Miami human placental lactogen and diabetes
PI3K is composed of the p85 regulatory unit and a catalytic subunit called p, which need to form a pp heterodimer and bind to IRS-1 for PI3K activation. Under the action of hPGH, the p85 monomer is selectively overexpressed and competes with the active pp heterodimer in a dominant-negative fashion for binding to IRS-1, thus decreasing the IRSassociated PI3K activity [ 13 ].
In turn, this reduction in PI3K activity results in the attenuation of the final step of the insulin signaling pathway, namely in the reduction of GLUT4 translocation from the cytoplasm to the plasma membrane [ 13 ]. As the fetus has very little capacity for gluconeogenesis, maternal glucose represents the main energy source for the placenta and the fetus.
Maternal glucose is crucial for normal fetal metabolism and growth [ 34 , 35 ]. However, passive diffusion of glucose across the placenta is insufficient to meet fetal glucose needs. Thus, facilitated diffusion using a variety of glucose transporters is required for this purpose. They are embedded in the microvillous maternal-facing and basal fetal-facing membranes of the syncytiotrophoblast, which is the main placental barrier layer [ 36 ].
While eight members of the GLUT family have been described in human placental tissue, only glucose transporter 1 GLUT1 protein has been identified in the syncytium. Basal membrane GLUT1 expression is upregulated over pregnancy, increased in diabetic pregnancy, and reduced in chronic hypoxia, while microvillous membrane GLUT1 expression remains unaffected [ 36 ].
As we previously mentioned, there is a coexisting balance between physiologic insulin resistance and an adaptive increase in beta-cell insulin production during pregnancy. In early pregnancy, the endocrine pancreas anticipates the increase in insulin resistance that occurs late in pregnancy through an early increase in beta-cell insulin secretion.
This adaptive increase in insulin secretion may occur through different mechanisms. Lowering the threshold for glucose-stimulated insulin secretion increased beta-cell glucose sensitivity is the primary mechanism of the adaptation of pancreatic islets to the increased demand for insulin under normal blood glucose concentrations during pregnancy [ 38 ].
In addition, there is an increase in beta-cell mass that occurs via beta-cell hyperplasia and hypertrophy processes and via upregulation of insulin synthesis and secretion [ 39 , 40 , 41 ]. Placental lactogens have also been suggested to play an important role in beta-cell adaptation during pregnancy, as these hormones increase beta-cell insulin secretion and beta-cell proliferation and survival, and lower the threshold for glucose-stimulated insulin secretion [ 42 ].
Interestingly, a pregnancy-induced increase in C-peptide concentrations associated with improved metabolic control during pregnancy has also been demonstrated in women with long-term T1DM, even in women with undetectable C-peptide concentrations in early pregnancy [ 43 ]. This phenomenon may be related to different factors, such as: i pregnancy-induced growth promoting factors influencing the rejuvenation of the beta cells; ii suppression of the immune system; and iii improvement in metabolic control leading to reduced beta-cell glucotoxicity [ 44 , 45 ].
Advertisement 5. Defective beta-cell adaptation during pregnancy and gestational diabetes mellitus GDM Gestational Diabetes Mellitus GDM is defined as glucose intolerance of various degrees with onset or first recognition during pregnancy, which is not clearly preexisting diabetes [ 46 ].
GDM is believed to result from pancreatic beta-cell dysfunction in women with preexisting insulin resistance [ 48 ]. In particular, defects in beta-cell adaptive mechanisms through which pancreatic islets adapt to the increased gestational insulin demand lead to the development of GDM. However, women with GDM fail to overcome peripheral insulin resistance with a proper compensatory increase in endogenous insulin secretion [ 22 ].
The reduction in insulin receptor tyrosine kinase phosphorylation and receptor tyrosine kinase activity is observed in pregnant women with normal glucose tolerance and in women with GDM. Yet, the latter group does not exhibit a significant improvement in insulin resistance postpartum [ 2 , 22 ]. Additionally, alterations in the placental structure may also negatively influence glucose homeostasis during pregnancy.
Indeed, it has been shown that the placental abnormalities most consistently associated with maternal diabetes are represented by an increased incidence of villous immaturity, increased measures of angiogenesis, and increased placental weight [ 50 ]. Also, comorbidities such as diabetes and obesity may further negatively impact the placental function and the insulin signaling in the placental tissue [ 51 ].
