fuel metabolism in pregnancy and in gestational diabetes mellitus pdf

Fuel Metabolism In Pregnancy And In Gestational Diabetes Mellitus Pdf

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Determinants of Maternal Insulin Resistance during Pregnancy: An Updated Overview

Insulin resistance changes over time during pregnancy, and in the last half of the pregnancy, insulin resistance increases considerably and can become severe, especially in women with gestational diabetes and type 2 diabetes. Numerous factors such as placental hormones, obesity, inactivity, an unhealthy diet, and genetic and epigenetic contributions influence insulin resistance in pregnancy, but the causal mechanisms are complex and still not completely elucidated.

In this review, we strive to give an overview of the many components that have been ascribed to contribute to the insulin resistance in pregnancy. Knowledge about the causes and consequences of insulin resistance is of extreme importance in order to establish the best possible treatment during pregnancy as severe insulin resistance can result in metabolic dysfunction in both mother and offspring on a short as well as long-term basis.

The physiology of insulin resistance during pregnancy is fascinating, from an evolutionary point of view designed to limit maternal glucose utilization and thereby shunt an adequate amount of supply to the growing fetus, which requires most of its energy source as glucose. Hence, the degree of maternal insulin resistance established during pregnancy is associated with the degree of glucose flux from the mother to the fetus [ 1 ].

Maternal hyperglycemia leads to fetal hyperglycemia and hyperinsulinemia, which cause fetal macrosomia—one of the most common and serious complications of maternal diabetes and obesity. Over the last decades, there has been an increase in obesity among women in the reproductive age, leading to a deterioration in the physiologic insulin resistance with a negative impact on the intrauterine environment, affecting perinatal programming and potentially resulting in metabolic dysfunction in the offspring.

The determinants and causal mechanisms of insulin resistance in pregnancy are complex and still not completely revealed, but in this review, we seek to give an overview of the hormonal and metabolic factors that have been described to have a role in the development of insulin resistance in human pregnancy until now. Insulin resistance is the decreased biological response to a given insulin dose, be it endogenous or exogenous, in the target tissue liver, muscle, or adipose tissue [ 2 ].

In a normal pregnancy, maternal tissues become increasingly insensitive to insulin. In women with normal glucose tolerance, the changes in insulin sensitivity are overcome by a sufficient increase in insulin production by pancreatic beta cells, but in women with diabetes, endogenous insulin secretion is insufficient during pregnancy [ 3 ].

From gestational week 11 to week 16, there is a minor decrease in insulin requirements as a consequence of an improvement in insulin sensitivity that is known to increase the risk of especially nocturnal hypoglycaemia in women with type 1 diabetes. From week 20, there is a substantial increase in insulin requirements as a result of a marked decrease in insulin sensitivity until week 33 [ 4 ]. The pattern of insulin requirements in pregnancy varies between women with type 1 and type 2 diabetes, suggesting a differential effect of pregnancy-mediated insulin resistance.

Women with type 2 diabetes require a much greater increase in insulin dose from the start to the end of each trimester, and insulin requirements do not decrease in early and late pregnancy as is the case in women with type 1 diabetes [ 5 , 6 ]. The changes in insulin sensitivity through pregnancy are believed to be caused partly by hormones from the placenta and partly by other obesity- and pregnancy-related factors that are not fully understood.

The known changes in glucose metabolism in gestational diabetes are described in detail by Catalano [ 3 ]. The metabolic dysfunction includes impaired insulin response in peripheral tissues, decreased hepatic suppression of glucose production during insulin infusion, and decreased insulin stimulated uptake in skeletal muscle.

Skeletal muscle and adipose tissue together represent the major sites of glucose disposal in the body. This is related to a decrease in the postreceptor insulin signaling cascade, specifically a decreased insulin receptor substrate 1 tyrosine phosphorylation, leading to a decreased ability to translocate the glucose transporter GLUT 4 to the surface of the muscle cell, which in turn mediates the transportation of glucose into the muscle cell.

The decrease in insulin receptor tyrosine kinase phosphorylation and receptor tyrosine kinase activity is seen both in pregnant women with normal glucose tolerance and in women with gestational diabetes, but the decrease is reversed postpartum in women with normal glucose tolerance [ 8 ], whereas it is not improved significantly in women with gestational diabetes postpartum [ 3 ].

The persistent insulin resistance in gestational diabetes may be related to inflammatory factors, mediated by action of placental hormones and other cytokines, affecting the postreceptor insulin signaling cascade [ 3 , 7 ]. In hyperinsulinemic euglycemic clamp studies with an insulin infusion rate of 1.

