Maternal obesity/diabetes severely affects the offspring’s metabolism not only during the fetal and early life development but also later on in the childhood and adulthood stages. Recent evidence suggested that maternal metformin treatment during pregnancy and breastfeeding might provide long-term metabolic beneﬁts on offspring’s glucose homeostasis. We employed a mouse model of maternal overnutrition induced by high fat diet (HFD) to investigate whether an early metformin treatment in mouse dams during lactation period attenuates the maternal HFD-induced metabolic complications in male offspring. The results showed that male offspring from metformin-exposed mothers during suckling period displayed lower body weight and decreased white fat contents. Furthermore, these male offspring had lower blood glucose levels, decreased hyperinsulinemia, enhanced glucose tolerance and insulin sensitivity. Moreover, we found that short-term metformin treatment during lactation period in mouse dams solely improved the glucose tolerance of male offspring exposed with high fat diet (HFD) during both in utero and early postnatal stages, which might primarily result from an increase in insulin secretion. However, this metformin treatment in mouse dams was enabled to abolish most of the metabolic complications of the male offspring exposed with HFD during lactation period. Together, these ﬁndings suggest that an early intervention in mouse dams by metformin treatment during lactation period may provide long-term metabolic beneﬁts in regulation of male offspring’s glucose homeostasis.
Neslihan Güngör. Overweight and obesity in children and adolescents. Journalofclinicalresearchinpediatricendocrinology, 6:129–43, 09 2014.
Caterina Neri and Andrea Edlow. Effects of maternal obesity on fetal programming: Molecular approaches. Cold Spring Harbor perspectives in medicine, 6, 09 2015.
G. A. Ribaroff, E. Wastnedge, A. J. Drake, R. M. Sharpe, and T. J. G. Chambers. Animal models of maternal high fat diet exposure and effects on metabolism in offspring: a metaregression analysis. Obesity reviews : an ofﬁcial journal of the International Association for the Study of Obesity, 18(6):673–686, Jun 2017. 28371083[pmid].
Tanyara Baliani Payolla, Simone Ferreira Lemes, Thaís de Fante, Andressa Reginato, Cristiano Mendes da Silva, Thayana de Oliveira Micheletti, Hosana Gomes Rodrigues, Adriana Souza Torsoni, Marciane Milanski, and Marcio Alberto Torsoni. High-fat diet during pregnancy and lactation impairs the cholinergic anti-inﬂammatory pathway in the liver and white adipose tissue of mouse offspring. Molecular and cellular endocrinology, 422:192—202, February 2016.
Hisashi Masuyama and Yuji Hiramatsu. Additive effects of maternal high fat diet during lactation on mouse offspring. PloS one, 9:e92805, 03 2014.
Lindsay Ellsworth, Emma Harman, Vasantha Padmanabhan, andBrigidGregg. Lactationalprogrammingofglucosehomeostasis: a window of opportunity. Reproduction (Cambridge, England), 156(2):R23–R42, Aug 2018. 29752297[pmid].
Elizabeth Sanchez-Rangel and Silvio E Inzucchi. Metformin: clinical use in type 2 diabetes. Diabetologia, 60(9):1586—1593, September 2017.
Vanita R. Aroda, William C. Knowler, Jill P. Crandall, Leigh Perreault, Sharon L. Edelstein, Susan L. Jeffries, Mark E. Molitch, Xavier Pi-Sunyer, Christine Darwin, Brandy M. Heckman-Stoddard, Marinella Temprosa, Steven E. Kahn, DavidM.Nathan,andDiabetesPreventionProgramResearch Group. Metformin for diabetes prevention: insights gained from the diabetes prevention program/diabetes prevention program outcomes study. Diabetologia, 60(9):1601–1611, Sep 2017. 28770322[pmid].
Kristi Kelley, Dana Carroll, and Allison Meyer. A review of current treatment strategies for gestational diabetes mellitus. Drugs in context, 4:212282, 07 2015.
Jane Tarry-Adkins, Catherine Aiken, and Susan Ozanne. Neonatal, infant, and childhood growth following metformin versus insulin treatment for gestational diabetes: A systematic review and meta-analysis. PLOS Medicine, 16:e1002848, 08 2019.
