Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Current Diabetes Reports
Published in: Current Diabetes Reports 9/2020

01-09-2020 | Obesity | Pathogenesis of Type 2 Diabetes and Insulin Resistance (ME Patti, Section Editor)

Type 2 Diabetes in Youth: the Role of Early Life Exposures

Authors: Ankur Rughani, Jacob E. Friedman, Jeanie B. Tryggestad

Published in: Current Diabetes Reports | Issue 9/2020

Login to get access

Abstract

Purpose of Review

This review examines the impact of early life exposures on glucose metabolism in the offspring and explores potential metabolic mechanisms leading to type 2 diabetes in childhood.

Recent Findings

One in five adolescents is diagnosed with prediabetes. Recent studies have elucidated the impact of early exposures such as maternal diabetes, but also hyperglycemia below the threshold of gestational diabetes, obesity, hyperlipidemia, and paternal obesity on the future metabolic health of the offspring. Mechanisms affecting the developmental programing of offspring toward type 2 diabetes include epigenetic modifications, alterations in stem cell differentiation, metabolome and microbiome variation, immune dysregulation, and neonatal nutrition.

Summary

The risk of type 2 diabetes in offspring is increased not only by diabetes exposure in utero but also by exposure to a heterogeneous milieu of factors that accompany maternal obesity that provoke a vicious cycle of metabolic disease. The key period for intervention to prevent type 2 diabetes is within the first 1000 days of life.
Literature
1.
Mayer-Davis EJ, Dabelea D, Lawrence JM. Incidence trends of type 1 and type 2 diabetes among youths, 2002-2012. N Engl J Med. 2017;377(3):301.PubMedPubMedCentral
2.
Andes LJ, Cheng YJ, Rolka DB, Gregg EW, Imperatore G. Prevalence of prediabetes among adolescents and Young adults in the United States, 2005-2016. JAMA Pediatr. 2019:e194498.
3.
Narayan KM, Boyle JP, Thompson TJ, Sorensen SW, Williamson DF. Lifetime risk for diabetes mellitus in the United States. JAMA. 2003;290(14):1884–90.PubMed
4.
Zeitler P, Hirst K, Pyle L, Linder B, Copeland K, Arslanian S, et al. A clinical trial to maintain glycemic control in youth with type 2 diabetes. N Engl J Med. 2012;366(24):2247–56.
5•.
Hales CN, Barker DJ. Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis. Diabetologia. 1992;35(7):595–601. An overview of the central hypothesis that maternal and early postnatal nutrition affect beta cell development and function, and may predispose infants to eventually develop type 2 diabetes.
6•.
Ong TP, Guest PC. Nutritional programming effects on development of metabolic disorders in later life. Methods Mol Biol. 1735;2018:3–17. A review summarizing factors affecting developmental programming in utero that lead to future type 2 diabetes, obesity and cardiovascular disease in offspring while exploring the molecular mechanism underlying these risks, and proposing potential interventions.
7•.
Dunford AR, Sangster JM. Maternal and paternal periconceptional nutrition as an indicator of offspring metabolic syndrome risk in later life through epigenetic imprinting: a systematic review. Diabetes Metab Syndr. 2017;11(Suppl 2):S655–S62. A review exploring the impact of parental nutrition—both maternal and paternal—on DNA methylation in the offspring and the subsequent risk of metabolic syndrome.
8•.
Ramos-Roman MA. Breast milk: a postnatal link between maternal life choices and the prevention of childhood obesity. Clin Ther. 2018;40(10):1655–8. A brief review of the evidence in favor of breastmilk nutrition on offspring body composition and metabolic function.
9.
Gunderson EP, Greenspan LC, Faith MS, Hurston SR, Quesenberry CP Jr, Investigators SOS. Breastfeeding and growth during infancy among offspring of mothers with gestational diabetes mellitus: a prospective cohort study. Pediatr Obes. 2018;13(8):492–504.PubMedPubMedCentral
10•.
Bider-Canfield Z, Martinez MP, Wang X, Yu W, Bautista MP, Brookey J, et al. Maternal obesity, gestational diabetes, breastfeeding and childhood overweight at age 2 years. Pediatr Obes. 2017;12(2):171–8. A retrospective longitudinal cohort study finding maternal pre-pregnancy overweight and obesity as well as excessive gestational weight gain were independently associated with an increased risk of childhood overweight at age 2 years, whereas breastfeeding ≥6 months was protective.
11.
Yang J, Cummings EA, O'Connell C, Jangaard K. Fetal and neonatal outcomes of diabetic pregnancies. Obstet Gynecol. 2006;108(3 Pt 1):644–50.PubMed
12.
