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Subjects:
Obstetrics & Gynaecology
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Medicine, General & Internal
Gestational diabetes mellitus (GDM) is a disorder defined as carbohydrate intolerance that manifests during the second or third trimester of pregnancy. To prevent them, it is important to keep glucose levels under control. As much as 15–30% of GDM patients will require treatment with insulin, metformin, or glyburide. With that in mind, it is crucial to keep searching for novel and improved pharmacotherapies. Nowadays, there are ongoing studies investigating the use of other groups of drugs that have proven successful in the treatment of T2DM. Glucagon-like peptide-1 (GLP-1) receptor agonist and dipeptidyl peptidase-4 (DPP-4) inhibitor are among the drugs targeting the incretin system and are currently receiving significant attention. GLP-1 is a peptide that is produced through the proteolysis of proglucagon, a protein expressed in L cells in the intestinal mucosa, α cells of the pancreas, as well as in the nucleus of the solitary tract (NTS) in the brainstem. GLP-1 has access to a specific GLP-1 receptor (GLP-1R) that is expressed in a wide range of target tissues. It is secreted mainly after the ingestion of glucose, lipids, or mixed meals, and increases glucose-stimulated insulin secretion at physiological plasma concentrations, which meets all the criteria for an incretin hormone.
- GDM
- GLP-1
- DPP-4
- incretins
1. GLP-1 and Pregnancy
Valsamakis et al. investigated the possible physiological associations of gut hormone levels (including GLP-1) in a group of non-obese, non-diabetic pregnant women during three trimesters of pregnancy with maternal glucose homeostasis, body weight, and fetal growth [38]. Fasting GLP-1 levels increased from the second to the third trimester and correlated negatively with fetal abdominal circumference, birth weight, and maternal insulin secretion. The authors revealed that GLP-1 levels in the first trimester were the best negative predictors of fetal abdominal circumference in the second trimester and maternal weight change during pregnancy. Their results indicate that during physiological pregnancy, maternal GLP-1 may be involved in mechanisms that compensate for pregnancy-related increases in glycemia and insulin resistance, suggesting a role for this peptide in maternal metabolism and body weight, as well as in fetal growth [38].
It is proven that GDM poses a higher risk of developing T2DM in the future; both conditions have a similar spectrum of metabolic changes [39]. The incretin effect is reduced in T2DM, which may be due to decreased secretion of the incretin hormones or reduced response of the pancreatic β-cells to them. The role of GLP-1 in the pathogenesis of GDM is still unclear.
Bonde et al. investigated the GLP-1 response in pregnant women with and without GDM and again after the delivery when normal glucose tolerance (NGT) was restored [40]. The authors observed that pregnancy was associated with a low postprandial GLP-1 response. The patients with GDM had decreased postprandial GLP-1 levels during pregnancy compared to the 3–4 months postpartum period. Bonde et al. suggested that patients with GDM are characterized by impaired postprandial incretin hormonal responses with decreased GLP-1 activity during pregnancy that normalizes postpartum [40]. The reversibility of the reduced postprandial GLP-1 response in GDM patients may suggest that it develops secondary to insulin resistance or diabetes and is not the major pathogenetic defect in the development of diabetes [40].
In addition, Kosinski et al. indicate that women with GDM show a reduced incretin effect, which is completely reversible with the restoration of normal glucose homeostasis [41]. Mosavat et al. found reduced GLP-1 levels during pregnancy in patients with GDM compared to a control group [19]. Confirming previous studies, GLP-1 levels in the GDM group showed a decrease during pregnancy and immediately after delivery and then increased in the late post-puerperium [19]. Based on current knowledge, a decrease in incretin levels might represent the mechanisms that compensate for the tendency to pregnancy-related increase in glycemia and insulin resistance. Decreased GLP-1 function in GDM may be an early abnormality that may signify the need for appropriate monitoring and treatment.
2. DPP-4—State of the Art
The DPP family consists of enzymes such as DPP-4, fibroblast activation protein α (FAP; seprase), DPP-8, DPP-9, and prolyl carboxypeptidase (PCP; angiotensinase C) [46]. DPP-4, also known as T-cell differentiation antigen CD26, is a serine protease present in the circulation as two isoforms—a soluble protein and plasma membrane-bound [47,48]. The soluble isoform enables intercellular contact by cleaving protein substrates in body fluids, while the plasma membrane-bound affects intercellular communication through receptor activity [48].
Human DPP-4/CD26 has a short intracellular domain (6 amino acids), a transmembrane region, and an extracellular domain that possesses DPP activity [46]. DPP-4 expression was observed in numerous cells such as intestinal K cells, hepatocytes, adipocytes, renal brush border membranes, bone marrow cells, pancreatic cells, placental cytotrophoblasts, endothelial cells, and on the surface of lymphocytes [46,48,49,50,51].
