Exploring the causes and consequences of maternal metabolic maladaptations during pregnancy: Lessons from animal models

Exploring the causes and consequences of maternal metabolic maladaptations during pregnancy: Lessons from animal models

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Journal Pre-proof Exploring the causes and consequences of maternal metabolic maladaptations during pregnancy: Lessons from animal models Amanda N. Sferruzzi-Perri, Jorge Lopez-Tello, Tina Napso, Hannah E.J. Yong PII:





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Received Date: 15 October 2019 Revised Date:

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Accepted Date: 29 January 2020

Please cite this article as: Sferruzzi-Perri AN, Lopez-Tello J, Napso T, Yong HEJ, Exploring the causes and consequences of maternal metabolic maladaptations during pregnancy: Lessons from animal models, Placenta (2020), doi: https://doi.org/10.1016/j.placenta.2020.01.015. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier Ltd.


Exploring the causes and consequences of maternal metabolic maladaptations during


pregnancy: lessons from animal models

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Amanda N. Sferruzzi-Perri1, Jorge Lopez-Tello, Tina Napso and Hannah E.J. Yong

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Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience,


Downing Street, University of Cambridge, Cambridge, UK CB2 3EG

8 9


Corresponding author:


Amanda Sferruzzi-Perri


Centre for Trophoblast Research,


Department of Physiology, Development and Neuroscience,


University of Cambridge,


Cambridge, UK CB2 3EG


Telephone: +44 (0) 1223333807


Email: [email protected]

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Keywords: gestational diabetes; metabolism; fetal growth; placenta; hormones; pregnancy;


nutrient partitioning

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Running title: Maternal metabolic maladaptations during pregnancy

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Pregnancy is a remarkable physiological state, during which the metabolic system of the mother


adapts to ensure that nutrients are made available for transfer to the fetus for growth and


development. Adaptations of maternal metabolism during pregnancy are influenced by the


metabolic and nutritional status of the mother and the production of endocrine factors by the


placenta that exert metabolic effects. Insufficient or inappropriate adaptations in maternal


metabolism during pregnancy may lead to pregnancy complications with important short- and long-


term effects for both the health of the child and mother. This is very evident in gestational diabetes,


which is marked by greater glucose intolerance and insulin resistance above that expected of a


normal pregnancy. Gestational diabetes is associated with increased fetal weight and/or increased


adiposity, higher instrumented delivery rates and greater risks for both mother and child of


developing type 2 diabetes in the long-term. However, despite the negative health impacts of such


metabolic imbalances during pregnancy, the precise mechanisms responsible for orchestrating


these changes remain largely unknown. The present review describes the dynamic pregnancy-


specific changes that occur in the metabolic system of the mother during pregnancy. It also 1


discusses findings using surgical, pharmacological, genetic and dietary methods in experimental


animals that highlight the role of pathways in maternal tissues that lead to metabolic dysfunction,


with a particular focus on gestational diabetes. Finally, it summarises the work largely employing


gene targeting and hormone administration in rodents that have illuminated the involvement of


placental endocrine function in driving maternal metabolic adaptations. While current animal


models may not fully replicate what is observed in humans, these have been instrumental in


showing that there is a dynamic interplay between changes in maternal metabolic physiology and


the placental production of endocrine factors that govern the availability of nutrients to the growing


fetus. However, more work is required to specifically identify the placenta-driven changes in


maternal metabolic physiology that ensure the appropriate level of insulin production and action


during pregnancy. In doing so, these studies may pave the way to understanding the development


of pregnancy complications like gestational diabetes, as well as further our understanding of type-2


diabetes and the control of metabolic physiology more broadly.

52 53 54



Maternal metabolic adaptation during pregnancy and its importance for life-long health


Pregnancy is a remarkable physiological state, during which the metabolic system of the mother


adapts to ensure that nutrients are made available for transfer to the fetus for growth and


development. Adaptations of maternal metabolism during pregnancy are influenced by the


metabolic and nutritional status of the mother (from before pregnancy) and the production of


endocrine factors by the placenta that exert metabolic effects. If maternal health status before


getting pregnant is unfavourable (e.g. increased body adiposity) and/or adaptations in maternal


metabolism during pregnancy are insufficient or inappropriate, these could lead to abnormal


nutrient partitioning to the fetus and pregnancy complications such as gestational diabetes (GDM)


and abnormal fetal growth. These pregnancy complications can have important short- and long-


term effects for both the health of the mother and child. In the mother, GDM raises the risk of


hypertension during pregnancy, an instrumented delivery and the development of type-2 diabetes


in later motherhood. In the child, alterations in intrauterine growth (indicated by being born either


small or large for gestational age), significantly increase the risk of neonatal hypoglycaemia and


perinatal mortality, as well as increase the risk of developing obesity and type-2 diabetes in later


adult life. Pre-existing maternal obesity predisposes a woman to developing GDM and abnormal


fetal growth during pregnancy. Many countries are now contending with the burden of obesity and


type-2 diabetes, which have assumed epidemic proportions. Moreover, pregnancy complications


impose major financial drains on the health services around the world. With these in mind, it is


important to understand the mechanisms driving changes in maternal metabolic function during


pregnancy as these will likely be useful in devising strategies to prevent pregnancy complications


and the associated lifelong impacts in women and their child. Therefore, this review aims to 1)


describe the dynamic pregnancy-specific changes that occur in the metabolic system of the mother


during pregnancy, 2) discuss the findings from experimental animals that highlight the role of


pathways in maternal tissues that lead to metabolic dysfunction, with a particular focus on GDM,


and 3) summarise the work largely undertaken in rodents, which illuminate the involvement of


placental endocrine function in driving maternal metabolic adaptations.

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Maternal metabolic alterations during normal and complicated pregnancies


Maternal metabolism changes dynamically during gestation, in line with the metabolic demands of


the growing fetus (Figure 1). There are changes in insulin sensitivity, which affects the availability


and fate of nutrients in both mother and conceptus. In particular, early pregnancy is characterised


by a period of maternal tissue growth (eg liver, kidneys, pancreas and adipose tissue), energy


accumulation (eg lipid storage) and sometimes, increased insulin sensitivity [1-5]. In contrast, later


pregnancy is characterised by energy reserve (lipid) mobilization and decreased insulin sensitivity


of maternal tissues, including the skeletal muscle and white adipose tissue, which increases fatty


acid and glucose availability for fetal growth [4, 6-8]. The increased availability of lipids in the


mother can also contribute to the decreased insulin sensitivity observed in late pregnancy [9]. To 3


balance the normal state of insulin resistance in the mother, pancreatic β-cell mass and glucose-


stimulated insulin release increases in the second half of the pregnancy [10-12]. In pregnant


women with GDM, there is evidence for impaired pancreatic insulin secretion, dyslipidemia and


defects in the insulin signalling pathway in the skeletal muscle and adipose tissue that relate to the


altered glucose-insulin handling and higher prevalence of increased fetal adiposity and large for


gestational age babies seen [1, 13-15]. However, less is known about the metabolic physiology of


women who deliver babies that are small for gestational age, and particularly, whether an inability


of the mother to metabolically adapt, such as acquire insulin resistance and glucose intolerance in


mid-late gestation may be associated with poor fetal outcomes. Thus, further work is required to


understand the mechanisms driving changes in maternal metabolism and insulin resistance during


the course of gestation in both normal and complicated pregnancies.

