Intrauterine growth restriction (IUGR) is a common complication of pregnancy and increases the risk of the offspring developing type 2 diabetes mellitus (T2DM) later in life. Alterations in the immune system are implicated in the pathogenesis of IUGR-induced T2DM. The development of the fetal immune system is a delicate balance as it must remain tolerant of maternal antigens whilst also preparing for the post-birth environment. In addition, the fetal immune system is susceptible to an altered intrauterine milieu caused by maternal and placental inflammatory mediators or secondary to nutrient and oxygen deprivation. Pancreatic-resident macrophages populate the pancreas during fetal development, and their phenotype is dynamic through the neonatal period. Furthermore, macrophages in the islets are instrumental in islet development as they influence β-cell proliferation and islet neogenesis. In addition, cytokines, derived from β-cells and macrophages, are important to islet homeostasis in the fetus and adult and, when perturbed, can cause islet dysfunction. Several activated immune pathways have been identified in the islets of people who experienced IUGR, with alternations in the levels of IL-1β and IL-4 as well as changes in TGFβ signalling. Leptin levels are also altered. Immunomodulation has shown therapeutic benefit in T2DM and might be particularly useful in IUGR-induced T2DM.
Fetal immune development is susceptible to an abnormal intrauterine milieu, and alterations have been implicated in the development of type 2 diabetes mellitus (T2DM) following intrauterine growth restriction (IUGR).
Pancreatic islet macrophages are instrumental in islet development and homeostasis in adults.
Levels of cytokines and immune mediators that are involved in T2DM pathogenesis are also elevated in offspring exposed to IUGR.
Leptin stimulates IL-1β production in islets, and levels of leptin are reduced in fetal islets and elevated in adult islets of offspring exposed to IUGR.
The results of limited reports evaluating the therapeutic effect of immunomodulation are promising for the treatment of IUGR-induced T2DM.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
BMC Medicine Open Access 08 December 2021
Subscribe to Nature+
Get immediate online access to the entire Nature family of 50+ journals
Subscribe to Journal
Get full journal access for 1 year
only $8.25 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Boehmer, B. H., Limesand, S. W. & Rozance, P. J. The impact of IUGR on pancreatic islet development and β-cell function. J. Endocrinol. 235, R63–R76 (2017).
Rashid, C. S., Bansal, A. & Simmons, R. A. Oxidative stress, intrauterine growth restriction, and developmental programming of type 2 diabetes. Physiology 33, 348–359 (2018).
Barker, D. J., Winter, P. D., Osmond, C., Margetts, B. & Simmonds, S. J. Weight in infancy and death from ischaemic heart disease. Lancet 2, 577–580 (1989).
Hales, C. N. & Barker, D. J. Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis. Diabetologia 35, 595–601 (1992).
Kermack, W. O., McKendrick, A. G. & McKinlay, P. L. Death-rates in Great Britain and Sweden: expression of specific mortality rates as products of two factors, and some consequences thereof. J. Hyg. 34, 433–457 (1934).
Ravelli, G. P., Stein, Z. A. & Susser, M. W. Obesity in young men after famine exposure in utero and early infancy. N. Engl. J. Med. 295, 349–353 (1976).
Barker, D. J. et al. Type 2 (non-insulin-dependent) diabetes mellitus, hypertension and hyperlipidaemia (syndrome X): relation to reduced fetal growth. Diabetologia 36, 62–67 (1993).
Fall, C. H. et al. Fetal and infant growth and cardiovascular risk factors in women. BMJ 310, 428–432 (1995).
Hales, C. N. et al. Fetal and infant growth and impaired glucose tolerance at age 64. BMJ 303, 1019–1022 (1991).
Phipps, K. et al. Fetal growth and impaired glucose tolerance in men and women. Diabetologia 36, 225–228 (1993).
Curhan, G. C. et al. Birth weight and adult hypertension, diabetes mellitus, and obesity in US men. Circulation 94, 3246–3250 (1996).