According to the research, DPP-4 plays a role in regulating metabolism, appetite, energy expenditure, and body composition [48]. The abnormal expression and activity of DPP-4 has been observed to be associated with the occurrence of hyperglycemia and an increase in body mass index, implying that this enzyme may contribute to the development of diseases such as T2DM and obesity by mediating inflammation and insulin resistance in adipose tissue [48]. Some of the other functions of DPP-4 include interactions with various proteins such as streptokinase and plasminogen, extracellular matrix components (collagen, fibronectin), and the role of binding sites for the chemokine CXCR4 receptor. In addition, sCD26 has the potential to enhance the congenital immune response [50]. Due to the diverse functions of DPP-4, the dysfunction of this molecule has additional implications for the onset of inflammatory, viral entry, and immune-mediated diseases [47,52].
However, DPP-4 is most known for the mediation of GLP-1 and GIP inactivation. GLP-1 and GIP, through their effects on pancreatic β-cells, are responsible for stimulating insulin secretion [53]. In addition, by affecting α-cells, they mediate the inhibition of glucagon release and thus reduce hepatic glucose production [49]. Through repression of the activity of DPP-4, it is possible to prevent the degradation of GLP-1 and GIP, thereby increasing their concentrations by 2–3 times and leading to an increase in postprandial glucose-dependent insulin concentration and a decrease in glucagon release [54,55]. For this mechanism to be effective, having preserved endogenous incretin production is required [55]. DPP-4 inhibition also appears to affect insulin sensitivity through non-enzymatic interactions with membrane proteins such as caveolin-1 [47]. In conclusion, DPP-4 inhibition improves pancreatic β-cell proliferation by inhibiting apoptosis pathways and thus mediates improved glucose homeostasis without inducing hypoglycemia [53,56].
The group of DPP-4 inhibitors includes vildagliptin, sitagliptin, saxagliptin, linagliptin, and alogliptin [57]. Their activity is based on stimulating insulin secretion in a glucose-dependent mechanism, and compared to other groups of antidiabetic drugs, demonstrates a less rapid glucose-lowering effect. Moreover, gliptins are weight neutral due to a limited increase in GLP-1 activity [53]. These drugs are primarily used in adults with T2DM in monotherapy in case of contraindications or lack of efficacy of metformin treatment and in combination with other antidiabetic drugs, including insulin [51]. All approved DPP-4 inhibitors appear to have similar glycemic effectiveness resulting in a reduction in HbA1c; however they provide fewer advantages compared to GLP-1R agonists and sulfonylureas [51,55].
In addition to their evident glucose-lowering effects, DPP-4 inhibitors exhibit anti-inflammatory activity, which, according to the research, controls vascular aging [49]. Furthermore, they show nephroprotective effects; however, the mechanisms have not been documented so far. Saxagliptin seems to be the most effective since, according to studies, it can inhibit the progression of microalbuminuria [58]. On the other hand, alogliptin and sitagliptin show protective effects on the cardiovascular system [59].
3. DPP-4 in GDM
The role of DPP-4 activity in the pathogenesis of GDM is not fully understood. Its significance in fetal development is also under investigation. An important issue in this context is the concept of fetal programming. Montaniel et al. [48] point out that the children of mothers who are obese during pregnancy are more likely to develop obesity during their lives, but the mechanisms behind this correlation are still unknown. The researchers suggest that plasma DPP-4 activity, which is elevated in the male offspring of mothers with obesity, may play an essential role here. Montaniel et al. used a mouse model of maternal high-fat diet-induced obesity and sitagliptin to assess whether it can inhibit DPP-4 activity in vivo and, thus, block fetal programming toward obesity. This analysis proved that sitagliptin is effective only on male offspring, without an effect on female ones. They indicate that DPP-4 inhibitor therapy during pregnancy could inhibit fetal programming toward obesity in the offspring of obese mothers, but more detailed research is required to confirm this observation [48].
Al-Aissa et al. [60] conducted a study to evaluate DPP-4 activity in the cord blood samples from 270 patients—111 with GDM and 159 controls. The GDM patients received effective diet or insulin treatment. As a result, they demonstrated lower DPP-4 enzymatic activity in newborns of mothers with GDM compared to healthy controls. They believe it may represent a regulatory mechanism involved in fetal programming, which may affect the development of metabolic diseases in these offspring in the future [60].
