It refers to different degrees of abnormal glucose metabolism caused by impaired glucose tolerance that occurs or is first detected during pregnancy, and the prevalence is about 3% in China, and epidemiological data show that the incidence of GDM is increasing year by year with the change of people’s lifestyle and the increase of disease detection rate [2]. Insulin sensitivity decreases during pregnancy compared to pre-pregnancy, predisposes to insulin resistance, and GDM can occur in approximately 6% of pregnant women.
It has been established that Ca2+, as an important intracellular second messenger, plays a role in the insulin signaling pathway. It is now believed that insulin resistance is closely related to the transmembrane operation and metabolism of Ca2+, among others. This paper gives a lecture on this topic.
I. Characteristics of calcium metabolism during pregnancy
1. Characteristics of calcium homeostasis during pregnancy.
The calcium needs of women increase during pregnancy, and the absorption of calcium by pregnant women is higher than that of non-pregnant women, which is more obvious in the middle and late stages of pregnancy. In the process of fetal growth and development, a large amount of calcium needs to be absorbed from pregnant women to ensure the normal calcification of fetal skull, spine, limbs and teeth. The reason for the relatively low serum Ca2+ level in pregnant women is: the increase in blood volume and extracellular fluid during pregnancy makes the serum Ca2+ level relatively lower; the increase in secretion of corticosteroids, thyroid hormone and growth hormone as well as the increase in glomerular filtration rate during pregnancy increases urinary calcium excretion; the increase in estrogen level during pregnancy inhibits the reabsorption of bone calcium to a certain extent; plasma albumin, which has the function of calcium The plasma albumin, which has a calcium storage function, decreases with the increase of gestational weeks. As a result, the serum Ca2+ level in pregnant women decreases compared to non-pregnant women. Several studies have shown that the level of calcium deficiency in healthy pregnant women increases substantially with increasing gestation; GDM patients tend to have lower serum Ca2+ levels than healthy pregnant women.
2, the reasons for the decrease in serum Ca2+ levels in GDM patients.
(1)A large amount of glucose is excreted from the urine during hyperglycemia, and the osmotic diuretic effect excretes a large amount of calcium and phosphorus ions out of the body, while lowering the blood Ca2+ level; increased urinary sugar level also reduces the renal tubular reabsorption of calcium, aggravating calcium loss and eventually causing low blood calcium.
(2) Long-term hyperglycemia and insulin deficiency in GDM patients can lead to 1α-hydroxylase deficiency or functional limitation, resulting in reduced 1,25-(OH)2D3 production, reduced intestinal calcium absorption, and lower serum Ca2+ levels. Other related studies have also confirmed that serum 1,25-(OH)2D3 levels are negatively correlated with fasting glucose in GDM patients.
(3) Glucose can undergo non-enzymatic glycosylation reactions with the lysine ε-amino group or the amino-terminal α-amino group of proteins. Chronic hyperglycemia can cause excessive glycosylation of many proteins in the body, resulting in changes in their structure and function. chronic hyperglycemia in GDM patients can directly inhibit the activity of Ca2+-Mg2+-adenosine triphosphate (ATP) on the one hand, and can also lead to excessive glycosylation of Ca2+-Mg2+-ATP enzymes, thus inhibiting Ca2+-Mg2+-ATP activity and making extracellular Ca2+ into the cell, leading to a decrease in serum Ca2+ levels and an increase in intracellular Ca2+ levels.
