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Cited by 34Birth, Development, and HealthGestational Diabetes Research and ManagementDiabetes, Cardiovascular Risks, and Lipoproteins

Recent Experimental Studies of Maternal Obesity, Diabetes during Pregnancy and the Developmental Origins of Cardiovascular Disease

Open access
Kereliuk, Stephanie M., Dolinsky, Vernon W.·2022·International Journal of Molecular Sciences
DOI 10.3390/ijms23084467PMC PMC9027277
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Abstract

Globally, cardiovascular disease remains the leading cause of death. Most concerning is the rise in cardiovascular risk factors including obesity, diabetes and hypertension among youth, which increases the likelihood of the development of earlier and more severe cardiovascular disease. While lifestyle factors are involved in these trends, an increasing body of evidence implicates environmental exposures in early life on health outcomes in adulthood. Maternal obesity and diabetes during pregnancy, which have increased dramatically in recent years, also have profound effects on fetal growth and development. Mounting evidence is emerging that maternal obesity and diabetes during pregnancy have lifelong effects on cardiovascular risk factors and heart disease development. However, the mechanisms responsible for these observations are unknown. In this review, we summarize the findings of recent experimental studies, showing that maternal obesity and diabetes during pregnancy affect energy metabolism and heart disease development in the offspring, with a focus on the mechanisms involved. We also evaluate early proof-of-concept studies for interventions that could mitigate maternal obesity and gestational diabetes-induced cardiovascular disease risk in the offspring.

AI snapshot

Written from the paper’s full text.

TL;DR

This narrative review summarizes recent rodent experimental studies showing that maternal obesity and diabetes during pregnancy program cardiovascular and metabolic disease in offspring, with cardiac mitochondrial dysfunction emerging as a prominent mechanism. It also evaluates early proof-of-concept interventions (maternal exercise, berberine) that may mitigate this inherited risk.

Key findings

  • Maternal obesity and diabetes during pregnancy produce lasting cardiovascular effects in offspring across animal models: cardiac hypertrophy (increased heart weight, LV wall thickness, Nppb/Acta1 expression, Myh7:Myh6 ratio) in young offspring that is transient, but persistent diastolic dysfunction, fibrosis, and reduced SERCA2a/troponin expression.
  • Diabetes during pregnancy (STZ and high-fat + STZ models) causes sex-specific cardiac dysfunction in offspring — male offspring showed reduced diastolic function without systolic impairment, while females showed systolic dysfunction without diastolic dysfunction — plus increased ischemia-induced infarction and cardiomyocyte apoptosis.
  • Mitochondrial dysfunction is a recurring mechanism: reduced respiration, altered fission/fusion dynamics, elevated mitolysosomes, and altered expression of PGC1α, FGF receptor-2, and SIRT1 (linked to Sirt1 hypermethylation).
  • Maternal exercise prevented obesity-induced cardiac hypertrophy and cardiomyocyte enlargement in 8-week-old offspring and improved vascular endothelial function, but did not prevent hypertension; berberine supplementation (160 mg/kg/day) in GDM offspring lowered body weight, improved islet insulin secretion, and improved systolic and diastolic heart function.
  • Contextual epidemiology cited: WHO estimated 17.9 million CVD deaths in 2020; ~463 million people live with diabetes, projected to reach 700 million by 2045; in CARDIA, 26.7% of overweight women with ≥1 cardiometabolic risk factor developed GDM versus 7.4% with none; one in six of 20 million annual live births affected by hyperglycemia (16% diabetes, 84% GDM).

Methods

  • Narrative review of experimental (predominantly rodent) studies, supplemented by human epidemiological and cohort evidence, organized around the developmental origins of health and disease (DOHaD) framework.
  • Covers animal models including STZ-induced insulin-deficient diabetes, high-fat/high-fat-and-sucrose diet-induced maternal obesity and GDM, and combined high-fat diet plus late-gestation STZ; outcomes span cardiac morphology/function, metabolomics, transcriptomics, mitochondrial respiration, vascular function, and epigenetics.
  • Intervention evidence reviewed includes maternal treadmill/voluntary wheel exercise and postnatal berberine supplementation, plus a cited systematic review of exercise in pregnancy.

Limitations

  • Stated by the paper: human studies examining intergenerational effects of diabetes during pregnancy and maternal obesity on offspring cardiovascular endpoints are lacking; few cohort studies reach middle age when major CVD endpoints appear; confounding from multifaceted early-life exposures and postnatal environment makes isolating single exposures difficult in prospective mother-offspring studies.
  • Stated by the paper: animal models have inherent limitations versus human pregnancy, including differences in placental morphology, gestational length, parturition, number of offspring per pregnancy, and windows of fetal/neonatal cellular differentiation and organogenesis; STZ-induced insulin deficiency more closely approximates type 1 diabetes and may not accurately model GDM mechanisms.
  • Evident from the text: the review is narrative rather than systematic, so no formal search strategy, inclusion criteria, or quantitative synthesis is reported; several mechanistic findings rest on single studies or specific models, and the authors repeatedly note that animal findings require replication in human populations.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.3390/ijms23084467

Cites

148 of 148 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

201 of 289 cited sources checked · 88 supported · 6 flagged · accuracy not yet measured

  • Premisecitation

    In rat offspring of high-fat diet and STZ-induced diabetes dams aged up to 12 months, LV hypertrophy was not observed compared to controls.

    “While LV hypertrophy was not observed in these offspring compared to controls, female offspring exhibited some systolic dysfunction (e.g., reduced ejection fraction) without diastolic dysfunction [111].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [111] Louwagie, 2020, Age and Sex Influence Mitochondria and Cardiac Health in Offspring Exposed to Maternal Glucolipotoxicity, iScience source

      The Results section on cardiac mass (page unavailable) reports larger heart-to-body-weight ratios at birth, particularly in offspring exposed to both maternal high-fat diet and diabetes. It also reports significantly larger ratios in diet-exposed males at 12 months and says left ventricular mass followed a similar pattern. These findings contradict the unqualified claim that LV hypertrophy was not observed through 12 months. (LLM, conf=0.85)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
  • Premisecitation

    Basal respiration in permeabilized cardiomyocytes from neonatal and 12-month-old offspring in the high-fat diet and STZ-induced diabetes model is similar.

    “While basal respiration in permeabilized cardiomyocytes from neonatal and 12-month-old offspring were similar, altered state 3 respiration was apparent in mitochondria from 12-month-old offspring, particularly when using complex I fuels as substrates [111].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [111] Louwagie, 2020, Age and Sex Influence Mitochondria and Cardiac Health in Offspring Exposed to Maternal Glucolipotoxicity, iScience source

      The Results section on permeabilized cardiomyocytes (page unavailable) reports differences in basal oxygen consumption at 12 months: it is higher in diet-exposed females and lower in diabetes-exposed males. It does not support a blanket statement that basal respiration is similar in neonatal and 12-month-old offspring; the Results also report a 70-fold developmental increase in basal respiration in control cardiomyocytes. (LLM, conf=0.78)

      Checked by a reasoning model — may be wrong.

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  • Interpretationcitation

    The lack of effect of maternal diabetes on mitochondrial dynamics in female offspring cardiomyocytes is likely a consequence of higher protein expression of Mitofusin-2 and OPA1 that could protect against mitophagy-mediated cell death.

