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Gruber, B.L.M.; Dolinsky, V.W. Adiponectin during Pregnancy and Gestational Diabetes. Encyclopedia. Available online: https://encyclopedia.pub/entry/48252 (accessed on 23 June 2024).
Gruber BLM, Dolinsky VW. Adiponectin during Pregnancy and Gestational Diabetes. Encyclopedia. Available at: https://encyclopedia.pub/entry/48252. Accessed June 23, 2024.
Gruber, Brittany L. Moyce, Vernon W. Dolinsky. "Adiponectin during Pregnancy and Gestational Diabetes" Encyclopedia, https://encyclopedia.pub/entry/48252 (accessed June 23, 2024).
Gruber, B.L.M., & Dolinsky, V.W. (2023, August 21). Adiponectin during Pregnancy and Gestational Diabetes. In Encyclopedia. https://encyclopedia.pub/entry/48252
Gruber, Brittany L. Moyce and Vernon W. Dolinsky. "Adiponectin during Pregnancy and Gestational Diabetes." Encyclopedia. Web. 21 August, 2023.
Adiponectin during Pregnancy and Gestational Diabetes
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Pregnancy involves a range of metabolic adaptations to supply adequate energy for fetal growth and development. Gestational diabetes (GDM) is defined as hyperglycemia with first onset during pregnancy. GDM is a recognized risk factor for both pregnancy complications and long-term maternal and offspring risk of cardiometabolic disease development. Pregnancy changes maternal metabolism, GDM can be viewed as a maladaptation by maternal systems to pregnancy, which may include mechanisms such as insufficient insulin secretion, dysregulated hepatic glucose output, mitochondrial dysfunction and lipotoxicity. Adiponectin is an adipose-tissue-derived adipokine that circulates in the body and regulates a diverse range of physiologic mechanisms including energy metabolism and insulin sensitivity. In pregnant women, circulating adiponectin levels decrease correspondingly with insulin sensitivity, and adiponectin levels are low in GDM.

adiponectin pregnancy gestational diabetes

1. Metabolic Adaptations during Pregnancy

In mammals, several adaptations are required to sustain pregnancy. For instance, the maternal system exhibits increased blood volume and cardiac output accompanied by a corresponding increase in renal activity [1]. In addition, increased respiratory capacity and neurological changes, specifically increased neural plasticity and increased neurogenesis also occur during pregnancy and lactation [1][2]. Furthermore, metabolic adaptations are a necessary response to the changing metabolic demands of the mother and fetus (Figure 1). These can be broadly divided into two phases. In the first phase, which corresponds to the first two trimesters in a human pregnancy, there is an overall anabolic period. During this stage, the maternal system builds up energy stores, increasing lipid storage in tissues to prepare for increased breakdown and use later in pregnancy [3][4]. To achieve this, maternal energy consumption increases, as does de novo hepatic lipogenesis. In the later stages of pregnancy, lipid deposits are preferentially broken down for fatty acid oxidation, which spares glucose for fetal growth [3][4][5][6].
Figure 1. Metabolic adaptations of late gestation and the impact of gestational diabetes. ↑ increased, ↓ decreased.
Many hormonal, metabolic and immunological changes, including insulin resistance, are set in motion to adequately adapt to maternal and fetal needs during gestation (reviewed in [7][8][9]). Hormones such as human placental growth hormone (hPGH) increase progressively throughout pregnancy [10] and reduce signalling through the insulin receptor substrate–1(IRS-1), as well as glucose transporter (GLUT)-4 mediated glucose uptake. Later in gestation, maternal metabolism shifts to a catabolic phase and lipids are transiently increased, and mild hyperinsulinemia occurs. Despite these changes, in most pregnancies, normoglycemia is maintained and, in some cases, decreases, which could be due to the dilution effect as blood volume increases in the maternal system [11]. Additionally, increased insulin production and secretion by the maternal pancreas contribute to the maintenance of maternal glycemia [12]. In pregnancy, peripheral tissues become more insulin-resistant [3][13], and hepatic glucose output is not suppressed by insulin. In order to achieve glucose homeostasis in a healthy pregnancy, circulating insulin is increased to overcome insulin resistance [4]. Postnatally, these hormonal and metabolic changes return to baseline [14].
Changes to circulating hormones and cytokines in pregnancy impact insulin tolerance of peripheral tissues and compensatory adaptations of pancreatic β-cells that include increased proliferation, reduced apoptosis and enhanced glucose-stimulated insulin secretion (GSIS) [15]. In the third trimester, progesterone increases and may have a role in increasing adipose tissue lipolysis and decreasing insulin sensitivity and glucose uptake in peripheral tissues, including adipose tissue [16][17]. Increased lipolysis from adipose tissue may lead to increased fatty acid uptake by the liver and reduced hepatic insulin sensitivity. Human placental growth hormone (hPGH) increases significantly throughout gestation and has a role in stimulating pregnancy-induced β-cell adaptations [18][19]. Prolactin (PrL) and placental lactogen (PL) have been implicated in pregnancy-associated β-cell adaptations [20], as well as in peripheral insulin resistance and increased lipolysis [21]. Tumour necrosis factor (TNF)-α increases in the circulation towards the end of pregnancy and has been shown to mediate the insulin resistance that occurs in the third trimester of pregnancy [22][23]. In GDM, more severe insulin resistance occurs, as well as increased inflammation and lipotoxicity, which lead to impairments in the necessary adaptations by pancreatic β cells [15]. Additionally, impaired insulin sensitivity in the liver leads to increased hepatic glucose output and reduced β oxidation. Lipid spillover from adipose tissue because of impaired expandability can lead to hepatic fat deposition and lipotoxicity in both the pancreas and the liver [24][25].

