Introduction

Gestational diabetes is defined as “any degree of glucose intolerance with onset or first recognition during pregnancy”. It is said to affect 3-10% of pregnancies and is believed to be due to the hormones produced during pregnancy that increase a woman’s insulin resistance.

The precise mechanisms underlying gestational diabetes remain unknown. The hallmark of GDM is increased insulin resistance. Pregnancy hormones and other factors are thought to interfere with the action of insulin as it binds to the insulin receptor. The interference probably occurs at the level of the cell signalling pathway behind the insulin receptor. Since insulin promotes the entry of glucose into most cells, insulin resistance prevents glucose from entering the cells properly. As a result, glucose remains in the bloodstream, where glucose levels rise. More insulin is needed to overcome this resistance; about 1.5-2.5 times more insulin is produced than in a normal pregnancy.

Gestational diabetes mellitus (GDM) is associated with increases in maternal and perinatal morbidity, including caesarean section, neonatal hypoglycaemia, and macrosomia.1, 2 Moreover, human epidemiological and animal studies suggest that the intrauterine diabetic environment increases risk for hypertension, obesity, and type II diabetes in adulthood. These findings suggest that measurement of cord serum leptin and c peptide levels is of considerable interest.

In humans and animals, plasma leptin increases early during gestation, derived primarily from the placenta.3, 4, 5 Although leptin and its receptor messenger RNA (mRNA) are expressed by the placenta,5, 6, 7 the role of increased leptin during pregnancy in maternal-fetal metabolism and intrauterine growth remains unclear. The leptin gene has a placenta-specific upstream enhancer,8 implying that placental leptin is differentially regulated from leptin of adipose origin. In the mouse, leptin protein and mRNA are colocalized to the trophoblast giant cells at the maternal interface of the placenta and to the cytotrophoblasts in close proximity to the developing fetus.5, 9 There is no correlation between maternal leptin levels and fetal weight; however, several studies have reported that umbilical cord blood leptin levels are positively correlated with fetal insulin, birth weight, ponderal index(kilograms per cm³), and length and head circumference,10, 11, 12 suggesting a potential relationship between placental leptin and fetal growth. The higher leptin levels in umbilical veins than umbilical arteries and the marked fall after placental delivery indicate that the placenta is one of the major sources of leptin in the fetal circulation.13

Leptin is a protein hormone that plays a key role in regulating energy intake and energy expenditure, acting through the hypothalamus. It is one of the most important adipose derived hormones. It is manufactured primarily in the adipocytes of white adipose tissue, and the level of circulating leptin is directly proportional to the total amount of fat in the body. In addition to white adipose tissue—the major source of leptin—it can also be produced by placenta (syncytiotrophoblasts) during pregnancy. Leptin normally reduces appetite and increases energy expenditure, acting through the hypothalamus.14, 15 Leptin also has direct metabolic effects on several tissues, resulting in increased glucose utilization and lipolysis.16, 17, 18, 19 Although the effect of leptin on insulin secretion is controversial, some investigators report that leptin inhibits insulin secretion.20, 21, 22

The marked increase in maternal leptin, an appetite suppressant, suggests there is some form of maternal leptin resistance, or perhaps there is an alternative role for maternal leptin. Leptin also serves as a mitogen for a growing number of cell types, including endothelial cells, hemopoietic cells, lung epithelial cells, and pancreatic ß-cells in vitro.23, 24, 25, 26 Leptin could therefore be acting as a mitogen for the placenta in addition to stimulating growth of tissues in the developing fetus.

Materials and Methods

Results

Table 1 shows that leptin levels are significantly elevated in GDM and type 2 DM than in controls. Ponderal index, again is higher in cases than in controls. One way ANOVA has been done to find the significance. Birth weight and Placental weight have also been significantly elevated in cases than in controls.

Table 2 shows significant correlation has been found between leptin, c peptide levels and ponderal index in GDM, Type 2 DM and controls.

Table 3 shows significant correlation between gestational age of mothers and leptin, C Peptide in babies.

Table 4 shows significant correlation between leptin and anthropometric measures of babies.

Table 5 shows there is difference between leptin levels in males and females in each population, but the difference is not very significant

Table 6 shows significant difference within male and female populations across all 3 groups. But no significant difference between males and females in each individual group

Table 7 shows no significance in parity between the 3 groups

Discussion

The fact that all pregnancies, especially diabetic pregnancies are associated with maternal leptin resistance suggests that fetal macrosomia would more likely be associated with changes in placental or fetal leptin expression. The factors that increase fetal leptin levels in macrosomia are not known. In the rodent there is very little or no fetal adipose tissue; thus, the macrosomia may be a function of increased placental production, whereas in other animal models, fetal leptin correlates with adipose tissue mass.

