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Gestational diabetes mellitus (GDM) has become a major public health problem and one of the most discussed issues in modern obstetrics. GDM is associated with serious adverse perinatal outcomes and long-term health consequences for both the mother and child. Currently, the importance and purposefulness of finding a biopredictor that will enable the identification of women with an increased risk of developing GDM as early as the beginning of pregnancy are highly emphasized. Both “older” molecules, such as adiponectin and leptin, and “newer” adipokines, including fatty acid-binding protein 4 (FABP4), have proven to be of pathophysiological importance in GDM.
- gestational diabetes mellitus
- biomolecules
- CMPF
- ANGPTL-8
- nesfatin-1
- afamin
- adropin
- fetuin-A
- zonulin
- SFRPs
1. Introduction
Gestational diabetes mellitus (GDM) has become a major public health problem and one of the most discussed issues in modern obstetrics, given that it is one of the most common metabolic disorders in obstetrics [1][2][3]. The scientific literature defines GDM as a state of hyperglycemia developing in pregnancy as a result of insulin resistance or reduced insulin production, which resolve following delivery [4][5][6][7]. Given the various diagnostic criteria and ethnicity, in many countries the epidemiology of GDM still remains unknown [8][9]. It is estimated that the prevalence of GDM has increased by more than 35% in the last few decades and is still growing, which is rather alarming [10]. The risk factors for GDM include pre-pregnancy overweight and obesity, advanced maternal age, excessive gestational weight gain (EGWG), family history of type 2 diabetes mellitus (T2DM), GDM during previous pregnancies, previously giving birth to a baby with a birth weight greater than 4000 g, multiparity, and polycystic ovary syndrome (PCOS) [11][12].
A pregnant woman’s metabolism determines both the mother’s own health and the health of her child [13][14][15]. Excessive intake of carbohydrates and lipids, reduced consumption of vegetables and fruit, reduced physical activity, and genetic predisposition may lead to the development of hyperglycemia. Peripheral insulin resistance, which gets worse with each passing week of pregnancy, involves a physiological maternal adaptation process that makes it possible for the mother to comply with the increasing energy demand of a rapidly developing fetus [16]. It is observed that insulin resistance increases considerably in pregnant women with pre-pregnancy overweight and obesity in comparison to those with pre-pregnancy normal weight. This triggers immune and inflammatory responses in the white adipose tissue, which in turn leads to the development of a low-grade systemic chronic inflammation known as metabolic inflammation [17]. It is common knowledge that an increased inflammatory response associated with excessive body fat is a key factor in reducing the action of insulin [16][18][19][20]. Furthermore, it also reduces the β-cell compensatory response, which promotes the development of GDM [21]. In the vicious cycle of GDM, the production of various pro-inflammatory cytokines increases, whereas the expression of anti-inflammatory biomolecules is inhibited.
Elevated glucose levels stimulate the pancreas to release insulin, and the tissues and cells developing insulin resistance stimulate the pancreatic β cells to produce more insulin, thereby impairing their function. Exposure to maternal hyperglycemia may impede fetal development and cause many adverse pregnancy outcomes, such as a high risk of premature birth, macrosomia, neonatal respiratory complications, postnatal hypoglycemia, and hypoxia [22][23]. Also, exposing the fetus to persistent hyperglycemia induces ‘glycemic memory’ in the fetus, which may contribute to epigenetic changes, i.e., DNA methylation disturbances [24][25]. Furthermore, a hypoxic memory can affect the kidneys and cause an acute kidney injury [26]. Hyperglycemia may also impair the autonomic nervous system (ANS). Changes in the fetal ANS are manifested by high blood pressure, tachycardia, and respiratory complications [27]. Extended hypoxia enhances angiogenesis, endothelial dysfunction, cell proliferation, and inflammation [28][29][30]. GDM can also have long-term consequences for the offspring, such as an increased risk of obesity, T2DM, and cardiovascular diseases (CVDs) in their adult life [28]. On the other hand, women with a history of GDM are also at a higher risk of maternal programming for the development of diseases of civilization later in their lives, with T2DM being the most prevalent among them. Women who have had GDM are at a 35–60% higher risk of developing T2DM in the next 10–20 years [31].