Clamp studies conducted as a dose response study in severely insulin-resistant nonpregnant type 2 diabetic patients have shown that endogenous glucose production is not completely suppressed before a dose as high as 5. Obesity is a pivotal cause of insulin resistance, and the changes in insulin sensitivity through pregnancy are partly related to maternal fat mass. Thus, changes in insulin sensitivity in early pregnancy in lean women are inversely related to changes in maternal fat mass, and a significant increase in fat mass in both lean and obese women is seen during pregnancy.

Lipid metabolism is also affected as a consequence of insulin resistance during pregnancy leading to doubled or tripled concentrations of triglycerides and cholesterol late in gestation. The increase in free fatty acids is consequently due to an attenuated effect of insulin on lipolysis [ 2 ]. In obese pregnant women, upper-body fat depots are predominant and the predilection for storing fat centrally increases the concentrations of free fatty acids and lipotoxicity that leads to inflammation, endothelial dysfunction, a decrease in trophoblast invasion, and consequently a reduction in placental metabolism and function [ 10 ].

The combination of excess lipid and glucose supplies to the fetus and a suboptimal placental function and metabolic environment in utero consequently also increase the risk of metabolic disease in the offspring [ 10 ].

As obesity plays a central role in insulin resistance, different aspects of it will also be addressed in further details in the following sections. Visceral adiposity amplifies and worsens metabolic and reproductive outcomes and increases insulin resistance through an increase in lipolysis and free fatty acids, leading to compensatory hyperinsulinemia, which in turn increases adipogenesis and inflammatory adipokines and increases insulin resistance even more [ 11 ].

Obese women with PCOS have decreased levels of sex hormone-binding globulin SHBG , increased testosterone, more hirsutism, higher glucose levels, and increased insulin resistance, leading to a higher risk of menstrual irregularity, infertility, miscarriage, hypertension in pregnancy, gestational diabetes, premature delivery, biochemical and clinical hyperandrogenism, glucose-intolerance, type 2 diabetes, and the metabolic syndrome.

In addition, the body mass index BMI has a greater impact on insulin resistance in women with PCOS in general compared to healthy controls [ 11 ]. In pregnancy, PCOS is associated with a higher gestational weight gain and accordingly worsened pregnancy and infant outcomes [ 12 ].

Some studies however indicate that nonpregnant lean women with PCOS might be as insulin-sensitive as age- and weight-matched controls, as this has been shown in a few studies using the hyperinsulinemic euglycemic clamp technique. These studies thus underline the importance of being normal weight to avoid insulin resistance [ 13 — 15 ].

Placenta indeed plays a crucial role in the development of insulin resistance in pregnancy. Thus, it is noteworthy that there is a characteristic rapid restoration of glucose homeostasis immediately after the expulsion of the placenta at delivery, but the potential linkages between the placenta and insulin resistance still remain to be elucidated in further detail. Placenta is placed as the interface between the maternal and fetal environments, and alterations in placental structure and function may influence fetal growth and development.

The exchange of glucose between a mother and a fetus is pivotal for fetal growth and well-being, and glucose is a major placental energy substrate. Due to the important role of the placenta and the glucose metabolism herein, it readily influences the complications of maternal diabetes. In relation to the duality between the maternal glucose homeostasis and placental function, a recent study demonstrated toxic effects of insulin resistance and circulating insulin levels on placental tissues, at least in early pregnancy [ 16 ].

Maternal obesity and diabetes are associated with specific structural placental changes such as increased placental weight, increased angiogenesis, and delayed villous maturation [ 17 ]. It is suggested that these changes are closely related to the level of glycemic control in pregnancy.

In addition, placental function may be compromised in pregnancies complicated by maternal obesity and diabetes. It may also be a result of impaired mitochondrial function because of increased oxidative stress [ 18 ]. In addition, the activity of specific amino acid transporter proteins in placenta may be altered [ 19 ]. The specific association between placental structure and function and the degree of peripheral insulin resistance remains to be explored, but potential linkages between the placenta and insulin resistance have been suggested to be mediated through the secretion of hormones, cytokines, and adipokines or through the release of other substances from the placenta to the maternal circulation.

During pregnancy, many hormonal axes are influenced by placenta. The placenta secretes pregnancy-specific hormones into the maternal circulation. In other instances, the placenta secretes hormones that circumvent the normal hormonal regulation or even take over normal regulatory pathways. Placental hormones may also influence hormone secretion by structural similarities to hormones also found in the nonpregnant state.

Examples of hormones specific to pregnancy are human chorionic gonadotropin hCG , human placental lactogen hPL , and human placental growth hormone hPGH.

Prolactin, estradiol, and cortisol are examples of hormones that are found in increasing amounts in the maternal circulation during pregnancy. An example of the take-over of the maternal metabolism is the growth hormone axis: pituitary growth hormone GH is gradually replaced by hPGH during pregnancy.