    “Notably, mitochondrial dynamics in cardiomyocytes from the female offspring were not affected by exposure to maternal diabetes, likely as a consequence of higher protein expression of Mitofusin-2 and OPA1 that could protect against mitophagy-mediated cell death.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [116] Larsen, T.D., Sabey, K.H., Knutson, A.J., Gandy, T.C.T., Louwagie, E.J., Lauterboeck, L., Mdaki, K.S., and Baack, M.L. (2019). Diabetic Pregnancy and Maternal High-Fat Diet Impair Mitochondrial Dynamism in the Developing Fetal Rat Heart by Sex-Specific Mechanisms. Int. J. Mol. Sci., 20. source

      Results §2.3 (page unavailable) says maternal diabetes impaired mitochondrial dynamics similarly in female and male rat cardiomyocytes, contrary to the claimed lack of effect in females. Results §2.5 reports higher OPA1 expression in diet-exposed males, not females; the Discussion also describes higher MFN2 as a possible contributor to cardiomyocyte death rather than protection from it. (LLM, conf=0.93)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
  • Premisereasoning

    Mitochondrial dynamics in cardiomyocytes from female offspring were not affected by exposure to maternal diabetes.

    “Notably, mitochondrial dynamics in cardiomyocytes from the female offspring were not affected by exposure to maternal diabetes, likely as a consequence of higher protein expression of Mitofusin-2 and OPA1 that could protect against mitophagy-mediated cell death.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [116] Larsen, T.D., Sabey, K.H., Knutson, A.J., Gandy, T.C.T., Louwagie, E.J., Lauterboeck, L., Mdaki, K.S., and Baack, M.L. (2019). Diabetic Pregnancy and Maternal High-Fat Diet Impair Mitochondrial Dynamism in the Developing Fetal Rat Heart by Sex-Specific Mechanisms. Int. J. Mol. Sci., 20. source

      Results §2.3 states that diabetes and diet impaired mitochondrial dynamism in both female and male neonatal rat cardiomyocytes; it specifically concludes that diabetes exposure impaired dynamism similarly in both sexes. Although the Discussion reports higher fusion-protein expression in female hearts, that does not support the claim that maternal diabetes left their mitochondrial dynamics unaffected. (LLM, conf=0.93)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
  • Premisecitation

    Hypertension and obesity in childhood result in poor cardiovascular outcomes with age.

    “Many groups have established that hypertension and obesity in childhood result in poor cardiovascular outcomes with age [23,24,25,26,27].”
    Quote in the paperNot a substantial claim2 of 5 sources checked
    • cites [23] Crowley, 2011, Cardiovascular impact of the pediatric obesity epidemic: Higher left ventricular mass is related to higher body mass index, J. Pediatr. source
    • cites [24] Li, 2003, Childhood cardiovascular risk factors and carotid vascular changes in adulthood: The Bogalusa Heart Study, JAMA source

      The Results (page not provided) report that childhood BMI and systolic blood pressure correlated with carotid intima-media thickness (IMT) in young adulthood, but only childhood BMI was a significant predictor in the multivariable analysis. The Comment (page not provided) says the study was observational and measured carotid IMT in young adults too young to experience coronary events. It therefore supports an association with a marker of cardiovascular risk, not that childhood hypertension and obesity cause poor clinical outcomes with age. (LLM, conf=0.90)

      Experimental — accuracy not yet measured
    • cites [25] Juonala, 2011, Childhood adiposity, adult adiposity, and cardiovascular risk factors, N. Engl. J. Med. source
    • cites [26] Raitakari, 2003, Cardiovascular risk factors in childhood and carotid artery intima-media thickness in adulthood: The Cardiovascular Risk in Young Finns Study, JAMA source

      The Comment section (page not supplied) reports that childhood systolic blood pressure and BMI were associated with adult carotid intima-media thickness, a surrogate marker of cardiovascular health. It also explicitly says there were no direct data linking childhood risk factors to adult cardiovascular disease. The claim overstates an association with a surrogate marker as a causal finding about cardiovascular outcomes. (LLM, conf=0.90)

      Experimental — accuracy not yet measured
    • cites [27] Urbina, 1995, Effect of body size, ponderosity, and blood pressure on left ventricular growth in children and young adults in the Bogalusa Heart Study, Circulation source
  • May combine two claims. 46
  • The quote only partly states this claim. 5
  • Classified as probably not a substantial claim. 18

  • May combine two claims. The quote only partly states this claim.

    Premisecitation

    A total of 122 genes were significantly reduced while 201 genes were increased in the hearts of newborn rats in the high-fat diet and STZ-induced diabetes model.

    “A total of 122 genes were significantly reduced while 201 genes were increased.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [123] Preston, 2020, Maternal High Fat Diet and Diabetes Disrupts Transcriptomic Pathways That Regulate Cardiac Metabolism and Cell Fate in Newborn Rat Hearts, Front. Endocrinol. source

      The Figure 2 caption in the Results states 122 downregulated and 201 upregulated genes in the combined diabetes and high-fat-diet group, matching the claim. But the accompanying Results text reverses those directions, stating 122 upregulated and 201 downregulated genes. Our copy is internally contradictory on the claimed counts. (LLM, conf=0.78)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In cardiomyocytes from male offspring from a high-fat diet and diabetes during pregnancy, mitochondrial fusion and fission events are reduced, but the balance is tipped in favour of more fission events over fusion events.

    “However, in cardiomyocytes from the male offspring from a high-fat diet and diabetes during pregnancy, mitochondrial fusion and fission events were reduced, but the balance was tipped in favour of more fission events over fusion events [116].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [116] Larsen, T.D., Sabey, K.H., Knutson, A.J., Gandy, T.C.T., Louwagie, E.J., Lauterboeck, L., Mdaki, K.S., and Baack, M.L. (2019). Diabetic Pregnancy and Maternal High-Fat Diet Impair Mitochondrial Dynamism in the Developing Fetal Rat Heart by Sex-Specific Mechanisms. Int. J. Mol. Sci., 20. source

      Results §2.3 reports that diabetes and diet impaired mitochondrial dynamism in both sexes, supporting the reduction in events. But for high-fat-diet-exposed male cardiomyocytes, it reports an anti-fission ratio of 0.88, not a balance favoring fission. The Discussion likewise contrasts males’ anti-fission balance with females’ pro-fission balance. The paper does not establish the claimed pro-fission balance for males exposed to both diet and diabetes. (LLM, conf=0.90)

      Checked by a reasoning model — may be wrong.

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Individuals with type 1 diabetes have a ten-times-greater risk of cardiovascular events than age-matched populations without diabetes.

    “Individuals with type 1 diabetes have a ten-times-greater risk of cardiovascular events than age-matched populations without diabetes [6].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [6] Orchard, 2006, Type 1 diabetes and coronary artery disease, Diabetes Care source

      The 'Magnitude of the Problem' section reports 10-fold or greater coronary heart disease mortality relative to expected U.S. national rates. It does not establish a tenfold risk of cardiovascular events compared with age-matched people without diabetes; its event-incidence figures are for people with type 1 diabetes only. Page numbers were not available in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Cardiogenesis begins on embryonic day 6.5 in mice, 8.5 in rats and 18-19 in humans.

