PRACA ORYGINALNA / ORIGINAL ARTICLE

PATOGENEZA INSULINOOPORNOŚCI U KOBIET CIĘŻARNYCH Z OTYŁOŚCIĄ

Kostiantyn V. Tarasenko, Antonina M. Gromova, Kateryna V. Pikul, Ruslan B. Lysenko, Leonid A. Nesterenko

HIGHER STATE EDUCATIONAL ESTABLISHMENT OF UKRAINE, UKRAINIAN MEDICAL STOMATOLOGICAL ACADEMY, POLTAVA, UKRAINE

ABSTRACT

Introduction: Obesity is one of the most important medical and social problems in many countries of the world, as it is associated with the development of the most common non-communicable diseases: cardiovascular, type II diabetes mellitus, motor disorders, non-alcoholic fatty liver disease (NHAHP) and others.

The aim of this paper is to analyze the pathogenetic mechanisms of insulin resistance development in pregnant women with varying obesity degrees in early and late gestation periods.

Materials and methods: 459 pregnant women were examined at the Poltava City Clinical Maternity Hospital in the early (9-13 weeks) and late gestation periods (34-38 weeks). Metabolic disorders in pregnant women were studied by carbohydrate and lipid metabolism indices.

Results: Due to increased insulin resistance and reduced glucose absorption by tissues of pregnant women with obesity, there are prerequisites for the development of energy insufficiency. Obese women pregnancy runs on the background of hypertriglyceridemia and type IV hyperlipoproteinemia. The general pathogenic consequence of the insulin resistance progression during pregnancy in obese women is an energy deficiency increase, which causes a threatening obstetric and perinatal complications frequency increase.

Conclusions: The progression of insulin resistance during pregnancy of women with varying degrees of obesity is the pathogenetic basis of energy insufficiency and the reduction of adaptive mechanisms of pregnant women with obesity, as evidenced by the increase in obstetric and perinatal complications frequency.

 

Wiad Lek 2018, 71, 4, -806

 

INTRODUCTION

Obesity is one of the most important medical and social problems in many countries of the world, as it is associated with the development of the most common non-communicable diseases: cardiovascular, type II diabetes mellitus, motor disorders, non-alcoholic fatty liver disease (NHAHP) and others [1, 2, 3, 4].

Obesity is linked with changes in the lifestyle of a modern person, i.e. the availability of high-calorie products and a sharp limitation of physical activity. The prevalence of obesity among the female population of Ukraine is 29,7-35,5% [5, 6], and the alimentary-constitutional obesity is almost 95% [7, 8]. It is emphasized that the rate of prevalence of childhood obesity is constantly increasing and today it is 10 times higher than in the 1970s [9]. In most adults obesity begins in childhood and adolescence. These data conclusively showed that the leading role in the genesis of obesity plays a nutritional factor.

The medical and social significance of obesity in pregnant women is in the high frequency of obstetric complications such as miscarriage, gestosis, placental insufficiency, abnormal labor, perinatal hemorrhage, intrauterine programming of infectious [10-16] and extragenital descendants diseases [17-20].

The key role in the development of metabolic disorders in cases of obesity plays insulin resistance, i.e. reduction of the sensitivity of cells to the biological effects of insulin [21-23]. Pregnancy of women with normal body weight is accompanied by physiological insulin resistance, which has an adaptive value, as it provides the growing fetus needs of the energy substrates. [24, 25]. The question about the nature of insulin resistance in pregnant women with obesity (obese pregnant women) and its pathogenic effects is not sufficiently revealed.

THE AIM

The aim of this paper is to analyze the pathogenetic mechanisms of insulin resistance development in pregnant women with varying obesity degrees in early and late gestation periods.

MATERIALS AND METHODS

459 pregnant women were examined at the Poltava City Clinical Maternity Hospital in the early (9-13 weeks) and late gestation periods (34-38 weeks). The pregnant women were divided into three groups by severity of obesity: the first group – 149 pregnant women with I degree obesity, the second group – 73 pregnant women with II degree obesity, the third group – 46 pregnant women with III degree obesity. Body weight of the pregnant women with I degree obesity at the late stages of pregnancy was 85,2±1,2 kg, of the pregnant women with II degree obesity – 88,3±1,0 kg, of the women with III degree obesity – 102,8±2,7 kg.