It almost completely replaces pituitary growth hormone in the maternal circulation by approximately 20 weeks of pregnancy and is secreted tonically rather than in a pulsatile fashion, unlike GH [ 20 ]. Furthermore, the serum level of hPGH is comparable to acromegalic levels, i. Especially, hPGH has been described as a somatogenic rather than a lactogenic bioactivity compared to GH [ 21 ].

The hPGH may also have the same diabetogenic effects as pituitary growth hormone such as hyperinsulinemia, decreased insulin-stimulated glucose uptake and glycogen synthesis, and impairment of the ability of insulin to suppress hepatic gluconeogenesis. Some of these effects have been demonstrated in rodents in vitro [ 22 ], whereas the effects during human pregnancy are less evident [ 23 ]. Interestingly, the pregnancy-associated plasma protein A PAPP-A , which due to its first trimester abundancy is used for first trimester risk assessment at the time of the nuchal translucency scan, appears to be intricately associated to the IGF-BPs and thereby the growth hormone-IGF axis during pregnancy [ 26 ].

Such findings clearly implicate a role for the growth hormone-IGF axis during pregnancy. Estradiol, progesterone, prolactin, cortisol, hPL, and hPGH have previously been described to be mediators of the change in insulin sensitivity during gestation.

However, in a study by Kirwan et al. The authors only found a significant correlation between insulin sensitivity and cortisol levels [ 27 ]. McIntyre et al. Thus, at present, no single hormone has been found to explain the insulin resistance of pregnancy. Many placental hormones have very short half-lives in the maternal circulation, and within 24 to 48 hours after delivery, the effect of such placental hormones have vanished and nonpregnant physiology is in many ways restored [ 28 , 29 ].

A clinical implication of this is that within one or two days after delivery, restoration of insulin requirements towards prepregnancy levels, or even lower, is seen in mothers with type 1 diabetes [ 30 ].

Alterations in cytokines have also been studied as a potential pathophysiological mechanism behind the increase in insulin resistance in pregnancy. Nayak et al. However, in a later study by McIntyre et al. All the available studies have only examined the inflammatory changes in pregnant women with normal glucose metabolism or gestational diabetes. Studies on how inflammatory markers and hormones affect insulin sensitivity in pregnant women with type 1 diabetes, type 2 diabetes, and severe insulin resistance remain to be performed.

As circulating levels of placental hormones do not correlate well with maternal insulin sensitivity [ 27 ], other, previously unrecognized, mechanisms may be involved.

New data suggest that exosomes i. Exosomes are secreted from both the placenta and adipose tissue [ 32 ] and have been demonstrated to contain many different substances that are also found intracellularly in their tissue of origin.

Such substances may relate to immunomodulatory processes in placental exosomes, potentially linking inflammatory processes and insulin resistance.

The content in exosomes derived from adipose tissue—e. It has been found that the levels of circulating exosomes total and placenta-derived are higher in gestational diabetes compared to normal pregnancies across gestation [ 33 ] and hyperglycemia increases the release of exosomes from primary human first trimester trophoblast cells [ 34 ], suggesting an association between the circulating levels of placental exosomes and the maternal metabolic status during pregnancy.

It is well established that exercise or physical activity reduces insulin resistance in nonpregnant human beings by stimulating the glucose transporters onto the surface of skeletal muscle cells and thereby improving glucose uptake [ 35 , 36 ].

Furthermore, the level of exercise has been associated with a decreased risk of type 2 diabetes for decades [ 37 ]. A recent systematic review and meta-analysis also demonstrated a reduction in blood glucose concentrations in women with and without diabetes in pregnancy both during and following acute as well as chronic exercise interventions [ 38 ]. In addition, several studies have shown that exercise can delay or prevent the occurrence of gestational diabetes mellitus [ 39 ], not to mention the beneficial effects of exercise in the treatment of women with gestational diabetes [ 40 ].

Thus, in a recent randomized controlled trial RCT study, exercise initiated early in pregnancy, lasting at least 30 minutes 3 times per week, reduced the risk of gestational diabetes significantly in overweight and obese pregnant women by One of the factors that might also have an important impact on glucose homeostasis is the gut microbiota.

Several studies have shown differential microbial abundance between healthy individuals and individuals with prediabetes, insulin resistance, and type 2 diabetes [ 43 — 45 ]. Koren et al. In the same study, germ-free nonpregnant mice were inoculated with stool samples from the study cohort and it was found that the third trimester microbiota induced greater adiposity and insulin resistance compared with first trimester stool inoculation [ 47 ].

These results indicate that in pregnancy, the gut microbiota may contribute to the maternal metabolic changes. Likewise, a Danish study investigated gut microbiota profiles in 50 women with gestational diabetes and in healthy pregnant women and found that in the third trimester of pregnancy, gestational diabetes was associated with an altered gut microbiota compared to pregnant women with a normal glucose tolerance [ 48 ]. A possible explanation for the difference in the two studies could be that the metabolic burden of obesity in the second study was so severe that it could not be overcome by the potentially beneficial effects of fish oil or probiotic in regulating glucose metabolism.