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Maternal manipulations to study metabolic alterations during pregnancy


Multiple animal models have been used to study maternal metabolic alterations during pregnancy


and, in particular, with regard to the pathophysiology of GDM (Table 1). All these models are based


on inducing diabetes during pregnancy by surgical, chemical, genetic or dietary methods, but many


of these are not dependent on the pregnancy. For example, surgical removal of the pancreas in


rats [16] or administration of drugs like streptozotocin or alloxan, which induce death of pancreatic


β cells in mice, rats, rabbits, pigs and sheep [17-23] can lead to the development of a GDM


phenotype (hyperglycemia or glucose intolerance) in association with failed β cell mass expansion


and insulin insufficiency. Maternal global genetic manipulation of genes including the leptin


receptor, adiponectin, vascular-derived connective tissue growth factor, free fatty acid receptor-2


and serotonin receptor 5-hydroxytryptamine receptor-2b [24-33] or conditional alterations in the


insulin-producing β cells of the pancreas by manipulating genes such as aryl-hydrocarbon receptor


nuclear translocator, menin, Mafb, c-Met, adenosine receptor A2a, forehead box transcription


factors and islet amyloid polypeptide in mice [34-39] also compromise β cell mass expansion and


lead to hyperglycemia and glucose intolerance. However, in the case of some genetic


manipulations, investigators have failed to fully recapitulate maternal metabolic alterations; for


instance deletion of the leptin receptor in mice is not always associated with glucose intolerance in


the mother during pregnancy [40-42]. Moreover, only a few of the aforementioned animal models


reported increased fetal/birth weight [17, 24, 26, 43] and the majority of the surgical and


pharmacological animal models were linked to fetal hyperglycemia, perinatal loss and


developmental defects [16, 18-22], which are typically observed in women with type 1 and type 2


diabetes. Notwithstanding, the findings overall highlight the importance of β cell mass expansion


and insulin production in balancing the pregnancy-induced decline in insulin sensitivity of the



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In mice, selectively altering the expression of insulin-responsive genes (insulin receptor,


phosphoinositol 3-kinase isoforms, hexokinase) in the mother or specifically in her liver also leads


to a GDM phenotype (hyperglycemia, hyperinsulinemia and/or glucose intolerance during


pregnancy) although this is related to increased insulin resistance in the dam and unchanged or


reduced fetal/birth weight [44-46]. Metabolic studies in mouse dams with deletion of SOCS3 from


leptin-receptor expressing cells have also highlighted a role for increased leptin resistance in the


development of a GDM phenotype [47].

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Consumption of diets containing high amounts of fat and sugar lead to insulin and leptin resistance


[48]. In developed societies, such diets are now the norm and contribute to the increasing rates of


women who are overweight or obese during pregnancy, which is a risk factor for GDM, as well as


abnormal birthweight. In rodents and dogs, a maternal diet high in fat and/or sugar induces a


GDM-like phenotype (hyperglycemia, hyperinsulinemia, glucose intolerance and insulin resistance)


(Table 1). This is accompanied with disrupted expression of glucose and lipid metabolic proteins


and insulin signaling components (including insulin receptor and phosphoinositol 3-kinase


isoforms) in the liver, skeletal muscle and white adipose of the mother in late gestation [49-57].


There may also be insufficient β-cell mass expansion in diet-induced GDM-like mice [50, 58],


although work is required to assess the expression of genes involved in β-cell proliferation and


glucose-stimulated insulin release (as shown in Table 1; global and β-cell specific gene


manipulation). The specific composition of the diet, when the diet is fed (from prior to or just during


pregnancy) and level of adiposity in the mother appears to dictate the specific changes observed in


maternal metabolism and whether these are accompanied with reduced, increased or unchanged


fetal weight [59]. However, regardless, several of these models of diet-induced maternal metabolic


maladaptation are associated with programmed changes in the metabolic function of the adult


rodent offspring [51, 59-61]. Interestingly, a period of maternal exercise prevents the development


of insulin resistance in the mouse dams fed a high fat or high sugar and high fat diet during


pregnancy, as well as in their offspring postnatally [51, 53]. Most notably, improved insulin handling


in the mother is linked to a restoration of insulin signaling primarily in the white adipose tissue,


although there are also some changes in the maternal skeletal muscle and liver [53, 62].

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Fascinatingly, in rats, exposure to mild maternal diabetes during development was linked to


alterations in the metabolism of female offspring that emerged when they were pregnant


(resembling GDM; hyperglycemia, hyperinsulinemia, hypertriglyceridemia, hypercholesterolemia)


[63]. These findings are interesting given that a family history of diabetes is a risk factor for


developing GDM during pregnancy. Female rat offspring that experienced reduced supply of


nutrients and oxygen in utero, also developed alterations in glucose and insulin handling when they


were pregnant [64]. Together, these findings highlight the importance of a family history of



diabetes/genetic factors, as well as exposure to a suboptimal environment during intrauterine /


early postnatal life in determining the subsequent development of GDM during pregnancy.

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Thus, studies in experimental animals collectively signify the role of genetics, signalling pathways,


obesogenic diets and even the process of developmental programming in the pathogenesis of


metabolic problems in the mother during pregnancy, like GDM (Figure 2). They also demonstrate


the importance of adequate insulin production and insulin sensitivity of maternal tissues, like the


skeletal muscle and white adipose fat depot in the appropriate control of glucose-insulin handling in


the mother during pregnancy. Indeed, exacerbated insulin resistance or insufficient insulin


production can result in abnormal metabolic responses resembling GDM. However, the majority of


the animal models that have been employed thus far, also show metabolic derangements, such as


abnormal pancreatic development, hyperglycemia, glucose intolerance, hyperphagia and/or


adiposity in the female prior to pregnancy, which limits their utility as an accurate model to study


pregnancy-induced changes in maternal metabolism. Moreover, whilst fetal growth/birthweight is


not reported to be altered in most of the animal models, human pregnancy metabolic disorders, like


GDM also do not always lead to altered birthweight. Rather, metabolic disorders, like GDM are


associated with increased fetal adiposity – an index challenging to measure in small experimental


animals for which the majority of data are available (Table 1). Thus, additional work is required to


precisely study the molecular and cellular mechanisms underlying maternal metabolic imbalances


and alterations in fetal growth and body composition during gestation, as well as the increased risk


of the mother and child to developing conditions like type 2 diabetes after delivery.

188 189 190

The endocrine placenta and maternal metabolic alterations


Adaptations in maternal metabolism are signalled, at least partly, by changes in placental hormone


production during gestation. The placenta secretes hormones, cytokines, neuropeptides and other


endocrine factors into the mother to modulate her glycemic control, as well as lipid metabolism,


which is likely to happen mainly by influencing insulin secretion and action [59, 65, 66]. The


function of placental hormones during pregnancy has been assessed experimentally by either


exogenous administration or genetically manipulating the expression of specific hormones and


hormone receptors in rodents in vivo (Table 2). Placental-derived hormones such as prolactin


(PRL), placental lactogen (PL), growth hormone (GH) variant, insulin-like growth factor-2 (IGF2),


parathyroid hormone-related protein, placental growth factor and progesterone increase in the


maternal circulation from early pregnancy and change pancreatic β cell proliferation and insulin


secretion [43, 67-84]. Changes in proliferation and insulin secretion with PRL and PL are mediated


through downregulating Menin gene expression and inducing serotonin synthesis and signalling in


the pancreatic β cells during pregnancy [28, 35, 85]. They can also increase maternal adiposity


and reduce whole body insulin sensitivity and glucose utilisation, particularly by disrupting insulin 6


signaling pathway components like phosphoinositol 3-kinase isoforms in skeletal muscle and white


adipose tissue [13, 77, 86-88]. However, other placentally-derived hormones, like estrogen, which


peak in the maternal circulation in late pregnancy, have been shown to both decrease and


increase whole body insulin sensitivity, depending on the hormonal milieu of the mother [83, 89-


96]. Placental-derived hormones that rise in the circulation towards term and are able to increase


insulin sensitivity likely play a role in re-partitioning glucose and lipid use to the mother in


anticipation of delivery and lactation [4]. Placental hormones thus, appear to interact to help drive


changes in maternal metabolic physiology at different stages of pregnancy.