The COVID-19 pandemic has changed the world situation considerably. Social distancing, less physical activity, and changes in lifestyle and eating habits have contributed to increased weight gain [32][33]. The excessive energy balance of the body promotes the accumulation of adipose tissue and, consequently, the overexpression of adipokines, which possess pro-thrombotic, pro-inflammatory, pro-atherosclerotic, and pro-diabetic properties. Even though there is a clear-cut relationship between obesity and diabetes [17][34], there is still no answer to the question of why this disease does not develop in all obese people and how its development can be predicted.
Although GDM cannot be completely prevented, its early diagnosis and prompt management significantly improve both the development of the fetus and the course of pregnancy, delivery, and the postpartum period. There is a strong need to focus on disease screening. The greater the number of available diagnostic methods, the more likely it is to detect the disease at its early stage. Currently, the scientific literature emphasizes the importance of finding biopredictors that will allow for the identification of women with an increased risk of developing GDM at the beginning of pregnancy. Many adipokines have proven to be of pathophysiological importance in GDM. These include both “older” molecules, such as adiponectin and leptin, as well as “newer” adipokines, including fatty acid binding protein 4 (FABP4) [35][36][37][38][39].
2. Biomolecules
2.1. CMPF
The furan fatty acid metabolite, CMPF—a fish oil metabolite—is an endogenous uremic toxin involved in the glycolipid processes and islet β-cell dysfunction that enters the β-cell through the human organic anion transporter 3 (OAT3) [40][41]. CMPF is also associated with thyroid dysfunction. It has the ability to cross the blood-brain barrier, thereby contributing to various neurological abnormalities. Abnormal concentrations of CMPF were detected in patients with colorectal adenoma [42]. CMPF was first detected in human urine in 1979. CMPFs are coupled with triglycerides, phospholipids, and cholesterol esters [43]. They demonstrate high protein-binding ratios (above 95%) and are found in green plants, champignons, vegetable oils, fish, or algae [44][45]. In humans, CMPF cannot be synthesized de novo. A metabolite of the furan fatty acid, dicarboxylic acid, is excreted in urine, and it may be detected in serum, feces, and urine. The CMPF blood levels differ between males and females, and they are significantly elevated in the former. Many factors may affect the CMPF levels in serum and they include: inter alia, ethnic background, and dietary and/or metabolic components.
The role of CMPF in the etiology of GDM is still unclear [46][47]. Some studies have shown that the level of CMPF may be increased in patients with T2DM and GDM [48][49]. It might also be accumulated in patients with kidney diseases [50]. Since the early 1990s, it has been suggested that CMPFs contribute to renal tubular damage by interacting with the superoxide anion and peroxy radicals. It is worth adding that an elevated serum concentration of CMPF is not associated with mortality and cardiovascular morbidity. Ji et al. conducted a study that revealed significantly higher serum CMPF levels in the investigated GDM group of patients in comparison to healthy controls [51]. Moreover, there was a positive correlation between an elevated CMPF serum level and glycated hemoglobin (HbA1c), fasting plasma glucose, one-hour plasma glucose, and two-hour plasma glucose in an oral glucose tolerance test (OGTT). Additionally, CMPF manifested no correlation between total cholesterol, triglycerides, high-density lipoprotein (HDL), and low-density lipoprotein (LDL), which were increased in the GDM group. In another study conducted by Prentice et al., patients with impaired glucose tolerance and GDM still had elevated CMPF serum levels, even one year after delivery [48]. Liu et al. underlined the fact that patients with an upregulated furan fatty acid metabolite may develop T2DM within the next 5 years [49]. The same study also reports that those women who developed T2DM had had significantly higher levels of CMPF 4 years previously, while pre-diabetics maintained elevated but stable CMPF levels [49].