On the other hand, two recent meta-analyses have shown that the use of probiotics was associated with an improved glucose and lipid metabolism in pregnant women and might also reduce the risk of gestational diabetes [ 51 , 52 ]. Yet another meta-analysis showed that supplementation with probiotic reduced insulin resistance HOMA-IR and fasting serum insulin in women with gestational diabetes significantly, compared to healthy pregnant controls [ 53 ].

The question whether gut modification could be an effective tool in reducing insulin resistance in pregnant women is complicated, and studies are ongoing. Results differ as the human gut houses a complex microbial ecosystem, and the present studies have used different either pre- or probiotics or multistrain probiotics, making it difficult to compare studies and to make a final conclusion at the moment.

The genetic heritage of a woman can predispose her to excess insulin resistance, but early life experiences can also alter insulin resistance later in life.

Diet restriction in Ramadan and the effect of fasting on glucose levels in pregnancy

Pregnancy offers a window of opportunity to program the future health of both mothers and offspring. During gestation, women experience a series of physical and metabolic modifications and adaptations, which aim to protect the fetus development and are closely related to both pre-gestational nutritional status and gestational weight gain. Moreover, pre-gestational obesity represents a challenge of treatment, and nowadays there are new evidence as regard its management, especially the adequate weight gain. Recent evidence has highlighted the determinant role of nutritional status and maternal diet on both pregnancy outcomes and long-term risk of chronic diseases, through a transgenerational flow, conceptualized by the Development Origin of Health and Diseases Dohad theory. In this review we will analyse the physiological and endocrine adaptation in pregnancy, and the metabolic complications, thus the focal points for nutritional and therapeutic strategies that we must early implement, virtually before conception, to safeguard the health of both mother and progeny. We will summarize the current nutritional recommendations and the use of nutraceuticals in pregnancy, with a focus on the management of pregnancy complicated by obesity and hyperglycemia, assessing the most recent evidence about the effects of ante-natal nutrition on the long-term, on either maternal health or metabolic risk of the offspring. Pregnancy is a period of physical, hormonal and humoral changes, aimed to ensure the development and the necessary supply of nutrients to the fetus, and to prepare the maternal organism to delivery and breastfeeding.

FUEL METABOLISM IN PREGNANCY AND IN GESTATIONAL DIABETES MELLITUS Insulin secretion and insulin resistance in pregnancy and GDM.

Glucose Metabolism in Pregnancy

Metrics details. Maternal diet restriction might be associated with adverse maternal and perinatal outcomes due to metabolic changes. This study aimed to investigate the prevalence of changes in glucose levels due to Ramadan fasting in Emirati pregnant women.

Maternal lipids are strong determinants of fetal fat mass. Here we review the overall lipid metabolism in normal and gestational diabetes mellitus GDM pregnancies. During early pregnancy, the increase in maternal fat depots is facilitated by insulin, followed by increased adipose tissue breakdown and subsequent hypertriglyceridemia, mainly as a result of insulin resistance IR and estrogen effects.

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Principles of Perinatal-Neonatal Metabolism pp Cite as. Pregnancy is a state of ever-increasing fetal demand for fuel. This demand is met through increased caloric intake, hyperinsulinemia, insulin resistance, and maternal pancreatic islet hypertrophy. In addition, fasting in the pregnant state results in maternal hypoglycemia, elevated plasma lipid concentrations, and hypoaminoacidemia. These maternal adaptive changes serve the unique purpose of self-preservation, with an attempt to use lipid as an alternative fuel in the face of the uninterrupted siphoning of glucose and amino acids to the fetus.

Insulin resistance changes over time during pregnancy, and in the last half of the pregnancy, insulin resistance increases considerably and can become severe, especially in women with gestational diabetes and type 2 diabetes. Numerous factors such as placental hormones, obesity, inactivity, an unhealthy diet, and genetic and epigenetic contributions influence insulin resistance in pregnancy, but the causal mechanisms are complex and still not completely elucidated. In this review, we strive to give an overview of the many components that have been ascribed to contribute to the insulin resistance in pregnancy.

Gestational diabetes is a risk factor for perinatal complications; include shoulder dystocia, birth injuries such as bone fractures and nerve palsies. It is associated with later development of type 2 diabetes, the risk of macrosomia and other long-term health effects of infants born to diabetic mothers. The study assesses placental peptides and maternal factors as potential predictors of gestational diabetes among pregnant women. A total of pregnant women were recruited for the study, pregnant women without pre gestational diabetes including 50 women with low risk factors of diabetes as controls and 50 other pregnant women with pregestational diabetes as control.

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