Placental structural abnormalities in gestational diabetes and when they develop: A scoping review.

Gestational diabetes mellitus (GDM) is defined as diabetes with onset or first recognition during gestation. It is a common complication of pregnancy that has become more prevalent over the past few decades. Abnormalities in fetal growth, including increased incidence of both large and small for gestational age babies, suggest placental dysfunction. The major goal of this scoping review is to determine what is known about abnormalities in placentas delivered from GDM pregnancies, and how early in gestation these abnormalities arise. A secondary goal is to review to what extent other selected factors, in particular obesity, have been found to influence or modify the reported effects of GDM on placental development, and whether these are considered in the study of GDM placentas. PubMed and Scopus databases were searched using the key terms: "gestational diabetes AND (woman OR human) AND placenta AND (ultrasound OR ultrastructure OR imaging OR histology OR pathology). Studies of gross morphology and histoarchitecture in placentas delivered from GDM pregnancies consistently report increased placental size, villous immaturity and a range of vascular lesions when compared to uncomplicated pregnancies. In contrast, a small number of ultrasound studies have examined placental development in GDM pregnancies in the second, and especially, the first trimester. Relatively few studies have analyzed interactions with maternal BMI, but these do suggest that it may play a role in placental abnormalities. Further examination of placental development early in pregnancy is needed to understand when it becomes disrupted in GDM, as a first step to identifying the underlying causes.

Leprdb/+ Dams Protect Wild-type Male Offspring Bone Strength from the Detrimental Effects of a High-Fat Diet.

The prevalence of maternal obesity is increasing at an alarming rate and increases the life-long risk of developing cardiometabolic disease in adult offspring. Leptin, an adipokine, is systemically elevated in the obese milieu. We recently showed that maternal hyperleptinemia without obesity improves offspring insulin sensitivity and glucose tolerance while protecting against weight gain on a high-fat, high-sugar (HFD). Here, we investigate the effect of maternal hyperleptinemia on offspring bone by using 2 independent maternal models. First, we compared wild-type (WT) offspring from severely hyperleptinemic Leprdb/+ (DB/+) dams with those from WT dams. In the second model, WT females were implanted with miniosmotic pumps that released either saline (group SAL) or leptin (group LEP; 650ng/hour) and the WT offspring were compared. At 23 weeks of age, a subset of offspring were challenged with a HFD for 8 weeks. When the offspring were 31 weeks of age, bone geometry, strength, and material properties were investigated. The HFD increased trabecular bone volume but decreased both total breaking strength and material strength of femora from the offspring of WT dams. However, male offspring of DB/+ dams were protected from the detrimental effects of a HFD, while offspring of LEP dams were not. Further material analysis revealed a modest decrease in advanced glycation end product accumulation coupled with increased collagen crosslinking in male offspring from DB/+ dams on a HFD. These data suggest that while maternal leptin may protect bone quality from the effects of a HFD, additional factors of the maternal environment controlled by leptin receptor signaling are likely also involved.

Morphology and gene expression in mouse placentas lacking leptin receptors.

In the pregnant mouse, the hormone leptin is primarily produced by adipose tissue and does not significantly cross the placenta into fetal circulation. Nonetheless, leptin treatment during gestation affects offspring phenotypes. Leptin treatment also affects placental trophoblast cells in vitro, by altering proliferation, invasion and nutrient transport. The goal of the present study was to determine whether the absence of placental leptin receptors alters placental development and gene expression. Leprdb-3j+ mice possessing only one functional copy of the leptin receptor were mated to obtain wildtype, Leprdb-3j+ and Leprdb-3j/db-3j conceptuses, which were then transferred to wildtype recipient dams. Placentas were collected at gestational d18.5 to examine placental morphology and gene expression. Placentas lacking functional leptin receptor had reduced weights, but were otherwise morphologically indistinguishable from control placentas. Relative mRNA levels, however, were altered in Leprdb-3j/db-3j placentas, particularly transcripts related to amino acid and lipid metabolism and transport. Consistent with a previous in vitro study, leptin was found to promote expression of stathmin, a positive regulator of trophoblast invasion, and of serotonin receptors, potential mediators of offspring neurological development. Overall placental leptin receptor was found not to play a significant role in morphological development of the placenta, but to regulate placental gene expression, including in metabolic pathways that affect fetal growth.

Developmental origins of ovarian disorder: impact of maternal lean gestational diabetes on the offspring ovarian proteome in mice†.