2.2. ANGPTL-8
The structure of ANGPTLs is similar to angiopoietins [52]. They are secreted by the adipose tissue, liver, and vascular and hematopoietic systems, and their main functions include the regulation of glucose homeostasis, lipid metabolism, inflammation, and angiogenesis [53][54][55]. ANGPTL-8, otherwise known as betatrophin, TD26, lipasin, or C19orf80, is secreted mainly by the liver and adipose tissue, and its role seems to be significant in lipid metabolism and the maintenance of glucose homeostasis. It appears that the disruption of its function may contribute to the development of GDM during pregnancy [55][56].
It has been observed that the expression of ANGPTL-8 is stimulated by insulin, food intake, and cold exposure, while it is inhibited by starvation [54][57]. ANGPTL-8 seems to play a supporting role in stimulating proliferation and increasing the pancreatic β-cell mass as well as improving glucose tolerance in insulin resistance, presumably by increasing insulin secretion [55][58]. However, not all researchers see eye to eye about this. Jiao et al. were able to document pancreatic β-cell replication by stimulating ANGPTL-8 in mice, however, they failed to increase human β-cell DNA replication in the transplanted setting [59].
There are reports that ANGPTL-8 levels are dependent on lipid and carbohydrate disorders, which appear to be related to its inhibition of the lipoprotein lipase enzyme activity [54][60]. The ANGPTL-8 gene contains a carbohydrate responsive element that is activated by high glucose and lipid levels [52]. It also appears to be associated with the development of type 1 diabetes [52], T2DM [61], hypertension, and metabolic syndrome [60].
2.3. Nesfatin-1
Nesfatin-1, derived from the precursor protein nucleobindin-2 (NUCB2), consists of an 82-amino acid peptide [62]. It is secreted by the peripheral tissues, such as the pancreas, duodenum, and adipose tissue, as well as the peripheral and central nervous system (arcuate, paraventricular nuclei, and nucleus of the solitary tract) [63][64].
One of the key functions of nesfatin-1 is the regulation of carbohydrate metabolism [65]. It stimulates the pre-proinsulin mRNA expression and increases glucose-induced insulin release. Nesfatin-1 also inhibits glucagon secretion [66]. The NUCB2/nesfatin-1 cells have been observed to be localized on the pancreatic β-islets in mice and rats [67]. It is believed that nesfatin-1 is released from the β-islets of the pancreas as a response to the exposure of these cells to glucose [68]. When intravenously injected to hyperglycemic animals, nesfatin-1 had an antihyperglycemic effect [69]. However, the oral glucose tolerance test (OGTT) in healthy patients did not affect NUCB2/nesfatin-1 levels, which may suggest a local activity of nesfatin-1 around the β-islets of the pancreas rather than an endocrine effect [66].
Nesfatin-1 is also secreted by the hypothalamus, and thus affects the regulation of hunger and satiety, which secondarily contributes to body weight regulation [62]. An increase in the nesfatin-1 concentration has been observed after food consumption [65]. It is believed that nesfatin-1 may decrease food intake by reducing appetite and inducing satiety [70]. On the other hand, it is likely that reduced nesfatin-1 levels may be associated with hyperphagia in T2DM [63]. These findings suggest that nesfatin-1, via its inter alia anti-hyperglycemic and anorexigenic effects, may significantly affect metabolic regulation [69]. Thus, nesfatin-1 may serve as an important protective factor in the development of GDM [19].
2.4. Afamin
Afamin is a glycoprotein that belongs to the albumin family, as do α-fetoprotein and albumin [71][72]. It is mainly produced by the liver [71] and peripheral tissues, such as the placenta [73].
