**3. Insulin resistance and insulin sensitivity in normal and GDM pregnancy**

Pregnancy is a normal physiological state of insulin resistance, and it presents a physiological stress model of pancreatic β-cells [172, 173]. It is associated with a decrease in insulin sensitivity of an approximate 50–60% by the latter half of pregnancy and a 200–250% increase in insulin secretion with purpose to maintain euglycemia in the mother [10]. The increased resistance is caused by post-insulin receptor events and is brought about by the cellular effects of the increased levels of some pregnancy-associated hormones [174]. In gestational diabetes, insulin resistance is not adequately compensated by insulin hypersecretion because of defective β-cell function. Insulin resistance during pregnancy reveals limitations in insulin secretion; on the other hand, increasing insulin resistance and subsequent insulin hypersecretion may worsen the level of β-cell failure [174]. As a result, pregnant women with GDM have a higher level of insulin resistance compared to healthy pregnant women.

Some studies demonstrate that the insulin secretion and sensitivity capacities of Asian women are different from those of women in Western countries. Since even in Asians, the pancreatic β-cell mass is relatively smaller than in Westerners, and insulin secretion capacity is also lower on the background of abdominal obesity is more common in Asians than in Westerners with similar body weights [175]. A study assesses the change in insulin resistance and β-cell function in a multiethnic population-based cohort of pregnant women. Pregnant women from East Asia and South Asia are more insulin resistant and show poorer β-cell function (HOMA-β) than Western Europeans [176]. The mechanisms leading to increased insulin secretion in pregnancy, primary or compensatory to resistance, are not entirely elucidated yet. They are partly related to metabolic effects of several hormones and cytokines which are elevated in maternal circulation during pregnancy [177]. Decreased insulin sensitivity or increased insulin resistance is defined as the decreased biological response of a nutrient to a given concentration of insulin at the target tissue, e.g., liver, muscle, or adipose tissue. Obesity is the most common risk factor related to decreased insulin sensitivity. During the pregnancy, it is related with maternal energy metabolism, and visceral fat accumulation has important biological meaning. In this relation, the influence of visceral fat, respectfully BMI, and insulin sensitivity are too important [178].

different ethnic groups. The proposed BMI cut-off points ranging from 18·3 to 29·7 kg/m<sup>2</sup>

pared with normal-weight women at the beginning of their pregnancies [166].

of maternal diabetes, hypertension, and other chronic diseases [171].

higher level of insulin resistance compared to healthy pregnant women.

**3. Insulin resistance and insulin sensitivity in normal and GDM** 

Pregnancy is a normal physiological state of insulin resistance, and it presents a physiological stress model of pancreatic β-cells [172, 173]. It is associated with a decrease in insulin sensitivity of an approximate 50–60% by the latter half of pregnancy and a 200–250% increase in insulin secretion with purpose to maintain euglycemia in the mother [10]. The increased resistance is caused by post-insulin receptor events and is brought about by the cellular effects of the increased levels of some pregnancy-associated hormones [174]. In gestational diabetes, insulin resistance is not adequately compensated by insulin hypersecretion because of defective β-cell function. Insulin resistance during pregnancy reveals limitations in insulin secretion; on the other hand, increasing insulin resistance and subsequent insulin hypersecretion may worsen the level of β-cell failure [174]. As a result, pregnant women with GDM have a