    “Cardiogenesis begins on embryonic day 6.5 in mice, 8.5 in rats and 18–19 in humans.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [35] Cui, 2018, Genetic and epigenetic regulation of cardiomyocytes in development, regeneration and disease, Development source

      The Introduction states that cardiogenesis begins around embryonic day 6.5 in mice. It does not give a starting day for rats or humans; the cited paper therefore supports only the mouse part of the claim. (LLM, conf=0.90)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The Framingham Heart Study has demonstrated that hypertension, coronary artery disease, cardiac hypertension and diabetes are cardiovascular risk factors associated with the future development of heart failure.

    “Over its 74-year length, the Framingham Heart Study has demonstrated that hypertension, coronary artery disease, cardiac hypertension and diabetes are cardiovascular risk factors associated with the future development of heart failure [2,3].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [2] Mahmood, 2014, The Framingham Heart Study and the epidemiology of cardiovascular disease: A historical perspective, Lancet source

      The sections on heart-failure epidemiology and metabolic risk factors report that hypertension and coronary artery disease preceded heart failure, and that diabetes was associated with substantially higher heart-failure risk. The paper does not identify “cardiac hypertension” as a separate risk factor; it mentions hypertensive heart disease as an outcome associated with diabetes. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [3] Andersson, 2019, 70-year legacy of the Framingham Heart Study, Nat. Rev. Cardiol. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Type 1 diabetes results from destruction of insulin-producing pancreatic beta cells due to an immune-associated or environmental insult.

    “Destruction of the insulin-producing pancreatic beta cells due to an immune-associated or environmental insult results in type 1 diabetes [5].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [5] Atkinson, 2014, Type 1 diabetes, Lancet source

      The Introduction describes type 1 diabetes as generally precipitated by immune-associated destruction of insulin-producing pancreatic β cells. The Natural history section says environmental influences might affect the onset and continuation of β-cell autoimmunity, but does not establish a separate environmental insult as a cause of β-cell destruction. The citing sentence presents that alternative more definitively than the source does. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    The heart begins to beat and pump blood on embryonic day 8 in mice, 10 in rats and 22 in humans.

    “The heart begins to beat and pump blood, its primary function, on embryonic day 8 in mice, 10 in rats and 22 in humans [35].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [35] Cui, 2018, Genetic and epigenetic regulation of cardiomyocytes in development, regeneration and disease, Development source

      The Introduction states that a beating heart tube has formed by embryonic day 8 in mice, supporting the mouse heartbeat timing. It does not give the claimed day 10 timing for rats or day 22 timing for humans, or explicitly date the onset of blood pumping to those days. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In type 2 diabetes, hyperinsulinemia is frequently featured because insulin target tissues are unable to perform glucose-lowering responses at normal plasma insulin levels, resulting in increased insulin secretion to compensate.

    “In T2D, hyperinsulinemia is frequently featured because insulin target tissues are unable to perform glucose-lowering responses at normal plasma insulin levels, resulting in increased insulin secretion to compensate [8,9].”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [8] Petersen, 2018, Mechanisms of Insulin Action and Insulin Resistance, Physiol. Rev. source
    • cites [9] Shulman, 2000, Cellular mechanisms of insulin resistance, J. Clin. Investig. source

      In “Contributions of muscle glycogen synthesis to whole-body insulin-stimulated glucose metabolism” (page not provided), the paper reports impaired insulin-stimulated glucose metabolism in people with type 2 diabetes. It does not establish that hyperinsulinemia is frequent in type 2 diabetes or that increased insulin secretion compensates for the impairment; its experiments used infused insulin. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Interpretationcitation

    These findings support the likelihood for parental transmission of cardiometabolic disease risk factors and a possible epigenetic contribution to cardiovascular disease risk in the general population.

    “These findings support the likelihood for parental transmission of cardiometabolic disease risk factors and a possible epigenetic contribution to CVD risk in the general population that merits further investigation [34].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [34] Mendelson, 2016, Association of Maternal Prepregnancy Dyslipidemia With Adult Offspring Dyslipidemia in Excess of Anthropometric, Lifestyle, and Genetic Factors in the Framingham Heart Study, JAMA Cardiol. source

      The Discussion reports an association between maternal pre-pregnancy LDL-C and adult offspring LDL-C, and says epigenetic mechanisms may contribute to CVD risk. It also reports a smaller, less robust paternal association. The claim broadens these findings to parental transmission of cardiometabolic risk factors generally, whereas the study examined LDL-C and did not establish transmission or directly test epigenetic mechanisms. (LLM, conf=0.83)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    As rates of obesity continue to rise in the general population, women are frequently reaching childbearing age obese, which is a key risk factor for the development of gestational diabetes mellitus.

    “As the rates of obesity continue to rise in the general population, women are frequently reaching childbearing age obese, which is a key risk factor for the development of gestational diabetes mellitus (GDM) [48,49].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [48] Catalano, 1999, Longitudinal changes in glucose metabolism during pregnancy in obese women with normal glucose tolerance and gestational diabetes mellitus, Am. J. Obstet. Gynecol. source
    • cites [49] Flegal, 2016, Trends in Obesity Among Adults in the United States, 2005 to 2014, JAMA source

      The Trend Analyses section (page not provided) reports increasing obesity prevalence among US women aged 20–39, supporting the point about women approaching childbearing age with obesity. The paper does not address gestational diabetes or establish obesity as a risk factor for it. Its findings also concern US adults, rather than the general population without qualification. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Gestational diabetes mellitus is associated with neonatal hyperinsulinemia and shoulder dystocia.

    “neonatal hyperinsulinemia and shoulder dystocia”
    Quote in the paperNot a substantial claim2 of 5 sources checked
    • cites [65] Horvath, 2010, Effects of treatment in women with gestational diabetes mellitus: Systematic review and meta-analysis, BMJ source

      The Introduction identifies shoulder dystocia as a complication associated with gestational diabetes mellitus. It lists neonatal hypoglycaemia, but not neonatal hyperinsulinemia; the Discussion mentions cord-blood C-peptide only as a surrogate endpoint in a trial, without stating the claimed association. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [66] Buchanan, 2012, Gestational diabetes mellitus: Risks and management during and after pregnancy, Nat. Rev. Endocrinol. source
    • cites [67] Metzger, 2010, International association of diabetes and pregnancy study groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy, Diabetes Care source
    • cites [68] Kapur, 2020, Towards a global consensus on GDM diagnosis: Light at the end of the tunnel?, Int. J. Gynaecol. Obstet. source
    • cites [69] Feig, 2014, Trends in incidence of diabetes in pregnancy and serious perinatal outcomes: A large, population-based study in Ontario, Canada, 1996–2010, Diabetes Care source

  • May combine two claims.

    Premisecitation

    Gestational diabetes mellitus is associated with greater incidence of large-for-gestational-age infants, fetal adiposity and macrosomia.

