Genetic Susceptibility Determines β-Cell Function and Fasting Glycemia Trajectories Throughout Childhood: A 12-Year Cohort Study (EarlyBird 76)

Carayol, Jérôme; Hosking, Joanne; Pinkney, Jonathan; Marquis, Julien; Charpagne, Aline; Métairon, Sylviane; Jeffery, Alison; Hager, Jörg; Martin, François‐Pierre J.

doi:10.2337/dc19-0806

Cited by 19 publications

(13 citation statements)

References 34 publications

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“…Thus, rs12970134 may reflect susceptibility to more extreme HbA1c elevation. This finding is consistent with recent data from the EarlyBird cohort, where the rs12970134 A‐allele was associated with 12‐year fasting glucose trajectory >75th percentile in healthy children, but not associated when a 50th percentile cut‐point was examined 28 …”

Section: Discussionsupporting

confidence: 92%

Heterogeneous long‐term trajectories of glycaemic control in type 1 diabetes

et al. 2021

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We aimed to identify long-term HbA1c trajectories and examine associated characteristics in an observational, childhood-onset (<17 years) type 1 diabetes cohort. Methods: Data are from the Epidemiology of Diabetes Complications study, comprising 405 participants with ≥2 of seven possible HbA1c measurements over follow-up (1988-2013) and available DNA (baseline mean diabetes duration 21 years, 53% men). HbA1c trajectories were estimated using latent class growth models. Baseline and change in participant characteristics were compared across trajectories. Results: Five HbA1c trajectories were identified: low (51%), intermediate stable (22%), improved (19%), high stable (6%), and worsened (2%; not included in analyses). Age, diabetes duration, diabetes onset age, and sex did not differ across trajectories. Characteristics did not differ significantly between intermediate stable and low trajectories at baseline, though albumin excretion rate (AER, p = 0.0002) and estimated glomerular filtration rate (eGFR, p = 0.001) worsened slightly more in intermediate stable over time. Improved and high stable trajectories had higher baseline LDL-c (p = 0.002 and 0.003, respectively). Improved trajectory increased median self-monitoring of blood glucose from <1 to 3.5 times/day (p < 0.0001) and had larger LDL-c improvement (p = 0.004) but greater worsening of AER (p < 0.0001) and eGFR (p < 0.0001) than low. The A allele of rs12970134 (near MC4R) was associated with improved (p = 0.0003) or high stable (p = 0.001) HbA1c trajectory, both patterns with high baseline HbA1c. Conclusions: Long-term HbA1c trajectories were primarily associated with modifiable factors in this type 1 diabetes cohort. The intermediate stable pattern had a risk factor profile that suggests some protection against adverse metabolic effects of chronic hyperglycaemia, warranting further study.

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Section: Discussionsupporting

confidence: 92%

Heterogeneous long‐term trajectories of glycaemic control in type 1 diabetes

et al. 2021

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“…Weight gain and obesity further exacerbate the physiological insulin resistance of puberty and fasting glycemia, and will favor atherogenic changes in the lipid profile and pathways, such as one carbon metabolism. This is in line with our other findings which suggested that weight gain and increasing insulin resistance will exacerbate hyperglycaemia ( 15 ) in adolescence, especially in those who also have genetic impairment of pancreatic beta cell function ( 13 , 15 ).…”

Section: Discussionsupporting

confidence: 93%

“…The children who developed IFG already exhibited higher fasting blood glucose levels at 5 years of age, compared with those who did not subsequently develop IFG, and this effect was independent of BMI ( 12 ). Recently, we reported that the occurrence of an early defect in β-cell function among children who go on to develop prediabetes ( 12 ), was genetically determined and independent of BMI ( 13 ). These studies also revealed how genetic markers are associated with normal glycemic trajectories during childhood.…”

Section: Introductionmentioning

confidence: 99%

Contributions of Fat and Carbohydrate Metabolism to Glucose Homeostasis in Childhood Change With Age and Puberty: A 12-Years Cohort Study (EARLYBIRD 77)

Cominetti¹,

Hosking

Jeffery

et al. 2020

Front. Nutr.

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Puberty—a period when susceptibility to the onset of Type 2 diabetes (T2D) increases—is marked with profound physiological and metabolic changes. In the EarlyBird cohort, children who developed impaired fasting glycemia in adolescence already exhibited higher fasting blood glucose at 5 years of age, independent of their body mass index (BMI), suggesting that pubertal factors may modify existing predisposition. Understanding how the physiological changes during childhood influence glucose homeostasis and how the central energy metabolism may help deciphering the mechanisms that underlie the risk of developing T2D in children and adults. We investigated these associations by analyzing glycemic variations with molecular markers of central energy metabolism, substrate oxidation status and pubertal stages in the EarlyBird cohort. The EarlyBird study is a non-interventional, prospective cohort study, that recruited 307 healthy UK children at age 5, and followed them annually throughout childhood for 12 years. Longitudinal data on blood biochemistry, respiratory exchange ratio, and anthropometry, available from 150 children were integrated with fasting glycemia. The gradual rise in blood glucose during childhood associates with age-dependent changes in molecular processes and substrate oxidation status, namely (i) greater pre-pubertal fat utilization, ketogenesis, and fatty acid oxidation, and (ii) greater pubertal carbohydrate oxidation and glycolytic metabolism (Cori and Cahill Cycles) associated with different amino acid exchanges between muscle and other tissues (proline, glutamine, alanine). Since children's metabolic and nutritional requirements evolve during childhood, this study has potential clinical implications for the development of nutritional strategies for disease prevention in children.

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“…5). Recent work from the EarlyBird cohort demonstrated that genetic markers associated with type 2 diabetes in adults are also present in youths [105]. These markers were more commonly associated with beta cell dysfunction and increasing glucose, independent of BMI or insulin resistance.…”

Section: Areas For Future Workmentioning

confidence: 99%

Early beta cell dysfunction vs insulin hypersecretion as the primary event in the pathogenesis of dysglycaemia

2020

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Obesity and insulin resistance are associated with the development of type 2 diabetes. It is well accepted that beta cell dysfunction is required for hyperglycaemia to occur. The prevailing view is that, in the presence of insulin resistance, beta cell dysfunction that occurs early in the course of the disease process is the critical abnormality. An alternative model has been proposed in which primary beta cell overstimulation results in insulin hypersecretion that then leads to the development of obesity and insulin resistance, and ultimately to beta cell exhaustion. In this review, data from preclinical and clinical studies, including intervention studies, are discussed in the context of these models. The preponderance of the data supports the view that an early beta cell functional defect is the more likely mechanism underlying the pathogenesis of hyperglycaemia in the majority of individuals who develop type 2 diabetes.

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Genetic Susceptibility Determines β-Cell Function and Fasting Glycemia Trajectories Throughout Childhood: A 12-Year Cohort Study (EarlyBird 76)

Abstract: Genetic susceptibility determines -cell function and fasting glycaemia trajectories throughout childhood: a 12-yr cohort study (EARLYBIRD 76).

Cited by 19 publications

References 34 publications

Heterogeneous long‐term trajectories of glycaemic control in type 1 diabetes

Heterogeneous long‐term trajectories of glycaemic control in type 1 diabetes

Contributions of Fat and Carbohydrate Metabolism to Glucose Homeostasis in Childhood Change With Age and Puberty: A 12-Years Cohort Study (EARLYBIRD 77)

Early beta cell dysfunction vs insulin hypersecretion as the primary event in the pathogenesis of dysglycaemia

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