30 kg/m<sup>2</sup>

26 Body-mass Index and Health

For every 1 kg/m<sup>2</sup>

**pregnancy**

ing BMI index with 1 kg/m<sup>2</sup>

comparing overweight (BMI ≥26–29 kg/m<sup>2</sup>

children and adolescents aged 5–19 years, which correspond to the adult obesity threshold of

global cut-off points to define overweight and obesity remains contentious. Given the marked variations in different world regions, countries, and populations within countries, the use of these values may underestimate the health hazards of adult obesity [160]. Current studies show that maybe visceral fat mass is a novel risk factor for predicting gestational diabetes in obese pregnant women [161]. Central obesity as assessed by early pregnancy waist-hip ratio (WHR) and visceral fat mass (VFM) measured by bioimpedance is an independent predictor of GDM in addition to classical risk factors [162]. In a prospective study of 485 women cohort in Canada, elevated first trimester visceral and total adipose tissue depth independently predict the risk of subsequent dysglycemia in pregnancy [163]. Measures of central/abdominal obesity such as WC and WHR have been compared to BMI for their association with adverse cardiovascular and metabolic consequences [164]. BMI and WHR are significant risk factors for development of gestational diabetes and IR, but this association varies among different ethnicities [165]. Results of meta-analysis of 20 studies show that the risk of developing GDM is about two, four, and eight times higher among overweight, obese, or severely obese com-

.These cut-offs are on the base of data from the USA population [159]. The use of these

increase in BMI, the prevalence of GDM increases by 0.92% [42]. The increas-

) vs. obese (BMI ≥ 30 kg/m<sup>2</sup>

trend in the risk of severe adverse obstetric outcomes, rising along with increasing maternal BMI, exists [168]. Maternal overweight and obesity, diabetes, and excessive gestational weight gain are associated with fetal overgrowth and large for gestational age (LGA), which then can lead to an increased risk in the offspring for later obesity and diabetes [169, 170]. It has been found that in Finnish obstetric population, the maternal morbidity rises markedly when

increased the risk of GDM developing with 9.9% [167] Increasing

) women: the incidence

for

In healthy pregnant women, pancreatic β-cells increase their insulin production through hyperplasia, hypertrophy, and hyperfunction to compensate for the pregnancy-induced insulin resistance [176]. Maternal islets adapt to this increased demand mainly through enhanced insulin secretion per β-cell and increased β-cell proliferation [179]. Like other forms of hyperglycemia, GDM is characterized by pancreatic β-cell dysfunction that is insufficient to meet the body's insulin needs. Available data suggest that β-cell defects in GDM are a result from the same spectrum of causes that underlie hyperglycemia in general, including autoimmune disease, monogenic causes, and insulin resistance [180]. In normal pregnancies, the dynamic changes in glucose homeostasis and insulin sensitivity are in connection with alterations in lipid and protein metabolism. Longitudinal studies of glucose tolerance during gestation demonstrate an increased insulin response to oral glucose in the first trimester relative to prepregnancy values [10], with a subsequent progressive increased insulin responses in consistent with progressive IR [10]. Remarkably, there is an independent effect of pregnancy on β-cell function independent of the observed changes in insulin; but the etiology of this effect is at present unknown, although may include the role of incretins [181, 182]. The impact of obesity on these changes is significant; in particular, the decline in fasting glucose at early gestation is reduced, but not reduced at all in severely obese women [183]. In late gestation, the normal reduction in peripheral insulin sensitivity of 50% is reduced in obese women [10]. In addition to significant peripheral and hepatic insulin resistance, which manifests as reduced insulin-mediated glucose disposal, there is a large reduction in insulin-stimulated carbohydrate oxidation and a reduction in insulin suppression of endogenous glucose production, all of which are reversed in the postpartum period [184]. Importantly, the overall effects of this impaired insulin resistance are not influenced only on the glucose. In the postprandial state, this obesity-related insulin resistance overacts the normal circulatory increases in metabolic fuels, i.e., glucose, lipids, and amino acids. The fasting, postprandial, and integrated 24-h plasma concentrations of all basic macronutrients are affected by enhanced insulin resistance in obese pregnant women [185].