Egeland, G. M., Skjaerven, R. & Irgens, L. M. Birth characteristics of women who develop gestational diabetes: population based study. BMJ 321, 546–547 (2000).
Hales, C. N. & Barker, D. J. The thrifty phenotype hypothesis. Br. Med. Bull. 60, 5–20 (2001).
Jaquet, D., Gaboriau, A., Czernichow, P. & Levy-Marchal, C. Insulin resistance early in adulthood in subjects born with intrauterine growth retardation. J. Clin. Endocrinol. Metab. 85, 1401–1406 (2000).
Leger, J. et al. Reduced final height and indications for insulin resistance in 20 year olds born small for gestational age: regional cohort study. BMJ 315, 341–347 (1997).
Lithell, H. O. et al. Relation of size at birth to non-insulin dependent diabetes and insulin concentrations in men aged 50–60 years. BMJ 312, 406–410 (1996).
McKeigue, P. M., Lithell, H. O. & Leon, D. A. Glucose tolerance and resistance to insulin-stimulated glucose uptake in men aged 70 years in relation to size at birth. Diabetologia 41, 1133–1138 (1998).
Rich-Edwards, J. W. et al. Longitudinal study of birth weight and adult body mass index in predicting risk of coronary heart disease and stroke in women. BMJ 330, 1115 (2005).
Valdez, R., Athens, M. A., Thompson, G. H., Bradshaw, B. S. & Stern, M. P. Birthweight and adult health outcomes in a biethnic population in the USA. Diabetologia 37, 624–631 (1994).
Forsen, T. et al. The fetal and childhood growth of persons who develop type 2 diabetes. Ann. Intern. Med. 133, 176–182 (2000).
Davey Smith, G. et al. Education and occupational social class: which is the more important indicator of mortality risk? J. Epidemiol. Community Health 52, 153–160 (1998).
Banderali, G. et al. Short and long term health effects of parental tobacco smoking during pregnancy and lactation: a descriptive review. J. Transl Med. 13, 327 (2015).
Lindsay, K. L., Buss, C., Wadhwa, P. D. & Entringer, S. The interplay between maternal nutrition and stress during pregnancy: issues and considerations. Ann. Nutr. Metab. 70, 191–200 (2017).
Parker, J. D., Schoendorf, K. C. & Kiely, J. L. Associations between measures of socioeconomic status and low birth weight, small for gestational age, and premature delivery in the United States. Ann. Epidemiol. 4, 271–278 (1994).
Rich-Edwards, J. W. et al. Birth weight and risk of cardiovascular disease in a cohort of women followed up since 1976. BMJ 315, 396–400 (1997).
de Rooij, S. R., Wouters, H., Yonker, J. E., Painter, R. C. & Roseboom, T. J. Prenatal undernutrition and cognitive function in late adulthood. Proc. Natl Acad. Sci. USA 107, 16881–16886 (2010).
Roseboom, T., de Rooij, S. & Painter, R. The Dutch famine and its long-term consequences for adult health. Early Hum. Dev. 82, 485–491 (2006).
Ravelli, A. C. et al. Glucose tolerance in adults after prenatal exposure to famine. Lancet 351, 173–177 (1998).
Zur, R. L., Kingdom, J. C., Parks, W. T. & Hobson, S. R. The placental basis of fetal growth restriction. Obstet. Gynecol. Clin. North Am. 47, 81–98 (2020).
Geelhoed, J. J. et al. Preeclampsia and gestational hypertension are associated with childhood blood pressure independently of family adiposity measures: the Avon Longitudinal Study of Parents and Children. Circulation 122, 1192–1199 (2010).
Palmsten, K., Buka, S. L. & Michels, K. B. Maternal pregnancy-related hypertension and risk for hypertension in offspring later in life. Obstet. Gynecol. 116, 858–864 (2010).
Sproul, D., Gilbert, N. & Bickmore, W. A. The role of chromatin structure in regulating the expression of clustered genes. Nat. Rev. Genet. 6, 775–781 (2005).