Nehring I, Chmitorz A, Reulen H, von Kries R, Ensenauer R. Gestational diabetes predicts the risk of childhood overweight and abdominal circumference independent of maternal obesity. Diabet Med. 2013;30(12):1449–56.PubMed
13•.
Pitchika A, Vehik K, Hummel S, Norris JM, Uusitalo UM, Yang J, et al. Associations of maternal diabetes during pregnancy with overweight in offspring: results from the prospective teddy study. Obesity (Silver Spring). 2018;26(9):1457–66. Prospective cohort data from the TEDDY study demonstrating increased risk of overweight offspring to mothers with GDM and prepregnancy obesity, an association that strengthened with increasing age of the child.
14.
Holder T, Giannini C, Santoro N, Pierpont B, Shaw M, Duran E, et al. A low disposition index in adolescent offspring of mothers with gestational diabetes: a risk marker for the development of impaired glucose tolerance in youth. Diabetologia. 2014;57(11):2413–20.PubMed
15.
Chernausek SD, Arslanian S, Caprio S, Copeland KC, El ghormli L, Kelsey MM, et al. Relationship between parental diabetes and presentation of metabolic and glycemic function in youth with type 2 diabetes: baseline findings from the today trial. Diabetes Care. 2016;39(1):110–7.
16•.
Sauder KA, Hockett CW, Ringham BM, Glueck DH, Dabelea D. Fetal overnutrition and offspring insulin resistance and β-cell function: the exploring perinatal outcomes among children (EPOCH) study. Diabet Med. 2017;34(10):1392–9. This longitudinal cohort study examined the impact of in utero exposure to on offspring at ages 10 and 16 finding that intrauterine exposure to DM or obesity was associated with greater offspring insulin resistance in childhood and adolescence.
17•.
Grunnet LG, Hansen S, Hjort L, Madsen CM, Kampmann FB, Thuesen ACB, et al. Adiposity, dysmetabolic traits, and earlier onset of female puberty in adolescent offspring of women with gestational diabetes mellitus: a clinical study within the danish national birth cohort. Diabetes Care. 2017;40(12):1746–55. A longitudinal prospective cohort study from Denmark exploring the impact of maternal DM on offspring finding adolescent offspring exposed to maternal DM have increased adiposity, worse cardiometabolic profiles, and earlier onset of puberty in girls.
18.
Short KR, Teague AM, Fields DA, Lyons T, Chernausek SD. Lower resting energy expenditure and fat oxidation in native American and Hispanic infants born to mothers with diabetes. J Pediatr. 2015;166(4):884–9.PubMedPubMedCentral
19•.
Scholtens DM, Kuang A, Lowe LP, Hamilton J, Lawrence JM, Lebenthal Y, et al. Hyperglycemia and adverse pregnancy outcome follow-up study (HAPO FUS): maternal Glycemia and childhood glucose metabolism. Diabetes Care. 2019;42(3):381–92. A follow up of the observational HAPO study at ages 10-14 years in the offspring revealed in utero exposure to higher levels of glucose is significantly associated with childhood glucose and insulin resistance independent of maternal and childhood BMI and family history of diabetes.
20•.
Lowe WL Jr, Scholtens DM, Kuang A, Linder B, Lawrence JM, Lebenthal Y, et al. Hyperglycemia and adverse pregnancy outcome follow-up study (HAPO FUS): maternal gestational diabetes mellitus and childhood glucose metabolism. Diabetes Care. 2019;42(3):372–80. A follow up of the observational HAPO study at 10-14 years in the offspring revealed offspring exposed to maternal GDM in utero are insulin resistant with limited β-cell compensation, and that GDM exposure is significantly and independently associated with offspring impaired glucose tolerance.
21.
Lowe WL Jr, Scholtens DM, Lowe LP, Kuang A, Nodzenski M, Talbot O, et al. Association of Gestational Diabetes with Maternal Disorders of glucose metabolism and childhood adiposity. JAMA. 2018;320(10):1005–16.PubMedPubMedCentral
22.
Lowe WL Jr, Lowe LP, Kuang A, Catalano PM, Nodzenski M, Talbot O, et al. Maternal glucose levels during pregnancy and childhood adiposity in the hyperglycemia and adverse pregnancy outcome follow-up study. Diabetologia. 2019;62(4):598–610.PubMedPubMedCentral
23.
Tam WH, Ma RCW, Ozaki R, Li AM, Chan MHM, Yuen LY, et al. In utero exposure to maternal hyperglycemia increases childhood Cardiometabolic risk in offspring. Diabetes Care. 2017;40(5):679–86.PubMedPubMedCentral
24•.
Gomes D, von Kries R, Delius M, Mansmann U, Nast M, Stubert M, et al. Latepregnancy dysglycemia in obese pregnancies after negative testing for gestational diabetes and risk of future childhood overweight: an interim analysis from a longitudinal mother-child cohort study. PLoS Med. 2018;15(10):e1002681-e. A prospective cohort study assessed the impact of late-pregnancy dysglycemia in obese pregnancies with negative testing for GDM founding that offspring at age 4 years of obese mothers treated because of a diagnosis of GDM appeared to have a better BMI outcome than those of obese mothers who developed dysglycemia after a negative GDM screen.
