Maternal dysglycaemia, changes in the infant's epigenome modified with a diet and physical activity intervention in pregnancy: Secondary analysis of a randomised control trial.
PLoS medicine. 2020;17(11):e1003229
Plain language summary
Diabetes and raised blood sugar levels that develop during pregnancy are associated with poor health outcomes in the offspring, increasing their future risk for disorders such as obesity. It is believed that this is due to the mothers raised blood sugar levels modifying genes during gestation, however previous evidence is mainly observational, highlighting a need for substantial trials. This secondary analysis of a randomised control trial of 557 women with obesity aimed to identify genetic modifications in infants and assess whether lifestyle interventions targeted at levelling blood sugars in the mother would change these. The results showed that diabetes and raised blood sugar during pregnancy was associated with genetic modifications in offspring and these were reduced with diet and physical activity during the second trimester. It was concluded that diabetes and raised blood sugar during pregnancy alters the genes of the offspring and lifestyle interventions in the second trimester could improve the health outcomes of future generations. This study could be used by health professionals to understand the importance of introducing diet and exercise in the second trimester to improve the health of mothers and their unborn children.
BACKGROUND Higher maternal plasma glucose (PG) concentrations, even below gestational diabetes mellitus (GDM) thresholds, are associated with adverse offspring outcomes, with DNA methylation proposed as a mediating mechanism. Here, we examined the relationships between maternal dysglycaemia at 24 to 28 weeks' gestation and DNA methylation in neonates and whether a dietary and physical activity intervention in pregnant women with obesity modified the methylation signatures associated with maternal dysglycaemia. METHODS AND FINDINGS We investigated 557 women, recruited between 2009 and 2014 from the UK Pregnancies Better Eating and Activity Trial (UPBEAT), a randomised controlled trial (RCT), of a lifestyle intervention (low glycaemic index (GI) diet plus physical activity) in pregnant women with obesity (294 contol, 263 intervention). Between 27 and 28 weeks of pregnancy, participants had an oral glucose (75 g) tolerance test (OGTT), and GDM diagnosis was based on diagnostic criteria recommended by the International Association of Diabetes and Pregnancy Study Groups (IADPSG), with 159 women having a diagnosis of GDM. Cord blood DNA samples from the infants were interrogated for genome-wide DNA methylation levels using the Infinium Human MethylationEPIC BeadChip array. Robust regression was carried out, adjusting for maternal age, smoking, parity, ethnicity, neonate sex, and predicted cell-type composition. Maternal GDM, fasting glucose, 1-h, and 2-h glucose concentrations following an OGTT were associated with 242, 1, 592, and 17 differentially methylated cytosine-phosphate-guanine (dmCpG) sites (false discovery rate (FDR) ≤ 0.05), respectively, in the infant's cord blood DNA. The most significantly GDM-associated CpG was cg03566881 located within the leucine-rich repeat-containing G-protein coupled receptor 6 (LGR6) (FDR = 0.0002). Moreover, we show that the GDM and 1-h glucose-associated methylation signatures in the cord blood of the infant appeared to be attenuated by the dietary and physical activity intervention during pregnancy; in the intervention arm, there were no GDM and two 1-h glucose-associated dmCpGs, whereas in the standard care arm, there were 41 GDM and 160 1-h glucose-associated dmCpGs. A total of 87% of the GDM and 77% of the 1-h glucose-associated dmCpGs had smaller effect sizes in the intervention compared to the standard care arm; the adjusted r2 for the association of LGR6 cg03566881 with GDM was 0.317 (95% confidence interval (CI) 0.012, 0.022) in the standard care and 0.240 (95% CI 0.001, 0.015) in the intervention arm. Limitations included measurement of DNA methylation in cord blood, where the functional significance of such changes are unclear, and because of the strong collinearity between treatment modality and severity of hyperglycaemia, we cannot exclude that treatment-related differences are potential confounders. CONCLUSIONS Maternal dysglycaemia was associated with significant changes in the epigenome of the infants. Moreover, we found that the epigenetic impact of a dysglycaemic prenatal maternal environment appeared to be modified by a lifestyle intervention in pregnancy. Further research will be needed to investigate possible medical implications of the findings. TRIAL REGISTRATION ISRCTN89971375.
Systematic review of the prospective association of daily step counts with risk of mortality, cardiovascular disease, and dysglycemia.
The international journal of behavioral nutrition and physical activity. 2020;17(1):78
Plain language summary
The health benefits of physical activity for people of all ages, fitness levels, and sociodemographic backgrounds are well-documented. The main aim of this study was to provide an updated description of the association between daily step counts and subsequent cardiovascular disease (CVD) morbidity or mortality, dysglycaemia, and all-cause mortality in adults and the patterns of these associations. This study is a systemic review of 17 studies from 13 different cohorts. Participants’ mean age ranged from 49.7 to 78.9 years with samples comprised of 46.9% female participants on average. Results showed that increasing steps per day is beneficial for health: taking more steps per day was associated with lower risk of all-cause mortality, and lower risk of CVD morbidity or mortality. These associations appear to hold across age, gender, and weight status. Authors conclude that this additional evidence will help guide meaningful volume targets that can be used for health care, education, and behavioural interventions, and potentially inform the development of public health guidelines for steps and health.