Pinheiro, T. V., Brunetto, S., Ramos, J. G., Bernardi, J. R. & Goldani, M. Z. Hypertensive disorders during pregnancy and health outcomes in the offspring: a systematic review. J. Dev. Orig. Health Dis. 7, 391–407 (2016).
Prins, J. R. et al. Smoking during pregnancy influences the maternal immune response in mice and humans. Am. J. Obstet. Gynecol. 207, 76.e1–76.e14 (2012).
Yessoufou, A. & Moutairou, K. Maternal diabetes in pregnancy: early and long-term outcomes on the offspring and the concept of “metabolic memory”. Exp. Diabetes Res. 2011, 218598 (2011).
Cornelius, D. C. Preeclampsia: from inflammation to immunoregulation. Clin. Med. Insights Blood Disord. 11, 1179545X17752325 (2018).
Harmon, A. C. et al. The role of inflammation in the pathology of preeclampsia. Clin. Sci. 130, 409–419 (2016).
De Luccia, T. P. B. et al. Unveiling the pathophysiology of gestational diabetes: Studies on local and peripheral immune cells. Scand. J. Immunol. 91, e12860 (2020).
Zatterale, F. et al. Chronic adipose tissue inflammation linking obesity to insulin resistance and type 2 diabetes. Front. Physiol. 10, 1607 (2020).
Gammill, H. S. & Nelson, J. L. Naturally acquired microchimerism. Int. J. Dev. Biol. 54, 531–543 (2010).
Lo, Y. M., Lau, T. K., Chan, L. Y., Leung, T. N. & Chang, A. M. Quantitative analysis of the bidirectional fetomaternal transfer of nucleated cells and plasma DNA. Clin. Chem. 46, 1301–1309 (2000).
Loubiere, L. S. et al. Maternal microchimerism in healthy adults in lymphocytes, monocyte/macrophages and NK cells. Lab. Invest. 86, 1185–1192 (2006).
Maloney, S. et al. Microchimerism of maternal origin persists into adult life. J. Clin. Invest. 104, 41–47 (1999).
Mold, J. E. et al. Maternal alloantigens promote the development of tolerogenic fetal regulatory T cells in utero. Science 322, 1562–1565 (2008).
Cupedo, T., Nagasawa, M., Weijer, K., Blom, B. & Spits, H. Development and activation of regulatory T cells in the human fetus. Eur. J. Immunol. 35, 383–390 (2005).
Michaelsson, J., Mold, J. E., McCune, J. M. & Nixon, D. F. Regulation of T cell responses in the developing human fetus. J. Immunol. 176, 5741–5748 (2006).
Havran, W. L. & Allison, J. P. Developmentally ordered appearance of thymocytes expressing different T-cell antigen receptors. Nature 335, 443–445 (1988).
Hardy, R. R., Hayakawa, K., Haaijman, J. & Herzenberg, L. A. B-cell subpopulations identifiable by two-color fluorescence analysis using a dual-laser FACS. Ann. NY Acad. Sci. 399, 112–121 (1982).
Mold, J. E. et al. Fetal and adult hematopoietic stem cells give rise to distinct T cell lineages in humans. Science 330, 1695–1699 (2010).
Krow-Lucal, E. R., Kim, C. C., Burt, T. D. & McCune, J. M. Distinct functional programming of human fetal and adult monocytes. Blood 123, 1897–1904 (2014).
Kumaravelu, P. et al. Quantitative developmental anatomy of definitive haematopoietic stem cells/long-term repopulating units (HSC/RUs): role of the aorta-gonad-mesonephros (AGM) region and the yolk sac in colonisation of the mouse embryonic liver. Development 129, 4891–4899 (2002).
Medvinsky, A. L., Gan, O. I., Semenova, M. L. & Samoylina, N. L. Development of day-8 colony-forming unit-spleen hematopoietic progenitors during early murine embryogenesis: spatial and temporal mapping. Blood 87, 557–566 (1996).
Godin, I. & Cumano, A. Of birds and mice: hematopoietic stem cell development. Int. J. Dev. Biol. 49, 251–257 (2005).