1.1. The Endocrine Pancreas and Its Adaptation to Pregnancy

Islet architecture varies between species, but mice and rats have relatively well-defined pancreatic islet structures, with abundant β-cells (in mice, making up 60–80% of cells in the islet) and scarcer polypeptide (PP) cells, δ-cells and α-cells [26][27][28]. Studies in human and animal models have provided evidence for plasticity of the pancreatic islet during pregnancy [12][27][29], which allows for increases in mass and hormone secretory capacity to compensate for the metabolic demands of pregnancy. This research has largely focused on β-cells and, to a lesser extent, α-cells due to their role in the management of blood glucose levels.
The pancreatic islet responds to the demands of pregnancy involving a range of adaptive mechanisms, including β-cell hyperplasia and hyper-functionality, that are driven by transcription factors and cell cycle regulators [15][30][31][32]. Pregnancy-induced β-cell expansion is achieved by proliferation, hypertrophic expansion and possibly neogenesis from progenitor cells; these mechanisms are accompanied by a temporary reduction in apoptosis [12][30][33] that has also been observed in islets during human pregnancy [12]. These changes may be mediated by crosstalk between increased placental signalling, the maternal pancreas and peripheral tissues, which have been illustrated by the use of animal models [34][35][36]. While some adaptive mechanisms are conserved between species, there are variations in the primary adaptive responses between rodent and human islets in pregnancy. For instance, in rodent models of pregnancy, neogenesis may only contribute a small amount to the expansion of β-cell mass, with proliferation playing a more significant role [37]. In human pregnancy, neogenesis may exceed proliferation as an adaptive mechanism [33][38]. However, human islets isolated during pregnancy are scarce, and samples were heterogenous in origin (from pregnancies of varying gestational length, maternal ages, ethnicities and causes of death), complicating the interpretation [12]. Despite the heterogeneity of available samples, human islets isolated during pregnancy show increases in β-cell area relative to non-pregnant controls [12][29].
In mice, pregnancy also increases alpha-cell mass, pancreatic glucagon-like peptide (GLP-1), and pancreatic and circulating glucagon levels [39] in association with a transient increase in serum glucagon, which was previously reported in human pregnancy [40]. Additionally, pregnant mice lacking α-cells were reported to exhibit impaired glucose tolerance, which was rescued by administration of glucagon-like peptide (GLP)-1 receptor agonists [39], illustrating a role of α-cells in insulin secretion and islet adaptation to pregnancy. Hormones secreted by cells adjacent to β-cells provide an additional layer of control over insulin secretion [41], which is only beginning to be explored in pregnancy.

