Gestational diabetes mellitus (GDM) is one of the most common metabolic complications in pregnancy women with development of glucose intolerance. Up to 2–25% of pregnancies are diagnosed with GDM all round the world and about 11.9% of pregnancies in China[1–4]. The large variation in incidence is probably due to the broad criteria of hyperglycemia for diagnosis. Women with GDM demonstrate glucose intolerance and insulin insufficiency during pregnancy with onset or first recognition[5, 6], especially in the second or third trimester. Insulin production ability by pancreas of women with GDM cannot resistant to the insulin-inhibiting effects of placental hormones such as oestrogen, human placental lactogen and cortisol[7], which could be resolved along delivery.
Many risk factors is associated with GDM including obesity, non-white ethnicity, increased maternal age, family history of diabetes and history of giving birth to large infants[8, 9]. As up high to 50% of GDM women develop T2DM within 5 years after pregnancy [10–12], and about 70% within 22–28 years [13, 14]. Moreover, pregnant women with GDM provide a hyperglycemic environment in utero to fetus. Long time of exposure to hyperglycemic environment increased the tendency of obesity, metabolic syndrome, and other cardiometabolic disorders in the offspring[15, 16]. And the risk of adverse mother, developing fetus, and offspring shows continuously increase along the change of maternal glycemia in the final stage at 24–28 weeks[17], which may cause the occurrence of preeclampsia, increased newborn percent body fat, fetal macrosomia, obstructed shoulder delivery, cesarean delivery, postpartum hemorrhaging, neonatal asphyxia or death[6].
The precise mechanisms underlying the occurrence of GDM are not clear currently. The secretion of several anti-insulin hormones by the placenta gradually increases along with the pregnancy progress, for example, estradiol, placental growth hormone, progesterone, and prolactin. Those secreted hormones may cause an elevated insulin demand from pancreatic β cells[6]. In the normal pregnancy progress, β-cell number increases via proliferation and thereby the secretion of insulin is up-regulated to adapt to elevated insulin resistance[18]. However, Women with GDM demonstrate abnormally more anti-insulin hormones secretion and/or β-cell dysfunction causing the imbalance of glucose metabolism and insulin secretion[19]. Besides, normal pregnancy is also characteristic by increased total adipose mass and gain of about 30% of recommended weight[20]. Gain of adipose tissue is mechanistically associated with systemic glucose homeostasis in the nonpregnant situation. In this scenario, modulating the systemic glucose homeostasis during pregnancy, especially in the second and third trimester may provide an option for prevention of GDM. The first line of therapeutic approach for GDM currently relies mainly on nutrient supplementation and exercise intervention. For pregnant woman who still cannot restore glucose homeostasis to control hyperglycemia despite improving their lifestyle, insulin therapy should be often prescribed[21]. However, there are several drawbacks relating to insulin treatment, such as poor treatment outcomes, lack of universal compliance, and/or increasing levels of anxiety[22]. Therefore, new therapeutic strategies with potential to improve insulin sensitivity and decrease side effects is significant important for the short- and long-term prognosis and prevention of GDM.
One of the symptoms of GDM is deficiency of vitamin D (VDD) in blood. Vitamin D is a kind of fat-soluble secosteroids hormone, which is produced in the body under sunlight exposure and response to parathyroid hormone[23]. 7-dehydrocholesteroln is photolysied under sunlight exposure into previtamin D3, followed by transformation to vitamin D3 rapidly. After two sequential hydroxylation in liver and kidney respectively, vitamin D3 is activated into physiological active form, 1a,25-dihydroxyvitamin D3 (1,25(OH)2D3), which is able to be recognized by vitamin D receptor (VDR)[24, 25]. The most reported function of vitamin D is to maintain calcium homeostasis and bone integrity. Vitamin D is also reported to facilitate to immunomodulatory and anti-inflammatory effects, which regulates the insulin secretion to modulate glucose metabolism[26–28]. The function of anti-inflammation via NF-κB signaling pathway has been approved in adult mouse-derived adipose tissue and adipocytes[29]. One of the vitamin D3 metabolites lactone-vitamin D3 is identified to selectively bind to the hydroxyacylCoA dehydrogenase trifunctional multienzyme complex subunit alpha (HADHA) which catalyzes β-oxidation of long-chain fatty acids on the mitochondria. These reports suggest the function of vitamin D in lipid metabolism. A case-control study evaluated the association of 25(OH)D concentrations in pregnant women blood with risk of GDM[30].
Daily intake of vitamins D is a highly compliant strategy for pregnant women to prevent VDD, thereby to decrease the risk of GDM. Li et al. estimated the effects of administration of vitamin D3-supplemented yogurt on glucose metabolism and lipid concentrations in pregnant women with GDM[31]. After 16 weeks supplementation, the fasting plasma glucose and lipid concentration in vitamin D3-supplemented yogurt intervention group were both significantly decreased compared to control group[24]. All above reports support that vitamin D acts as an important factor to regulate glucose and lipid metabolism homeostasis. However, there has been still seldom studies regarding the systematically effects of vitamin D on insulin resistance in pregnant women with GDM and even the offspring.
In this study, we systematically evaluated the function of vitamin D supplementation in pregnant mice with GDM and their offspring. 2 weeks vitamin D intervention prevented the GDM syndromes and significantly alleviated plasma glucose and lipid levels, as well as improved the outcomes of offspring. This study provides support for vitamin supplementation to alleviate GDM in clinical practice.