Liu et al. [61], to assess the impact of DPP-4 on the pathogenesis of GDM, decided to perform research in order to compare the values of this molecule in maternal and umbilical cord serum in pregnant GDM patients and healthy controls. Insulin values decrease during pregnancy in women with GDM. The researchers hypothesized that DPP-4 concentrations might be higher in these patients due to its ability to lower insulin via the degradation of incretins. A strong correlation was found between maternal and umbilical cord venous DPP-4 levels. However, no significant difference was presented in maternal or umbilical cord venous DPP-4 concentrations when comparing the GDM and control group. In addition, the researchers were interested in evaluating the molecule’s correlation with neonatal birth anthropometry; however, no association was documented. The investigators believe that DPP-4 probably does not play a significant role in the pathogenesis of GDM and has no effect on fetal development [61].
Kandzija et al. [62] conducted a study to investigate the activity and concentrations of DPP-4 associated with syncytiotrophoblast-derived extracellular vesicles (STB-EVs) in patients with pregnancies complicated by GDM. A syncytiotrophoblast is responsible for releasing extracellular vesicles (EVs) into the maternal circulation to mediate intercellular communication between the placenta and maternal metabolism. The concentration of STB-EVs increases with the duration of pregnancy and positively correlates with the onset of insulin resistance during gestation. The researchers documented an increase in the concentration of circulating small STB-EVs in maternal plasma in pregnant patients complicated by GDM compared to healthy controls. In addition, they also noted that STB-EVs contain active enzyme DPP-4 capable of degrading GLP-1-DPP-4 values, which were more than eight times higher in women with GDM. However, they note the limitations of their analysis, including the small sample size (n = 6 for both GDM and controls), and emphasize the need for further studies on a larger scale to clarify the roles of DPP-4 associated with STB-EV [62].
Although DPP-4 inhibitors are widely used among adult T2DM patients, the number of studies evaluating their use in women with pregnancies complicated with GDM and during the postpartum period is still limited.
Sun et al. [63] evaluated the ability of sitagliptin to reduce insulin resistance and alleviate GDM symptoms. They examined 206 patients diagnosed with GDM during the second trimester of pregnancy, 102 of them were treated with sitagliptin, while 104 women received a placebo. After 16 weeks of the study, patients in the sitagliptin group achieved significant reductions in FPG and serum insulin levels over values of the above parameters obtained at the beginning of the study, compared to patients in the placebo group. In addition, they showed that the use of sitagliptin helped down-regulate retinol-binding protein-4 (RBP-4), a molecule that is known to be positively correlated with the severity of glucose intolerance and insulin resistance in women with previous GDM. Among patients receiving sitagliptin and their newborns, no adverse effects were observed during the follow-up [63].
Hummel et al. [64] assessed the effectiveness of vildagliptin for the prevention of postpartum diabetes in women with a recent history of insulin-requiring GDM. The study included 113 women—58 received vildagliptin and 55 placebo pills. The patients received 50 mg of vildagliptin twice a day for 24 months, starting therapy on average about 9 months after delivery, and were additionally monitored for 12 months after completing the treatment. However, the researchers were unable to demonstrate an advantage of taking vildagliptin over a placebo in terms of reducing the risk of postpartum diabetes. Moreover, indicators related to insulin resistance, glucose control, or pancreatic β-cell function were not significantly different between the two groups [64].
In turn, Elkind-Hirsch et al. [65] proved that combined therapy consisting of sitagliptin and metformin was more effective in women with impaired postpartum glucose regulation compared to metformin alone or placebo in women with a history of GDM.
The presented studies differ in the size of the study group, the population risk of diabetes, as well as in the diagnostic criteria for GDM. The criteria of 75 g OGTT (according to IADPSG) were included in the studies conducted by Liu et al. [61], Kandzija et al. [62], and Sun et al. [63], while the criteria of 100 g OGTT (according to Carpenter–Coustan) in the study performed by Elkind-Hirsch et al. [65]. The research by Al-Aissa et al. [60] took place in two countries that used different diagnostic criteria for GDM: the Austrian group according to the IADPSG criteria, while the Hungarian group followed the modified 1999 WHO recommendation, namely-75 g OGTT at 24–28 gestational weeks, where FPG ≥ 6.1 mmol/L or 2-h plasma glucose ≥ 7.8 mmol/L qualified for a diagnosis of GDM. Hummel et al. [64] classified women as having GDM if two of three capillary blood glucose values measured during a 75 g OGTT were: FPG >5 mmol/L, 1-h plasma glucose >10.6 mmol/L or 2-h plasma glucose >8.9 mmol/L.
There are some mixed conclusions from the abovementioned studies. Undoubtedly, further research on the use of DPP-4 inhibitors in the treatment of GDM and their possible impact on reducing fetal programming for obesity and metabolic diseases.
This entry is adapted from the peer-reviewed paper 10.3390/ijms231710101
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