#### **3.1. Homeostasis model assessment of insulin resistance (HOMA-IR)**

The homeostatic model assessment (HOMA) is a method used to quantify insulin resistance and β-cell function, based on a single measurement of fasting glucose and insulin or C-peptide concentrations in the blood [186]. The easiest and most popular assessment of β-cell function is the homeostatic index HOMA-B. It is widely used because of its simplicity and it reflects the release of insulin under nonstimulated conditions [187]. HOMA model is considered as a structural model of the underlying physiological basis for the feedback loop between the liver and the β-cell in fasting [188]. HOMA-IR has been observed to have a linear correlation with the glucose clamp and considered as minimal model for estimations of insulin sensitivity/resistance in various studies [188, 189]. HOMA-IR determines the relationship between the liver and pancreas. This index reflects more the liver insulin resistance in comparison to peripheral insulin resistance [190], and it is a good indicator of overall insulin sensitivity during pregnancy. Although surrogate marker HOMA-B is less evaluated as an index, it provides high reliability in the measurement of β-cell function. Both indices, HOMA-B and HOMA-IR, submit better overall picture of the essential metabolic disorder [191]. Disadvantage of HOMA model is related to the fact that it underlines the lack of linearity at deepening of insulin resistance [192]. This model is a widely used and well correlates with the insulin sensitivity, as measured by the venous clamp technique in various studies [188, 189].

of serum metal ions, such as, iron and zinc [205]. Maternal overweight (BMI ≥ 25 kg/m<sup>2</sup>

the odds ratios for developing GDM are 1.97–2.14 in overweight (BMI ≥ 25 kg/m<sup>2</sup>

obese (most studies BMI ≥ 30 kg/m<sup>2</sup>

BMI ≥ 25 kg/m<sup>2</sup>

women compared with normal weight women [154].

**3.3. The effect of BMI on insulin sensitivity indices**

been shown to be the strongest risk factor for GDM. Two meta-regression analyses show that

Body Mass Index and Insulin Sensitivity/Resistance: Cross Talks in Gestational Diabetes, Normal…

In late gestation, the normal reduction in peripheral insulin sensitivity of 50% [206] is reduced in obese women as determined by the quantitative insulin sensitivity check index and that insulin sensitivity in women with GDM worsened as gestation progressed [207]. The indexes of insulin sensitivity QUICKI and HOMA significantly correlated with a direct measurement of insulin sensitivity using the euglycemic-hyperinsulinemic clamp during pregnancy [208]. The mechanism for the decrease in insulin sensitivity in pregnancy is not fully understood and is part of the natural process during pregnancy, although the insulin signaling pathway can be interrupted by several factors, such as increased levels of serum cortisol, TNF α, and some interleukin cytokines, leading to insulin resistance, during normal pregnancy [104]. In this connection, it would appear that preconceptual fat mass is one of a major determinant, because lean women exhibit an inverse correlation between changes in insulin sensitivity and fat mass, which is not seen in obese women [209]. Obese women exhibit a negative relationship between the decrease in insulin sensitivity and accretion of fat mass from prepregnancy to late gestation [210]. Visceral fat volume in human body has important biological meaning, which is well expressed during the pregnancy. In this relation, the influence of visceral fat, respectfully BMI, on the insulin sensitivity is too important. A study has announced diminished insulin sensitivity in pregnant women with GDM compared to healthy pregnant women for BMI (P > 0.05) with significantly higher body fat percentage, expressed by connection QUICKI index-BMI (r = −0.384, P < 0.01) [211]. These results are similar to other author′s results—lower level of insulin sensitivity index QUICKI in pregnant women with GDM in comparison to NGT Р = 0.001, a reverse correlation between QUICKI index and BMI in the both of group (r = −0.458 for NGT and r = −0.603 for GDM) [167]. Insulin sensitivity measured during the clamp was higher during pregnancy in the NGT group than in the GDM group (P < 0.05) [208]. Values of QUICKI index in overweight women with normal glucose tolerance (NGT) and in women with GDM have been significantly lower (P < 0.01) than those in normal-weight women with NGT, and QUICKI in women with GDM has been decreased significantly (P < 0.05) during pregnancy, according to Endo et al. [207]. Furthermore, other authors have reported significant interaction between race and BMI (under/normal weight, overweight/obese) for glucose, insulin, and HOMA-IR at or above the 75th percentile and QUICKI less than the 25th percentile in mid-trimester [212]. Other authors have detected lower levels of QUICKI index in overweight compared to normal-weight women at third trimester of pregnancy [199]. Changes in insulin sensitivity are a hallmark of pregnancy and contribute to the metabolic changes, while nutrient transfer to the fetus impacts maternal metabolite levels [213, 214]. Studies show that values for HOMA-S% between pregnant with GDM and matched control NGT subject are highly significant different (P < 0.001) [215, 216]. Some authors found lower level for HOMA S% in GDM pregnant with prepregnancy