1.2. White Adipose Tissue in Pregnancy

Maternal white adipose tissue (WAT) undergoes expansion during early pregnancy, providing energy stores of fat as fuel for later stages of pregnancy. High levels of insulin increase de novo lipogenesis, suppress adipose tissue lipolysis [7][42] and lower circulating free fatty acids [43]. Because a significant amount of glucose is utilized during the early stages of pregnancy, insulin increases glucose transport from serum and increases glycolysis. There is also evidence that crosstalk with the placenta during pregnancy may promote adipose tissue expansion [44]. Previously, it was found that during pregnancy, increased plasma protein A (PAPP-A) stimulates proteolysis of insulin-like growth factor (IGF)-binding protein-5, which releases IGF-1 and promotes adipose tissue expansion and proliferation to enable energy storage and prevent excess ectopic lipid deposition elsewhere in the body [45]. A follow-up study in mice showed that a lack of PAPP-A impaired adipose tissue expansion, pregnancy-induced insulin resistance and ectopic fat deposition in the form of hepatic steatosis—all factors that are associated with a GDM phenotype [46]. Expansion of adipose tissue can be achieved through hypertrophic adipocytes (to accommodate larger lipid droplets) or hyperplasia, which is the production of new adipocytes from precursors [45]. However, all forms of adipose tissue expansion are not equal; hyperplasia is linked to better glucose control, whereas hypertrophy is associated with more severe insulin resistance and is more prone to inflammation [47].
As pregnancy progresses, maternal glucose utilization is reduced, and maternal metabolism shifts into a catabolic phase, during which adipose tissue energy stores are broken down [43][48][49]. Steady increases in circulating free fatty acid (FFA) and glycerol, as well as decreases in adipocyte size and WAT mass, occur towards the end of gestation. During this phase of pregnancy, maternal metabolism relies more heavily on fatty acid oxidation for energetic needs, so the increased availability of lipids is an important physiological adaptation to late gestation. Indeed, hormonal changes associated with pregnancy, including circulating human placental lactogen (HPL) and increased TNF-α increase insulin resistance, thereby reducing the inhibitory effects of insulin on lipolysis [50].

1.3. Adaptations of Liver Metabolism during Pregnancy

The liver plays a significant role in maintaining maternal glucose homeostasis throughout gestation. Alterations in hepatic insulin signalling control these processes. In early pregnancy, when the metabolic demands of fetal growth are low, hepatic insulin sensitivity remains high, hepatic gluconeogenesis is inhibited by insulin and glucose is utilized for maternal energy [7][51]. In late pregnancy, hepatic insulin signalling is attenuated, which suppresses glycolysis and dysregulates gluconeogenesis, thereby directing more glucose to fetal growth. At the same time, there is an increase in the amount of fatty acid taken up and undergoing β-oxidation by the maternal liver [51][52].