Specific alterations in placental function have been described in the placentas of obese women as compared with the placentas of lean women, namely reduced mitochondrial respiration and adenosine triphosphate ATP generation in trophoblast [ 52 ]. Friedman et al. Authors found that insulin resistance to glucose transport during pregnancy is associated with a reduction in IRS-1 tyrosine phosphorylation, mainly due to decreased expression of IRS-1 protein.
Yet, in women with GDM, there was also a decrease in tyrosine phosphorylation of the insulin receptor beta-subunit that contributed to further decreases in glucose transport activity [ 53 ]. Accordingly, Chu et al. Moreover, GDM is associated with an increased risk of fetal complications macrosomia, polyhydramnios, neonatal hypoglycemia, shoulder dystocia, respiratory-distress syndrome, increased perinatal mortality and maternal complications hypertension, preeclampsia, increased risk of cesarean delivery [ 47 , 55 ].
One of the most common and serious complications of GDM is macrosomia, which arises from maternal hyperglycemia. High maternal glucose levels cross the placenta and cause fetal hyperglycemia, which, in turn, stimulates the release of insulin by the fetal beta-cells and causes hyperinsulinemia, resulting in subsequent macrosomia as insulin anabolic properties induce an increased growth rate of fetal tissues [ 47 ]. It is worth reminding that insulin is present in the fetal pancreas as early as the 10th gestational week and in fetal plasma from the 12th gestational week [ 56 , 57 , 58 ].
These risk factors include overweight and obesity, excessive gestational weight gain, advanced maternal age, multiparity, family history of T2DM or GDM, polycystic ovary syndrome PCOS , physical inactivity, GDM in the previous pregnancy, certain ethnicities including Asian ethnicity , a previous macrosomic child, Westernized diet, genetic polymorphisms, and intrauterine environment low or high birth weight [ 48 , 59 , 60 , 61 , 62 , 63 , 64 , 65 ].
Screening for GDM should be performed particularly in at-risk women through a 2-hour, g oral glucose tolerance test OGTT performed at 24—28 weeks of gestation. All patients with any risk factor for GDM should receive healthy lifestyle counseling to address modifiable risk factors, such as excessive weight gain and physical inactivity, to prevent GDM [ 67 ]. Management of established GDM involves lifestyle intervention consisting of diet counseling aimed at limiting glycemic excursions and ensuring appropriate weight gain weight control , coupled with self-monitoring of blood glucose SMBG and promotion of safe and insulin-sensitizing physical activity regimens.
Indeed, it is well known that physical exercise induces a rapid increase in the rate of glucose uptake in the contracting skeletal muscles. This augmented membrane glucose transport capacity is due to the recruitment of GLUT4 transporters to the sarcolemma [ 68 ]. Pharmacotherapy is usually started when lifestyle intervention alone fails to lead to adequate glucose control in women with GDM.
Pharmacological treatment of GDM involves the use of oral antidiabetic medications metformin or glibenclamide or, more frequently, exogenous insulin therapy [ 69 , 70 ]. Indeed, insulin therapy is considered the first-line pharmacologic therapy for GDM, as insulin does not cross the placenta to a significant degree.
Fasting hyperglycemia is treated with basal long-acting insulin analogs, while postprandial hyperglycemia is treated with rapid-acting prandial insulin analogs. Prandial and basal insulin can be used separately or in combination, based on the individual glycemic profile [ 71 ]. Remarkably, appropriate treatment of GDM has been shown to reduce the risk of both maternal and fetal complications of GDM, such as macrosomia, large for gestational age newborns, shoulder dystocia, cesarean section, preeclampsia, and respiratory distress syndrome [ 72 ].
Finally, prevention and adequate management of GDM are critical to stop the vicious cycle that increases the risk of developing metabolic dysfunctions such as obesity and diabetes in the offspring [ 26 , 73 , 74 ]. Advertisement 6. Conclusions Normal pregnancy is physiologically characterized by a progressive increase in insulin resistance, which acts as a physiological adaptation aimed to ensure the adequate supply of glucose to the rapidly growing fetus.
However, an early adaptive increase in beta-cell glucose sensitivity and beta-cell insulin secretion ensures the maintenance of glucose homeostasis in normal pregnancy. When on the institution site, please use the credentials provided by your institution. Do not use an Oxford Academic personal account. Following successful sign in, you will be returned to Oxford Academic.
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