25.
Catalano PM, Farrell K, Thomas A, Huston-Presley L, Mencin P, de Mouzon SH, et al. Perinatal risk factors for childhood obesity and metabolic dysregulation. Am J Clin Nutr. 2009;90(5):1303–13.PubMedPubMedCentral
26.
Gaillard R, Steegers EA, Duijts L, Felix JF, Hofman A, Franco OH, et al. Childhood cardiometabolic outcomes of maternal obesity during pregnancy: the generation R study. Hypertension. 2014;63(4):683–91.PubMed
27.
Starling AP, Brinton JT, Glueck DH, Shapiro AL, Harrod CS, Lynch AM, et al. Associations of maternal BMI and gestational weight gain with neonatal adiposity in the healthy start study. Am J Clin Nutr. 2015;101(2):302–9.PubMed
28.
Crume TL, Shapiro AL, Brinton JT, Glueck DH, Martinez M, Kohn M, et al. Maternal fuels and metabolic measures during pregnancy and neonatal body composition: the healthy start study. J Clin Endocrinol Metab. 2015;100(4):1672–80.PubMedPubMedCentral
29.
Oostvogels AJJM, Stronks K, Roseboom TJ, van der Post JAM, van Eijsden M, Vrijkotte TGM. Maternal prepregnancy BMI, offspring's early postnatal growth, and metabolic profile at age 5-6 years: the ABCD study. J Clin Endocrinol Metab. 2014;99(10):3845–54.PubMed
30•.
Lahti-Pulkkinen M, Bhattacharya S, Wild SH, Lindsay RS, Räikkönen K, Norman JE, et al. Consequences of being overweight or obese during pregnancy on diabetes in the offspring: a record linkage study in Aberdeen, Scotland. Diabetologia. 2019;62(8):1412–9. A retrospective cohort analysis from Scotland demmonstrated that maternal overweight or obesity was associated with increased incidence of T2DM in the offspring, independent of other perinatal and sociodemographic factors.
31.
Karachaliou M, Georgiou V, Roumeliotaki T, Chalkiadaki G, Daraki V, Koinaki S, et al. Association of trimester-specific gestational weight gain with fetal growth, offspring obesity, and cardiometabolic traits in early childhood. Am J Obstet Gynecol. 2015;212(4):502 e1–14.
32.
Kaar JL, Crume T, Brinton JT, Bischoff KJ, McDuffie R, Dabelea D. Maternal obesity, gestational weight gain, and offspring adiposity: the exploring perinatal outcomes among children study. J Pediatr. 2014;165(3):509–15.PubMedPubMedCentral
33.
Heerwagen MJR, Gumina DL, Hernandez TL, Van Pelt RE, Kramer AW, Janssen RC, et al. Placental lipoprotein lipase activity is positively associated with newborn adiposity. Placenta. 2018;64:53–60.PubMed
34•.
Barbour LA, Hernandez TL. Maternal lipids and fetal overgrowth: making fat from fat. Clin Ther. 2018;40(10):1638–47. This review explores the relationship between elevated maternal triglycerides and fetal fat accretion even in the absence of GDM.
35•.
Barbour LA, Farabi SS, Friedman JE, Hirsch NM, Reece MS, Van Pelt RE, et al. Postprandial triglycerides predict newborn fat more strongly than glucose in women with obesity in early pregnancy. Obesity (Silver Spring). 2018;26(8):1347–56. This prospective study explores the association between fasting and postprandial triglycerides in pregnant women of normal weight and obese without GDM and newborn percent fat suggesting that postprandial triglycerides may be a clinical marker of future child obesity risk.
36•.
Cena H, Calder PC. Defining a healthy diet: evidence for the role of contemporary dietary patterns in health and disease. Nutrients. 2020;12(2). This review describes diets that have been shown to positively impact health using clinical and epidemiological data.
37•.
Statovci D, Aguilera M, MacSharry J, Melgar S. The impact of western diet and nutrients on the microbiota and immune response at mucosal interfaces. Front Immunol. 2017;8:838. This review focuses on the impact of western diets and component macronutrients and micronutrients on host inflammatory responses that may be contributing to chronic autoimmune conditions.
38.
Cordain L, Eaton SB, Sebastian A, Mann N, Lindeberg S, Watkins BA, et al. Origins and evolution of the Western diet: health implications for the 21st century. Am J Clin Nutr. 2005;81(2):341–54.
39.
Crume TL, Brinton JT, Shapiro A, Kaar J, Glueck DH, Siega-Riz AM, et al. Maternal dietary intake during pregnancy and offspring body composition: the healthy start study. Am J Obstet Gynecol. 2016;215(5):609 e1–8.
40.