    “GDM is associated with greater incidence of large-for-gestational-age infants, fetal adiposity and macrosomia”
    Quote in the paperSubstantial claim2 of 5 sources checked
    • cites [65] Horvath, 2010, Effects of treatment in women with gestational diabetes mellitus: Systematic review and meta-analysis, BMJ source

      The Introduction states that fetal macrosomia is associated with gestational diabetes. The Results (Specific treatment versus usual care, pool A) report fewer large-for-gestational-age infants and fewer cases of macrosomia with treatment. Our copy does not report an association with fetal adiposity, so that part of the claim is unsupported. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [66] Buchanan, 2012, Gestational diabetes mellitus: Risks and management during and after pregnancy, Nat. Rev. Endocrinol. source
    • cites [67] Metzger, 2010, International association of diabetes and pregnancy study groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy, Diabetes Care source
    • cites [68] Kapur, 2020, Towards a global consensus on GDM diagnosis: Light at the end of the tunnel?, Int. J. Gynaecol. Obstet. source

      Section 3 (page not available) states that, under IADPSG and WHO diagnostic criteria, GDM is associated with almost twice the risk of large-for-gestational-age babies and with increased fetal adiposity. Our copy does not state an association with macrosomia, so that part of the claim is unsupported. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [69] Feig, 2014, Trends in incidence of diabetes in pregnancy and serious perinatal outcomes: A large, population-based study in Ontario, Canada, 1996–2010, Diabetes Care source

  • May combine two claims.

    Premisecitation

    Fetal hypertrophic cardiomyopathy is a well-recognized feature of gestational diabetes mellitus, though it was believed that this resolved within a few months of birth.

    “Fetal hypertrophic cardiomyopathy is a well-recognized feature of GDM, though it was believed that this resolved within a few months of birth [78,79,80,81,82].”
    Quote in the paperSubstantial claim1 of 5 sources checked
    • cites [78] Turan, 2011, Decreased fetal cardiac performance in the first trimester correlates with hyperglycemia in pregestational maternal diabetes, Ultrasound Obs. Gynecol. source
    • cites [79] Wong, 2003, Cardiac function in fetuses of poorly-controlled pre-gestational diabetic pregnancies—A pilot study, Gynecol. Obs. Investig. source
    • cites [80] Agoudemos, 2011, Programming of adult cardiovascular disease following exposure to late-gestation hyperglycemia, Neonatology source

      The Introduction describes neonatal hypertrophic cardiomyopathy similar to that found in human offspring of diabetic mothers, supporting its association with maternal diabetes. The Discussion says that cardiac changes persisted into adulthood in the study’s rat model, but it does not say that human fetal cardiomyopathy was believed to resolve within a few months of birth. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [81] Aman, 2011, Increased fat mass and cardiac septal hypertrophy in newborn infants of mothers with well-controlled diabetes during pregnancy, Neonatology source
    • cites [82] Sheehan, 1986, Maternal diabetic control and hypertrophic cardiomyopathy in infants of diabetic mothers, Clin. Pediatr. source

  • May combine two claims.

    Premisecitation

    Offspring exposed to gestational diabetes mellitus exhibited skeletal muscle lipotoxicity and insulin resistance.

    “Subsequent studies using this approach have demonstrated that offspring exposed to GDM exhibited skeletal muscle lipotoxicity and insulin resistance [105,106] (Figure 1).”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [105] Martens, 2021, BNIP3L/Nix-induced mitochondrial fission, mitophagy, and impaired myocyte glucose uptake are abrogated by PRKA/PKA phosphorylation, Autophagy source

      The Results (Metabolomics and gene expression screen) report elevated lipids in the soleus muscle of high-fat-fed rats, and the Discussion describes a lipotoxicity-related pathway that impairs insulin signaling. The paper does not report these findings in offspring exposed to gestational diabetes: its Materials and methods describe rats assigned to low- or high-fat diets after weaning. The References mention gestational-diabetes-exposed offspring only in the title of a study about hepatic steatosis. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [106] Mughal, 2015, A conserved MADS-box phosphorylation motif regulates differentiation and mitochondrial function in skeletal, cardiac, and smooth muscle cells, Cell Death Dis. source

  • May combine two claims.

    Findingown data

    Gestational diabetes mellitus exposure conditioned 3-month-old offspring to the development of obesity, hepatic steatosis, glucose intolerance and pancreatic islet dysfunction.

    “we demonstrated that GDM exposure conditioned 3-month-old offspring to the development of obesity, hepatic steatosis, glucose intolerance [102] and pancreatic islet dysfunction [103,104] (Figure 1).”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [102] Pereira, 2015, Maternal obesity characterized by gestational diabetes increases the susceptibility of rat offspring to hepatic steatosis via a disrupted liver metabolome, J. Physiol. source

      The Abstract reports that offspring of GDM dams developed excess adiposity and hepatic steatosis. The Methods and Results report impaired insulin tolerance and insulin resistance in the offspring, but impaired glucose tolerance is reported for the dams, not the offspring. Pancreatic islet dysfunction is attached to citations [103,104], not to this source’s citation [102]. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [103] Agarwal, 2019, Gestational Diabetes Adversely Affects Pancreatic Islet Architecture and Function in the Male Rat Offspring, Endocrinology source
    • cites [104] Brawerman, 2019, Maternal resveratrol administration protects against gestational diabetes-induced glucose intolerance and islet dysfunction in the rat offspring, J. Physiol. source

  • May combine two claims.

    Findingcitation

    Offspring from the gestational diabetes mellitus model exhibit a hyperactive immune response that manifests in neuroinflammation, which was correlated with cognitive impairment and reduced synaptic integrity.

    “Further studies using this GDM model have demonstrated that the offspring exhibit a hyperactive immune response [108] that manifests in neuroinflammation, which was correlated with cognitive impairment and reduced synaptic integrity [109].”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [108] Li, 2016, In utero exposure to gestational diabetes mellitus conditions TLR4 and TLR2 activated IL-1beta responses in spleen cells from rat offspring, Biochim. Biophys. Acta source
    • cites [109] Vuong, 2017, Exposure to gestational diabetes mellitus induces neuroinflammation, derangement of hippocampal neurons, and cognitive changes in rat offspring, J. Neuroinflamm. source

  • May combine two claims.

    Findingcitation

    Feeding female Sprague-Dawley rats a high-fat-and-sucrose diet prior to mating and throughout pregnancy increased pre-pregnancy weight, and during pregnancy caused excessive gestational weight gain, hyperglycemia and hyperinsulinemia and glucose intolerance at mid-gestation characteristic of gestational diabetes mellitus.

    “Our group showed that compared to low-fat-fed control females, feeding female Sprague-Dawley rats a high-fat-and-sucrose diet prior to mating and throughout pregnancy increased pre-pregnancy weight, and then during pregnancy caused excessive gestational weight gain, hyperglycemia and hyperinsulinemia and glucose intolerance at mid-gestation that are characteristic of GDM [102].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [102] Pereira, 2015, Maternal obesity characterized by gestational diabetes increases the susceptibility of rat offspring to hepatic steatosis via a disrupted liver metabolome, J. Physiol. source

  • May combine two claims.

    Findingcitation

    Activation of Protein Kinase C-δ was associated with the metabolomic changes and inhibits insulin signalling in muscle tissue.