BACKGROUND Daily step counts is an intuitive metric that has demonstrated success in motivating physical activity in adults and may hold potential for future public health physical activity recommendations. This review seeks to clarify the pattern of the associations between daily steps and subsequent all-cause mortality, cardiovascular disease (CVD) morbidity and mortality, and dysglycemia, as well as the number of daily steps needed for health outcomes. METHODS A systematic review was conducted to identify prospective studies assessing daily step count measured by pedometer or accelerometer and their associations with all-cause mortality, CVD morbidity or mortality, and dysglycemia (dysglycemia or diabetes incidence, insulin sensitivity, fasting glucose, HbA1c). The search was performed across the Medline, Embase, CINAHL, and the Cochrane Library databases from inception to August 1, 2019. Eligibility criteria included longitudinal design with health outcomes assessed at baseline and subsequent timepoints; defining steps per day as the exposure; reporting all-cause mortality, CVD morbidity or mortality, and/or dysglycemia outcomes; adults ≥18 years old; and non-patient populations. RESULTS Seventeen prospective studies involving over 30,000 adults were identified. Five studies reported on all-cause mortality (follow-up time 4-10 years), four on cardiovascular risk or events (6 months to 6 years), and eight on dysglycemia outcomes (3 months to 5 years). For each 1000 daily step count increase at baseline, risk reductions in all-cause mortality (6-36%) and CVD (5-21%) at follow-up were estimated across a subsample of included studies. There was no evidence of significant interaction by age, sex, health conditions or behaviors (e.g., alcohol use, smoking status, diet) among studies that tested for interactions. Studies examining dysglycemia outcomes report inconsistent findings, partially due to heterogeneity across studies of glycemia-related biomarker outcomes, analytic approaches, and sample characteristics. CONCLUSIONS Evidence from longitudinal data consistently demonstrated that walking an additional 1000 steps per day can help lower the risk of all-cause mortality, and CVD morbidity and mortality in adults, and that health benefits are present below 10,000 steps per day. However, the shape of the dose-response relation is not yet clear. Data are currently lacking to identify a specific minimum threshold of daily step counts needed to obtain overall health benefit.
Dietary Glycemic Index and Load and the Risk of Type 2 Diabetes: Assessment of Causal Relations.
Plain language summary
It is generally accepted that certain diet and lifestyle choices contribute to a person’s risk of developing type 2 diabetes (T2D). In this meta-analysis, researchers set out to review previous studies and assess whether there is any evidence that the amount and type of carbohydrate (measured by Glycaemic Index (GI) and Glycaemic Load (GL)) in a person’s diet has a direct influence on their risk of developing T2D. The authors concluded with a high level of confidence that eating high GI and GL foods can lead to a higher risk of developing T2D. They suggest that nutrition advice that favours low GI and GL foods could produce significant cost savings for public healthcare.
While dietary factors are important modifiable risk factors for type 2 diabetes (T2D), the causal role of carbohydrate quality in nutrition remains controversial. Dietary glycemic index (GI) and glycemic load (GL) have been examined in relation to the risk of T2D in multiple prospective cohort studies. Previous meta-analyses indicate significant relations but consideration of causality has been minimal. Here, the results of our recent meta-analyses of prospective cohort studies of 4 to 26-y follow-up are interpreted in the context of the nine Bradford-Hill criteria for causality, that is: (1) Strength of Association, (2) Consistency, (3) Specificity, (4) Temporality, (5) Biological Gradient, (6) Plausibility, (7) Experimental evidence, (8) Analogy, and (9) Coherence. These criteria necessitated referral to a body of literature wider than prospective cohort studies alone, especially in criteria 6 to 9. In this analysis, all nine of the Hill's criteria were met for GI and GL indicating that we can be confident of a role for GI and GL as causal factors contributing to incident T2D. In addition, neither dietary fiber nor cereal fiber nor wholegrain were found to be reliable or effective surrogate measures of GI or GL. Finally, our cost-benefit analysis suggests food and nutrition advice favors lower GI or GL and would produce significant potential cost savings in national healthcare budgets. The high confidence in causal associations for incident T2D is sufficient to consider inclusion of GI and GL in food and nutrient-based recommendations.
Postprandial Effects of Blueberry ( ) Consumption on Glucose Metabolism, Gastrointestinal Hormone Response, and Perceived Appetite in Healthy Adults: A Randomized, Placebo-Controlled Crossover Trial.