Ginhoux, F. & Guilliams, M. Tissue-resident macrophage ontogeny and homeostasis. Immunity 44, 439–449 (2016).
Park, J. E., Jardine, L., Gottgens, B., Teichmann, S. A. & Haniffa, M. Prenatal development of human immunity. Science 368, 600–603 (2020).
Amdi, C., Lynegaard, J. C., Thymann, T. & Williams, A. R. Intrauterine growth restriction in piglets alters blood cell counts and impairs cytokine responses in peripheral mononuclear cells 24 days post-partum. Sci. Rep. 10, 4683 (2020).
Che, L. et al. Flaxseed oil supplementation improves intestinal function and immunity, associated with altered intestinal microbiome and fatty acid profile in pigs with intrauterine growth retardation. Food Funct. 10, 8149–8160 (2019).
Jaeckle Santos, L. J. et al. Neutralizing Th2 inflammation in neonatal islets prevents β-cell failure in adult IUGR rats. Diabetes 63, 1672–1684 (2014).
Li, J. et al. Vγ9Vδ2-T lymphocytes have impaired antiviral function in small-for-gestational-age and preterm neonates. Cell Mol. Immunol. 10, 253–260 (2013).
Li, J. et al. Impaired NK cell antiviral cytokine response against influenza virus in small-for-gestational-age neonates. Cell Mol. Immunol. 10, 437–443 (2013).
Wirbelauer, J., Thomas, W., Rieger, L. & Speer, C. P. Intrauterine growth retardation in preterm infants</=32 weeks of gestation is associated with low white blood cell counts. Am. J. Perinatol. 27, 819–824 (2010).
Zhong, X. et al. Impairment of cellular immunity is associated with overexpression of heat shock protein 70 in neonatal pigs with intrauterine growth retardation. Cell Stress. Chaperones 17, 495–505 (2012).
Kelly, A. C. et al. RNA sequencing exposes adaptive and immune responses to intrauterine growth restriction in Fetal Sheep Islets. Endocrinology 158, 743–755 (2017).
Longo, S., Borghesi, A., Tzialla, C. & Stronati, M. IUGR and infections. Early Hum. Dev. 90 (Suppl. 1), S42–S44 (2014).
Hasselbalch, H., Jeppesen, D. L., Ersboll, A. K. & Nielsen, M. B. Thymus size in preterm infants evaluated by ultrasound. A preliminary report. Acta Radiol. 40, 37–40 (1999).
Olearo, E. et al. Thymic volume in healthy, small for gestational age and growth restricted fetuses. Prenat. Diagn. 32, 662–667 (2012).
Geutskens, S. B., Otonkoski, T., Pulkkinen, M. A., Drexhage, H. A. & Leenen, P. J. Macrophages in the murine pancreas and their involvement in fetal endocrine development in vitro. J. Leukoc. Biol. 78, 845–852 (2005).
Calderon, B. et al. The pancreas anatomy conditions the origin and properties of resident macrophages. J. Exp. Med. 212, 1497–1512 (2015).
Calderon, B., Suri, A., Miller, M. J. & Unanue, E. R. Dendritic cells in islets of Langerhans constitutively present beta cell-derived peptides bound to their class II MHC molecules. Proc. Natl Acad. Sci. USA 105, 6121–6126 (2008).
Ferris, S. T. et al. A minor subset of Batf3-dependent antigen-presenting cells in islets of Langerhans is essential for the development of autoimmune diabetes. Immunity 41, 657–669 (2014).
Ferris, S. T. et al. The islet-resident macrophage is in an inflammatory state and senses microbial products in blood. J. Exp. Med. 214, 2369–2385 (2017).
Banaei-Bouchareb, L. et al. Insulin cell mass is altered in Csf1op/Csf1op macrophage-deficient mice. J. Leukoc. Biol. 76, 359–367 (2004).
Zinselmeyer, B. H. et al. The resident macrophages in murine pancreatic islets are constantly probing their local environment, capturing beta cell granules and blood particles. Diabetologia 61, 1374–1383 (2018).