Chatzi L, Rifas-Shiman SL, Georgiou V, Joung KE, Koinaki S, Chalkiadaki G, et al. Adherence to the Mediterranean diet during pregnancy and offspring adiposity and cardiometabolic traits in childhood. Pediatr Obes. 2017;12(Suppl 1):47–56.PubMedPubMedCentral
41•.
Shareef M, Saleh L, van den Meiracker AH, Visser W. The impact of implementing the WHO-2013 criteria for gestational diabetes mellitus on its prevalence and pregnancy outcomes:a comparison of the WHO-1999 and WHO-2013 diagnostic thresholds. Eur J Obstet Gynecol Reprod Biol. 2019;246:14–8. This retrospective study from the Netherlands found that GDM as defined by the updated WHO criteria demonstrated increased prevalence of GDM and supported the use of a lower fasting glucose threshold.
42.
DeSisto CL, Kim SY, Sharma AJ. Prevalence estimates of gestational diabetes mellitus in the United States, pregnancy risk assessment monitoring system (PRAMS), 2007-2010. Prev Chronic Dis. 2014;11:E104.PubMedPubMedCentral
43.
de Seymour J, Chia A, Colega M, Jones B, McKenzie E, Shirong C, et al. Maternal dietary patterns and gestational diabetes mellitus in a multi-ethnic Asian cohort: the GUSTO study. Nutrients. 2016;8(9).
44.
45.
Branum AM, Kirmeyer SE, Gregory EC. Prepregnancy body mass index by maternal characteristics and state: data from the birth certificate, 2014. Natl Vital Stat Rep. 2016;65(6):1–11.PubMed
46.
Deputy NP, Dub B, Sharma AJ. Prevalence and trends in Prepregnancy Normal weight - 48 states, new York City, and District of Columbia, 2011-2015. MMWR Morb Mortal Wkly Rep. 2018;66(51–52):1402–7.PubMedPubMedCentral
47•.
Singh GK, DiBari JN. Marked disparities in pre-pregnancy obesity and overweight prevalence among us women by race/ethnicity, nativity/immigrant status, and sociodemographic characteristics, 2012-2014. J Obes. 2019;2019:2419263. This retrospective population-based study explores the heterogeneity in metabolic risks across racial and immigrant groups.
48.
Dani C, Bresci C, Berti E, Ottanelli S, Mello G, Mecacci F, et al. Metabolomic profile of term infants of gestational diabetic mothers. The Journal of Maternal-Fetal & Neonatal Medicine : the official Journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstet. 2014;27(6):537–42.
49•.
Schlueter RJ, Alakwaa FM, Benny PA, Gurary A, Xie G, Jia W, et al. Pre-pregnant obesity of mothers in a multi-ethnic cohort is associated with cord blood metabolomic changes in offspring. J Proteome Res. 2020. A case-control study investigated the metabolomic changes in cord blood from infants exposed to obese vs. normal weight mothers and identified several cord blood metabolites associated with maternal obesity.
50•.
Shokry E, Marchioro L, Uhl O, Bermudez MG, Garcia-Santos JA, Segura MT, et al. Impact of maternal BMI and gestational diabetes mellitus on maternal and cord blood metabolome: results from the PREOBE cohort study. Acta Diabetol. 2019;56(4):421–30. A German study that examines metabolites in maternal and fetal blood with associations noted between BMI and branched chain amino acids, as well as inflammation and beta oxidation with GDM.
51.
Lowe WL Jr, Bain JR, Nodzenski M, Reisetter AC, Muehlbauer MJ, Stevens RD, et al. Maternal BMI and Glycemia impact the fetal metabolome. Diabetes Care. 2017;40(7):902–10.PubMedPubMedCentral
52•.
Perng W, Ringham BM, Smith HA, Michelotti G, Kechris KM, Dabelea D. A prospective study of associations between in utero exposure to gestational diabetes mellitus and metabolomic profiles during late childhood and adolescence. Diabetologia. 2020;63(2):296–312. This prospective study performed investigated the impact of exposure to GDM on metabolite patterns from childhood through adolescence and found higher circulating phospholipids in offspring exposed to GDM which were associated with higher adiposity and worse metabolic profile in females.
53.
Lynch CJ, Adams SH. Branched-chain amino acids in metabolic signalling and insulin resistance. Nat Rev Endocrinol. 2014;10(12):723–36.PubMedPubMedCentral
54•.
Broadney MM, Chahal N, Michels KA, McLain AC, Ghassabian A, Lawrence DA, et al. Impact of parental obesity on neonatal markers of inflammation and immune response. Int J Obes. 2017;41(1):30–7. This study examined the association between parental BMI and gestational weight gain and markers of inflammation and immune function in the offspring identifying an association between maternal (but not paternal) BMI and systemic inflammation in newborns.
55.
Sureshchandra S, Wilson RM, Rais M, Marshall NE, Purnell JQ, Thornburg KL, et al. Maternal Pregravid obesity remodels the DNA methylation landscape of cord blood monocytes disrupting their inflammatory program. J Immunol. 2017;199(8):2729–44.PubMedPubMedCentral