    “This was associated with activation of Protein Kinase C (PKC)-δ [106] which inhibits insulin signalling in muscle tissue [107].”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [106] Mughal, 2015, A conserved MADS-box phosphorylation motif regulates differentiation and mitochondrial function in skeletal, cardiac, and smooth muscle cells, Cell Death Dis. source
    • cites [107] Itani, 2002, Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C, and IkappaB-alpha, Diabetes source

  • May combine two claims.

    Findingcitation

    Protein Kinase C-δ inhibited the expression of miR-133a, which elevated expression of its target, Nix, a mitophagy and cell-death-modulating protein.

    “Mechanistically, PKC-δ inhibited the expression of miR-133a, which elevated expression of its target, Nix, a mitophagy and cell-death-modulating protein [106].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [106] Mughal, 2015, A conserved MADS-box phosphorylation motif regulates differentiation and mitochondrial function in skeletal, cardiac, and smooth muscle cells, Cell Death Dis. source

  • May combine two claims.

    Premisecitation

    Pregnant obese mice fed a high-fat diet supplemented with sweetened condensed milk were hyperinsulinemic, but without hyperglycemia.

    “These pregnant, obese mice were hyperinsulinemic, but without hyperglycemia [94].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [94] Samuelsson, 2008, Diet-induced obesity in female mice leads to offspring hyperphagia, adiposity, hypertension, and insulin resistance: A novel murine model of developmental programming, Hypertension source

  • May combine two claims.

    Premisecitation

    Streptozotocin has been used to cause β-cell destruction in order to produce maternal insulin deficiency and hyperglycemia, though this more closely approximates type 1 diabetes.

    “To model diabetes during pregnancy, streptozotocin (STZ) has been used to cause β-cell destruction in order to produce maternal insulin deficiency and hyperglycemia, though this more closely approximates type 1 diabetes [90,91,92].”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [90] Aerts, 1997, The endocrine pancreas in virgin and pregnant offspring of diabetic pregnant rats, Diabetes Res. Clin. Pract. source
    • cites [91] Holemans, 1991, Evidence for an insulin resistance in the adult offspring of pregnant streptozotocin-diabetic rats, Diabetologia source

      The Animals section reports that streptozotocin was injected on day one of pregnancy and that the rats became severely hyperglycaemic; the Results section also reports maternal hypoinsulinaemia. Our copy does not state that streptozotocin destroyed maternal β-cells or that this model more closely approximates type 1 diabetes. Its discussion of β-cell changes concerns the fetuses, not the mothers. Page numbers are unavailable in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [92] Han, 2007, Rat maternal diabetes impairs pancreatic beta-cell function in the offspring, Am. J. Physiol. Endocrinol. Metab. source

  • May combine two claims.

    Premisecitation

    Several studies have reported hyperlipidemia in offspring of maternal obesity, including elevated free fatty acids, plasma triacylglycerol and reduced total and HDL cholesterol, though one study did not observe alterations in plasma lipids.

    “Several of these studies have reported hyperlipidemia [96,100], including elevated free fatty acids, plasma triacylglycerol and reduced total and HDL cholesterol in the offspring, though one study did not observe alterations in plasma lipids [101].”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [96] Mouralidarane, 2013, Maternal obesity programs offspring nonalcoholic fatty liver disease by innate immune dysfunction in mice, Hepatology source

      The citation to this paper is attached to the assertion that one study found no alterations in plasma lipids. The Materials and Methods section (page unavailable) says plasma was assayed for ALT, while triglycerides were measured in liver tissue. The Results and Discussion discuss hepatic triglycerides, not unchanged plasma lipids; searches for plasma lipid and cholesterol findings found no supporting passage. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • cites [100] Khan, 2003, Gender-linked hypertension in offspring of lard-fed pregnant rats, Hypertension source
    • cites [101] Taylor, 2005, Impaired glucose homeostasis and mitochondrial abnormalities in offspring of rats fed a fat-rich diet in pregnancy, Am. J. Physiol. Regul. Integr. Comp. Physiol. source

  • May combine two claims.

    Premisecitation

    Increased expression of Ppara, Cpt1, Cpt2 and Acot2 in both male and female offspring of obese dams was validated by qPCR, consistent with increased fat oxidation.

    “Increased expression of Ppara Cpt1, Cpt2 and Acot2 in both male and female offspring of obese dams was validated by qPCR [115], consistent with increased fat oxidation.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [115] Pantaleao, 2022, Maternal diet-induced obesity during pregnancy alters lipid supply to mouse E18.5 fetuses and changes the cardiac tissue lipidome in a sex-dependent manner, Elife source

      The Results (Figure 5E; no page available) say that qPCR validated key lipid-metabolism genes in hearts from both male and female fetuses, and the Methods list primers for Ppara, Cpt1, Cpt2 and Acot2. The text does not establish that all four increased in both sexes. The Results report increased oleic-acid oxidation only in isolated female cardiomyocytes; the Discussion cautions that fetal-heart fatty-acid oxidation rates remain to be determined. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Gata-4 is upregulated in cardiac hypertrophy.

    “Fernandez-Twinn et al. [93] discovered that exposure of the offspring to maternal obesity increased the cardiac expression of miR-133 and reduced the mRNA expression of one of its putative targets, Gata-4, which is upregulated in cardiac hypertrophy.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [93] Blackmore, 2012, The programming of cardiac hypertrophy in the offspring by maternal obesity is associated with hyperinsulinemia, AKT, ERK, and mTOR activation, Endocrinology source

  • May combine two claims.

    Premisecitation

    Maternal obesity reduced left ventricular developed pressure and increased left ventricular end diastolic volume using Langendorff heart perfusion, revealing the presence of diastolic dysfunction in the offspring.

    “Maternal obesity reduced LV-developed pressure and increased LV end diastolic volume using Langendorff heart perfusion, revealing the presence of diastolic dysfunction in the offspring [112].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [112] Blackmore, 2014, Maternal diet-induced obesity programs cardiovascular dysfunction in adult male mouse offspring independent of current body weight, Endocrinology source

      The Results section reports that Langendorff perfusion showed reduced LV developed pressure and increased LV end-diastolic pressure in offspring of obese dams; it identifies the latter as a marker of diastolic dysfunction. The claim substitutes end-diastolic volume for pressure. Although a separate Results section reports increased LV volume, that was assessed by stereology, not Langendorff perfusion. (LLM, conf=0.90)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Maternal obesity increased the expression of β1-adrenergic receptors and reduced the expression of troponin and sarcoplasmic/endoplasmic reticulum calcium transporter-2a.

    “Examination of proteins that regulate the contractile properties of the heart revealed that maternal obesity increased the expression of β1-adrenergic receptors and reduced the expression of troponin and sarcoplasmic/endoplasmic reticulum calcium transporter-2a (SERCA2a) [112].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [112] Blackmore, 2014, Maternal diet-induced obesity programs cardiovascular dysfunction in adult male mouse offspring independent of current body weight, Endocrinology source

  • May combine two claims.

    Premisecitation

    At 12 weeks of age, heart weights were not different, consistent with no differences in body weight, adiposity or circulating lipids.