Vomund, A. N. et al. Beta cells transfer vesicles containing insulin to phagocytes for presentation to T cells. Proc. Natl Acad. Sci. USA 112, E5496–E5502 (2015).
German, M. et al. The insulin gene promoter. A simplified nomenclature. Diabetes 44, 1002–1004 (1995).
German, M. S., Moss, L. G., Wang, J. & Rutter, W. J. The insulin and islet amyloid polypeptide genes contain similar cell-specific promoter elements that bind identical beta-cell nuclear complexes. Mol. Cell Biol. 12, 1777–1788 (1992).
de Koning, E. J. et al. Macrophages and pancreatic islet amyloidosis. Amyloid 5, 247–254 (1998).
de Koning, E. J., Bodkin, N. L., Hansen, B. C. & Clark, A. Diabetes mellitus in Macaca mulatta monkeys is characterised by islet amyloidosis and reduction in beta-cell population. Diabetologia 36, 378–384 (1993).
Masters, S. L. et al. Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1beta in type 2 diabetes. Nat. Immunol. 11, 897–904 (2010).
Westwell-Roper, C. Y., Ehses, J. A. & Verchere, C. B. Resident macrophages mediate islet amyloid polypeptide-induced islet IL-1beta production and beta-cell dysfunction. Diabetes 63, 1698–1711 (2014).
Westermark, P., Andersson, A. & Westermark, G. T. Islet amyloid polypeptide, islet amyloid, and diabetes mellitus. Physiol. Rev. 91, 795–826 (2011).
Calderon, B., Carrero, J. A., Miller, M. J. & Unanue, E. R. Cellular and molecular events in the localization of diabetogenic T cells to islets of Langerhans. Proc. Natl Acad. Sci. USA 108, 1561–1566 (2011).
Calderon, B., Carrero, J. A., Miller, M. J. & Unanue, E. R. Entry of diabetogenic T cells into islets induces changes that lead to amplification of the cellular response. Proc. Natl Acad. Sci. USA 108, 1567–1572 (2011).
Ying, W. et al. Expansion of islet-resident macrophages leads to inflammation affecting beta cell proliferation and function in obesity. Cell Metab. 29, 457–474 (2019).
Ying, W., Fu, W., Lee, Y. S. & Olefsky, J. M. The role of macrophages in obesity-associated islet inflammation and beta-cell abnormalities. Nat. Rev. Endocrinol. 16, 81–90 (2020).
Anquetil, F. et al. Alpha cells, the main source of IL-1beta in human pancreas. J. Autoimmun. 81, 68–73 (2017).
Arnush, M., Scarim, A. L., Heitmeier, M. R., Kelly, C. B. & Corbett, J. A. Potential role of resident islet macrophage activation in the initiation of autoimmune diabetes. J. Immunol. 160, 2684–2691 (1998).
Boni-Schnetzler, M. et al. Increased interleukin (IL)-1beta messenger ribonucleic acid expression in beta -cells of individuals with type 2 diabetes and regulation of IL-1beta in human islets by glucose and autostimulation. J. Clin. Endocrinol. Metab. 93, 4065–4074 (2008).
Maedler, K. et al. Glucose-induced beta cell production of IL-1beta contributes to glucotoxicity in human pancreatic islets. J. Clin. Invest. 110, 851–860 (2002).
Haversen, L., Danielsson, K. N., Fogelstrand, L. & Wiklund, O. Induction of proinflammatory cytokines by long-chain saturated fatty acids in human macrophages. Atherosclerosis 202, 382–393 (2009).
Arous, C., Ferreira, P. G., Dermitzakis, E. T. & Halban, P. A. Short term exposure of beta cells to low concentrations of interleukin-1beta improves insulin secretion through focal adhesion and actin remodeling and regulation of gene expression. J. Biol. Chem. 290, 14491 (2015).
Ribaux, P. et al. Induction of CXCL1 by extracellular matrix and autocrine enhancement by interleukin-1 in rat pancreatic beta-cells. Endocrinology 148, 5582–5590 (2007).