56.
Segovia SA, Vickers MH, Gray C, Reynolds CM. Maternal obesity, inflammation, and developmental programming. Biomed Res Int. 2014;2014:418975.PubMedPubMedCentral
57.
Marques AH, Bjorke-Monsen AL, Teixeira AL, Silverman MN. Maternal stress, nutrition and physical activity: impact on immune function, CNS Development and Psychopathology. Brain Res. 1617;2015:28–46.
58.
Teague AM, Fields DA, Aston CE, Short KR, Lyons TJ, Chernausek SD. Cord blood adipokines, neonatal anthropometrics and postnatal growth in offspring of Hispanic and native American women with diabetes mellitus. Reprod Biol Endocrinol. 2015;13:68.PubMedPubMedCentral
59•.
Kampmann FB, Thuesen ACB, Hjort L, Bjerregaard AA, Chavarro J, Frystyk J, et al. Increased leptin, decreased adiponectin and FGF21 concentrations in adolescent offspring of women with gestational diabetes. Eur J Endocrinol. 2019. A cross-sectional Danish study of offspring aged 9—16 years measured body composition, pubertal status, and metabolic characteristics of offspring exposed to GDM in utero and found that GDM exposure was correlated with higher leptin, lower adiponectin, and lower FGF21 though leptin and adiponectin were likely associated with offspring obesity.
60.
Esteve E, Ricart W, Fernandez-Real JM. Adipocytokines and insulin resistance: the possible role of lipocalin-2, retinol binding protein-4, and adiponectin. Diabetes Care. 2009;32(Suppl 2):S362–7.PubMedPubMedCentral
61.
Amitani M, Asakawa A, Amitani H, Inui A. The role of leptin in the control of insulin glucose axis. Front Neurosci. 2013;7:51.PubMedPubMedCentral
62.
Cottrell EC, Cripps RL, Duncan JS, Barrett P, Mercer JG, Herwig A, et al. Developmental changes in hypothalamic leptin receptor: relationship with the postnatal leptin surge and energy balance neuropeptides in the postnatal rat. Am J Physiol Regul Integr Comp Physiol. 2009;296(3):R631–9.PubMedPubMedCentral
63.
Herzberg-Schafer S, Heni M, Stefan N, Haring HU, Fritsche A. Impairment of GLP1-induced insulin secretion: role of genetic background, insulin resistance and hyperglycaemia. Diabetes Obes Metab. 2012;14(Suppl 3):85–90.PubMed
64.
Chandler-Laney PC, Bush NC, Rouse DJ, Mancuso MS, Gower BA. Gut hormone activity of children born to women with and without gestational diabetes. Pediatr Obes. 2014;9(1):53–62.PubMed
65.
Kelstrup L, Clausen TD, Mathiesen ER, Hansen T, Holst JJ, Damm P. Incretin and glucagon levels in adult offspring exposed to maternal diabetes in pregnancy. J Clin Endocrinol Metab. 2015;100(5):1967–75.PubMed
66.
del Rosario MC, Ossowski V, Knowler WC, Bogardus C, Baier LJ, Hanson RL. Potential epigenetic dysregulation of genes associated with MODY and type 2 diabetes in humans exposed to a diabetic intrauterine environment: an analysis of genome-wide DNA methylation. Metabolism. 2014;63(5):654–60.PubMedPubMedCentral
67•.
Chen P, Piaggi P, Traurig M, Bogardus C, Knowler WC, Baier LJ, et al. Differential methylation of genes in individuals exposed to maternal diabetes in utero. Diabetologia. 2017;60(4):645–55. A genomewide DNA methylation study of peripheral blood from Pima Indian offspring revealed differentially methylated CpGs in 39 genomic regions associated with intrauterine DM exposure.
68•.
Lin X, Lim IY, Wu Y, Teh AL, Chen L, Aris IM, et al. Developmental pathways to adiposity begin before birth and are influenced by genotype, prenatal environment and epigenome. BMC Med. 2017;15(1):50.PubMedPubMedCentral
69•.
Hjort L, Martino D, Grunnet LG, Naeem H, Maksimovic J, Olsson AH, et al. Gestational diabetes and maternal obesity are associated with epigenome-wide methylation changes in children. JCI Insight. 2018;3(17). A Danish study genome-wide DNA methylation study comparing the DNA methylation profiles of GDM exposed and control offspring found differentially methylated CpGs in GDM exposed offspring at 9-16 years of age, however, a significant number of methylated CpGs were associated with prepregnancy maternal BMI rather than GDM.
70.
Sharp GC, Salas LA, Monnereau C, Allard C, Yousefi P, Everson TM, et al. Maternal BMI at the start of pregnancy and offspring epigenome-wide DNA methylation: findings from the pregnancy and childhood epigenetics (PACE) consortium. Hum Mol Genet. 2017;26(20):4067–85.PubMedPubMedCentral
71.
Thakali KM, Faske JB, Ishwar A, Alfaro MP, Cleves MA, Badger TM, et al. Maternal obesity and gestational weight gain are modestly associated with umbilical cord DNA methylation. Placenta. 2017;57:194–203.PubMed
72.