Studies have shown that environmental factors, including weight gain during pregnancy, maternal glucose levels, and fetal hyperinsulinemia, can contribute to fetal macrosomia.27, 28, 29 In our study, Table 2 shows significant correlation has been found between leptin, c peptide levels and ponderal index in GDM, Type 2 DM and controls.

Pregnant women with GDM have more severe insulin resistance and abnormal insulin secretion (impaired glucose tolerance) compared with weight-matched pregnant control subjects.30, 31, 32 The mechanisms for insulin resistance in GDM include a 30–40% decrease in insulin receptor tyrosine kinase activity in skeletal muscle compared with obese pregnant controls33 and is exacerbated by decreased insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation, due in part to decreased IRS 1 expression.33 Given these abnormalities, there are animal studies that exogenous leptin treatment during late gestation might reduce insulin resistance, thereby lowering maternal glucose and preventing fetal over growth. Table 4 shows significant correlation between leptin and anthropometric measures of babies

These findings will be of help in humans as well.

There is evidence that leptin treatment in mice reduces adiposity and improves insulin sensitivity, suggesting it may potentially be an effective means of reducing the abnormal glucose tolerance associated with GDM. There is a role for fetal and placental leptin expression in the regulation of fetal growth, independent of maternal glucose. Placental leptin levels are increased in human diabetic pregnancies34 and decreased in pregnancies complicated by fetal growth retardation.35 Leptin’s ability to influence fetal growth could have important implications for susceptibility to adult disease with higher concentrations of leptin in cord blood and placenta. A role for leptin in stimulating fetal pancreatic development has been suggested,26, 36 which could result in early insulin production and stimulate an increase in fetal growth. Alternatively, fetal hyperinsulinemia could stimulate increased fetal and placental leptin, which, in turn, could contribute to increased fetal growth in tissues expressing the leptin receptor. Studies are currently underway to determine whether maternal leptin administration alters insulin and the b-cell gene expression profile in neonatal mice.

However, in our study, Table 1 shows that leptin levels are significantly elevated in GDM and type 2 DM than in controls. Ponderal index, again is higher in cases than in controls. One way ANOVA has been done to find the significance. Birth weight and Placental weight have also been significantly elevated in cases than in controls. Studies have proved the differences in the leptin concentration between sexes.37, 38, 39 In our study, Table 6 shows significant difference within male and female populations across all 3 groups. But no significant difference between males and females in each individual group.

Various mechanisms have been postulated to explain this difference. The most accepted explanation is the differential adiposity between the genders.40, 41, 42 The gender dimorphism in leptin production which is observed in the very early life may also indicate the genetic difference in leptin production. Although we have observed gender difference in leptin levels in our study ,between males and females in each group, this difference is not very significant as shown in Table 5. However, when we compare leptin levels between male babies in all 3 groups, there is a significant difference and we observe a similar significant difference when female babies between the 3 groups are compared as seen in Table 6.

Higher leptin in the offspring of diabetic mother has been largely attributed to the increase in the adiposity of the offspring of diabetic mother. Insulin might regulate the production of leptin. Placental production of leptin might be responsible for hyperinsulinemia in the offspring of DM. The cause for differences in leptin concentration between the genders is also controversial.

Despite leptin resistance, human recombinant leptin administration lessened maternal weight gain and improved glucose tolerance in mouse. One of the main reasons for the effectiveness of peripherally administered human leptin in mouse may be the relatively higher and sustained half-life of the leptin immune adhesion compared with native leptin.41 High levels of leptin have been shown to reduce fat content in rats by blocking intracellular FFA esterification and by enhancing intra cellular oxidation of lipids. Leptin administration had only marginal effects on appetite, but significantly reduced insulin resistance in pregnant mice, in part through an improvement in skeletal muscle insulin signal transduction at the level of IRS-1. Leptin also down-regulated the endogenous leptin expression levels in mice, which may have contributed to the reduced sensitivity. Previous studies have found that the leptin receptor mediates autocrine regulation of leptin mRNA expression in a tissue-specific manner. Leptin administration reduces leptin synthesis in adipose tissue, whereas in skeletal muscle it induces the protein independently of differences in fat mass or insulin levels. Placental leptin protein was also found to be reduced with leptin administration.

Conclusion

Serum leptin levels are significantly elevated in cord blood of newborns born to GDM and type 2 DM mothers, and they correlate well with the neonatal anthropometric measurements. However in our study we did not find a significant difference in the leptin levels between male and female babies born to GDM and type 2 DM mothers.

Leptin’s ability to influence fetal growth could have important implications for susceptibility to adult disease and will be an important area for future research.

Source of Funding

None.

Conflict of Interest

None.