in comparison to GDM with prepregnancy BMI <25 kg/m<sup>2</sup>

), and 5.55–8.56 in severely obese (BMI ≥ 35–45 kg/m<sup>2</sup>

http://dx.doi.org/10.5772/intechopen.78363

) has

)

29

), 3.01–3.56 in

(P < 0.001) [217].

#### **3.2. Assessment of insulin sensitivity by using quantitative insulin sensitivity check index (QUICKI) and HOMA2 variant insulin sensitivity (HOMA %S)**

The quantitative insulin sensitivity check index (QUICKI) is an empirically derived mathematical transformation of fasting blood glucose and plasma insulin concentrations [193, 194]. QUICKI is a simple, robust, accurate, and reproducible method that appropriately predicts changes in insulin sensitivity after therapeutic interventions as well as the onset of diabetes [195]. QUICKI has been seen to have a significantly better linear correlation with glucose clamp determinations of insulin sensitivity than minimal-model estimates [196]. Its calculation is used to evaluate the insulin sensitivity [197] including during early and late pregnancy [190]. The index assumes that the circulating glucose and insulin are determined by a feedback loop between the liver and pancreatic β-cells [198]. Insulin sensitivity has been modeled by proportionately decreasing the effect of plasma insulin concentrations at both the liver and the periphery [199]. Other parameter to assess insulin sensitivity is HOMA-S%. The computer model can be used to determine insulin sensitivity (HOMA–S%) from paired fasting plasma glucose and insulin concentrations. The data from individual subjects determine unique combinations of insulin sensitivity (HOMA %S) and beta cell function (HOMA %B) from steadystate conditions [200]. HOMA can be used to track changes in insulin sensitivity and β-cell function in individuals. Also, it can be used in individuals to indicate whether reduced insulin sensitivity or β-cell failure predominates. Determination of HOMA-%S is used to establish the prevailing normal over a normoglycemic population in each comparative group [188]. Maternal obesity is associated with higher maternal glucose and GDM risk; its association with newborn size at birth is, in part, independent of maternal glycemia [201–204]. BMI is an indicator of the tissue quantity (weight) over the skeletal frame (height), including adipose tissue and muscle. BMI is known to increase blood volume and to reduce the concentration of serum metal ions, such as, iron and zinc [205]. Maternal overweight (BMI ≥ 25 kg/m<sup>2</sup> ) has been shown to be the strongest risk factor for GDM. Two meta-regression analyses show that the odds ratios for developing GDM are 1.97–2.14 in overweight (BMI ≥ 25 kg/m<sup>2</sup> ), 3.01–3.56 in obese (most studies BMI ≥ 30 kg/m<sup>2</sup> ), and 5.55–8.56 in severely obese (BMI ≥ 35–45 kg/m<sup>2</sup> ) women compared with normal weight women [154].

#### **3.3. The effect of BMI on insulin sensitivity indices**

**3.1. Homeostasis model assessment of insulin resistance (HOMA-IR)**

28 Body-mass Index and Health

as measured by the venous clamp technique in various studies [188, 189].