Ehses, J. A. et al. IL-1 antagonism reduces hyperglycemia and tissue inflammation in the type 2 diabetic GK rat. Proc. Natl Acad. Sci. USA 106, 13998–14003 (2009).
Zhao, G., Dharmadhikari, G., Maedler, K. & Meyer-Hermann, M. Possible role of interleukin-1beta in type 2 diabetes onset and implications for anti-inflammatory therapy strategies. PLoS Comput. Biol. 10, e1003798 (2014).
Maedler, K. et al. Leptin modulates beta cell expression of IL-1 receptor antagonist and release of IL-1beta in human islets. Proc. Natl Acad. Sci. USA 101, 8138–8143 (2004).
Glas, R. et al. Purinergic P2X7 receptors regulate secretion of interleukin-1 receptor antagonist and beta cell function and survival. Diabetologia 52, 1579–1588 (2009).
Tabak, A. G. et al. Trajectories of glycaemia, insulin sensitivity, and insulin secretion before diagnosis of type 2 diabetes: an analysis from the Whitehall II study. Lancet 373, 2215–2221 (2009).
Herder, C. et al. Elevated levels of the anti-inflammatory interleukin-1 receptor antagonist precede the onset of type 2 diabetes: the Whitehall II study. Diabetes Care 32, 421–423 (2009).
Equils, O. et al. Intra-uterine growth restriction downregulates the hepatic toll like receptor-4 expression and function. Clin. Dev. Immunol. 12, 59–66 (2005).
Roman, A. et al. Maternal magnesium supplementation reduces intrauterine growth restriction and suppresses inflammation in a rat model. Am. J. Obstet. Gynecol. 208, 383.e1–7 (2013).
Sanvito, F. et al. TGF-beta 1 influences the relative development of the exocrine and endocrine pancreas in vitro. Development 120, 3451–3462 (1994).
Dichmann, D. S., Miller, C. P., Jensen, J., Scott Heller, R. & Serup, P. Expression and misexpression of members of the FGF and TGFbeta families of growth factors in the developing mouse pancreas. Dev. Dyn. 226, 663–674 (2003).
Miralles, F., Battelino, T., Czernichow, P. & Scharfmann, R. TGF-beta plays a key role in morphogenesis of the pancreatic islets of Langerhans by controlling the activity of the matrix metalloproteinase MMP-2. J. Cell Biol. 143, 827–836 (1998).
Smart, N. G. et al. Conditional expression of Smad7 in pancreatic beta cells disrupts TGF-beta signaling and induces reversible diabetes mellitus. PLoS Biol. 4, e39 (2006).
Briana, D. D. et al. Fetal concentrations of the growth factors TGF-alpha and TGF-beta1 in relation to normal and restricted fetal growth at term. Cytokine 60, 157–161 (2012).
Lee, J. H. et al. Protection from beta-cell apoptosis by inhibition of TGF-beta/Smad3 signaling. Cell Death Dis. 11, 184 (2020).
Lee, Y. S., Wollam, J. & Olefsky, J. M. An integrated view of immunometabolism. Cell 172, 22–40 (2018).
Simmons, R. A., Templeton, L. J. & Gertz, S. J. Intrauterine growth retardation leads to the development of type 2 diabetes in the rat. Diabetes 50, 2279–2286 (2001).
Stoffers, D. A., Desai, B. M., DeLeon, D. D. & Simmons, R. A. Neonatal exendin-4 prevents the development of diabetes in the intrauterine growth retarded rat. Diabetes 52, 734–740 (2003).
Papathanassoglou, E. et al. Leptin receptor expression and signaling in lymphocytes: kinetics during lymphocyte activation, role in lymphocyte survival, and response to high fat diet in mice. J. Immunol. 176, 7745–7752 (2006).
Gabay, C., Dreyer, M., Pellegrinelli, N., Chicheportiche, R. & Meier, C. A. Leptin directly induces the secretion of interleukin 1 receptor antagonist in human monocytes. J. Clin. Endocrinol. Metab. 86, 783–791 (2001).