    “Interestingly, at 12 weeks of age, heart weights were not different, consistent with no differences in body weight, adiposity or circulating lipids [112].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [112] Blackmore, 2014, Maternal diet-induced obesity programs cardiovascular dysfunction in adult male mouse offspring independent of current body weight, Endocrinology source

      The Results state that heart weights were similar between groups by 12 weeks, with no difference in growth trajectory or fat-pad weights at that age. They also report no overall maternal-diet effect on circulating lipids, but Table 1 contains lipid measurements only at 3, 5, and 8 weeks; it does not establish no lipid difference at 12 weeks. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingcitation

    In the combined maternal obesity and late-gestation streptozotocin model, body weights as well as serum glucose and triacylglycerol levels were similar to the respective male and female offspring of controls.

    “Using this model, body weights as well as serum glucose and triacylglycerol levels were similar to the respective male and female offspring of controls [111].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [111] Louwagie, 2020, Age and Sex Influence Mitochondria and Cardiac Health in Offspring Exposed to Maternal Glucolipotoxicity, iScience source

      The Results section, “Metabolic Syndrome Does Not Explain Cardiac Disease,” reports similar weights across groups at 10 weeks and 6 months and similar circulating lipids at 3 weeks. But it also reports higher blood glucose in combination-exposed newborns and transiently higher triglycerides in exposed offspring at 10 weeks. Thus, the unqualified claim that all three measures were similar to controls is too broad. Page numbers are unavailable in our copy. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    SIRT1 expression is reduced in the hearts from offspring of STZ-induced diabetes dams.

    “Some of these observations could be a consequence of reduced SIRT1 expression in the hearts from offspring of STZ-induced diabetes dams that is associated with hypermethylation of the Sirt1 gene [120].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [120] Chen, 2019, Epigenetic Down-Regulation of Sirt 1 via DNA Methylation and Oxidative Stress Signaling Contributes to the Gestational Diabetes Mellitus-Induced Fetal Programming of Heart Ischemia-Sensitive Phenotype in Late Life, Int. J. Biol. Sci. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Reduced SIRT1 expression in hearts from offspring of STZ-induced diabetes dams is associated with hypermethylation of the Sirt1 gene.

    “Some of these observations could be a consequence of reduced SIRT1 expression in the hearts from offspring of STZ-induced diabetes dams that is associated with hypermethylation of the Sirt1 gene [120].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [120] Chen, 2019, Epigenetic Down-Regulation of Sirt 1 via DNA Methylation and Oxidative Stress Signaling Contributes to the Gestational Diabetes Mellitus-Induced Fetal Programming of Heart Ischemia-Sensitive Phenotype in Late Life, Int. J. Biol. Sci. source

      The Results report reduced cardiac Sirt1 protein expression in offspring of STZ-treated dams, and the Discussion links Sirt1 repression to increased global DNA methylation in offspring hearts. The paper does not establish hypermethylation of the Sirt1 gene specifically; the Discussion says direct versus indirect regulation remains unknown. No page numbers are available in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Female offspring of diabetic dams exhibit systolic dysfunction but not diastolic dysfunction compared to controls.

    “Male offspring exhibited reduced diastolic function without systolic impairments, while female offspring exhibited systolic dysfunction, but not diastolic dysfunction, compared to controls [111].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [111] Louwagie, 2020, Age and Sex Influence Mitochondria and Cardiac Health in Offspring Exposed to Maternal Glucolipotoxicity, iScience source

      The Results section on cardiac function (page not provided) reports poorer systolic function in diabetes-exposed female offspring at 12 months, while reporting poorer diastolic function in males. The claim omits that age qualifier: the same section says both systolic and diastolic function were poorer in exposed offspring at birth, so the absence of diastolic dysfunction should not be stated generally. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Male offspring of high-fat diet and STZ-induced diabetes dams had only diastolic dysfunction (e.g., reduced E/A ratio) and no difference in systolic function.

    “In contrast, the male offspring had only diastolic dysfunction (e.g., reduced E/A ratio) and no difference in systolic function.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [111] Louwagie, 2020, Age and Sex Influence Mitochondria and Cardiac Health in Offspring Exposed to Maternal Glucolipotoxicity, iScience source

      The Results section on cardiac function reports poorer diastolic function in exposed males at 12 months and identifies E:A ratio as its measure; it reports poorer systolic function at that age in females, not males. But the claim omits the age qualifier: the same section reports impaired systolic function in exposed newborn males, so 'only diastolic dysfunction' does not hold across ages. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims. The quote only partly states this claim.

    Premisecitation

    Reduced respiratory capacity re-emerges in cardiomyocytes at 6 months of age and is present in cardiomyocytes from 12-month-old offspring in the high-fat diet and STZ-induced diabetes model.

    “Impaired glucose oxidation that was observed in neonatal cardiomyocytes was attenuated by 10 weeks of age, although reduced respiratory capacity re-emerges in cardiomyocytes at 6 months of age and is present in the cardiomyocytes from 12 months old offspring.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [111] Louwagie, 2020, Age and Sex Influence Mitochondria and Cardiac Health in Offspring Exposed to Maternal Glucolipotoxicity, iScience source

  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing), S4 (based). The quote only partly states this claim.

    Premisecitation

    Fetal cardiomyocytes from the high-fat diet and STZ-induced diabetes model demonstrated well-balanced fusion and fission events.

    “Fetal cardiomyocytes demonstrated well-balanced fusion and fission events.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [116] Larsen, T.D., Sabey, K.H., Knutson, A.J., Gandy, T.C.T., Louwagie, E.J., Lauterboeck, L., Mdaki, K.S., and Baack, M.L. (2019). Diabetic Pregnancy and Maternal High-Fat Diet Impair Mitochondrial Dynamism in the Developing Fetal Rat Heart by Sex-Specific Mechanisms. Int. J. Mol. Sci., 20. source

      Results §2.1 reports a balanced fission:fusion ratio of 0.99 in cardiomyocytes exposed to both maternal diabetes and a high-fat diet. But both types of event declined by 50%, and more mitochondria were adynamic and fragmented. Calling the events “well-balanced” without that qualification overstates the finding. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • The quote only partly states this claim.

    Premisecitation

    Reduced palmitate oxidation is apparent in neonatal cardiomyocytes from the high-fat diet and STZ-induced diabetes model.

    “In addition, reduced palmitate oxidation and glycolysis were apparent in the neonatal cardiomyocytes.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [111] Louwagie, 2020, Age and Sex Influence Mitochondria and Cardiac Health in Offspring Exposed to Maternal Glucolipotoxicity, iScience source

  • The quote only partly states this claim.

    Premisecitation

    Morphologically, mitochondria in these offspring from a high-fat diet and diabetes during pregnancy were shorter, wider and more fragmented.

    “Morphologically, these mitochondria were shorter, wider and more fragmented.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [111] Louwagie, 2020, Age and Sex Influence Mitochondria and Cardiac Health in Offspring Exposed to Maternal Glucolipotoxicity, iScience source

      The Results section on mitochondrial dynamism reports changes in fission- and fusion-related proteins, and the mitophagy Results report differences in mitochondrial clearance. Neither gives measurements showing that offspring mitochondria were shorter, wider, or more fragmented. Searches for those shape descriptions found no supporting passage in our copy. (LLM, conf=0.72)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Similar to the transcriptomic profile, genes involved in metabolic processes were highly represented.