Sharp GC, Lawlor DA, Richmond RC, Fraser A, Simpkin A, Suderman M, et al. Maternal pre-pregnancy BMI and gestational weight gain, offspring DNA methylation and later offspring adiposity: findings from the Avon longitudinal study of parents and children. Int J Epidemiol. 2015;44(4):1288–304.PubMedPubMedCentral
73.
Juvinao-Quintero DL, Hivert M-F, Sharp GC, Relton CL, Elliott HR. DNA methylation and type 2 diabetes: the use of Mendelian randomization to assess causality. Curr Genet Med Rep. 2019;7(4):191–207.PubMedPubMedCentral
74.
Tryggestad JB, Vishwanath A, Jiang S, Mallappa A, Teague AM, Takahashi Y, et al. Influence of gestational diabetes mellitus on human umbilical vein endothelial cell miRNA. Clin Sci (Lond). 2016;130(21):1955–67.
75.
Floris I, Descamps B, Vardeu A, Mitic T, Posadino AM, Shantikumar S, et al. Gestational diabetes mellitus impairs fetal endothelial cell functions through a mechanism involving microRNA-101 and histone methyltransferase enhancer of zester homolog-2. Arterioscler Thromb Vasc Biol. 2015;35(3):664–74.PubMed
76.
Houshmand-Oeregaard A, Schrolkamp M, Kelstrup L, Hansen NS, Hjort L, Thuesen ACB, et al. Increased expression of microRNA-15a and microRNA-15b in skeletal muscle from adult offspring of women with diabetes in pregnancy. Hum Mol Genet. 2018;27(10):1763–71.PubMed
77.
Jones A, Danielson KM, Benton MC, Ziegler O, Shah R, Stubbs RS, et al. miRNA signatures of insulin resistance in obesity. Obesity (Silver Spring). 2017;25(10):1734–44.
78.
Ma E, Fu Y, Garvey WT. Relationship of circulating miRNAs with insulin sensitivity and associated metabolic risk factors in humans. Metab Syndr Relat Disord. 2018;16(2):82–9.PubMedPubMedCentral
79.
Shah R, Murthy V, Pacold M, Danielson K, Tanriverdi K, Larson MG, et al. Extracellular RNAs are associated with insulin resistance and metabolic phenotypes. Diabetes Care. 2017;40(4):546–53.PubMedPubMedCentral
80•.
Noor N, Cardenas A, Rifas-Shiman SL, Pan H, Dreyfuss JM, Oken E, et al. Association of Periconception Paternal Body Mass Index with Persistent Changes in DNA methylation of offspring in childhood. JAMA Netw Open. 2019;2(12):e1916777. This prospective longitudinal study in the US (Project Viva) evaluated genome-wide DNA methylation patterns in offspring from 429 fathermother-child triads at ages 3 and 7 years finding that paternal BMI was associated with the offspring’s DNA methylation, birth weight, and childhood BMI.
81.
van Otterdijk SD, Michels KB. Transgenerational epigenetic inheritance in mammals: how good is the evidence? FASEB J. 2016;30(7):2457–65.PubMed
82.
Boyle KE, Patinkin ZW, Shapiro AL, Baker PR 2nd, Dabelea D, Friedman JE. Mesenchymal stem cells from infants born to obese mothers exhibit greater potential for Adipogenesis: the healthy start BabyBUMP project. Diabetes. 2016;65(3):647–59.PubMed
83.
Ullah I, Subbarao RB, Rho GJ. Human mesenchymal stem cells - current trends and future prospective. Biosci Rep. 2015;35(2).
84•.
Boyle KE, Patinkin ZW, Shapiro ALB, Bader C, Vanderlinden L, Kechris K, et al. Maternal obesity alters fatty acid oxidation, AMPK activity, and associated DNA methylation in mesenchymal stem cells from human infants. Mol Metab. 2017;6(11):1503–16. Using data from the Healthy Start longitudinal cohort, umbilical derived mesenchymal stem cells exhibit greater lipid accumulation, lower fatty acid oxidation, and dysregulation of AMPK activity when undergoing myogenesis in vitro.
85•.
Baker PR 2nd, Patinkin Z, Shapiro AL, De La Houssaye BA, Woontner M, Boyle KE, et al. Maternal obesity and increased neonatal adiposity correspond with altered infant mesenchymal stem cell metabolism. JCI Insight. 2017;2(21). This study explores the variation in energy metabolism and gene expression that occur in differentiating umbilical MSC myocytes and adipocytes in offspring of normal weight and obese mothers.
86•.
Baker PR 2nd, Patinkin ZW, Shapiro ALB, de la Houssaye BA, Janssen RC, Vanderlinden LA, et al. Altered gene expression and metabolism in fetal umbilical cord mesenchymal stem cells correspond with differences in 5-month-old infant adiposity gain. Sci Rep. 2017;7(1):18095. This study provides the first evidence of alterations in metabolic pathways in the adipocytes and myocytes in infants with rapid vs. lower postnatal gain in adiposity.
87•.
Iaffaldano L, Nardelli C, D'Alessio F, D'Argenio V, Nunziato M, Mauriello L, et al. Altered bioenergetic profile in umbilical cord and amniotic mesenchymal stem cells from newborns of obese women. Stem Cells Dev. 2018;27(3):199–206. This study showed that maternal obesity decreases the efficiency of glycolysis and mitochondrial respiration on placental and umbilical cord mesenchymal stem cells.