2. Gestational Diabetes Mellitus

While insulin resistance is a natural process that occurs during pregnancy, compensation by the endocrine pancreas and peripheral tissues maintain glucose homeostasis until parturition. GDM may develop when compensatory mechanisms are insufficient to overcome the insulin resistance of pregnancy, which is associated with excessive gestational weight gain or obesity that precedes pregnancy [53].
GDM is defined as the new onset of hyperglycemia and glucose intolerance mid-gestation. Worldwide, as many as one in seven pregnancies is affected by GDM [54]. Maternal obesity and advanced maternal age are risk factors for development of GDM [55][56]. As an increasing number of women are beginning pregnancies later in life and there are increasing numbers of obese or overweight women, there has been a corresponding rise in the incidence of GDM. The implications of GDM on maternal health include difficulties with pregnancy (such as pre-eclampsia), complications in labour and delivery and increased risk of postnatal maternal health complications [54][57][58]. Women who have had GDM are at higher risk of developing GDM during subsequent pregnancies, as well as of developing type 2 diabetes (T2D) later in life [59]. Diagnostic criteria can vary between health regions. Undiagnosed GDM due to less stringent diagnostic criteria was associated with higher rates of complications such as excessive gestational weight gain, caesarean delivery, macrosomia and large-for-gestational-age (LGA) infants [60][61]. The only outcome-based guidelines are the International Association of the Diabetes and Pregnancy Study Groups (IADPSG) criteria, which bases diagnosis on a fasting plasma glucose level exceeding 5.1 mmol/L or a plasma glucose level of 8.5 mmol/L 2 h after a 75 g oral glucose tolerance test [62]. Untreated GDM is associated with worse perinatal outcomes [63], and results from the Hyperglycemia and Adverse Pregnancy Outcomes study show more severe insulin resistance and glucose intolerance in offspring of mothers with untreated GDM [64]. Because the increased incidence of GDM reflects the metabolic health burden on women, clinical prevention strategies should target early preventive strategies for risk factors such as maternal obesity. The National Institute for Health and Care Excellence (NICE) prevention guidelines for pregnant women emphasize the importance of planning pregnancy and sharing information about diabetes outcomes and risks for mother and baby with women who are planning to conceive. In addition, the NICE guidelines recommend using the 75 g 2 h oral glucose tolerance test in all women with GDM risk factors in the first and second trimesters, offering continuous glucose monitoring to initiate earlier interventions [65].
During the COVID-19 pandemic, stakeholders and healthcare professionals were concerned about the increased exposure of pregnant women to infection. This resulted in a change in protocol for GDM screening in multiple countries, including in Canada, from a glucose challenge test to an A1C measurement and random, non-fasting blood glucose [66]. It was predicted that this strategy, despite limiting exposure of pregnant women to COVID-19, could potentially lead to missed GDM diagnosis, and a 2022 review of outcomes in Ireland, where similar changes were made, confirmed a significant decrease in GDM diagnoses compared to 2019 [67]. A 2020 review suggested that as many as 80% of GDM cases went undiagnosed in 2020 due to changes in diagnostic strategies during the COVID-19 pandemic [68]. Interestingly, cases of GDM overlooked due to alterations in screening strategies did not lead to worse maternal or fetal outcomes [67][68]. However, women diagnosed in 2020 were more likely to require insulin or metformin at the time of diagnosis and at term than those diagnosed as a result of screening prior to the pandemic [67]. The results of these changes to screening protocols suggest that glucose challenge and glucose tolerance tests are necessary to identify GDM in pregnancy.
The developmental origins of disease theory links in utero environmental exposures to chronic disease and adverse health outcomes later in the life of the offspring [69]. Given this critical stage of fetal development, it is not surprising that GDM also influences the health of the offspring. Data from epidemiological, birth cohort and animal model studies shows that diabetes during pregnancy is associated with the development of cardiometabolic diseases such as obesity, diabetes, high blood pressure, and renal and heart disease later in life [70][71][72][73][74][75][76][77]. For example, the HAPO follow-up study showed a linear relationship between higher maternal blood glucose and impaired glucose tolerance in 10–14-year-old offspring, independent of maternal and childhood BMI and family history of diabetes [78]. Glucose intolerance is also associated with leptin levels in five-year-old children [79]. These findings emphasize the necessity of earlier and more aggressive screening and treatment of GDM.