213 214

Although much of the data on the roles of placental hormones in vivo are from non-pregnant


animals or genetically-altered mice that have pre-pregnant metabolic alterations [43, 66, 68, 74,


75, 88, 92, 97], several studies have examined consequences of hormonal changes specifically


induced during pregnancy. In mice fed a high sugar and high fat diet just from the start of


pregnancy, expression PRL/PL genes by the placenta is perturbed and associated with maternal


hyperglycaemia, glucose intolerance and insulin resistance [50, 98]. Placental PRL/PL expression


is also altered in genetically-modified mice and aged rats that display insulin resistance during


gestation [46, 99]. However, in turn, the sensitivity of tissues in the mother to the effects of


placental hormones during pregnancy will be modified by maternal health state (such as nutrition


and obesity prior to and during pregnancy) [100]. The importance of placental hormones in the


development of metabolic conditions during pregnancy has been additionally inferred from


association studies in humans. Studies have reported alterations in the circulating abundance of


placental hormones in women with GDM [101-105]. Moreover, polymorphisms in the receptor for


PRL are associated with the development of GDM in women [106]. Further support for the notion


that placental endocrine dysfunction may underlie maternal metabolic imbalances during gestation


has been provided by observations in wildtype mice with genetically-altered mutant fetuses and


placentas. In particular, in mice, manipulating the expression of the Igf2, H19 and Dlk1 genes in


the conceptus, which results in overgrowth or undergrowth of the placenta (and hence changes in


placental endocrine output), is associated with alterations in maternal body composition and


glucose, lipid and insulin handling of wildtype dams during pregnancy [107-109]. Thus, the


placenta signals fetal needs to the mother, via its secretion of hormones which affect maternal


metabolic physiology and thus, the supply of nutrients for fetal growth [110] (Figure 2). However, a


placental-specific approach is required to definitively determine whether altered placental hormone


production has a causative role in the development of metabolic conditions, like GDM in the mother


during pregnancy and its long-term effects. Moreover, the application of unbiased gene and protein


sequencing approaches is needed to identify the complete repertoire of hormones and endocrine


factors released by the placenta that drive metabolic changes in the mother during pregnancy.

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Summary and conclusions 7


Taken together, there is a dynamic interplay between changes in maternal metabolic physiology


and the placental production of endocrine factors that govern the availability of glucose and other


nutrients to the growing fetus (Figure 2). However, more work is required to specifically identify the


placenta-driven changes in maternal metabolic physiology that ensure appropriate level of insulin


production and action during pregnancy. In doing so, these studies may hold the key to


understanding the development of pregnancy complications like abnormal fetal growth and GDM,


as well as further our understanding of type-2 diabetes and the control of metabolic physiology


more broadly. Ultimately, the findings of such work would aid in the development of diagnostic,


preventive and therapeutic strategies to combat pregnancy complications and metabolic


derangements like GDM and type-2 diabetes, the latter of which are rapidly increasing in many


parts of the world.

254 255



A.N.S.-P is supported by a Royal Society Dorothy Hodgkin Research Fellowship (RG74249), J.L.-T


is supported by a Royal Society Newton International Fellowship (NF170988), T.N. is supported by


salary paid from a Lister Institute Prize and Academy of Medical Science Grant to A.N.S.-P, and


H.E.J.Y is supported by an A*Star Fellowship. Presented at the PAA Placental Satellite


Symposium 2018, which was supported by NIH Conference Grant HD084096.

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Conflict of interest


There are no conflicts of interest to declare.

264 265

Figure 1. Maternal metabolism changes dynamically during gestation, in line with the metabolic


demands of the growing fetus.

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Figure 2. During pregnancy, there is a dynamic interplay between the placental production of




environmental/nutritional factors and health) that govern the availability of nutrients to the growing


fetus. Alterations in placental hormone production and maladaptations of maternal metabolism may


result in pregnancy complications like gestational diabetes and abnormal fetal growth.










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1. Di Cianni, G., Miccoli, R., Volpe, L., Lencioni, C. & Del Prato, S. (2003) Intermediate metabolism in normal pregnancy and in gestational diabetes, Diabetes/metabolism research and reviews. 19, 259-70. 2. Ramos, M. P., Crespo-Solans, M. D., del Campo, S., Cacho, J. & Herrera, E. (2003) Fat accumulation in the rat during early pregnancy is modulated by enhanced insulin responsiveness, Am J Physiol Endocrinol Metab. 285, E318-28. 3. Catalano, P. M. (2010) Obesity, insulin resistance, and pregnancy outcome, Reprod Suppl. 140, 365-71. 8

281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 329 330 331 332 333 334

4. Musial, B., Fernandez-Twinn, D. S., Vaughan, O. R., Ozanne, S. E., Voshol, P., Sferruzzi-Perri, A. N. & Fowden, A. L. (2016) Proximity to delivery alters insulin sensitivity and glucose metabolism in pregnant mice, Diabetes. 65(4):851-60. 5. McIlvride, S., Mushtaq, A., Papacleovoulou, G., Hurling, C., Steel, J., Jansen, E., Abu-Hayyeh, S. & Williamson, C. (2017) A progesterone-brown fat axis is involved in regulating fetal growth, Sci Rep. 7, 10671. 6. Butte, N. F. (2000) Carbohydrate and lipid metabolism in pregnancy: normal compared with gestational diabetes mellitus, The American journal of clinical nutrition. 71, 1256S-61S. 7. Catalano, P. M., Nizielski, S. E., Shao, J., Preston, L., Qiao, L. & Friedman, J. E. (2002) Downregulated IRS-1 and PPARgamma in obese women with gestational diabetes: relationship to FFA during pregnancy, Am J Physiol Endocrinol Metab. 282, E522-533. 8. Kalhan, S., Rossi, K., Gruca, L., Burkett, E. & O'Brien, A. (1997) Glucose turnover and gluconeogenesis in human pregnancy, The Journal of clinical investigation. 100, 1775-81. 9. Sivan, E. & Boden, G. (2003) Free fatty acids, insulin resistance, and pregnancy, Curr Diab Rep. 3, 319-22. 10. Ernst, S., Demirci, C., Valle, S., Velazquez-Garcia, S. & Garcia-Ocana, A. (2011) Mechanisms in the adaptation of maternal beta-cells during pregnancy, Diabetes management. 1, 239-248. 11. Butler, A. E., Cao-Minh, L., Galasso, R., Rizza, R. A., Corradin, A., Cobelli, C. & Butler, P. C. (2010) Adaptive changes in pancreatic beta cell fractional area and beta cell turnover in human pregnancy, Diabetologia. 53, 2167-76. 12. Beamish, C. A., Zhang, L., Szlapinski, S. K., Strutt, B. J. & Hill, D. J. (2017) An increase in immature betacells lacking Glut2 precedes the expansion of beta-cell mass in the pregnant mouse, PLoS One. 12, e0182256. 13. Barbour, L. A., McCurdy, C. E., Hernandez, T. L., Kirwan, J. P., Catalano, P. M. & Friedman, J. E. (2007) Cellular mechanisms for insulin resistance in normal pregnancy and gestational diabetes, Diabetes Care. 30 Suppl 2, S112-9. 14. Buchanan, T. A., Xiang, A., Kjos, S. L. & Watanabe, R. (2007) What Is Gestational Diabetes?, Diabetes Care 30, S105-S111. 15. Lu, L., Koulman, A., Petry, C. J., Jenkins, B., Matthews, L., Hughes, I. A., Acerini, C. L., Ong, K. K. & Dunger, D. B. (2016) An Unbiased Lipidomics Approach Identifies Early Second Trimester Lipids Predictive of Maternal Glycemic Traits and Gestational Diabetes Mellitus, Diabetes Care. 39, 2232-2239. 16. Jawerbaum, A., Catafau, J. R., Gonzales, E. T., Rodriguez, R. R., Gelpi, E., Gomez, G., Gimeno, A. L. & Gimeno, M. A. (1993) Eicosanoid production by uterine strips and by embryos obtained from diabetic pregnant rats, Prostaglandins. 45, 487-95. 17. Dickinson, J. E., Meyer, B. A., Chmielowiec, S. & Palmer, S. M. (1991) Streptozocin-induced diabetes mellitus in the pregnant ewe, Am J Obstet Gynecol. 165, 1673-7. 18. Viana, M., Aruoma, O. I., Herrera, E. & Bonet, B. (2000) Oxidative damage in pregnant diabetic rats and their embryos, Free Radic Biol Med. 29, 1115-21. 19. Tsai, M. Y., Schallinger, L. E., Josephson, M. W. & Brown, D. M. (1982) Disturbance of pulmonary prostaglandin metabolism in fetuses of alloxan-diabetic rabbits, Biochim Biophys Acta. 712, 395-9. 20. Ramsay, T. G., Wolverton, C. K. & Steele, N. C. (1994) Alteration in IGF-I mRNA content of fetal swine tissues in response to maternal diabetes, The American journal of physiology. 267, R1391-6. 21. Diamond, M. P., Moley, K. H., Pellicer, A., Vaughn, W. K. & DeCherney, A. H. (1989) Effects of streptozotocin- and alloxan-induced diabetes mellitus on mouse follicular and early embryo development, J Reprod Fertil. 86, 1-10. 22. Miodovnik, M., Mimouni, F., Berk, M. & Clark, K. E. (1989) Alloxan-induced diabetes mellitus in the pregnant ewe: metabolic and cardiovascular effects on the mother and her fetus, Am J Obstet Gynecol. 160, 1239-44. 23. Zhu, H., Chen, B., Cheng, Y., Zhou, Y., Yan, Y. S., Luo, Q., Jiang, Y., Sheng, J. Z., Ding, G. L. & Huang, H. F. (2019) Insulin Therapy for Gestational Diabetes Mellitus Does Not Fully Protect Offspring From DietInduced Metabolic Disorders, Diabetes. 68, 696-708. 24. Qiao, L., Wattez, J. S., Lee, S., Nguyen, A., Schaack, J., Hay, W. W., Jr. & Shao, J. (2017) Adiponectin Deficiency Impairs Maternal Metabolic Adaptation to Pregnancy in Mice, Diabetes. 66, 1126-1135. 25. Fuller, M., Priyadarshini, M., Gibbons, S. M., Angueira, A. R., Brodsky, M., Hayes, M. G., KovatchevaDatchary, P., Backhed, F., Gilbert, J. A., Lowe, W. L., Jr. & Layden, B. T. (2015) The short-chain fatty acid 9

