OBJECTIVE Whether hyperglycemia in utero less than overt diabetes is associated with altered childhood glucose metabolism is unknown. We examined associations of gestational diabetes mellitus (GDM) not confounded by treatment with childhood glycemia in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) cohort. RESEARCH DESIGN AND METHODS HAPO Follow-up Study (FUS) included 4,160 children ages 10–14 years who completed all or part of an oral glucose tolerance test (OGTT) and whose mothers had a 75-g OGTT at ∼28 weeks gestation with blinded glucose values. The primary predictor was GDM by World Health Organization criteria. Child outcomes were impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and type 2 diabetes. Additional measures included insulin sensitivity and secretion and oral disposition index. RESULTS For mothers with GDM, 10.6% of children had IGT compared with 5.0% of children of mothers without GDM; IFG frequencies were 9.2% and 7.4%, respectively. Type 2 diabetes cases were too few for analysis. Odds ratios (95% CI) adjusted for family history of diabetes, maternal BMI, and child BMI z score were 1.09 (0.78–1.52) for IFG and 1.96 (1.41–2.73) for IGT. GDM was positively associated with child’s 30-min, 1-h, and 2-h but not fasting glucose and inversely associated with insulin sensitivity and oral disposition index (adjusted mean difference −76.3 [95% CI −130.3 to −22.4] and −0.12 [−0.17 to −0.064]), respectively, but not insulinogenic index. CONCLUSIONS Offspring exposed to untreated GDM in utero are insulin resistant with limited β-cell compensation compared with offspring of mothers without GDM. GDM is significantly and independently associated with childhood IGT.

OBJECTIVE: This study examined associations of maternal glycemia during pregnancy with childhood glucose outcomes in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) cohort. RESEARCH DESIGN AND METHODS: HAPO was an observational international investigation that established associations of maternal glucose with adverse perinatal outcomes. The HAPO Follow-up Study included 4,832 children ages 10–14 years whose mothers had a 75-g oral glucose tolerance test (OGTT) at ∼28 weeks of gestation. Of these, 4,160 children were evaluated for glucose outcomes. Primary outcomes were child impaired glucose tolerance (IGT) and impaired fasting glucose (IFG). Additional outcomes were glucose-related measures using plasma glucose (PG), A1C, and C-peptide from the child OGTT. RESULTS: Maternal fasting plasma glucose (FPG) was positively associated with child FPG and A1C; maternal 1-h and 2-h PG were positively associated with child fasting, 30 min, 1-h, and 2-h PG, and A1C. Maternal FPG, 1-h, and 2-h PG were inversely associated with insulin sensitivity, whereas 1-h and 2-h PG were inversely associated with disposition index. Maternal FPG, but not 1-h or 2-h PG, was associated with child IFG, and maternal 1-h and 2-h PG, but not FPG, were associated with child IGT. All associations were independent of maternal and child BMI. Across increasing categories of maternal glucose, frequencies of child IFG and IGT, and timed PG measures and A1C were higher, whereas insulin sensitivity and disposition index decreased. CONCLUSIONS: Across the maternal glucose spectrum, exposure to higher levels in utero is significantly associated with childhood glucose and insulin resistance independent of maternal and childhood BMI and family history of diabetes.

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.

Background. Problems associated with the hepatic transplantation of islets may preclude the broad application of islet transplantation. Thus, we sought to develop an approach to the extrahepatic transplantation of islets using a synthetic biodegradable polymer scaffold. Methods. Microporous polymer scaffolds that allow vascular ingrowth and nutrient diffusion from host tissues were fabricated from copolymers of lactide and glycolide. Murine islets were transplanted without or with a scaffold onto intraperitoneal fat of syngeneic diabetic recipients. Bioluminescence imaging using a cooled charge-coupled device camera, immunohistochemistry, and glycemia were used to assess islet engraftment and function posttransplant. Results. By bioluminescence imaging, islets transplanted on a polymer scaffold remain localized to the transplant site and survive for an extended period of time. Islets transplanted on scaffolds retained the architecture of native islets and developed a functional islet vasculature. Transplantation of marginal masses of islets on the polymer scaffold demonstrated improved islet function compared to transplantation without a scaffold as assessed by the effectiveness of diabetes reversal, including mean time required to achieve euglycemia, weight gain, and glucose levels during an intraperitoneal glucose tolerance test. Conclusion. These findings indicate that a synthetic polymer scaffold can serve as a platform for islet transplantation and improves the function of extrahepatically transplanted islets compared to islets transplanted without a scaffold. The scaffold may also be useful to deliver bioactive molecules to modify the microenvironment surrounding the transplanted islets and, thus, enhance islet survival and function.

The timing of parturition is crucial for neonatal survival and infant health. Yet, its genetic basis remains largely unresolved. We present a maternal genome-wide meta-analysis of gestational duration (n = 195,555), identifying 22 associated loci (24 independent variants) and an enrichment in genes differentially expressed during labor. A meta-analysis of preterm delivery (18,797 cases, 260,246 controls) revealed seven associated loci and large genetic similarities with gestational duration. Analysis of the parental transmitted and nontransmitted alleles (n = 136,833) shows that 15 of the gestational duration genetic variants act through the maternal genome, whereas 7 act both through the maternal and fetal genomes and 2 act only via the fetal genome. Finally, the maternal effects on gestational duration show signs of antagonistic pleiotropy with the fetal effects on birth weight: maternal alleles that increase gestational duration have negative fetal effects on birth weight. The present study provides insights into the genetic effects on the timing of parturition and the complex maternal–fetal relationship between gestational duration and birth weight.

Transversions (Tv’s) are more likely to alter the amino acid sequence of proteins than transitions (Ts’s), and local deviations in the Ts:Tv ratio are indicative of evolutionary selection on genes. Whether the two different types of mutations have different effects in non-protein-coding sequences remains unknown. Genetic variants primarily impact gene expression by disrupting the binding of transcription factors (TFs) and other DNA-binding proteins. Because Tv’s cause larger changes in the shape of a DNA backbone, we hypothesized that Tv’s would have larger impacts on TF binding and gene expression. Here, we provide multiple lines of evidence demonstrating that Tv’s have larger impacts on regulatory DNA including analyses of TF binding motifs and allele-specific TF binding. In these analyses, we observed a depletion of Tv’s within TF binding motifs and TF binding sites. Using massively parallel population-scale reporter assays, we also provided empirical evidence that Tv’s have larger effects than Ts’s on the activity of human gene regulatory elements. Tv’s are more likely to disrupt TF binding, resulting in larger changes in gene expression. Although the observed differences are small, these findings represent a novel, fundamental property of regulatory variation. Understanding the features of functional non-coding variation could be valuable for revealing the genetic underpinnings of complex traits and diseases in future studies.