2.1. Impact of GDM on the Liver

Hepatic insulin resistance can contribute to more severe hyperglycemia during pregnancy, with dysregulation of hepatic gluconeogenesis resulting in excessive endogenous glucose production [6]. In addition, hyperlipidemia associated with maternal obesity and GDM can increase hepatic lipid synthesis and overload oxidative capacity, leading to secretion of very low-density lipoproteins (VLDL) with higher triacylglycerol content, as well as ectopic fat deposition in the liver [80]. The resultant lipotoxic and oxidative stress can exacerbate hepatic insulin resistance [81]. There are interesting links between the excessive storage of lipids in the liver, hepatic steatosis and GDM. The prevalence of non-alcoholic fatty liver disease (NAFLD) among women of childbearing age is estimated to be 10% [82]. Women with a history GDM are at higher risk of developing hepatic steatosis later in life [83]. Because hepatic steatosis contributes to insulin resistance, it is significant that development of fatty liver early in gestation (first trimester) can predict glucose intolerance mid-pregnancy [84] and precedes hyperglycemia in GDM [85]. Prospective cohort studies have shown that the presence of elevated visceral adipose tissue, together with sonographically detectable hepatic fat predicted GDM, independent of maternal age, ethnicity, and BMI [84][85]. The inclusion of NAFLD parameters such as hepatic steatosis and liver enzyme levels in an early prediction model for GDM improved the prediction of GDM development in women [86]. While GDM has been identified as a risk factor for the development of NAFLD [87], the mechanisms linking NAFLD to the development of GDM remain to be determined.

2.2. β-Cell Dysfunction in GDM

During pregnancy, β-cells must implement structural and functional changes to overcome insulin resistance and maintain normoglycemia. However, in a subset of women, functional and structural adaptations are impaired, contributing to GDM development. While the specific causes of impaired β-cell compensation in GDM continue to be investigated, this adaptive failure is likely multifactorial, involving genetic variants, nutrient overload and metabolic stress or increased inflammation [15][88][89]. Pancreatic β-cells have been shown to be affected by systemic inflammation [13]. Obese individuals and women with GDM have been found to have higher levels of circulating TNF-α, a proinflammatory cytokine linked to disrupted β-cell function and dedifferentiation [90][91]. Other markers of inflammation such as interleukin 1β (IL-1β) and interferon-γ (IFNγ) are reportedly increased under conditions of metabolic stress [92][93] and can trigger endoplasmic reticulum (ER) stress in β-cells, which prevents adaptation to insulin resistance during pregnancy, contributing to β-cell dysfunction [94].
Pancreatic β-cells are also susceptible to the effects of obesity and nutrient overload. Lipotoxicity and glucotoxicity are potential mechanisms involved in β-cell dysfunction in T2D and GDM [95]. Prolonged exposure to hyperglycemia can lead to impairments in β-cell function and reduced insulin secretion, which can become irreversible [96]. Exposure to high levels of lipids results in lipotoxic β-cell dysfunction [97]. ER stress [98] and oxidative stress [95] are triggered when lipids build up within the pancreatic islet and impair insulin production. Increased oxidative and ER stress can contribute to cell damage and β-cell apoptosis [95].

2.3. Impact of GDM on Adipose Tissue

In GDM, insulin resistance in WAT can result in excessive lipolysis, low-grade inflammation and dysregulated adipokine signalling [99]. While a degree of insulin resistance is a physiological adaptation in late gestation, in GDM, significant impairments can occur in downstream insulin signalling in WAT (e.g., decreased insulin receptor-β (IR-β) phosphorylation, downregulation of IRS1 and signalling through PI3K) [100]. Glucose uptake by adipose tissue is also blunted, with defects in GLUT4 translocation observed in GDM [51].
Insulin resistance in adipose tissue also impacts lipid metabolism, and impaired post-receptor signalling resulted in dramatically elevated WAT lipolysis in women with GDM [99]. Adipose tissue expansion is important to accommodate increased lipogenesis in early pregnancy. Without adequate WAT expansion, more severe insulin resistance and ectopic fat deposition in peripheral tissues, as well as adipose tissue inflammation occur [45]. Impairments in WAT expansion has been implicated in GDM [45]. In GDM, adipocytes become larger but show limited vascularization and reduced expression of markers associated with expandability. A proteomic study comparing adipose tissue isolated from women with GDM identified increases in fibrinogen and LUM, the former of which is associated with inflammation and the latter of which is an extracellular matrix protein, indicating adipose tissue rigidity and reduced flexibility [101]. Obesity in pregnancy is associated with increased insulin resistance, dyslipidemia, and inflammation [102]. This leads to a higher risk of endothelial dysfunction and lipotoxicity, worsening insulin resistance and metabolic dysfunction [103][104].

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