335 336 337 338 339 340 341 342 343 344 345 346 347 348 349 350 351 352 353 354 355 356 357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 386

receptor, FFA2, contributes to gestational glucose homeostasis, Am J Physiol Endocrinol Metab. 309, E84051. 26. Ishizuka, T., Klepcyk, P., Liu, S., Panko, L., Gibbs, E. M. & Friedman, J. E. (1999) Effects of overexpression of human GLUT4 gene on maternal diabetes and fetal growth in spontaneous gestational diabetic C57BLKS/J Lepr(db/+) mice, Diabetes. 48, 1061-9. 27. Pasek, R. C., Dunn, J. C., Elsakr, J. M., Aramandla, M., Matta, A. R. & Gannon, M. (2017) Vascularderived connective tissue growth factor (Ctgf) is critical for pregnancy-induced beta cell hyperplasia in adult mice, Islets. 9, 150-158. 28. Kim, H., Toyofuku, Y., Lynn, F. C., Chak, E., Uchida, T., Mizukami, H., Fujitani, Y., Kawamori, R., Miyatsuka, T., Kosaka, Y., Yang, K., Honig, G., van der Hart, M., Kishimoto, N., Wang, J., Yagihashi, S., Tecott, L. H., Watada, H. & German, M. S. (2010) Serotonin regulates pancreatic beta cell mass during pregnancy, Nat Med. 16, 804-8. 29. Shao, J., Yamashita, H., Qiao, L., Draznin, B. & Friedman, J. E. (2002) Phosphatidylinositol 3-Kinase Redistribution Is Associated With Skeletal Muscle Insulin Resistance in Gestational Diabetes Mellitus, Diabetes. 51, 19-29. 30. Yamashita, H., Shao, J., Ishizuka, T., Klepcyk, P. J., Muhlenkamp, P., Qiao, L., Hoggard, N. & Friedman, J. E. (2001) Leptin administration prevents spontaneous gestational diabetes in heterozygous Lepr(db/+) mice: effects on placental leptin and fetal growth, Endocrinology. 142, 2888-97. 31. Lu, X., Wu, F., Jiang, M., Sun, X. & Tian, G. (2019) Curcumin ameliorates gestational diabetes in mice partly through activating AMPK, Pharm Biol. 57, 250-254. 32. Yamashita, H., Shao, J., Qiao, L., Pagliassotti, M. & Friedman, J. E. (2003) Effect of spontaneous gestational diabetes on fetal and postnatal hepatic insulin resistance in Lepr(db/+) mice, Pediatr Res. 53, 411-8. 33. Zha, W., Ho, H. T. B., Hu, T., Hebert, M. F. & Wang, J. (2017) Serotonin transporter deficiency drives estrogen-dependent obesity and glucose intolerance, Sci Rep. 7, 1137. 34. Lau, S. M., Cha, K. M., Karunatillake, A., Stokes, R. A., Cheng, K., McLean, M., Cheung, N. W., Gonzalez, F. J. & Gunton, J. E. (2013) Beta-cell ARNT is required for normal glucose tolerance in murine pregnancy, PLoS One. 8, e77419. 35. Karnik, S. K., Chen, H., McLean, G. W., Heit, J. J., Gu, X., Zhang, A. Y., Fontaine, M., Yen, M. H. & Kim, S. K. (2007) Menin controls growth of pancreatic beta-cells in pregnant mice and promotes gestational diabetes mellitus, Science. 318, 806-9. 36. Demirci, C., Ernst, S., Alvarez-Perez, J. C., Rosa, T., Valle, S., Shridhar, V., Casinelli, G. P., Alonso, L. C., Vasavada, R. C. & Garcia-Ocana, A. (2012) Loss of HGF/c-Met signaling in pancreatic beta-cells leads to incomplete maternal beta-cell adaptation and gestational diabetes mellitus, Diabetes. 61, 1143-52. 37. Gurlo, T., Kim, S., Butler, A. E., Liu, C., Pei, L., Rosenberger, M. & Butler, P. C. (2019) Pregnancy in human IAPP transgenic mice recapitulates beta cell stress in type 2 diabetes, Diabetologia. 62, 1000-1010. 38. Plank, J. L., Frist, A. Y., LeGrone, A. W., Magnuson, M. A. & Labosky, P. A. (2011) Loss of Foxd3 results in decreased beta-cell proliferation and glucose intolerance during pregnancy, Endocrinology. 152, 4589-600. 39. Zhang, H., Zhang, J., Pope, C. F., Crawford, L. A., Vasavada, R. C., Jagasia, S. M. & Gannon, M. (2010) Gestational diabetes mellitus resulting from impaired beta-cell compensation in the absence of FoxM1, a novel downstream effector of placental lactogen, Diabetes. 59, 143-52. 40. Harrod, J. S., Rada, C. C., Pierce, S. L., England, S. K. & Lamping, K. G. (2011) Altered contribution of RhoA/Rho kinase signaling in contractile activity of myometrium in leptin receptor-deficient mice, Am J Physiol Endocrinol Metab. 301, E362-9. 41. Plows, J. F., Yu, X., Broadhurst, R., Vickers, M. H., Tong, C., Zhang, H., Qi, H., Stanley, J. L. & Baker, P. N. (2017) Absence of a gestational diabetes phenotype in the LepRdb/+ mouse is independent of control strain, diet, misty allele, or parity, Scientific reports. 7, 45130. 42. Pollock, K. E., Stevens, D., Pennington, K. A., Thaisrivongs, R., Kaiser, J., Ellersieck, M. R., Miller, D. K. & Schulz, L. C. (2015) Hyperleptinemia During Pregnancy Decreases Adult Weight of Offspring and Is Associated With Increased Offspring Locomotor Activity in Mice, Endocrinology. 156, 3777-90. 43. Nteeba, J., Kubota, K., Wang, W., Zhu, H., Vivian, J., Dai, G. & Soares, M. (2019) Pancreatic prolactin receptor signaling regulates maternal glucose homeostasis, J Endocrinol.