Plain language summary
Globally, type 2 diabetes is a growing public health problem. The consumption of blueberries, as well as the phenolic compounds they contain, may alter metabolic processes related to type 2 diabetes. The purpose of this study was to evaluate glucose metabolism, gastrointestinal hormone response, and perceived appetite following a higher-carbohydrate breakfast meal with or without whole blueberries As part of a randomised crossover design study, 17 healthy adults consumed a standardised higher-carbohydrate breakfast along with 2 treatments: (1) 140 g (1 cup) of whole blueberries and (2) a placebo gel (matched for calories, sugars, and fibre of the whole blueberries). Each subject participated in two 2-hour meal tests on separate visits at least 8 days apart. Blood samples and perceived appetite ratings were obtained prior to and at 30, 60, 90, and 120 minutes after consuming the breakfast meals. The results showed that glucose metabolism, several gastrointestinal hormone (glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), peptide YY (PYY)) concentrations and perceived appetite did not change significantly with blueberry consumption. However, pancreatic polypeptide (PP) concentrations were significantly higher at 30, 60, 90, and 120 minutes after consumption of the blueberry breakfast meal than the placebo breakfast meal. The authors concluded that additional research is needed to determine whether blueberries and other flavonoid-rich foods reduce type 2 diabetes risk by modifying gastrointestinal hormones and perceived appetite.
undefined: The consumption of blueberries, as well as the phenolic compounds they contain, may alter metabolic processes related to type 2 diabetes. The study investigated the effects of adding 140 g of blueberries to a higher-carbohydrate breakfast meal on postprandial glucose metabolism, gastrointestinal hormone response, and perceived appetite. As part of a randomized crossover design study, 17 healthy adults consumed a standardized higher-carbohydrate breakfast along with 2 treatments: (1) 140 g (1 cup) of whole blueberries and (2) a placebo gel (matched for calories, sugars, and fiber of the whole blueberries). Each subject participated in two 2-h meal tests on separate visits ≥8 days apart. Venous blood samples and perceived appetite ratings using visual analog scales were obtained prior to and at 30, 60, 90, and 120 min after consuming the breakfast meals. Results show that glucose metabolism, several gastrointestinal hormones, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), peptide YY (PYY) concentrations and perceived appetite did not change significantly with blueberry consumption. However, pancreatic polypeptide (PP) concentrations were statistically significantly higher ( = 0.0367), and the concentrations were higher during 30, 60, 90, and 120 min after consumption of the blueberry breakfast meal than the placebo breakfast meal. Additional research is needed to determine whether blueberries and other flavonoid-rich foods reduce type 2 diabetes risk by modifying gastrointestinal hormones and perceived appetite.
Glucotypes reveal new patterns of glucose dysregulation.
PLoS biology. 2018;16(7):e2005143
Plain language summary
One in 10 individuals is affected by diabetes, a condition involving abnormal regulation of blood glucose. Currently, diabetes is assessed using single-time or average measurements of blood glucose, without consideration for how blood glucose fluctuates over time. This study used continuous glucose monitoring (CGM) technology to evaluate how blood glucose fluctuates in individuals over time. The authors found that many individuals considered nondiabetic by standard measures experienced frequent elevations in blood glucose levels into the pre-diabetic or diabetic range (15% and 2% of the time, respectively). The authors developed a model for determining the “glucotype” (low, moderate or severe variability) of an individual, a more comprehensive measure of glucose patterns than the standard tests currently used. The authors argue that CGM should become an important tool in early identification of those at risk for type 2 diabetes.
Diabetes is an increasing problem worldwide; almost 30 million people, nearly 10% of the population, in the United States are diagnosed with diabetes. Another 84 million are prediabetic, and without intervention, up to 70% of these individuals may progress to type 2 diabetes. Current methods for quantifying blood glucose dysregulation in diabetes and prediabetes are limited by reliance on single-time-point measurements or on average measures of overall glycemia and neglect glucose dynamics. We have used continuous glucose monitoring (CGM) to evaluate the frequency with which individuals demonstrate elevations in postprandial glucose, the types of patterns, and how patterns vary between individuals given an identical nutrient challenge. Measurement of insulin resistance and secretion highlights the fact that the physiology underlying dysglycemia is highly variable between individuals. We developed an analytical framework that can group individuals according to specific patterns of glycemic responses called "glucotypes" that reveal heterogeneity, or subphenotypes, within traditional diagnostic categories of glucose regulation. Importantly, we found that even individuals considered normoglycemic by standard measures exhibit high glucose variability using CGM, with glucose levels reaching prediabetic and diabetic ranges 15% and 2% of the time, respectively. We thus show that glucose dysregulation, as characterized by CGM, is more prevalent and heterogeneous than previously thought and can affect individuals considered normoglycemic by standard measures, and specific patterns of glycemic responses reflect variable underlying physiology. The interindividual variability in glycemic responses to standardized meals also highlights the personal nature of glucose regulation. Through extensive phenotyping, we developed a model for identifying potential mechanisms of personal glucose dysregulation and built a webtool for visualizing a user-uploaded CGM profile and classifying individualized glucose patterns into glucotypes.