Francisco, V. et al. Obesity, fat mass and immune system: role for leptin. Front. Physiol. 9, 640 (2018).
Fernandez-Riejos, P., Goberna, R. & Sanchez-Margalet, V. Leptin promotes cell survival and activates Jurkat T lymphocytes by stimulation of mitogen-activated protein kinase. Clin. Exp. Immunol. 151, 505–518 (2008).
Amarilyo, G. et al. Leptin promotes lupus T-cell autoimmunity. Clin. Immunol. 149, 530–533 (2013).
La Cava, A. Leptin in inflammation and autoimmunity. Cytokine 98, 51–58 (2017).
Cohen, S., Danzaki, K. & MacIver, N. J. Nutritional effects on T-cell immunometabolism. Eur. J. Immunol. 47, 225–235 (2017).
Pighetti, M. et al. Maternal serum and umbilical cord blood leptin concentrations with fetal growth restriction. Obstet. Gynecol. 102, 535–543 (2003).
Varvarigou, A., Mantzoros, C. S. & Beratis, N. G. Cord blood leptin concentrations in relation to intrauterine growth. Clin. Endocrinol. 50, 177–183 (1999).
Jaquet, D., Leger, J., Levy-Marchal, C., Oury, J. F. & Czernichow, P. Ontogeny of leptin in human fetuses and newborns: effect of intrauterine growth retardation on serum leptin concentrations. J. Clin. Endocrinol. Metab. 83, 1243–1246 (1998).
Valuniene, M. et al. Leptin levels at birth and in early postnatal life in small- and appropriate-for-gestational-age infants. Medicina 43, 784–791 (2007).
Cetin, I. et al. Fetal plasma leptin concentrations: relationship with different intrauterine growth patterns from 19 weeks to term. Pediatr. Res. 48, 646–651 (2000).
Martinez-Cordero, C., Amador-Licona, N., Guizar-Mendoza, J. M., Hernandez-Mendez, J. & Ruelas-Orozco, G. Body fat at birth and cord blood levels of insulin, adiponectin, leptin, and insulin-like growth factor-I in small-for-gestational-age infants. Arch. Med. Res. 37, 490–494 (2006).
Jaquet, D., Leger, J., Tabone, M. D., Czernichow, P. & Levy-Marchal, C. High serum leptin concentrations during catch-up growth of children born with intrauterine growth retardation. J. Clin. Endocrinol. Metab. 84, 1949–1953 (1999).
Yajnik, C. S. et al. Adiposity and hyperinsulinemia in Indians are present at birth. J. Clin. Endocrinol. Metab. 87, 5575–5580 (2002).
Phillips, D. I. et al. Size at birth and plasma leptin concentrations in adult life. Int. J. Obes. Relat. Metab. Disord. 23, 1025–1029 (1999).
Ohashi, K. et al. Adiponectin promotes macrophage polarization toward an anti-inflammatory phenotype. J. Biol. Chem. 285, 6153–6160 (2010).
Luo, Y. & Liu, M. Adiponectin: a versatile player of innate immunity. J. Mol. Cell Biol. 8, 120–128 (2016).
Sivan, E. et al. Adiponectin in human cord blood: relation to fetal birth weight and gender. J. Clin. Endocrinol. Metab. 88, 5656–5660 (2003).
Visentin, S. et al. Adiponectin levels are reduced while markers of systemic inflammation and aortic remodelling are increased in intrauterine growth restricted mother-child couple. Biomed. Res. Int. 2014, 401595 (2014).
Kyriakakou, M. et al. Leptin and adiponectin concentrations in intrauterine growth restricted and appropriate for gestational age fetuses, neonates, and their mothers. Eur. J. Endocrinol. 158, 343–348 (2008).
Pinney, S. E., Jaeckle Santos, L. J., Han, Y., Stoffers, D. A. & Simmons, R. A. Exendin-4 increases histone acetylase activity and reverses epigenetic modifications that silence Pdx1 in the intrauterine growth retarded rat. Diabetologia 54, 2606–2614 (2011).