II. Insulin resistance and calcium metabolism
1. Characteristics of insulin resistance in pregnant women with GDM.
Insulin resistance is a decrease in tissue sensitivity to insulin, including tissue resistance to insulin-mediated glucose uptake, abnormal glucose tolerance, hyperinsulinemia, and elevated triglyceride levels, called metabolic syndrome or syndrome X [14]. The common pathogenesis of hypertension, diabetes mellitus, cardiovascular diseases and lipid metabolism disorders is reported in the literature as insulin resistance.GDM shares a similar pathophysiological basis with type 2 diabetes mellitus, namely insulin resistance and hyperinsulinemia as well as impaired islet β-cell function. After studying 32 patients with GDM, 47 healthy pregnant women and 43 non-pregnant women, Li Pu et al [17] found that fasting glucose and fasting insulin levels were significantly higher in GDM patients than in healthy pregnant women and non-pregnant women, while insulin sensitivity index was significantly lower than the latter two, indicating that GDM patients have hyperglycemia and hyperinsulinemia and insulin resistance.
Along with the increase of gestation time, especially in late pregnancy, the level of antagonistic hormones of insulin keeps rising, causing a decrease of insulin sensitivity in target organs and target tissues of insulin, inhibiting hepatic glucose output, weakening the utilization of blood glucose, and increasing insulin resistance in peripheral tissues. Studies have shown that the insulin sensitivity of GDM patients is significantly lower than that of normal glucose tolerant pregnant women in early and late pregnancy, and some GDM pregnant women still have insulin resistance after delivery. the offspring of GDM patients have reduced insulin receptors, decreased affinity and obesity, which are closely related to insulin resistance.
2. Calcium metabolism and insulin resistance.
The regulatory mechanism of intracellular Ca2+ homeostasis mainly includes Ca2+ channels on the cell membrane, Na+-Ca2+ exchange and calcium pump, among which, calcium pump is an important way to discharge Ca2+. The function of calcium pump, Ca2+-Mg2+-ATPase, is to pump Ca2+ out and maintain low intracellular Ca2+ levels, and a decrease in its activity level will cause an increase in intracellular Ca2+ levels. Pancreatic β-cells have several types of Ca2+ channels that are mainly involved in the glucose-stimulated Ca2+-dependent insulin secretion process [20]. Li Pu et al [17] found that simultaneous measurement of Ca2+ and Ca2+-Mg2+-ATPase activities in erythrocytes of GDM patients, healthy pregnant women and non-pregnant women showed that Ca2+ levels were elevated in erythrocytes of GDM patients, while Ca2+-Mg2+-ATPase activity was significantly reduced.
It suggests that insulin resistance in GDM patients may be positively correlated with intracellular Ca2+ levels and negatively correlated with cell membrane calcium pump activity. Zhang Yong and Zasan [21] conducted a comparative study of 42 patients with gestational hypertensive disorders and 34 healthy pregnant women to determine their fasting insulin levels, erythrocyte intracytoplasmic free calcium levels and erythrocyte lysate calcium pump activity, and found that the cell membrane Ca2+-ATPase activity was decreased and intracellular Ca2+ levels were increased in hyperinsulinemic patients, in agreement with the findings of Li Pu et al [17 . On the other hand, many scholars have found that serum Ca2+ levels in patients with GDM are also negatively correlated with fasting insulin levels and insulin resistance index [9, 22]. a study by Pittas et al [10] showed that reduced Ca2+ levels in target tissues lead to the development of insulin resistance.
In summary, it is reasonable to speculate that the development of insulin resistance is closely related to intracellular Ca2+ levels, calcium pump activity on the cell membrane and serum Ca2+ levels. On the one hand, lower serum Ca2+ levels lead to increased permeability of the cell membrane, and a severe deficiency will cause loss of cell membrane integrity, resulting in increased Ca2+ inward flow, leading to higher intracellular Ca2+ levels. On the other hand, lower serum Ca2+ levels stimulate the secretion of parathyroid hormone, which activates adenylyl cyclase (AC), leading to an increase in intracellular cyclic adenosine monophosphate (cAMP) levels and the release of calcium from the mitochondria into the cytoplasm; parathyroid hormone also increases the permeability of the cell membrane, leading to an increase in the flow of extracellular Ca2+ into the cell; increased levels of parathyroid hormone can also reduce sodium pump activity, leading to a decrease in Na+ exchange with Ca2+ and a corresponding increase in intracellular Ca2+ levels. Through the above factors, the intracellular Ca2+ level is significantly increased, presenting a “state of overload”, and intracellular Ca2+ overload is the final pathway of cell death caused by various reasons.