88.
89•.
Kumbhare SV, Patangia DVV, Patil RH, Shouche YS, Patil NP. Factors influencing the gut microbiome in children: from infancy to childhood. J Biosci. 2019;44(2). A review of factors that influence microbiome composition in children starting in the fetus through childhood.
90•.
Robertson RC, Manges AR, Finlay BB, Prendergast AJ. The human microbiome and child growth - first 1000 days and beyond. Trends Microbiol. 2019;27(2):131–47. A review highlighting the emerging evidence on the importance of the microbiome to child health and growth, especially during the first 3 years of life.
91•.
Soderborg TK, Clark SE, Mulligan CE, Janssen RC, Babcock L, Ir D, et al. The gut microbiota in infants of obese mothers increases inflammation and susceptibility to NAFLD. Nat Commun. 2018;9(1):4462. A germ-free mouse model with fecal transplant from infants born to mothers with obesity compared to those born to normal weight mothers demonstrated that early changes to the gut microbiome in infants alters gut permeability, macrophage activity, and hepatic inflammation.
92•.
Paun A, Danska JS. Modulation of type 1 and type 2 diabetes risk by the intestinal microbiome. Pediatr Diabetes. 2016;17(7):469–77. This review highlights the association of microbiome composition to pancreatic immunity, insulin resistance, and obesity.
93•.
Kimura I, Miyamoto J, Ohue-Kitano R, Watanabe K, Yamada T, Onuki M, et al. Maternal gut microbiota in pregnancy influences offspring metabolic phenotype in mice. Science. 2020;367(6481). This murine study demonstrated the importance of short-chain fatty acids from maternal gut microbiota during pregnancy on the development of metabolic syndrome in the offspring.
94.
Lemas DJ, Young BE, Baker PR 2nd, Tomczik AC, Soderborg TK, Hernandez TL, et al. Alterations in human milk leptin and insulin are associated with early changes in the infant intestinal microbiome. Am J Clin Nutr. 2016;103(5):1291–300.PubMedPubMedCentral
95•.
Young BE, Levek C, Reynolds RM, Rudolph MC, MacLean P, Hernandez TL, et al. Bioactive components in human milk are differentially associated with rates of lean and fat mass deposition in infants of mothers with normal vs. elevated BMI. Pediatr Obes. 2018;13(10):598–606. This longitudinal observational study examines the impact of human milk components on infant body composition.
96•.
Isganaitis E, Venditti S, Matthews TJ, Lerin C, Demerath EW, Fields DA. Maternal obesity and the human milk metabolome: associations with infant body composition and postnatal weight gain. Am J Clin Nutr. 2019;110(1):111–20. This prospective study analyzed differences in human milk metabolites from overweight/obese and lean mothers, and the resulting changes to infant body composition suggesting that obesity-associated human milk may play a role in childhood obesity.
97•.
Heard-Lipsmeyer ME, Diaz EC, Sims CR, Sobik SR, Ruebel ML, Thakali KM, et al. Maternal adiposity is associated with fat mass accretion in female but not male offspring during the first 2 years of life. Obesity (Silver Spring). 2020;28(3):624–30. This study examined determinants of adiposity in the first 2 years of life of children demonstrating sex specific effects.
98.
Yan J, Liu L, Zhu Y, Huang G, Wang PP. The association between breastfeeding and childhood obesity: a meta-analysis. BMC Public Health. 2014;14:1267.PubMedPubMedCentral
99.
Herrera E, Desoye G. Maternal and fetal lipid metabolism under normal and gestational diabetic conditions. Horm Mol Biol Clin Investig. 2016;26(2):109–27.PubMed
100•.
Catalano PM, Shankar K. Obesity and pregnancy: mechanisms of short term and long term adverse consequences for mother and child. BMJ. 2017;356:j1. This is a comprehensive review of the pathophysiology and mechanisms underlying adverse perinatal outcomes associated with maternal obesity, insulin resistance, inflammation, and oxidative stress.
101.
Simmons D. Prevention of gestational diabetes mellitus: where are we now? Diabetes Obes Metab. 2015;17(9):824–34.PubMed
102.
Desoye G, Nolan CJ. The fetal glucose steal: an underappreciated phenomenon in diabetic pregnancy. Diabetologia. 2016;59(6):1089–94.PubMedPubMedCentral
Metadata
Title
Type 2 Diabetes in Youth: the Role of Early Life Exposures
Authors
Ankur Rughani
Jacob E. Friedman
Jeanie B. Tryggestad
Publication date
01-09-2020
Publisher
Springer US
Published in
Current Diabetes Reports / Issue 9/2020
Print ISSN: 1534-4827
Electronic ISSN: 1539-0829
DOI
https://doi.org/10.1007/s11892-020-01328-6