387 388 389 390 391 392 393 394 395 396 397 398 399 400 401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438

44. Kahraman, S., Dirice, E., De Jesus, D. F., Hu, J. & Kulkarni, R. N. (2014) Maternal insulin resistance and transient hyperglycemia impact the metabolic and endocrine phenotypes of offspring, Am J Physiol Endocrinol Metab. 307, E906-18. 45. Khan, M. W., Priyadarshini, M., Cordoba-Chacon, J., Becker, T. C. & Layden, B. T. (2019) Hepatic hexokinase domain containing 1 (HKDC1) improves whole body glucose tolerance and insulin sensitivity in pregnant mice, Biochim Biophys Acta Mol Basis Dis. 1865, 678-687. 46. Sferruzzi-Perri, A. N., Lopez-Tello, J., Fowden, A. L. & Constancia, M. (2016) Maternal and fetal genomes interplay through phosphoinositol 3-kinase(PI3K)-p110α signalling to modify placental resource allocation, Proc Natl Acad Sci USA. 113(40), 11255-11260. 47. Zampieri, T. T., Ramos-Lobo, A. M., Furigo, I. C., Pedroso, J. A., Buonfiglio, D. C. & Donato, J., Jr. (2015) SOCS3 deficiency in leptin receptor-expressing cells mitigates the development of pregnancy-induced metabolic changes, Mol Metab. 4, 237-45. 48. Lin, S., Thomas, T. C., Storlien, L. H. & Huang, X. F. (2000) Development of high fat diet-induced obesity and leptin resistance in C57Bl/6J mice, Int J Obes Relat Metab Disord. 24, 639-46. 49. Sferruzzi-Perri, A. N., Vaughan, O. R., Haro, M., Cooper, W. N., Musial, B., Charalambous, M., Pestana, D., Ayyar, S., Ferguson-Smith, A. C., Burton, G. J., Constancia, M. & Fowden, A. L. (2013) An obesogenic diet during mouse pregnancy modifies maternal nutrient partitioning and the fetal growth trajectory, FASEB. 27, 3928-37. 50. Musial, B., Vaughan, O. R., Fernandez-Twinn, D. S., Voshol, P., Ozanne, S. E., Fowden, A. L. & SferruzziPerri, A. N. (2017) A Western-style obesogenic diet alters maternal metabolic physiology with consequences for fetal nutrient acquisition in mice, J Physiol. 595, 4875-4892. 51. Fernandez-Twinn, D. S., Gascoin, G., Musial, B., Carr, S., Duque-Guimaraes, D., Blackmore, H. L., Alfaradhi, M. Z., Loche, E., Sferruzzi-Perri, A. N., Fowden, A. L. & Ozanne, S. E. (2017) Exercise rescues obese mothers' insulin sensitivity, placental hypoxia and male offspring insulin sensitivity, Sci Rep. 7, 44650. 52. Rosario, F. J., Kanai, Y., Powell, T. L. & Jansson, T. (2015) Increased placental nutrient transport in a novel mouse model of maternal obesity with fetal overgrowth, Obesity (Silver Spring). 23, 1663-70. 53. Carter, L. G., Ngo Tenlep, S. Y., Woollett, L. A. & Pearson, K. J. (2015) Exercise Improves Glucose Disposal and Insulin Signaling in Pregnant Mice Fed a High Fat Diet, J Diabetes Metab. 6, pii: 634. 54. Holemans, K., Caluwaerts, S., Poston, L. & Van Assche, F. A. (2004) Diet-induced obesity in the rat: A model for gestational diabetes mellitus, Am J Obstet Gynecol. 190, 858-865. 55. Moore, M. C., Menon, R., Coate, K. C., Gannon, M., Smith, M. S., Farmer, B. & Williams, P. E. (2011) Diet-induced impaired glucose tolerance and gestational diabetes in the dog, J Appl Physiol (1985). 110, 458-467. 56. Aye, I. L., Rosario, F. J., Powell, T. L. & Jansson, T. (2015) Adiponectin supplementation in pregnant mice prevents the adverse effects of maternal obesity on placental function and fetal growth, Proc Natl Acad Sci U S A. 112, 12858-63. 57. Alzamendi, A., Del Zotto, H., Castrogiovanni, D., Romero, J., Giovambattista, A. & Spinedi, E. (2012) Oral metformin treatment prevents enhanced insulin demand and placental dysfunction in the pregnant rat fed a fructose-rich diet, ISRN Endocrinol. 2012, 757913. 58. Pennington, K. A., van der Walt, N., Pollock, K. E., Talton, O. O. & Schulz, L. C. (2017) Effects of acute exposure to a high-fat, high-sucrose diet on gestational glucose tolerance and subsequent maternal health in mice, Biol Reprod. 96, 435-445. 59. Sferruzzi-Perri, A. N. & Camm, E. J. (2016) The programming power of the placenta, Front Physiol. 7:33. 60. Ashino, N. G., Saito, K. N., Souza, F. D., Nakutz, F. S., Roman, E. A., Velloso, L. A., Torsoni, A. S. & Torsoni, M. A. (2012) Maternal high-fat feeding through pregnancy and lactation predisposes mouse offspring to molecular insulin resistance and fatty liver, J Nutr Biochem. 23, 341-8. 61. Franco, J. G., Fernandes, T. P., Rocha, C. P., Calvino, C., Pazos-Moura, C. C., Lisboa, P. C., Moura, E. G. & Trevenzoli, I. H. (2012) Maternal high-fat diet induces obesity and adrenal and thyroid dysfunction in male rat offspring at weaning, J Physiol. 590, 5503-18. 62. Musial, B., Fernandez-Twinn, D. S., Duque-Guimaraes, D., Carr, S. K., Fowden, A. L., Ozanne, S. E. & Sferruzzi-Perri, A. N. (2019) Exercise alters obese mothers' tissue insulin sensitivity and lipid handling in mice, Physiological reports. 7, e14202.


439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480 481 482 483 484 485 486 487 488 489 490 491 492

63. Capobianco, E., Fornes, D., Linenberg, I., Powell, T. L., Jansson, T. & Jawerbaum, A. (2016) A novel rat model of gestational diabetes induced by intrauterine programming is associated with alterations in placental signaling and fetal overgrowth, Mol Cell Endocrinol. 422, 221-32. 64. Gallo, L. A., Tran, M., Moritz, K. M., Mazzuca, M. Q., Parry, L. J., Westcott, K. T., Jefferies, A. J., CullenMcEwen, L. A. & Wlodek, M. E. (2012a) Cardio-renal and metabolic adaptations during pregnancy in female rats born small: implications for maternal health and second generation fetal growth, J Physiol. 590, 617-30. 65. Carter, A. M. (2012) Evolution of placental function in mammals: the molecular basis of gas and nutrient transfer, hormone secretion, and immune responses, Physiol Rev. 92, 1543-76. 66. Napso, T., Yong, H. E., Lopez-Tello, J. & Sferruzzi-Perri, A. N. (2018) The role of placental hormones in mediating maternal adaptations to support pregnancy and lactation, Front Physiology. 9:1091. 67. Brelje, T. C., Stout, L. E., Bhagroo, N. V. & Sorenson, R. L. (2004) Distinctive roles for prolactin and growth hormone in the activation of signal transducer and activator of transcription 5 in pancreatic islets of langerhans, Endocrinology. 145, 4162-75. 68. Huang, C., Snider, F. & Cross, J. C. (2009) Prolactin Receptor Is Required for Normal Glucose Homeostasis and Modulation of {beta}-Cell Mass during Pregnancy, Endocrinology. 150, 1618-1626. 69. Hill, D. J. (2018) Placental control of metabolic adaptations in the mother for an optimal pregnancy outcome. What goes wrong in gestational diabetes?, Placenta. 69, 162-168. 70. Banerjee, R. R., Cyphert, H. A., Walker, E. M., Chakravarthy, H., Peiris, H., Gu, X., Liu, Y., Conrad, E., Goodrich, L., Stein, R. W. & Kim, S. K. (2016) Gestational Diabetes Mellitus From Inactivation of Prolactin Receptor and MafB in Islet beta-Cells, Diabetes. 65, 2331-41. 71. Schulz, N., Liu, K. C., Charbord, J., Mattsson, C. L., Tao, L., Tworus, D. & Andersson, O. (2016) Critical role for adenosine receptor A2a in beta-cell proliferation, Mol Metab. 5, 1138-1146. 72. Modi, H., Jacovetti, C., Tarussio, D., Metref, S., Madsen, O. D., Zhang, F. P., Rantakari, P., Poutanen, M., Nef, S., Gorman, T., Regazzi, R. & Thorens, B. (2015) Autocrine Action of IGF2 Regulates Adult beta-Cell Mass and Function, Diabetes. 64, 4148-57. 73. Li, J., Ying, H., Cai, G., Guo, Q. & Chen, L. (2015) Impaired proliferation of pancreatic beta cells, by reduced placental growth factor in pre-eclampsia, as a cause for gestational diabetes mellitus, Cell Prolif. 48, 166-74. 74. Vasavada, R. C., Cavaliere, C., D'Ercole, A. J., Dann, P., Burtis, W. J., Madlener, A. L., Zawalich, K., Zawalich, W., Philbrick, W. & Stewart, A. F. (1996) Overexpression of parathyroid hormone-related protein in the pancreatic islets of transgenic mice causes islet hyperplasia, hyperinsulinemia, and hypoglycemia, J Biol Chem. 271, 1200-8. 75. Liao, S., Vickers, M. H., Evans, A., Stanley, J. L., Baker, P. N. & Perry, J. K. (2016) Comparison of pulsatile vs. continuous administration of human placental growth hormone in female C57BL/6J mice, Endocrine. 54, 169-181. 76. Barbour, L. A., Shao, J., Qiao, L., Leitner, W., Anderson, M., Friedman, J. E. & Draznin, B. (2004) Human placental growth hormone increases expression of the p85 regulatory unit of phosphatidylinositol 3-kinase and triggers severe insulin resistance in skeletal muscle, Endocrinology. 145, 1144-50. 77. Barbour, L. A., Shao, J., Qiao, L., Pulawa, L. K., Jensen, D. R., Bartke, A., Garrity, M., Draznin, B. & Friedman, J. E. (2002) Human placental growth hormone causes severe insulin resistance in transgenic mice, Am J Obstet Gynecol. 186, 512-7. 78. del Rincon, J. P., Iida, K., Gaylinn, B. D., McCurdy, C. E., Leitner, J. W., Barbour, L. A., Kopchick, J. J., Friedman, J. E., Draznin, B. & Thorner, M. O. (2007) Growth hormone regulation of p85alpha expression and phosphoinositide 3-kinase activity in adipose tissue: mechanism for growth hormone-mediated insulin resistance, Diabetes. 56, 1638-46. 79. Freemark, M., Fleenor, D., Driscoll, P., Binart, N. & Kelly, P. (2001) Body weight and fat deposition in prolactin receptor-deficient mice, Endocrinology. 142, 532-7. 80. Rawn, S. M., Huang, C., Hughes, M., Shaykhutdinov, R., Vogel, H. J. & Cross, J. C. (2015) Pregnancy Hyperglycemia in Prolactin Receptor Mutant, but Not Prolactin Mutant, Mice and Feeding-Responsive Regulation of Placental Lactogen Genes Implies Placental Control of Maternal Glucose Homeostasis, Biol Reprod. 93, 75. 81. Picard, F., Wanatabe, M., Schoonjans, K., Lydon, J., O'Malley, B. W. & Auwerx, J. (2002) Progesterone receptor knockout mice have an improved glucose homeostasis secondary to beta -cell proliferation, Proc Natl Acad Sci U S A. 99, 15644-8. 12