Afamin is able to bind vitamin E in the extravascular fluids, and, due to hormonal changes, its levels increase during the duration of pregnancy [74][75]. Vitamin E acts as an antioxidant in the pancreatic cells, and animal studies have shown its anti-apoptotic effects against them [72][76].
Owing to its anti-apoptotic and antioxidant qualities [75][76], afamin is believed to contribute to the effects of oxidative stress [26][30]. It has been observed that an increase in oxidative stress and the occurrence of related conditions (metabolic syndrome, T2DM, insulin resistance, obesity) [74][76] correlate with elevating the serum afamin concentrations [76]. An imbalance between oxidants and antioxidants appears to be related to the development of diabetic complications and the development of GDM [76].
Given its properties, afamin is thought to be useful as an early marker of carbohydrate and lipid disorders during pregnancy [73]. Elevated levels of afamin seem to be related to the conditions that increase the risk of metabolic syndrome, such as dyslipidemia, hypertension, impaired carbohydrate metabolism, and obesity [72][75]. A study conducted in mice revealed a strong correlation between the increased afamin levels and development of metabolic syndrome and its components, i.e., hyperlipidemia, hyperglycemia, and increased body weight [77].
The role of afamin in the pathogeneses of both T2DM and GDM is suggested by its association with the occurrence of insulin resistance [71]. Increased insulin resistance at the beginning of pregnancy significantly correlates with the development of GDM later during gestation [72]. In vitro studies have shown a direct association between afamin and glucose concentrations [71]. The levels of afamin are independent of fasting status, age, sex, and they increase linearly by approximately 2-fold during an uncomplicated pregnancy [72].
Furthermore, it seems that afamin may be connected to other pathologies associated with pregnancy. There is some evidence of a correlation between increased afamin concentrations in the first trimester of pregnancy and the occurrence of pre-eclampsia [78].
2.5. Adropin
Adropin is a novel regulatory protein encoded by the Energy Homeostasis (ENHO)-associated gene. It is mainly expressed in the liver and brain, but also in the kidneys, pancreas, and umbilical vein. Adropin is a regulatory factor in glucose and lipid homeostasis. It has been shown to correlate with obesity and is involved in the prevention of insulin resistance, dyslipidemia, and impaired glucose tolerance [79]. There is a noticeably higher level of adropin in patients with T2DM [80]. Considering the importance of adropin in energy homeostasis and insulin resistance, it is worth exploring the potential role of this protein in the pathogenesis of GDM. The available research into the changes in adropin levels in GDM is conflicting, with reports showing a significant increase or decrease in its levels in GDM patients compared with controls.
2.6. Fetuin-A
Fetuin-A, also known as a2-HS-glycoprotein (AHSG), is a member of the cystatin protease inhibitor superfamily [81]. It is mainly synthesized and secreted by the liver and adipose tissue. Fetuin-A is involved in many physiological and pathophysiological processes in the human body [82]. Recent studies indicate that high levels of fetuin-A are associated with several metabolic disorders, such as insulin resistance, PCOS, and T2DM [82]. Fetuin-A is a ligand for TLR-4, through which lipids induce insulin resistance. In addition, high concentrations of AHSG induce inflammatory signaling [83]. Novel cross-sectional studies have shown a correlation between high levels of this glycoprotein and the risk of developing GDM.
2.7. Zonulin
Zonulin is a physiological modulator of intercellular tight junctions (TJs) between the intestinal epithelial cells. Gliadin and bacteria induce the secretion of zonulin mainly from the liver [84]. This leads to a loss of protein interaction, resulting in increased intestinal permeability, introducing foreign antigens into the immune system, and causing inflammation [85]. Increased zonulin levels are observed in autoimmune diseases associated with TJ dysfunction, including celiac disease [86][87]. In addition, zonulin has been implicated in the pathogenesis of neurodegenerative diseases and cancer. Recent studies investigating the association between increased serum zonulin levels and the probability of developing GDM are very promising.