Gestational diabetes mellitus (GDM) is an obstetric disorder affecting approximately 10% of pregnancies. The four high-fat, high-sucrose (HFHS) mouse model emulates GDM in lean women. Dams are fed a HFHS diet 1 week prior to mating and throughout gestation resulting in inadequate insulin response to glucose in mid-late pregnancy. The offspring of HFHS dams have increased adiposity, thus, we hypothesized that maternal metabolic alterations during lean GDM would compromise ovarian function in offspring both basally and in response to a control or HFHS diet in adulthood. Briefly, DLPL were lean dams and control diet pups; DLPH were lean dams and HFHS pups; DHPL were HFHS dams and control diet pups; and DHPH were HFHS dams and HFHS pups. A HFHS challenge in the absence of maternal GDM (DLPL vs. DLPH) increased 3 and decreased 30 ovarian proteins. Maternal GDM in the absence of a dietary stress (DLPL vs. DHPL) increased abundance of 4 proteins and decreased abundance of 85 proteins in the offspring ovary. Finally, 87 proteins increased, and 4 proteins decreased in offspring ovaries due to dietary challenge and exposure to maternal GDM in utero (DLPL vs. DHPH). Canopy FGF signaling regulator 2, deleted in azoospermia-associated protein 1, septin 7, and serine/arginine-rich splicing factor 2 were altered across multiple offspring groups. Together, these findings suggest a possible impact on fertility and oocyte quality in relation to GDM exposure in utero as well as in response to a western diet in later life.

Lean maternal hyperglycemia alters offspring lipid metabolism and susceptibility to diet-induced obesity in mice†.

We previously developed a model of gestational diabetes mellitus (GDM) in which dams exhibit glucose intolerance, insulin resistance, and reduced insulin response to glucose challenge only during pregnancy, without accompanying obesity. Here, we aimed to determine how lean gestational glucose intolerance affects offspring risk of metabolic dysfunction. One cohort of offspring was sacrificed at 19 weeks, and one at 31 weeks, with half of the second cohort placed on a high-fat, high-sucrose diet (HFHS) at 23 weeks. Exposure to maternal glucose intolerance increased weights of HFHS-fed offspring. Chow-fed offspring of GDM dams exhibited higher body fat percentages at 4, 12, and 20 weeks of age. At 28 weeks, offspring of GDM dams fed the HFHS but not the chow diet (CD) also had higher body fat percentages than offspring of controls (CON). Exposure to GDM increased the respiratory quotient (Vol CO2/Vol O2) in offspring. Maternal GDM increased adipose mRNA levels of peroxisome proliferator-activated receptor gamma (Pparg) and adiponectin (Adipoq) in 31-week-old CD-fed male offspring, and increased mRNA levels of insulin receptor (Insr) and lipoprotein lipase (Lpl) in 31-week-old male offspring on both diets. In liver at 31 weeks, mRNA levels of peroxisome proliferator-activated receptor alpha (Ppara) were elevated in CD-fed male offspring of GDM dams, and male offspring of GDM dams exhibited higher mRNA levels of Insr on both diets. Neither fasting insulin nor glucose tolerance was affected by exposure to GDM. Our findings show that GDM comprising glucose intolerance only during pregnancy programs increased adiposity in offspring, and suggests increased insulin sensitivity of subcutaneous adipose tissue.

In Utero and Postnatal Exposure to High Fat, High Sucrose Diet Suppressed Testis Apoptosis and Reduced Sperm Count.

Obesity affects male fertility and maternal diabetes affects the offspring sperm epigenome. However, the effects of in utero exposure to maternal glucose intolerance in combination with postnatal high fat, high sucrose (HFHS) diet consumption on offspring spermatogenesis is not clear. The present study was designed to test these effects. One week before and during pregnancy, dams were fed either control or HFHS diet to induce gestational glucose intolerance, and returned to standard diet during lactation. Male offspring from each maternal group were split into control and HFHS-fed groups for eight weeks prior to sacrifice at 11, 19 or 31 weeks of age, and reproductive tissues were harvested for analysis of testicular germ cell apoptosis and sperm output. Postnatal HFHS diet suppressed spermatogonia apoptosis in all age groups and maternal HFHS diet reduced testosterone levels at 11 weeks. At 31 weeks of age, the postnatal HFHS diet increased body weight, and reduced epididymis weight and sperm count. The combination of in utero and postnatal exposure impacted sperm counts most significantly. In summary, HFHS diet during pregnancy puts male offspring at greater risk of infertility, particularly when combined with postnatal high fat diet feeding.

Effects of acute exposure to a high-fat, high-sucrose diet on gestational glucose tolerance and subsequent maternal health in mice.