**index (QUICKI) and HOMA2 variant insulin sensitivity (HOMA %S)**

**3.2. Assessment of insulin sensitivity by using quantitative insulin sensitivity check** 

The quantitative insulin sensitivity check index (QUICKI) is an empirically derived mathematical transformation of fasting blood glucose and plasma insulin concentrations [193, 194]. QUICKI is a simple, robust, accurate, and reproducible method that appropriately predicts changes in insulin sensitivity after therapeutic interventions as well as the onset of diabetes [195]. QUICKI has been seen to have a significantly better linear correlation with glucose clamp determinations of insulin sensitivity than minimal-model estimates [196]. Its calculation is used to evaluate the insulin sensitivity [197] including during early and late pregnancy [190]. The index assumes that the circulating glucose and insulin are determined by a feedback loop between the liver and pancreatic β-cells [198]. Insulin sensitivity has been modeled by proportionately decreasing the effect of plasma insulin concentrations at both the liver and the periphery [199]. Other parameter to assess insulin sensitivity is HOMA-S%. The computer model can be used to determine insulin sensitivity (HOMA–S%) from paired fasting plasma glucose and insulin concentrations. The data from individual subjects determine unique combinations of insulin sensitivity (HOMA %S) and beta cell function (HOMA %B) from steadystate conditions [200]. HOMA can be used to track changes in insulin sensitivity and β-cell function in individuals. Also, it can be used in individuals to indicate whether reduced insulin sensitivity or β-cell failure predominates. Determination of HOMA-%S is used to establish the prevailing normal over a normoglycemic population in each comparative group [188]. Maternal obesity is associated with higher maternal glucose and GDM risk; its association with newborn size at birth is, in part, independent of maternal glycemia [201–204]. BMI is an indicator of the tissue quantity (weight) over the skeletal frame (height), including adipose tissue and muscle. BMI is known to increase blood volume and to reduce the concentration

The homeostatic model assessment (HOMA) is a method used to quantify insulin resistance and β-cell function, based on a single measurement of fasting glucose and insulin or C-peptide concentrations in the blood [186]. The easiest and most popular assessment of β-cell function is the homeostatic index HOMA-B. It is widely used because of its simplicity and it reflects the release of insulin under nonstimulated conditions [187]. HOMA model is considered as a structural model of the underlying physiological basis for the feedback loop between the liver and the β-cell in fasting [188]. HOMA-IR has been observed to have a linear correlation with the glucose clamp and considered as minimal model for estimations of insulin sensitivity/resistance in various studies [188, 189]. HOMA-IR determines the relationship between the liver and pancreas. This index reflects more the liver insulin resistance in comparison to peripheral insulin resistance [190], and it is a good indicator of overall insulin sensitivity during pregnancy. Although surrogate marker HOMA-B is less evaluated as an index, it provides high reliability in the measurement of β-cell function. Both indices, HOMA-B and HOMA-IR, submit better overall picture of the essential metabolic disorder [191]. Disadvantage of HOMA model is related to the fact that it underlines the lack of linearity at deepening of insulin resistance [192]. This model is a widely used and well correlates with the insulin sensitivity,

In late gestation, the normal reduction in peripheral insulin sensitivity of 50% [206] is reduced in obese women as determined by the quantitative insulin sensitivity check index and that insulin sensitivity in women with GDM worsened as gestation progressed [207]. The indexes of insulin sensitivity QUICKI and HOMA significantly correlated with a direct measurement of insulin sensitivity using the euglycemic-hyperinsulinemic clamp during pregnancy [208]. The mechanism for the decrease in insulin sensitivity in pregnancy is not fully understood and is part of the natural process during pregnancy, although the insulin signaling pathway can be interrupted by several factors, such as increased levels of serum cortisol, TNF α, and some interleukin cytokines, leading to insulin resistance, during normal pregnancy [104]. In this connection, it would appear that preconceptual fat mass is one of a major determinant, because lean women exhibit an inverse correlation between changes in insulin sensitivity and fat mass, which is not seen in obese women [209]. Obese women exhibit a negative relationship between the decrease in insulin sensitivity and accretion of fat mass from prepregnancy to late gestation [210]. Visceral fat volume in human body has important biological meaning, which is well expressed during the pregnancy. In this relation, the influence of visceral fat, respectfully BMI, on the insulin sensitivity is too important. A study has announced diminished insulin sensitivity in pregnant women with GDM compared to healthy pregnant women for BMI (P > 0.05) with significantly higher body fat percentage, expressed by connection QUICKI index-BMI (r = −0.384, P < 0.01) [211]. These results are similar to other author′s results—lower level of insulin sensitivity index QUICKI in pregnant women with GDM in comparison to NGT Р = 0.001, a reverse correlation between QUICKI index and BMI in the both of group (r = −0.458 for NGT and r = −0.603 for GDM) [167]. Insulin sensitivity measured during the clamp was higher during pregnancy in the NGT group than in the GDM group (P < 0.05) [208]. Values of QUICKI index in overweight women with normal glucose tolerance (NGT) and in women with GDM have been significantly lower (P < 0.01) than those in normal-weight women with NGT, and QUICKI in women with GDM has been decreased significantly (P < 0.05) during pregnancy, according to Endo et al. [207]. Furthermore, other authors have reported significant interaction between race and BMI (under/normal weight, overweight/obese) for glucose, insulin, and HOMA-IR at or above the 75th percentile and QUICKI less than the 25th percentile in mid-trimester [212]. Other authors have detected lower levels of QUICKI index in overweight compared to normal-weight women at third trimester of pregnancy [199]. Changes in insulin sensitivity are a hallmark of pregnancy and contribute to the metabolic changes, while nutrient transfer to the fetus impacts maternal metabolite levels [213, 214]. Studies show that values for HOMA-S% between pregnant with GDM and matched control NGT subject are highly significant different (P < 0.001) [215, 216]. Some authors found lower level for HOMA S% in GDM pregnant with prepregnancy BMI ≥ 25 kg/m<sup>2</sup> in comparison to GDM with prepregnancy BMI <25 kg/m<sup>2</sup> (P < 0.001) [217]. These values are not markedly different from those obtained in the other study [167]. In this study, there are statistically significant differences in HOMA-S% between the NGT and GDM groups (Р = 0.002). It is found a reverse correlation between HOMA-S% and BMI in the both NGT and GDM patient groups (r = −0.467 and r = −0.679, respectively). The authors' hypothesis is that as higher is a BMI, stronger is its influence on insulin sensitivity, expressed by HOMA-S% index [167]. The current studies confirm that GDM is associated with increased insulin resistance and β-cell dysfunction, as well as reduced insulin sensitivity and secretion.

are associated with GDM [248]. Some researchers determined the predictability of GDM with a 90% sensitivity and 61% specificity by ROC analysis in patients whose HOMA-IR scores are >2.08 in the first trimester [249]. A study reports that HOMA-IR at 21–28 gestational weeks is reliable risky factor to development of IR (OR = 0.677, 95% CI = 0.573–0.781, P = 0.002, sensitivity 54.7%, and specificity 24.5%). HOMA-IR is found with statistically significant impact on developing of GDM-OR = 2.039 (95% CI = 1.427–2.914, P < 0.0001). The increasing HOMA-IR index with unit increases the risk of GDM developing about two times. The predictive threshold values for developing insulin resistance in gestational pregnant at 21–28 gestational weeks are HOMA–IR > 1.8 [250]. According to the International Diabetes Federation (IDF) criteria, the HOMA-IR cut-off point to differentiate low and high value of insulin resistance is 2.38. Several previous studies performed on smaller populations have demonstrated that HOMA-IR index assessed at diagnosis of GDM is ranged from 1.6 to 25 [130, 176, 251, 252]. HOMA-IR values of ≥1.29 at diagnosis may indicate insulin resistance in the studied population of women and are associated with a higher value of the prepregnancy BMI [177]. Maternal obesity-prepregnancy at the time of GDM diagnosis is in connection to enhance insulin resistance. A positive correlation between BMI and HOMA-IR in NGT group r = 0.485 and in GDM pregnant r = 0.594 has been established without statistical difference between two pregnant groups in second to third trimester [250]. The results are similar to those of others studies [253–255]. Other study obtains no significant correlations between BMI and markers of insulin resistance, indicating that BMI is not a confounder in the elevated insulin resistance among the enrolled GDM subjects [256]. The correctness requires to be noted some authors refer to BMI, especially in pregnancy, to be a poor index of fat mass, and it could be superseded in the statistical models by other anthropometric measures, three of which were independent predictors of GDM. These simple measures (age, fasting blood glucose, and subcutaneous fat), while are recognized in a few earlier reports, they are largely ignored in assessment of GDM risk [257–259]. Other study finds trimester-specific strongly positive association between HOMA-IR and prepregnancy BMI in each trimester (P < 0.001 in trimester 1 and 2, P = 0.004 in trimester 3). Also, the results from these analyses support the notion that the maternal metabolome is predominantly influenced by obesity and less by dietary intake during pregnancy [219]. However, it appears that beginning of the pregnancy in the obese state disturbs normal anabolic activity through early-gestational insulin resistance [260]. This may suggest that the obesity induces various metabolic and hormone fluctuations, rather than insulin resistance alone. This study demonstrates for the first time an association between prepregnancy BMI and a pattern of metabolites

Body Mass Index and Insulin Sensitivity/Resistance: Cross Talks in Gestational Diabetes, Normal…

http://dx.doi.org/10.5772/intechopen.78363

31

related to obesity, which differs from nonpregnant cohorts [219].

Undoubtedly, in recent years, the frequency of GDM is increasing in tandem with the dramatic increase in the prevalence of overweight and obesity in women of childbearing age, assessing by BMI. Another risk factor for GDM is the excessive weight gain during the pregnancy, assessing by use of BMI. The optimal weight increase in pregnancy is well established on the base of studies, and is different depending on BMI prior to pregnancy. Some studies show, that excessive weight gain is a significant risk factor for GDM in all categories of BMI, but the relationship is more stringent in obese individuals. Most of studies observed that higher BMI decreases the

**4. Conclusions**

BMI, glucose, and insulin sensitivity are interrelated and alter maternal metabolism. A novel aspect of studies is identification of metabolic signatures uniquely associated with maternal BMI and glycemia, including differences in metabolites most strongly associated with these phenotypes [218]. The association of several plasma metabolites with maternal prepregnancy BMI across gestation in a cohort of 167 non-Hispanic and Hispanic ancestry women was reported [219]. Some of these metabolites have been found to have a role in aspects of metabolism such as insulin sensitivity and pancreatic β-cell function. A limited number of GDM metabolomics studies have been performed, evidence suggests that the metabolic signatures of T2D and GDM overlap [220]. Metabolomic studies of maternal metabolism during pregnancy are focused largely on normal pregnancy and GDM [221–227]. It is important to examine the associations of maternal BMI on the maternal metabolome, to consider estimated maternal insulin sensitivity as a predictor of the maternal metabolome. Furthermore, maternal BMI and insulin sensitivity impact a broad array of metabolites and have shared independent associations with the maternal metabolome [228].

#### **3.4. The effect of BMI on homeostasis model assessment of insulin resistance (HOMA-IR)**

Insulin resistance is, by definition, a disorder in the signal transduction of several known hormones [229]. Insulin resistance in peripheral tissues in women with GDM is exacerbated, but few studies have examined the extent of insulin resistance in placenta in this disease. It is possible that this insulin resistance could contribute to alter the placental transport of nutrients [230–232]. The degree of maternal insulin resistance manifested during pregnancy is theoretically associated with the degree of glucose flux from mother to fetus. Excessive insulin resistance during pregnancy is also observed in obese subjects without abnormal glucose tolerance [10]. Different studies found HOMA-IR values in the GDM group are significantly higher than in NGT patients, which indicated a significant insulin resistance [167, 215, 233–239]. Some studies report controversial results. They found that the HOMA-IR values are similar in GDM patients and healthy NGT controls [240–243]. Women with GDM in early pregnancy had significantly higher HOMA-IR values than those with GDM in later pregnancy or those with NGT [244] and results are similar to other from prior work [245]. Probably, higher BMIs among women with early-onset GDM are detected to at least partially explain this phenomenon [246]. An important goal is to identifying women with GDM during early pregnancy to minimize maternal and neonatal morbidity. One study reported that first trimester HOMA-IR values are independent predictors for the development of GDM in logistic regression analysis, and the HOMA-IR value is found to be a better marker (AUC ¼ 0.75; 95% CI, 0.67e0.83) than the other factors [247]. Another study detects borderline significance for risk of subsequent GDM for increased HOMA-IR values at gestational weeks 16–18, independent of other variables that are associated with GDM [248]. Some researchers determined the predictability of GDM with a 90% sensitivity and 61% specificity by ROC analysis in patients whose HOMA-IR scores are >2.08 in the first trimester [249]. A study reports that HOMA-IR at 21–28 gestational weeks is reliable risky factor to development of IR (OR = 0.677, 95% CI = 0.573–0.781, P = 0.002, sensitivity 54.7%, and specificity 24.5%). HOMA-IR is found with statistically significant impact on developing of GDM-OR = 2.039 (95% CI = 1.427–2.914, P < 0.0001). The increasing HOMA-IR index with unit increases the risk of GDM developing about two times. The predictive threshold values for developing insulin resistance in gestational pregnant at 21–28 gestational weeks are HOMA–IR > 1.8 [250]. According to the International Diabetes Federation (IDF) criteria, the HOMA-IR cut-off point to differentiate low and high value of insulin resistance is 2.38. Several previous studies performed on smaller populations have demonstrated that HOMA-IR index assessed at diagnosis of GDM is ranged from 1.6 to 25 [130, 176, 251, 252]. HOMA-IR values of ≥1.29 at diagnosis may indicate insulin resistance in the studied population of women and are associated with a higher value of the prepregnancy BMI [177]. Maternal obesity-prepregnancy at the time of GDM diagnosis is in connection to enhance insulin resistance. A positive correlation between BMI and HOMA-IR in NGT group r = 0.485 and in GDM pregnant r = 0.594 has been established without statistical difference between two pregnant groups in second to third trimester [250]. The results are similar to those of others studies [253–255]. Other study obtains no significant correlations between BMI and markers of insulin resistance, indicating that BMI is not a confounder in the elevated insulin resistance among the enrolled GDM subjects [256]. The correctness requires to be noted some authors refer to BMI, especially in pregnancy, to be a poor index of fat mass, and it could be superseded in the statistical models by other anthropometric measures, three of which were independent predictors of GDM. These simple measures (age, fasting blood glucose, and subcutaneous fat), while are recognized in a few earlier reports, they are largely ignored in assessment of GDM risk [257–259]. Other study finds trimester-specific strongly positive association between HOMA-IR and prepregnancy BMI in each trimester (P < 0.001 in trimester 1 and 2, P = 0.004 in trimester 3). Also, the results from these analyses support the notion that the maternal metabolome is predominantly influenced by obesity and less by dietary intake during pregnancy [219]. However, it appears that beginning of the pregnancy in the obese state disturbs normal anabolic activity through early-gestational insulin resistance [260]. This may suggest that the obesity induces various metabolic and hormone fluctuations, rather than insulin resistance alone. This study demonstrates for the first time an association between prepregnancy BMI and a pattern of metabolites related to obesity, which differs from nonpregnant cohorts [219].