2.8. SFRPs
SFRPs produced by adipose tissue are members of soluble, extracellular signaling ligands with a cysteine rich domain. SFRPs are the Wingless-related integration site (Wnt) signaling pathway antagonistic inhibitors that act through binding with the extracellular Wnt-5a or Wnt-3a [88][89][90]. The Wnt pathway is responsible for organismal growth and differentiation. In humans, five soluble, secreted glycoproteins, such as SFRP1, SFRP2, SFRP3, SFRP4, and SFRP5, are distinguished and coded by the gene on chromosome 10 [91]. The largest member of the SFRP family is SFRP4. SFRPs are also described as adipokines, which take part in adipogenesis [92][93][94]. They are expressed in many tissues, such as the urinary bladder, bone marrow, spleen, pancreas, and liver, and they take part in adipocyte differentiation, pathogenesis of hypophosphatemic diseases, bone cancers, CVDs, retinal degeneration, diabetes mellitus, and others [95][96][97]. SFRPs may be detected in serum and urine.
The molecular mechanisms of SFRP1, SFRP4, and SFRP5 may have a direct or indirect effect on the development of diabetes. The overexpression of SFRP1 may worsen insulin secretion by acting on the β cells through β-catenin, transcription factor 4 (TCF4), and CyclinD [98]. In contrast to SFRP1, SFRP3 is negatively related to the occurrence of diabetes. The ongoing inflammatory process and its components, such as IL-6 and interferons, cause a decrease in the level of SFRP3, which is responsible for sensitizing the skeletal muscle cells to insulin.
SFRP4 via the Wnt/Ca2+ signaling pathway enhances the intracellular Ca2+ and protein kinase C. Due to these interactions, calmodulin kinase II is activated. The overexpression of SFRP4 is positively and indirectly related to the development of diabetes. Some researchers report a positive correlation between SFRP4 and the level of HbA1c and fasting triglyceride [97][99][100][101]. In addition, glucose intolerance may occur due to the IL-1β stimulation to release more SFRP4 in serum [102]. The expression of SFRP4 is also connected with miR-30d, miR-146a, and miR-24, which are elevated in the serum of patients with diabetes [103]. SFRP4 leads to oxidative stress in the pancreas and impairs the exocytosis of insulin [104].
SFRP5 negatively interacts with the insulin receptor substrate-1 (IRS-1) [105][106][107]. Insulin resistance, which develops in pregnancy, is connected with increasing BMI values [108][109]. A study conducted by Trojnar et al. revealed a positive correlation between the level of SFRP5 and pre-pregnancy BMI, BMI at delivery, total cholesterol, and LDL, as well as the levels of triglycerides in women suffering from GDM [110]. The opposite results were observed in healthy controls [110].
2.9. Amylin
Amylin (i.e., Islet Amyloid Pancreatic Polypeptide; IAPP) is a hormone secreted along with insulin by pancreatic β-cells in a pulsatile pattern and seems to play a significant role in the regulation of glucose metabolism [111]. It helps to control gastric emptying, suppression of glucagon release, and regulation of satiety [112][113]. Amylin is the major component of amyloid, which is detected in the islet of Langerhans present in more than 90% of patients with T2DM. Amylin mature fibrils induce β-cell cytotoxicity through their penetration of the cell membrane, resulting in an imbalance of intracellular ions [114][115]. This results in the formation of reactive oxidant species, membrane damage, and the loss of β-cells, which leads to T2DM development [116].
Pregnancy is a condition with reduced tissue sensitivity to insulin, so in order to remain normoglycemic, it is necessary to increase insulin secretion. This effect is achieved by increasing β-cell mass. When this is not reachable, there is a risk of developing GDM [116]. It is possible that there is a similar mechanism of pathogenesis as in T2DM—amylin cytotoxicity leads to β-cell impairment and apoptosis, resulting in decreased insulin secretion and reduced glucose tolerance.
This entry is adapted from the peer-reviewed paper 10.3390/ijms23084364
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