The above findings lead to the following conclusions.
The decrease of calcium pump activity on the cell membrane, decrease of serum Ca2+ level or increase of intracellular Ca2+ level in GDM patients can increase insulin resistance in patients.
3, Possible mechanisms of cell membrane calcium activity leading to insulin resistance.
Currently, the mechanism by which cell membrane calcium activity leads to insulin resistance in patients with GDM is unclear. The possible mechanisms are as follows.
(1) Elevated intracytoplasmic Ca2+ levels can significantly inhibit phosphoserine phosphorylase (PSPH) activation in insulin target cells, and phosphorylation and activation of inhibitory factor 1 (WIF-1) mediates this process.
(2) The role of glucose transporter-4 (GLUT4) in the glucose transport mechanism is crucial, and its activation relies on insulin activation of DSPH-1, which in turn leads to GLUT4 dephosphorylation, while a significant increase in intracellular Ca2+ levels can severely interfere with the dephosphorylation process of GLUT4, causing GLUT4 inactivation This in turn affects the uptake of glucose by the cell membrane, leading to increased blood glucose and reduced insulin sensitivity in adipocytes.
(3) Elevated intracellular Ca2+ levels activate protein kinase C (PKC), which in turn blocks insulin signaling by inactivating insulin receptor β-subunit phosphorylation.
(4) Ca2+ has a strong regulatory effect on the binding of calmodulin to insulin receptor substrate 1 (IRS-1), and high levels of Ca2+ may also interfere with the signal transduction process of insulin action through this mechanism.
(5) Both 1,25-(OH)2D3 and parathyroid hormone have been shown to promote Ca2+ inward flow, and parathyroid hormone levels were found to be significantly higher in insulin-resistant patients than in healthy people, so both hormones may be involved in the development of insulin resistance through the mechanism of promoting Ca2+ inward flow. Among them, 1,25-(OH)2D3 may also promote Ca2+ inward flow through the membrane type vitamin D receptor on the cytosolic membrane of pancreatic β-cells in a non-genomic signaling mode, stimulating insulin secretion, inducing hyperinsulinemia and aggravating insulin resistance.
Third, the guiding significance of calcium metabolism on the clinical treatment of GDM
GDM is highly susceptible to serious complications such as infection, miscarriage, preterm delivery, hyperhydramnios, fetal malformation, fetal distress, macrosomia, neonatal hypoglycemia and neonatal respiratory distress syndrome [24].The hyperglycemic environment that occurs in GDM can also lead to the development of microangiopathy [25], and the most common complications include nephropathy, chronic hypertension, preeclampsia, preterm delivery and fetal growth restriction, so the GDM treatment of GDM is particularly important. It has been shown that serum 25-hydroxyvitamin D [25-(OH)D3] and serum Ca2+ levels are closely associated with insulin resistance.Asemi et al [27] conducted a randomized, double-blind, placebo-controlled clinical trial in 48 pregnant women at 25 weeks’ gestation, in which participants were randomly assigned to an experimental group supplemented with 400 U/d vitamin D and a placebo control group, and after 9 weeks, it was found that The results suggest a correlation between serum 25-(OH)D3, serum Ca2+ and insulin resistance. Supplementation with vitamin D or calcium to elevate serum 25-(OH)D3 and serum Ca2+ levels improved insulin sensitivity in patients with GDM.