493 494 495 496 497 498 499 500 501 502 503 504 505 506 507 508 509 510 511 512 513 514 515 516 517 518 519 520 521 522 523 524 525 526 527 528 529 530 531 532 533 534 535 536 537 538 539 540 541 542 543 544 545

82. Stelmanska, E. & Sucajtys-Szulc, E. (2014) Enhanced food intake by progesterone-treated female rats is related to changes in neuropeptide genes expression in hypothalamus, Endokrynol Pol. 65, 46-56. 83. Costrini, N. V. & Kalkhoff, R. K. (1971) Relative effects of pregnancy, estradiol, and progesterone on plasma insulin and pancreatic islet insulin secretion, The Journal of clinical investigation. 50, 992-9. 84. Vasavada, R. C., Garcia-Ocana, A., Zawalich, W. S., Sorenson, R. L., Dann, P., Syed, M., Ogren, L., Talamantes, F. & Stewart, A. F. (2000) Targeted expression of placental lactogen in the beta cells of transgenic mice results in beta cell proliferation, islet mass augmentation, and hypoglycemia, J Biol Chem. 275, 15399-406. 85. Ohara-Imaizumi, M., Kim, H., Yoshida, M., Fujiwara, T., Aoyagi, K., Toyofuku, Y., Nakamichi, Y., Nishiwaki, C., Okamura, T., Uchida, T., Fujitani, Y., Akagawa, K., Kakei, M., Watada, H., German, M. S. & Nagamatsu, S. (2013) Serotonin regulates glucose-stimulated insulin secretion from pancreatic beta cells during pregnancy, Proc Natl Acad Sci U S A. 110, 19420-5. 86. Vejrazkova, D., Vcelak, J., Vankova, M., Lukasova, P., Bradnova, O., Halkova, T., Kancheva, R. & Bendlova, B. (2014) Steroids and insulin resistance in pregnancy, J Steroid Biochem Mol Biol. 139, 122-9. 87. Liao, S., Vickers, M. H., Stanley, J. L., Ponnampalam, A. P., Baker, P. N. & Perry, J. K. (2016) The Placental Variant of Human Growth Hormone Reduces Maternal Insulin Sensitivity in a Dose-Dependent Manner in C57BL/6J Mice, Endocrinology. 157, 1175-86. 88. Fang, X., Wong, S. & Mitchell, B. F. (1997) Effects of RU486 on estrogen, progesterone, oxytocin, and their receptors in the rat uterus during late gestation, Endocrinology. 138, 2763-8. 89. Nadal, A., Alonso-Magdalena, P., Soriano, S., Ropero, A. B. & Quesada, I. (2009) The role of oestrogens in the adaptation of islets to insulin resistance, J Physiol. 587, 5031-7. 90. Narasimhan, A., Sampath, S., Jayaraman, S. & Karundevi, B. (2013) Estradiol favors glucose oxidation in gastrocnemius muscle through modulation of insulin signaling molecules in adult female rats, Endocr Res. 38, 251-62. 91. Gonzalez, C., Alonso, A., Grueso, N. A., Diaz, F., Esteban, M. M., Fernandez, S. & Patterson, A. M. (2002) Role of 17beta-estradiol administration on insulin sensitivity in the rat: implications for the insulin receptor, Steroids. 67, 993-1005. 92. Bryzgalova, G., Gao, H., Ahren, B., Zierath, J. R., Galuska, D., Steiler, T. L., Dahlman-Wright, K., Nilsson, S., Gustafsson, J. A., Efendic, S. & Khan, A. (2006) Evidence that oestrogen receptor-alpha plays an important role in the regulation of glucose homeostasis in mice: insulin sensitivity in the liver, Diabetologia. 49, 588-97. 93. Ribas, V., Drew, B. G., Le, J. A., Soleymani, T., Daraei, P., Sitz, D., Mohammad, L., Henstridge, D. C., Febbraio, M. A., Hewitt, S. C., Korach, K. S., Bensinger, S. J. & Hevener, A. L. (2011) Myeloid-specific estrogen receptor alpha deficiency impairs metabolic homeostasis and accelerates atherosclerotic lesion development, Proc Natl Acad Sci U S A. 108, 16457-62. 94. Ahmed-Sorour, H. & Bailey, C. J. (1980) Role of ovarian hormones in the long-term control of glucose homeostasis. Interaction with insulin, glucagon and epinephrine, Horm Res. 13, 396-403. 95. Fungfuang, W., Terada, M., Komatsu, N., Moon, C. & Saito, T. R. (2013) Effects of estrogen on food intake, serum leptin levels and leptin mRNA expression in adipose tissue of female rats, Lab Anim Res. 29, 168-73. 96. Gorres, B. K., Bomhoff, G. L., Morris, J. K. & Geiger, P. C. (2011) In vivo stimulation of oestrogen receptor alpha increases insulin-stimulated skeletal muscle glucose uptake, J Physiol. 589, 2041-54. 97. Pasek, R. C. & Gannon, M. (2013) Advancements and challenges in generating accurate animal models of gestational diabetes mellitus, Am J Physiol Endocrinol Metab. 305, E1327-38. 98. Vakili, H., Jin, Y., Menticoglou, S. & Cattini, P. A. (2013) CCAAT-enhancer-binding Protein beta (C/EBPbeta) and Downstream Human Placental Growth Hormone Genes Are Targets for Dysregulation in Pregnancies Complicated by Maternal Obesity, J Biol Chem. 288, 22849-61. 99. Napso, T., Hung, Y.-P., Davidge, S. T., Care, A. S. & Sferruzzi-Perri, A. N. Advanced maternal age compromises fetal growth and induces sex-specific changes in placental phenotype in rats, Sci Rep. In Press. 100. Nguyen-Ngo, C., Jayabalan, N., Salomon, C. & Lappas, M. (2019) Molecular pathways disrupted by gestational diabetes mellitus, J Mol Endocrinol. 101. Branisteanu, D. D. & Mathieu, C. (2003) Progesterone in gestational diabetes mellitus: guilty or not guilty?, Trends Endocrinol Metab. 14, 54-6. 13