Tremblay, A. J., Lamarche, B., Deacon, C. F., Weisnagel, S. J. & Couture, P. Effects of sitagliptin therapy on markers of low-grade inflammation and cell adhesion molecules in patients with type 2 diabetes. Metabolism 63, 1141–1148 (2014).
Ahern, T. et al. Glucagon-like peptide-1 analogue therapy for psoriasis patients with obesity and type 2 diabetes: a prospective cohort study. J. Eur. Acad. Dermatol. Venereol. 27, 1440–1443 (2013).
Marcucci, F., Romeo, E., Caserta, C. A., Rumio, C. & Lefoulon, F. Context-dependent pharmacological effects of metformin on the immune system. Trends Pharmacol. Sci. 41, 162–171 (2020).
Vasamsetti, S. B. et al. Metformin inhibits monocyte-to-macrophage differentiation via AMPK-mediated inhibition of STAT3 activation: potential role in atherosclerosis. Diabetes 64, 2028–2041 (2015).
Qing, L. et al. Metformin induces the M2 macrophage polarization to accelerate the wound healing via regulating AMPK/mTOR/NLRP3 inflammasome singling pathway. Am. J. Transl Res. 11, 655–668 (2019).
Tsoyi, K. et al. Metformin inhibits HMGB1 release in LPS-treated RAW 264.7 cells and increases survival rate of endotoxaemic mice. Br. J. Pharmacol. 162, 1498–1508 (2011).
Jing, Y. et al. Metformin improves obesity-associated inflammation by altering macrophages polarization. Mol. Cell Endocrinol. 461, 256–264 (2018).
Yang, Q. et al. Metformin ameliorates the progression of atherosclerosis via suppressing macrophage infiltration and inflammatory responses in rabbits. Life Sci. 198, 56–64 (2018).
Dandona, P. et al. Increased plasma concentration of macrophage migration inhibitory factor (MIF) and MIF mRNA in mononuclear cells in the obese and the suppressive action of metformin. J. Clin. Endocrinol. Metab. 89, 5043–5047 (2004).
Xiao, H. et al. Metformin is a novel suppressor for transforming growth factor (TGF)-beta1. Sci. Rep. 6, 28597 (2016).
LeBrasseur, N. K. et al. Thiazolidinediones can rapidly activate AMP-activated protein kinase in mammalian tissues. Am. J. Physiol. Endocrinol. Metab. 291, E175–E181 (2006).
Ceriello, A. Thiazolidinediones as anti-inflammatory and anti-atherogenic agents. Diabetes Metab. Res. Rev. 24, 14–26 (2008).
Shimizu, H. et al. Pioglitazone increases circulating adiponectin levels and subsequently reduces TNF-alpha levels in type 2 diabetic patients: a randomized study. Diabet. Med. 23, 253–257 (2006).
Dai, Y., Wang, X., Ding, Z., Dai, D. & Mehta, J. L. DPP-4 inhibitors repress foam cell formation by inhibiting scavenger receptors through protein kinase C pathway. Acta Diabetol. 51, 471–478 (2014).
The authors acknowledge the support of the National Institutes of Health grant #DK114054 (R.A.S.) and ES01985 (T.N.G.).
The authors declare no competing interests.
Peer review information
Nature Reviews Endocrinology thanks S. Limesand and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
- Small for gestational age
(SGA). Birth weight that is below the 10th percentile.
- Uteroplacental insufficiency
A complication of pregnancy when the placenta is unable to deliver an adequate supply of nutrients and oxygen to the fetus.
- Parabiosis studies
A laboratory technique to study physiology whereby two living organisms are joined together surgically to develop a single, shared physiological system.
- Glucose disposal
Storage of glucose as glycogen in tissues.
About this article
Cite this article
Golden, T.N., Simmons, R.A. Immune dysfunction in developmental programming of type 2 diabetes mellitus. Nat Rev Endocrinol 17, 235–245 (2021). https://doi.org/10.1038/s41574-020-00464-z