    “Similar to the transcriptomic profile, genes involved in metabolic processes were highly represented.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [124] Upadhyaya, B., Larsen, T., Barwari, S., Louwagie, E.J., Baack, M.L., and Dey, M. (2017). Prenatal Exposure to a Maternal High-Fat Diet Affects Histone Modification of Cardiometabolic Genes in Newborn Rats. Nutrients, 9. source

      Results §3.4 reports several genes associated with metabolic processes among those with differential histone-mark binding. But it says only genes with a gene-ontology hit for “metabolic process” are reported there, so that selection does not establish that such genes were highly represented overall. The paper also does not compare this finding with a transcriptomic profile. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Interpretationcitation

    Maternal administration of natural compounds could also protect offspring from cardiovascular dysfunction through direct effects on the heart or by mitigating GDM-induced obesity or other cardiometabolic conditions.

    “Therefore, maternal administration of natural compounds could also protect offspring from cardiovascular dysfunction through direct effects on the heart or by mitigating GDM-induced obesity or other cardiometabolic conditions.”
    Quote in the paperSubstantial claim3 of 5 sources checked
    • cites [142] Cole, 2021, Supplemental Berberine in a High-Fat Diet Reduces Adiposity and Cardiac Dysfunction in Offspring of Mouse Dams with Gestational Diabetes Mellitus, J. Nutr. source
    • cites [143] Cole, 2021, Berberine elevates cardiolipin in heart of offspring from mouse dams with high fat diet-induced gestational diabetes mellitus, Sci. Rep. source

      The Discussion links berberine to protection from cardiac dysfunction in GDM-exposed mouse offspring through improved cardiac mitochondrial function, and the Introduction reports reduced adiposity with berberine treatment. But the Abstract says berberine was given to the offspring at weaning, not administered to their mothers. The paper therefore supports a possible protective effect of a natural compound, but not the claimed maternal route of administration. (LLM, conf=0.89)

      Experimental — accuracy not yet measured
    • cites [144] Lu, Z., He, B., Chen, Z., Yan, M., and Wu, L. (2020). Anti-inflammatory activity of berberine in non-alcoholic fatty liver disease via the Angptl2 pathway. BMC Immunol., 21. source

      The Methods (Animal experiments; page unavailable) describe berberine treatment in male rats with high-fat-diet-induced fatty liver disease, and the Conclusions concern liver inflammation. Searches for maternal administration, offspring, GDM, and cardiac outcomes found no passage addressing whether natural compounds protect offspring from cardiovascular dysfunction. (LLM, conf=0.78)

      Experimental — accuracy not yet measured
    • cites [145] Cicero, 2016, Berberine and Its Role in Chronic Disease, Adv. Exp. Med. Biol. source
    • cites [146] Yeung, 2020, Berberine, a popular dietary supplement for human and animal health: Quantitative research literature analysis—A review, Anim. Sci. Pap. Rep.

      The Berberine research literature analysis section reports effects of berberine on weight, glucose regulation, and vascular function in animals and some human subjects. It does not address maternal administration, GDM-exposed offspring, or protection of offspring hearts, so the claim extends those findings to a different population and outcome. (LLM, conf=0.75)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Berberine has been shown to reduce serum LDL cholesterol levels by stabilizing the LDL receptor mRNA, which is a different mechanism of cholesterol lowering achieved by statins and red yeast rice.

    “Berberine has been shown to reduce serum LDL cholesterol levels by stabilizing the LDL receptor mRNA, which is a different mechanism of cholesterol lowering achieved by statins and red yeast rice [146].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [146] Yeung, 2020, Berberine, a popular dietary supplement for human and animal health: Quantitative research literature analysis—A review, Anim. Sci. Pap. Rep.

      The Berberine research literature analysis section reports reduced LDL cholesterol, and the Introduction says berberine may lower serum cholesterol through a post-transcriptional mechanism different from those of statins and red yeast rice. Our copy does not specify stabilization of LDL receptor mRNA, and it hedges the proposed mechanism as a possibility. No page numbers are available in the supplied copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In the systematic review, high-quality evidence was lacking because of variability in the type and duration of exercise, many studies combined exercise with dietary changes, and few evaluated health outcomes beyond birth weight in the offspring.

    “However, in this review, high-quality evidence was lacking since there was variability in the type and duration of exercise in these studies; many studies combined exercise with dietary changes and few evaluated health outcomes beyond birth weight in the offspring.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [140] Guillemette, 2018, Exercise in Pregnancy and Children’s Cardiometabolic Risk Factors: A Systematic Review and Meta-Analysis, Sports Med. Open source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Exercise by obese dams improved thoracic aorta endothelial-dependent vasodilation in adult male offspring fed a postnatal high-fat diet, but not offspring fed the control diet.

    “Exercise by obese dams improved thoracic aorta endothelial-dependent vasodilation in adult male offspring fed a postnatal high-fat diet, but not offspring fed the control diet.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [138] Boonpattrawong, 2020, Exercise during pregnancy mitigates the adverse effects of maternal obesity on adult male offspring vascular function and alters one-carbon metabolism, Physiol. Rep. source

  • May combine two claims.

    Findingreasoning

    Spontaneous mortality was significantly higher in the combined maternal obesity and hyperglycemia model, indicating possible confounding effects of exposure to diabetes during pregnancy on the development of cardiac birth defects.

    “However, spontaneous mortality was significantly higher, indicating possible confounding effects of exposure to diabetes during pregnancy on the development of cardiac birth defects.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    In type 2 diabetes, hyperglycemia is generally viewed to be a consequence of peripheral tissue insulin resistance and insufficient insulin secretion, though T2D is a heterogeneous disorder.

    “In T2D, hyperglycemia is generally viewed to be a consequence of peripheral tissue of insulin resistance and insufficient insulin secretion, though T2D is a heterogenous disorder [7].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [7] Chatterjee, 2017, Type 2 diabetes, Lancet source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    The heart is the first functional organ to develop in the mammalian embryo.

    “The heart is the first functional organ to develop in the mammalian embryo.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Parental history of coronary artery disease and parental death by coronary artery disease are significant independent predictors of offspring coronary artery disease.

    “parental history of coronary artery disease and parental death by coronary artery disease were observed to be significant independent predictors of offspring coronary artery disease [31].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [31] Myers, 1990, Parental history is an independent risk factor for coronary artery disease: The Framingham Study, Am. Heart J. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Obesity is a key risk factor for the development of type 2 diabetes by promoting insulin resistance.

    “Obesity is a key risk factor for the development of T2D by promoting insulin resistance [7,10].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [7] Chatterjee, 2017, Type 2 diabetes, Lancet source
    • cites [10] Mokdad, 2003, Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001, JAMA source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Approximately 463 million people currently live with diabetes, and current projections estimate that 700 million individuals will have diabetes by 2045.

    “According to the International Diabetes Federation, approximately 463 million people currently live with diabetes, and the incidence is continuing to rise; current projections estimate that a startling 700 million individuals will have diabetes by 2045 [4].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] International Diabetes Federation (2019). IDF Diabetes Atlas, International Diabetes Federation. [9th ed.]. Available online: http://www.diabetesatlas.org.