546 547 548 549 550 551 552 553 554 555 556 557 558 559 560 561 562 563 564 565 566 567 568 569 570 571 572 573 574 575

102. McIntyre, H. D., Serek, R., Crane, D. I., Veveris-Lowe, T., Parry, A., Johnson, S., Leung, K. C., Ho, K. K., Bougoussa, M., Hennen, G., Igout, A., Chan, F. Y., Cowley, D., Cotterill, A. & Barnard, R. (2000) Placental growth hormone (GH), GH-binding protein, and insulin-like growth factor axis in normal, growth-retarded, and diabetic pregnancies: correlations with fetal growth, The Journal of clinical endocrinology and metabolism. 85, 1143-50. 103. Newbern, D. & Freemark, M. (2011) Placental hormones and the control of maternal metabolism and fetal growth, Curr Opin Endocrinol Diabetes Obes. 18, 409-16. 104. Ngala, R. A., Fondjo, L. A., Gmagna, P., Ghartey, F. N. & Awe, M. A. (2017) Placental peptides metabolism and maternal factors as predictors of risk of gestational diabetes in pregnant women. A casecontrol study, PLoS One. 12, e0181613. 105. Liao, S., Vickers, M. H., Taylor, R. S., Fraser, M., McCowan, L. M. E., Baker, P. N. & Perry, J. K. (2017) Maternal serum placental growth hormone, insulin-like growth factors and their binding proteins at 20 weeks' gestation in pregnancies complicated by gestational diabetes mellitus, Hormones (Athens). 16, 282290. 106. Le, T. N., Elsea, S. H., Romero, R., Chaiworapongsa, T. & Francis, G. L. (2013) Prolactin receptor gene polymorphisms are associated with gestational diabetes, Genetic testing and molecular biomarkers. 17, 567-71. 107. Sferruzzi-Perri, A. N., Vaughan, O. R., Coan, P. M., Suciu, M. C., Darbyshire, R., Constancia, M., Burton, G. J. & Fowden, A. L. (2011) Placental-specific Igf2 deficiency alters developmental adaptations to undernutrition in mice, Endocrinology. 152, 3202-12. 108. Petry, C. J., Evans, M. L., Wingate, D. L., Ong, K. K., Reik, W., Constancia, M. & Dunger, D. B. (2010) Raised late pregnancy glucose concentrations in mice carrying pups with targeted disruption of H19Delta13., Diabetes. 59, 282-286. 109. Cleaton, M. A., Dent, C. L., Howard, M., Corish, J. A., Gutteridge, I., Sovio, U., Gaccioli, F., Takahashi, N., Bauer, S. R., Charnock-Jones, D. S., Powell, T. L., Smith, G. C., Ferguson-Smith, A. C. & Charalambous, M. (2016) Fetus-derived DLK1 is required for maternal metabolic adaptations to pregnancy and is associated with fetal growth restriction, Nat Genet. 48, 1473-1480. 110. Lopez-Tello, J., Khaira, J., Kusinski, L. C., Cooper, W., Andreani, A., Grant, I., Fernandez de Liger, E., Sandovici, I., Constancia, M. & Sferruzzi-Perri, A. N. (2019) Fetal and placental phosphoinositol 3-kinase (PI3K) p110α have distinct contributions in regulating resource allocation to the growing fetus, eLIFE. 8.

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Table 1 Maternal manipulations to study metabolic alterations during pregnancy Manipulation

Maternal metabolic phenotype

Fetal phenotype


Glucose intolerance, hyperglycaemia due to insulin deficiency

Compromised fetal


Surgical removal of beta cells Removal of pancreas in rats

development (increased resorptions) Pharmacological ablation of beta cells Alloxan during pregnancy in pigs

Hyperglycaemia due to insulin deficiency

Increased fetal glucose, no


change fetal weight Alloxan during pregnancy in

Hyperglycaemia due to insulin deficiency

rabbits Streptozotocin prior to pregnancy

Increased fetal glucose and


increased fetal mortality Hyperglycaemia due to insulin deficiency

in rats

Increased fetal malformations


and reduced fetal development (decreased crown-rump length)

Streptozotocin during pregnancy in

Hyperglycaemia due to insulin deficiency


No change birth weight but


offspring programmed for insulin resistance

Maternal genetic manipulation in mice to study metabolic changes during pregnancy Global gene manipulation Adiponectin deficiency (Adipoq-/-)

Glucose intolerant in late pregnancy due to defective pancreas

in female mated to wildtype male.

beta cell mass expansion and insulin deficiency. Reduced

Compared to reverse cross to

glycogen content and increased glucose production in the liver

Increased fetal weight



control litter genotype

and hyperlipidemia (increased triglycerides and fatty acids)

Leptin receptor heterozygous null

Glucose intolerant only during pregnancy with reduced peripheral

Increased fetal weight

females mated with males of same

tissue insulin sensitivity and GSIS. Increased food intake, hepatic

regardless of fetal genotype

genotype or wildtype males

glucose production, adiposity and hyperleptinemia

[26, 29-32]

Normal glucose tolerance despite hyperleptinemia and increased

Increased fetal length but no

adiposity during pregnancy, expect if fed a high fat diet

change in fetal weight

Increased glucose tolerance despite hyperleptinemia and



No change in pup number






increased weight during pregnancy Ffar2-/- mice

Fasting hyperglycemia and impaired glucose tolerance, beta cell mass expansion and insulin secretion during, but not before, pregnancy. No change in insulin tolerance before and during pregnancy. Estradiol induces Ffar2 expression in islets

Vascular-derived connective tissue

Impairment in maternal beta cell proliferation during pregnancy

growth factor (Ctgf)

but not apparent in non-pregnant state. Normal glucose tolerance

haploinsufficiency (Ctgf(LacZ/+))

and GSIS in non-pregnant and pregnant state

Serotonin receptor 5-

Impairment in beta cell proliferation during pregnancy and glucose ND

hydroxytryptamine receptor-2b

intolerance in pregnant but not in not-pregnant mice. Related to


prolactin and placental lactogen which induce serotonin synthesis and signalling in the beta cells

Serotonin receptor knockout Htr3a

Glucose intolerance and diminished GSIS (via increased resting


beta cell membrane potential) in pregnant but not in not-pregnant

No change in litter size


mice. No change in beta cell mass prior to or during pregnancy. Prolactin and placental lactogen induce serotonin synthesis and 16

signalling in the beta cells Serotonin transporter null

Failed brown adipose tissue expansion, increased white adipose



No change in fetal weight







tissue, reduced plasma insulin and improved glucose tolerance during pregnancy Phosphoinositol 3-kinase p110α

Reduced liver weight, hyperleptinemia, reduced triglycerides,

(Pik3ca) +/- female mated to

hyperinsulinemia and no change in glucose (insulin resistance)

wildtype male. Compared to

during pregnancy

reverse cross to control litter genotype Beta cell specific gene manipulation Transgenic mice expressing

Beta cell deficit and hyperglycemia in prior to and during

human IAPP in the beta cells in

pregnancy, but these worsen in the second pregnancy

not-pregnant and pregnant state following mating to wildtype males Beta cell loss of HGF-cMet in

Failed beta cell mass expansion, reduced GSIS and glucose

females mated to wildtype males

intolerance during pregnancy (but not in non-pregnant state). Related to reduced PRLR expression by beta cells. Estradiol increases cMet expression

Beta cell Menin overexpression in

Failed beta cell mass expansion, insulin deficiency,

No change in birthweight or

female pregnant mice

hyperglycaemia and glucose intolerance

litter size

Beta cell Foxm1 deletion in female

Failed beta cell mass expansion and glucose intolerance during




pregnancy but beta cell defect present in non-pregnant state.

Mildly increased fetal weight


Impacts on beta cells during pregnancy related to the effect of placental lactogen. Glucose handling restores postpartum Beta cell specific Arnt null mated to Mutants have impaired glucose tolerance secondary to defective


wildtype male. Compared to

insulin secretion in non-pregnant state, which worsens with

reverse parental cross


Liver specific gene manipulation Hepatic insulin receptor deficiency

Hyperinsulinemic with normal blood glucose levels before

Reduced birthweight followed

mated to wildtype males

pregnancy but became glucose intolerant and more insulin

by rapid postnatal catch up

resistant compared during pregnancy

growth and increased glucose,


insulin, glucagon, leptin and GLP1 Hepatic overexpression of

Lower insulin and GSIS but improved glucose tolerance in


association with increased hepatic, white adipose and skeletal





No effect on fetal outcome




muscle insulin signalling. Impacts observed only during pregnancy Hepatic deletion of hexokinase

Similar insulin but reduced glucose tolerance only during pregnancy

Cell specific gene manipulation-other SOCS3 deletion from leptin

Inability to undergo pregnancy-induced hyperphagia, body fat

receptor cells

accumulation, as well as inability to acquire leptin and insulin resistance. Protected females against long-term postpartum fat retention and streptozotocin-induced hyperglycaemia and glucose intolerance during pregnancy during to improved peripheral insulin sensitivity

Maternal obesogenic diet High fructose and high fat diet from Glucose intolerance, reduced hepatic and skeletal muscle insulin mid-pregnancy in dogs

sensitivity without a change in beta cell mass density or plasma insulin 18

High fructose diet just during

Increased adiposity, hyperinsulinemia and glucose intolerance

Increased fetal weight


pregnancy in rats

related to peripheral insulin resistance

High sugar and high fat just in

Increased adiposity, reduced glucose tolerance and reduced

Reduced fetal weight followed

[49, 50]

pregnancy in mice

peripheral insulin sensitivity but increased hepatic sensitivity and

by accelerated fetal growth

reduced glucose production. Changes in maternal metabolic

just prior to term

phenotype related to alterations in the expression of insulin signalling and glucose and lipid handling proteins in the liver, skeletal muscle and WAT, as well as reduced prolactin/placental lactogen genes in the placenta High sucrose and high fat for 1

Increased adiposity, reduced glucose tolerance related to reduced No change in fetal weight or

week prior to and during

beta cell mass, insulin deficiency, decreased GSIS and elevated

pregnancy in mice

leptin during pregnancy which is not apparent prior to pregnancy.


litter size

Glucose intolerance resolves after pregnancy, but dams have a propensity to develop glucose intolerance and hypertriglyceridemia on a high fat diet postpartum High fat diet for 3 weeks prior to

Increased adiposity, reduced glucose tolerance and

and during pregnancy in mice

hyperglycaemia prior to and during pregnancy. Exercise




ameliorated diet-induced maternal glucose intolerance and hyperglycaemia in association with changes in insulin signalling proteins primarily in WAT during pregnancy High sugar and high fat diet for 4

Increased adiposity, glucose intolerance and hyperinsulinemia

No change in fetal weight but

weeks prior to and during

which are aggravated by pregnancy

increased litter size

Diet fed 6 weeks prior to and

Increased adiposity, glucose intolerance, hyperinsulinemia,

Increased fetal weight and

during pregnancy in mice

hyperleptinemia and reduced adiponectin. Adiponectin


pregnancy in rats [52, 56]


ameliorated diet-induced maternal hyperinsulinemia, hyperleptinemia Diet fed 9 weeks prior to and

Increased adiposity, glucose intolerance, insulin resistance,

during pregnancy in mice

hyperinsulinemia and hyperleptinemia related to alterations in the

Reduced fetal weight

[51, 62]

expression of insulin signalling and glucose and lipid handling proteins in the liver, skeletal muscle and WAT. Exercise ameliorated diet-induced maternal glucose intolerance, insulin resistance and hyperinsulinemia in association with changes in insulin signalling proteins primarily in the WAT 580

GSIS: glucose-stimulated insulin secretion, ND: not determined, WAT: white adipose tissue.




Table 2 The function of placental hormones in driving metabolic changes assessed experimentally in rodents in vivo Hormone/manipulation

Maternal metabolic phenotype

Fetal phenotype


Exogenous administration of growth

Non-pregnant: Hyperinsulinemia and reduced insulin sensitivity



hormone or overexpression of human

associated with impaired stimulation of IRS1-PI3K signalling

placental growth hormone in mice

(increased PI3K-p85α) and GLUT4 in skeletal muscle and WAT.

Pregnant: Hyperinsulinemia and reduced insulin sensitivity associated

No change in litter


with reduced hepatic GLUT4 without a change in fasting glucose levels

size or fetal weight

and body weight.

but reduced fetal

Growth hormone

Increased body weight and IGF1 and reduced adiposity, adiponectin and free fatty acids.

crown-rump length. Deficiency of growth hormone in mice

Non-pregnant: Elevated adiponectin and increased adipocyte size with




higher insulin sensitivity related to reduced PI3K-p85α expression in WAT. Placental growth factor Pharmacological administration

Pregnant: increased β-cell proliferation during pregnancy in mice with

Fetal weight not

placental growth factor in mice

defects in β-cell mass expansion due to L-name treatment


Deficiency of prolactin receptor in

Non-pregnant: Reduced islet density, β-cell mass and insulin



content/islet and GSIS. Reduced body weight, adipose mass and

treated with L-NAME Prolactin [68, 79, 80]

plasma leptin. No change in glucose tolerance. 21

Deficiency of prolactin in mice

Pregnant: Glucose intolerant in association with failed β-cell

No change in litter

proliferation expansion and reduced GSIS.

size, fetal weight.

Pregnant: glycaemia is normal.

No change in litter

[68, 80]


size, fetal weight. Transgenic mice with deficiency of

Non-pregnant: Similar levels of glucose, insulin, glucose and insulin



the prolactin receptor in β-cells

tolerance, pancreatic weight and β-cell mass. Pregnant: Hyperglycaemic and glucose intolerant due to reduced β-cell

Increased fetal


proliferation and expansion of β-cell mass.


Transgenic mice with overexpression

Non-pregnant: Hypoglycaemia due to increased β-cell size, mass and



of placental lactogen 1 in β-cells






Placental lactogen

Parathyroid hormone-related protein Transgenic mice with overexpression

Non-pregnant: Reduced in size and have hypoglycaemia and

of parathyroid hormone-related

hyperinsulinemia due to expansion of β-cell mass.

protein in β-cells Insulin like growth factors Transgenic mice with loss of IGF2 in

Non-pregnant: Young mice have similar glucose tolerance, insulin


sensitivity and GSIS. However, aged females display lower levels of insulin, which is compensated by increased insulin sensitivity to maintain normal glucose tolerance. β-cell mass expansion in response high fat diet or pharmacological induction of insulin resistance is reduced.


Pregnant mice: have reduced β-cell proliferation.



Wildtype mice carrying litters with

Pregnant: Increased body weight, increased insulin and corticosterone

Reduced fetal and


placental loss of the Igf2 P0 isoform

and reduced α-amino nitrogen concentrations. Higher plasma glucose,

placental weights.

corticosterone and leptin in undernourished dams during pregnancy. Wildtype mice carrying litters with

Pregnant: Elevated circulating glucose and glucose intolerant.

placental overexpression of the Igf2

Increased fetal and


placental weights.

(H19 deletion) Estrogens Deficiency of estrogen receptor-α in

Non-pregnant: Hyperglycemia, hyperleptinemia, hyperinsulinemia,


reduced insulin sensitivity, hepatic insulin resistance, glucose


[92, 93]




[83, 90, 94-

intolerance and increased body weight. Deficiency of estrogen receptor-β in

Non-pregnant: Normal body size, glycaemia, insulinemia and glucose



Exogenous administration of

Non-pregnant: Increased insulin sensitivity and reduced plasma

estrogens to mice and rats

glucose levels due to increased insulin-stimulated PI3K signalling,


GLUT4 translocation and glucose uptake by the skeletal muscle. Increased plasma leptin and reduced food intake.

Pregnant: Increased insulin sensitivity and reduced plasma glucose in






[82, 83]

association with increased GSIS and β-cell size Progesterone Deficiency of progesterone

Non-pregnant: Reduced glucose levels and improved glucose

receptor in mice

tolerance due to increased β-cell proliferation and insulin secretion/production.

Exogenous administration of

Non-pregnant: Increased in food intake, body weight, adiposity and


estrogens to mice and rats 583

insulin secretion.

GSIS: glucose-stimulated insulin secretion, NA: not applicable, ND: not determined, PI3K: phosphoinositol 3-kinase, WAT: white adipose tissue.

584 585 586