Linda A. Barbour and Denice S. Feig. Metformin for gestational diabetes mellitus: Progeny, perspective, and a personalized approach. Diabetes Care, 42(3):396–399, 2019.
Suzanne N. Landi, Sarah Radke, Kim Boggess, Stephanie M. Engel, Til Stürmer, Anna S. Howe, and Michele Jonsson Funk. Comparative effectiveness of metformin versus insulin for gestational diabetes in new zealand. Pharmacoepidemiology and Drug Safety, 28(12):1609–1619, 2019.
Gonzalo Jorquera, Bárbara Echiburú, Nicolás Crisosto, Ramón Sotomayor-Zárate, Manuel Maliqueo, and Gonzalo Cruz. Metformin during pregnancy: Effects on offspring development and metabolic function. Frontiersin Pharmacology, 11:653, 06 2020.
Bo Sun, Ryan Purcell, Chantelle Terrillion, Jianqun Yan, Timothy Moran, and Kellie Tamashiro. Maternal high-fat diet during gestation or suckling differentially affects offspring leptin sensitivity and obesity. Diabetes, 61:2833–41, 06 2012.
BrigidGregg,NathalieBotezatu,JoshuaBrill,HannahHafner, Suryakiran Vadrevu, Leslie Satin, Emilyn Alejandro, and Ernesto Bernal-Mizrachi. Gestational exposure to metformin programs improved glucose tolerance and insulin secretion in adult male mouse offspring. Scientiﬁc Reports, 8, 12 2018.
Xingwei Liang, Qiyuan Yang, Lupei Zhang, Joseph Maricelli, Buel Rodgers, and Meijun Zhu. Maternal high-fat diet during lactation impairs thermogenic function of brown adipose tissue in offspring mice. Scientiﬁc reports, 6:34345, 09 2016.
Thomas Hale, J Kristensen, L Hackett, Rolland Kohan, and Kenneth Ilett. Transfer of metformin into human milk. Diabetologia, 45:1509–14, 12 2002.
Gerald G Briggs, Peter J Ambrose, Michael P Nageotte, Guadalupe Padilla, and Stephanie Wan. Excretion of metformin into breast milk and the effect on nursing infants. Obstetrics and gynecology, 105(6):1437—1441, June 2005.
ZachCarlson,HannahHafner,MollyMulcahy,KaylieBullock, AllenZhu,DaveBridges,ErnestoBernal-Mizrachi,andBrigid Gregg. Lactational metformin exposure programs offspring white adipose tissue glucose homeostasis and resilience to metabolic stress in a sex-dependent manner. American Journal
of Physiology-Endocrinology and Metabolism, 318(5):E600–E612, 2020. PMID: 32154743.
EszterVanky,JjNordskar,HLeithe,AkHjorth-Hansen,Marit Martinussen, and Sven Carlsen. Breast size increment during pregnancy and breastfeeding in mothers with polycystic ovary syndrome: A follow-up study of a randomised controlled trial on metformin versus placebo. BJOG : an international journal of obstetrics and gynaecology, 119:1403–1409, 07 2012.
Monika Słupecka-Ziemilska, Katarzyna Romanowicz, and Jarosław Wolin´ski. Maternal high-fat diet during pregnancy and lactation inﬂuences obestatin and ghrelin concentrations in milk and plasma of wistar rat dams and their offspring. International Journal of Endocrinology, 2016:1–9, 03 2016.
Gabriela E. Leghi, Merryn J. Netting, Philippa F. Middleton, MaryE.Wlodek,DonnaT.Geddes,Muhlhausler,andBeverly S. The impact of maternal obesity on human milk macronutrient composition: A systematic review and meta-analysis. Nutrients, 12(4):934, Mar 2020. 32230952[pmid].
Jeffrey Galley, Michael Bailey, Claire Kamp Dush, Sarah Schoppe-Sullivan, and Lisa Christian. Maternal obesity is associated with alterations in the gut microbiome in toddlers. PloS one, 9:e113026, 09 2014.
Derrick Chu, Kathleen Antony, Jun Ma, Amanda Prince, Lori Showalter, Michelle Moller, and Kjersti Aagaard. The early infant gut microbiome varies in association with a maternal high-fat diet. Genome Medicine, 8, 12 2016.