Gestational diabetes mellitus (GDM) is a common obstetric complication. Half of women who have GDM will go on to develop type 2 diabetes. Understanding the mechanisms by which this occurs requires an animal model of GDM without ongoing diabetes at conception. C57Bl/6J mice react acutely to a high-fat, high-sucrose (HFHS) challenge. Here, we hypothesized that a periconceptional HFHS challenge will induce glucose intolerance during gestation. C57Bl/6J female mice were placed on an HFHS either 1 or 3 weeks prior to mating and throughout pregnancy. Intraperitoneal glucose tolerance tests, insulin measurements, and histological analysis of pancreatic islets were used to assess the impact of acute HFHS. C57Bl/6J females fed HFHS beginning 1 week prior to pregnancy became severely glucose intolerant, with reduced insulin response to glucose, and decreased pancreatic islet expansion during pregnancy compared to control mice. These GDM characteristics did not occur when the HFHS diet was started 3 weeks prior to mating, suggesting the importance of acute metabolic stress. Additionally, HFHS feeding resulted in only mild insulin resistance in nonpregnant females. When the diet was discontinued at parturition, symptoms resolved within 3 weeks. However, mice that experienced glucose intolerance in pregnancy became glucose intolerant more readily in response to a HFHS challenge later in life than congenic females that experienced a normal pregnancy, or that were fed the same diet outside of pregnancy. Thus, acute HFHS challenge in C57Bl/6 mice results in a novel, nonobese, animal model that recapitulates the long-term risk of developing type 2 diabetes following GDM.

Maternal Hyperleptinemia Is Associated with Male Offspring's Altered Vascular Function and Structure in Mice.

Children of mothers with gestational diabetes have greater risk of developing hypertension but little is known about the mechanisms by which this occurs. The objective of this study was to test the hypothesis that high maternal concentrations of leptin during pregnancy, which are present in mothers with gestational diabetes and/or obesity, alter blood pressure, vascular structure and vascular function in offspring. Wildtype (WT) offspring of hyperleptinemic, normoglycemic, Leprdb/+ dams were compared to genotype matched offspring of WT-control dams. Vascular function was assessed in male offspring at 6, and at 31 weeks of age after half the offspring had been fed a high fat, high sucrose diet (HFD) for 6 weeks. Blood pressure was increased by HFD but not affected by maternal hyperleptinemia. On a standard diet, offspring of hyperleptinemic dams had outwardly remodeled mesenteric arteries and an enhanced vasodilatory response to insulin. In offspring of WT but not Leprdb/+ dams, HFD induced vessel hypertrophy and enhanced vasodilatory responses to acetylcholine, while HFD reduced insulin responsiveness in offspring of hyperleptinemic dams. Offspring of hyperleptinemic dams had stiffer arteries regardless of diet. Therefore, while maternal hyperleptinemia was largely beneficial to offspring vascular health under a standard diet, it had detrimental effects in offspring fed HFD. These results suggest that circulating maternal leptin concentrations may interact with other factors in the pre- and post -natal environments to contribute to altered vascular function in offspring of diabetic pregnancies.

Maternal Hyperleptinemia Improves Offspring Insulin Sensitivity in Mice.

Maternal obesity and gestational diabetes are prevalent worldwide. Offspring of mothers with these conditions weigh more and are predisposed to metabolic syndrome. A hallmark of both conditions is maternal hyperleptinemia, but the role of elevated leptin levels during pregnancy on developmental programming is largely unknown. We previously found that offspring of hyperleptinemic mothers weighed less and had increased activity. The goal of this study was to determine whether maternal leptin affects offspring insulin sensitivity by investigating offspring glucose metabolism and lipid accumulation. Offspring from two maternal hyperleptinemic models were compared. The first model of hyperleptinemia is the Lepr(db/+) mouse, which has a mutation in one copy of the gene that encodes the leptin receptor, resulting in a truncated long form of the receptor, and hyperleptinemia. Wild-type females served as the control for the Lepr(db/+) females. For the second hyperleptinemic model, wild-type females were implanted with miniosmotic pumps, which released leptin (350 ng/h) or saline (as the control) just prior to mating and throughout gestation. In the offspring of these dams, we measured glucose tolerance; serum leptin, insulin, and triglyceride levels; liver triglycerides; pancreatic α- and ß-cell numbers; body composition; incidence of nonalcoholic fatty liver disease; and the expression of key metabolic genes in the liver and adipose tissue. We found that the offspring of hyperleptinemic dams exhibited improved glucose tolerance, reduced insulin and leptin concentrations, reduced liver triglycerides, and a lower incidence of nonalcoholic fatty liver disease. Overall, maternal hyperleptinemia was beneficial for offspring glucose and lipid metabolism.