Other articles of this Issue 9/2020

Current Diabetes Reports 9/2020 Go to the issue

Pathogenesis of Type 1 Diabetes (A Pugliese and S Richardson, Section Editors)

miRNA Regulation of T Cells in Islet Autoimmunity and Type 1 Diabetes

Pathogenesis of Type 2 Diabetes and Insulin Resistance (ME Patti, Section Editor)

The Physiological Importance of Bile Acid Structure and Composition on Glucose Homeostasis

Other Forms of Diabetes and Its Complications (JJ Nolan and H Thabit, Section Editors)

Early Onset of Autoimmune Diabetes in Children with Down Syndrome—Two Separate Aetiologies or an Immune System Pre-Programmed for Autoimmunity?

Obesity (KM Gadde and P Singh, Section Editors)

Endocrine Mechanisms Connecting Exercise to Brown Adipose Tissue Metabolism: a Human Perspective

Pathogenesis of Type 1 Diabetes (A Pugliese and SJ Richardson, Section Editors)

Lipidomic Abnormalities During the Pathogenesis of Type 1 Diabetes: a Quantitative Review

Genetics (AP Morris, Section Editor)

Bariatric Surgery for Monogenic Non-syndromic and Syndromic Obesity Disorders
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Heart Failure Video

Year in Review: Heart failure and cardiomyopathies

Watch now

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits