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A Non-Obese Hyperglycemic Mouse Model that Develops after Birth with Low Birthweight.

ABSTRACT: The number of low birthweight (LBW) infants weighing below 2500 g has not decreased in Japan. This study aimed to develop an adult non-obese hyperglycemic mouse model born with LBW to study the pathogenesis. At 16.5 days of gestation, transient intrauterine ischemia (blocked blood flow in both uterine arteries for 15 min) was performed in a subgroup of pregnant mice (group I). Non-occluded dams were used as sham controls (group C). After birth, female pups in each group were weaned at 4 weeks of age and reared on the normal diet until 8 weeks of age (n = 7). Fasting blood glucose levels, serum immunoreactive insulin (IRI), and body composition were then measured. Metabolite analyses was performed on the liver tissues. Birthweight was significantly lower in group I compared with group C. Pups from group I remained underweight with low fat-free mass and showed hyperglycemia with high serum IRI and homeostasis model assessment of insulin resistance levels, indicating insulin resistance. Metabolite analyses showed significantly reduced adenosine triphosphate and nicotinamide adenine dinucleotide production and increased lactic acid in group I. The pathogenesis of our non-obese hyperglycemic mouse model may be due to increased myogenic insulin resistance based on mitochondrial dysfunction and reduced lean body mass.

SUBMITTER: Katayama D

PROVIDER: S-EPMC9312481 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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A Non-Obese Hyperglycemic Mouse Model that Develops after Birth with Low Birthweight.

Katayama Daichi D Nagano Nobuhiko N Shimizu Shoichi S Nakazaki Kimitaka K Matsuda Kengo K Tokunaga Wataru W Fuwa Kazumasa K Aoki Ryoji R Morioka Ichiro I

Biomedicines 20220708 7

The number of low birthweight (LBW) infants weighing below 2500 g has not decreased in Japan. This study aimed to develop an adult non-obese hyperglycemic mouse model born with LBW to study the pathogenesis. At 16.5 days of gestation, transient intrauterine ischemia (blocked blood flow in both uterine arteries for 15 min) was performed in a subgroup of pregnant mice (group I). Non-occluded dams were used as sham controls (group C). After birth, female pups in each group were weaned at 4 weeks of ...[more]

PMID: 35884949

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Project description:BackgroundTracking progress towards global newborn health targets depends largely on maternal reported data collected through large, nationally representative surveys. We evaluated the validity, across a range of recall period lengths (1 to 24 months post-delivery), of maternal report of birthweight, birth size and length of pregnancy.MethodsWe compared maternal reports to reference standards of birthweights measured within 72 hours of delivery and gestational age generated from reported first day of the last menstrual period (LMP) prospectively collected as part of a population-based study (n = 1502). We calculated sensitivity, specificity, area the under the receiver operating curve (AUC) as a measure of individual-level accuracy, and the inflation factor (IF) to quantify population-level bias for each indicator. We assessed if length of recall period modified accuracy by stratifying measurements across time bins and using a modified Poisson regression with robust error variance to estimate the relative risk (RR) of correctly classifying newborns as low birthweight (LBW) or preterm, adjusting for child sex, place of delivery, maternal age, maternal education, parity, and ethnicity.ResultsThe LBW indicator using maternally reported birthweight in grams had low individual-level accuracy (AUC = 0.69) and high population-level bias (inflation factor IF = 0.62). LBW using maternally reported birth size and the preterm birth indicator had lower individual-level accuracy (AUC = 0.58 and 0.56, respectively) and higher population-level bias (IF = 0.28 and 0.35, respectively) up to 24 months following birth. Length of recall time did not affect accuracy of LBW indicators. For the preterm birth indicator, accuracy did not change with length of recall up to 20 months after birth and improved slightly beyond 20 months.ConclusionsThe use of maternal reports may underestimate and bias indicators for LBW and preterm birth. In settings with high prevalence of LBW and preterm births, these indicators generated from maternal reports may be more vulnerable to misclassification. In populations where an important proportion of births occur at home or where weight is not routinely measured, mothers perhaps place less importance on remembering size at birth. Further work is needed to explore whether these conclusions on the validity of maternal reports hold in similar rural and low-income settings.

Project description:BackgroundIndividuals born very low birthweight (VLBW) are at increased risk of impaired cardiovascular and respiratory function in adulthood. To identify markers to predict future risk for VLBW individuals, we analyzed DNA methylation at birth and at 28 years in the New Zealand (NZ) VLBW cohort (all infants born < 1500 g in NZ in 1986) compared with age-matched, normal birthweight controls. Associations between neonatal methylation and cardiac structure and function (echocardiography), vascular function and respiratory outcomes at age 28 years were documented.ResultsGenomic DNA from archived newborn heel-prick blood (n = 109 VLBW, 51 controls) and from peripheral blood at ~ 28 years (n = 215 VLBW, 96 controls) was analyzed on Illumina Infinium MethylationEPIC 850 K arrays. Following quality assurance and normalization, methylation levels were compared between VLBW cases and controls at both ages by linear regression, with genome-wide significance set to p < 0.05 adjusted for false discovery rate (FDR, Benjamini-Hochberg). In neonates, methylation at over 16,400 CpG methylation sites differed between VLBW cases and controls and the canonical pathway most enriched for these CpGs was Cardiac Hypertrophy Signaling (p = 3.44E-11). The top 20 CpGs that differed most between VLBW cases and controls featured clusters in ARID3A, SPATA33, and PLCH1 and these 3 genes, along with MCF2L, TRBJ2-1 and SRC, led the list of 15,000 differentially methylated regions (DMRs) reaching FDR-adj significance. Fifteen of the 20 top CpGs in the neonate EWAS showed associations between methylation at birth and adult cardiovascular traits (particularly LnRHI). In 28-year-old adults, twelve CpGs differed between VLBW cases and controls at FDR-adjusted significance, including hypermethylation in EBF4 (four CpGs), CFI and UNC119B and hypomethylation at three CpGs in HIF3A and one in KCNQ1. DNA methylation GrimAge scores at 28 years were significantly greater in VLBW cases versus controls and weakly associated with cardiovascular traits. Four CpGs were identified where methylation differed between VLBW cases and controls in both neonates and adults, three reversing directions with age (two CpGs in EBF4, one in SNAI1 were hypomethylated in neonates, hypermethylated in adults). Of these, cg16426670 in EBF4 at birth showed associations with several cardiovascular traits in adults.ConclusionsThese findings suggest that methylation patterns in VLBW neonates may be informative about future adult cardiovascular and respiratory outcomes and have value in guiding early preventative care to improve adult health.

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A Non-Obese Hyperglycemic Mouse Model that Develops after Birth with Low Birthweight.

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A Non-Obese Hyperglycemic Mouse Model that Develops after Birth with Low Birthweight.

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