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The International Diabetes Federation estimates that one in six of the annual 20 million live births are affected by hyperglycemia, with 16% related to diabetes during pregnancy and the remaining 84% related to gestational diabetes mellitus, making it the most common complication of pregnancy.

    “The International Diabetes Federation estimates that one in six of the annual 20 million live births are affected by hyperglycemia, with 16% related to diabetes during pregnancy and the remaining 84% related to GDM, making it the most common complication of pregnancy [4].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] International Diabetes Federation (2019). IDF Diabetes Atlas, International Diabetes Federation. [9th ed.]. Available online: http://www.diabetesatlas.org.

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Gestational diabetes mellitus is characterized by hyperglycemia, insulin resistance and increased gestational weight gain.

    “GDM is characterized by hyperglycemia, insulin resistance and increased gestational weight gain.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Despite confounding factors, the controlled environment in animal model experiments is useful to confirm the independent impact of prenatal exposures and address how these impact the future cardiovascular health of the offspring.

    “Despite these confounding factors, the controlled environment in animal model experiments is useful to confirm the independent impact of prenatal exposures and address how these impact the future cardiovascular health of the offspring.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    These observations imply that cardiometabolic impairments exist in nondiabetic women prior to pregnancy and can indicate risk for future gestational diabetes mellitus development.

    “These observations imply that cardiometabolic impairments exist in nondiabetic women prior to pregnancy and can indicate risk for future GDM development.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisereasoning

    A healthy pregnancy is associated with increasing insulin resistance in order to spare more glucose for the fetus.

    “A healthy pregnancy is associated with increasing insulin resistance (in order to spare more glucose for the fetus).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Human studies are difficult to control for confounding factors over a lengthy and expensive study period, and genetic variability adds an additional level of complexity.

    “While human studies are important to the field, it is difficult to control for confounding factors over a lengthy and expensive study period, and genetic variability adds an additional level of complexity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    The majority of women experiencing diabetes during pregnancy do not exhibit insulin deficiency but are often hyperinsulinemic and do not display excessive hyperglycemia, both of which occur following streptozotocin administration.

    “The majority of women experiencing diabetes during pregnancy do not exhibit insulin deficiency but are often hyperinsulinemic and do not display excessive hyperglycemia, both of which occur following STZ administration.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Despite maternal plasma glucose levels exceeding the clinical definition of gestational diabetes mellitus, 80-day-old Wistar rat offspring and 15-week-old Sprague-Dawley rat offspring remained glucose tolerant with normal islet morphology and retained similar plasma glucose and insulin levels as controls.

    “Despite maternal plasma glucose levels exceeding the clinical definition of GDM, 80-day-old Wistar rat offspring [90] and 15-week-old Sprague-Dawley rat offspring [92] remained glucose tolerant with normal islet morphology [92] and retained similar plasma glucose and insulin levels as controls [90].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [90] Aerts, 1997, The endocrine pancreas in virgin and pregnant offspring of diabetic pregnant rats, Diabetes Res. Clin. Pract. source
    • cites [92] Han, 2007, Rat maternal diabetes impairs pancreatic beta-cell function in the offspring, Am. J. Physiol. Endocrinol. Metab. source

  • May combine two claims.

    Premisecitation

    Hydroxylated acylcarnitines were increased, as were C12:0 and C12:1 acylcarnitines in response to maternal obesity, whereas C20:0 and C22:5 were lower in female offspring and in males, C11:0 and C15:0 were higher and C3:0 acylcarnitine was reduced.

    “Hydroxylated acylcarnitines were increased, as were C12:0 and C12:1 acylcarnitines in response to maternal obesity whereas C20:0 and C22:5 were lower in female offspring and in males, C11:0 and C15:0 were higher and C3:0 acylcarnitine was reduced.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Changes in lipid species and acylcarnitines could reflect changes in cardiac gene expression.

    “Changes in lipid species and acylcarnitines could reflect changes in cardiac gene expression.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Most triacylglycerols were more abundant while most phosphatidylcholines and odd chain phosphatidylethanolamine phospholipids were less abundant in the hearts of male and female offspring of obese dams.

    “Interestingly, most triacylglycerols were more abundant while most phosphatidylcholines and odd chain phosphatidylethanolamine phospholipids were less abundant in the hearts of male and female offspring of obese dams.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    These findings suggest that maternal obesity has transient effects on cardiac hypertrophy in the offspring, but persistent effects on diastolic function of the left ventricle.

    “These findings suggest that maternal obesity has transient effects on cardiac hypertrophy in the offspring, but persistent effects on diastolic function of the LV.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    While maternal obesity and the postnatal high-fat diet independently promoted cardiac hypertrophy and systolic dysfunction, these effects were not additive.

    “While maternal obesity and the postnatal high-fat diet independently promoted cardiac hypertrophy and systolic dysfunction, these effects were not additive.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Maternal obesity significantly increased the abundance of cardiac sphingomyelin in female offspring and reduced cholesterol ester levels in male and female offspring.

    “Maternal obesity significantly increased the abundance of cardiac sphingomyelin in female offspring and reduced cholesterol ester levels in male and female offspring.”
    Quote in the paperNot a substantial claim
61 of 61

  • The paper relies on this without support.

    The mechanisms responsible for the effects of maternal obesity and diabetes during pregnancy on offspring cardiovascular risk factors and heart disease development are unknown.

    “However, the mechanisms responsible for these observations are unknown.”

  • The paper relies on this without support.

    Human studies examining the intergenerational effects of diabetes during pregnancy and maternal obesity on cardiovascular end-points in the offspring at both the population level and in prospective cohort studies are lacking.

    “On the other hand, human studies examining the intergenerational effects of diabetes during pregnancy and maternal obesity on cardiovascular end-points in the offspring at both the population level and in prospective cohort studies are lacking.”
2 of 2

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Authors
Kereliuk, S. M., & Dolinsky, V. W.
Affiliations
Children's Hospital Research Institute of Manitoba (CA)
Corresponding author
Dolinsky, Vernon W.
ORCID
Venue
International Journal of Molecular Sciences
Publisher
MDPI AG
Published
2022-04-18
Volume
23
Issue
8
Pages
4467
ISSN
1422-0067 (ISSN-L)
DOI
10.3390/ijms23084467
PMC
PMC9027277
OpenAlex
W4224209993
Cited by
34
References
148
Citations by year
2026: 6 · 2025: 3 · 2024: 8 · 2023: 13 · 2022: 4
FWCI
6.93
Type
journal article
Language
en
Open access
Licence
Locations
  • International Journal of Molecular Sciences (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Research Manitoba
  • Manitoba Medical Service Foundation
Topics
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Birth, Development, and Health
  • Health Sciences › Medicine › Obstetrics and Gynecology › Gestational Diabetes Research and Management
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
Keywords
maternal obesity, gestational diabetes mellitus, fetal programming, offspring cardiovascular risk, energy metabolism, fetal growth
MeSH terms
Pregnancy in Obesity, Obesity, Maternal, Adolescent, Adult, Cardiovascular Diseases, Female, Heart Diseases, Humans, Pregnancy, Pregnancy Complications, Prenatal Exposure Delayed Effects, Diabetes, Gestational

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-20.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-20.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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