Vitamin D improves insulin resistance probably by acting on calcium-dependent endonucleases in pancreatic β-cells, accelerating the conversion of proinsulin to insulin and promoting insulin release. In addition, 25-(OH)D3 is an immunosuppressant that downregulates inflammatory mediators such as tumor necrosis factor alpha (TNF-α), interleukin (IL)18, and IL-2 [28], which also play an important role in improving insulin resistance in the body. Moreover, S. rensen et al [29] also confirmed that vitamin D supplementation in pregnant women can reduce the risk of type 1 diabetes in their offspring. Therefore, it is recommended that pregnant women can moderately increase outdoor activities and eat more vitamin D-rich foods during pregnancy and take appropriate calcium supplements, which may be beneficial to prevent or improve the onset, development and regression of insulin resistance.
In addition, intracellular hypercalcemia is an important factor leading to decreased insulin sensitivity. If Ca2+ inward flow into cells is prevented, insulin resistance may be improved, blood glucose levels stabilized and the effect of insulin therapy enhanced. Calcium antagonists mainly inhibit Ca2+ channels in the cytosolic membrane of cardiac muscle and vascular smooth muscle cells, and reduce intracellular Ca2+ level by inhibiting Ca2+ inward flow, which is especially suitable for the combined treatment of diabetes combined with hypertension, and is effective in elderly patients with hypertension with coronary atherosclerotic heart disease and peripheral vascular disease, diabetes or abnormal glucose tolerance combined with kidney damage, with no absolute contraindication.
Angiotensin-converting enzyme inhibitors (ACEIs) combined with calcium antagonists have been found to be more effective in lowering blood pressure and relieving diabetic symptoms in elderly patients with diabetes mellitus combined with hypertension than alone, and are particularly suitable for the treatment of elderly patients with cardiovascular disease. In the non-diabetic population, calcium antagonists can inhibit insulin secretion and increase insulin sensitivity. In the type 2 diabetic population, calcium antagonists can reduce insulin levels 2 h after meals without raising blood glucose. Therefore, it can be boldly speculated that calcium antagonists can also be used in GDM patients to block the inward flow of extracellular Ca2+, thus reducing the intracellular Ca2+ level, improving the phenomenon of insulin resistance and enhancing the effect of insulin therapy; it should be more suitable for those with GDM combined with hypertension.
However, some foreign scholars have found that nifedipine may block the biological effect of insulin and disrupt the balance of glucose metabolism, which is likely to increase blood glucose and worsen the disease if the body loses its ability to compensate (such as when developing diabetes). Short-term trials in diabetic populations have demonstrated that calcium antagonists interfere with glucose metabolism and insulin secretion to some extent, while long-term trials have shown no effect. Different calcium antagonists have different effects on pancreatic β-cell function and glucose metabolism, and although the mechanisms that produce these results may be different, in general, calcium antagonists have adverse but mild effects on glucose metabolism in diabetic patients without serious consequences.
Studies in recent years have shown that both GDM and type 2 diabetes are associated with insulin resistance and impaired islet β-cell function [31-32]. From a clinical point of view, GDM is not an absolute contraindication to all calcium antagonists, but clinical use should pay attention to monitoring patients’ islet β-cell function and glucose metabolism indicators.
Finally, some studies have shown that erythrocyte cytosolic activity in GDM patients is positively correlated with insulin sensitivity index, suggesting that insulin resistance in GDM patients may be related to erythrocyte cytosolic calcium pump activity, and if patients have improved erythrocyte cytosolic activity, it can reduce intracellular Ca2+ level and thus reduce insulin resistance. However, there are fewer studies on drugs that activate erythrocyte cytosolic calcium pump activity, and at present, it is still impossible to judge their usefulness.
In summary
Serum Ca2+ levels in GDM patients are significantly lower than those in healthy pregnant women, and there is a significant phenomenon of insulin resistance, which is negatively correlated with erythrocyte cytosolic calcium pump activity and serum Ca2+ levels and positively correlated with intracellular Ca2+ levels. Therefore, timely glycemic control, appropriate exercise, calcium and vitamin D supplementation, and Ca2+ antagonists may improve insulin sensitivity and enhance the effect of insulin therapy in GDM patients, which is important for clinical treatment.