhood (median age: 3.1 y). We estimated average treatment effects (ATEs) using IP weighting of MSMs to adjust for both confounding and selection bias due to censored outcomes and examined effect modification by child sex and breastfeeding compared with formula feeding at 6 mo. RESULTS: Twelve percent of mothers delayed introducing sweets/fruit juice, 93% continued offering initially refused foods, and 32% introduced flavor/texture variety early. The mean ± SD YHEI score was 52.8 ± 9.2 points. In adjusted models, we estimated a higher mean YHEI score with delayed (compared with early) sweets and fruit juice among breastfeeding children (ATE: 4.5 points; 95% CI: 1.0, 7.4 points), as well as with continued (compared with ceased) offering of refused foods among females (ATE: 5.4 points; 95% CI: 0.8, 9.1 points). The ATE for early (compared with late) flavor/texture variety was 1.7 points (95% CI: 0.3, 3.2 points) overall and stronger (2.8 points; 95% CI: 0.7, 5.1 points) among the formula-fed group. CONCLUSIONS: Delayed introduction of sweets/juice, continued offering of refused foods, and early flavor/texture variety may all result in higher childhood diet quality. Effects may depend on child sex and infant breastfeeding status.

Associations of Early Parental Concerns and Feeding Behaviors with Child's Diet Quality through Mid-Childhood.

Parental feeding practices have been associated with children's dietary intakes, yet the directionality of these associations remains unclear. Among 1172 mother-child pairs from Project Viva, we aimed to examine associations of parental concerns and feeding behaviors at 2 years (behaviors dichotomized as yes vs. no), with diet quality (Youth Healthy Eating Index; YHEI) in early (mean 3.2, SD 0.3 years; n = 1076) and mid-childhood (mean 7.8, SD 0.7 years; n = 993). We used multivariable linear regression models adjusted for sociodemographic characteristics, parental body mass index (BMI), maternal diet quality in pregnancy, and child's BMI z-score and diet quality at 2 years. Early parental concerns about their child becoming overweight (15%) was associated with lower YHEI (ß -1.54 points; 95%CI -2.75, -0.33; fully adjusted model) in early childhood. Early parental concerns about their child becoming underweight (7%) was associated with lower YHEI (-2.19 points; -4.31, -0.07) in early childhood, but the association was attenuated after adjustment for child's BMI z-score and diet quality at 2 years. We did not find associations of parental restrictive feeding (8%) and parental pressure to eat (47%) with child's YHEI through mid-childhood. In conclusion, we found no evidence that early parental concerns and feeding behaviors independently contribute to child's diet quality through childhood.

Early life exposure to green space and insulin resistance: An assessment from infancy to early adolescence.

BACKGROUND: Recent studies suggest that greater exposure to natural vegetation, or "green space" is associated with lower diabetes risk, possibly through increasing physical activity. However, there is limited research on green space and insulin resistance in youth. We hypothesized greater green space at early-life sensitive time periods would be associated with lower insulin resistance in youth. METHODS: We used data from Project Viva (N = 460), a pre-birth cohort study that recruited pregnant women in eastern Massachusetts, 1999-2002, and followed offspring into adolescence. We defined residential green space exposure at infancy (median age - 1.1 years), early childhood (3.2 years), mid-childhood (7.7 years), and early adolescence (12.8 years), using 30 m resolution Landsat satellite imagery to estimate the Normalized Difference Vegetation Index [NDVI]. Our main outcome was early adolescence estimated insulin resistance (HOMA-IR). We used multiple imputation to account for missing data and multiple linear regression models adjusted for age, sex, race/ethnicity, parental education, household income, and neighborhood median household income. RESULTS: The highest green space tertile had the highest percentage of white participants (85%), college-educated mothers (87%) and fathers (85%), and households with income higher than US$70,000 (86%). Unadjusted models showed that participants living in the highest green space tertile at infancy had a 0.15 unit lower HOMA-IR (95% CI: -0.23, -0.06) in early adolescence, than those living in the lowest tertile. However, in adjusted models, we did not observe evidence of associations between green space from infancy to early adolescence and HOMA-IR in early adolescence, although some point estimates were in the hypothesized direction. For example, participants in the highest green space tertile in infancy had 0.03 units lower HOMA-IR (95%CI: -0.14, 0.08) than those living in the lowest tertile. CONCLUSIONS: Exposure to green space at early life sensitive time periods was not associated with HOMA-IR in youth. Early-life longitudinal studies across diverse populations are needed to confirm or refute our results.