The control group included 101 females with a physiological body weight (BMI = 18,5-25,0 kg/m2). The degree of obesity in pregnant women was estimated in accordance to the calculation tables by N.S. Lutsenko [26]. Metabolic disorders in pregnant women were studied by carbohydrate and lipid metabolism indices. Glucose levels in serum were determined by glucose-oxidase method, the level of immunoreactive insulin in serum was determined by the method of immunoassay analysis using the reagents of «DRG Instrument GmbH» company (Germany). Insulin resistance index HOMA-IR was calculated according to the formula:

НОМА-ІR = insulin level (IU/ml) × blood glucose (mmol/l) / 22,5

Lipid metabolism study was based on indicators of total cholesterol (CHS), triglycerides, very low density lipoprotein cholesterol (VLDL cholesterol), low density lipoprotein cholesterol (LDL cholesterol), high density lipoprotein cholesterol (HDL cholesterol), which were determined by the enzymatic colorimetric method with using sets of diagnostic reagents manufactured by HUMAN Gesellschaft fur Biochemica und Diagnostica mbH (Germany).

Complication rates during pregnancy, childbirth, postpartum period, and the state of newborns was compared in the experimental and control groups of women. Statistical processing of the obtained data was carried out using the program STATISTICA 6.0 (StatSoftInc, USA).

RESULTS AND DISCUSSION

In early gestation periods, HOMA-IR index in pregnant women with obesity of varying degrees was accurately 2,8 times higher than the one of the corresponding control group (table І), which reflects the decrease in cellular sensitivity to insulin, inhibition of glucose permeability in cells involving GLUT-4 transporters, decrease in its concentration in cells cytosol (glycopenia) and deterioration of their energy supply.

The progression of insulin resistance of pregnant women with obesity was observed in later gestation periods, especially in cases of women with obesity II degree (table І). It should be noted that in the late pregnancy period the blood glucose concentration of pregnant women with obesity III degree was significantly increased as compared to the control (from 4,12±0,19 to 4,63±0,68 mmol/l; р<0,05), which may indicate the beginning of carbohydrate exchange metabolic decompensation due to insulin deficiency. At the same time, in the control group of pregnant women, the HOMA-IR index did not exceed the physiological (2,77 standard unit). The rate of insulin stimulated glucose absorption by the muscles of the persons with insulin resistance was 60% lower than the one of the insulin-sensitive individuals in the control group [27].

Thereby, due to increased insulin resistance and reduced glucose absorption by tissues of pregnant women with obesity, there are prerequisites for the development of energy insufficiency.

In the study of pregnant women with obesity lipid metabolism in early gestation period significant increase of middle-level blood triglycerides and their transport form – low-density lipoprotein (LDL) in the serum was found, it was the most pronounced in cases of pregnant women with II degree obesity (table ІІ). Other indicators of lipid metabolism in the study group of women with obesity did not differ significantly from the control values (table ІІ). The changes in the lipid spectrum of blood were revealed indicating the type IV hyperlipoproteinemia in pregnant women, which is characterized by a high atherogenicity [28]. The level of VLDL in serum is a more sensitive risk factor for atherogenesis than the total cholesterol level [29].

A further significant increase of triglycerides and VLDL in serum was observed at late stage of pregnancy of women with obesity (table ІІІ). While the level of total cholesterol in the blood of the experimental and control groups of pregnant women did not differ significantly. The content of triglycerides in serum of women with a physiological body weight during pregnancy was maintained at a constant level (table ІІІ).

Thus, obese women pregnancy runs on the background of hypertriglyceridemia and type IV hyperlipoproteinemia. Carbohydrate and lipid metabolism disorders of pregnant women with obesity are closely interrelated. It is known that with insufficient glucose uptake in cells, according to the Randle principle, the free fatty acid metabolism compensatorily increases. But this mechanism for obesity cannot be fully realized, because atherogenic lipoproteins have an inhibitory effect on the insulin biological effects, that is they increase insulin resistance [30]. It has been proven that the content of intracellular lipids of persons with insulin resistance increased by an average of 80%, mitochondrial phosphorylation decreased by 30% [27].

Dislipidemia as a component of obesity and metabolic syndrome is recognized as a risk factor for cardiovascular disorders. The increase of the HOMA-IR index per unit is accompanied by increase of the risk of cardiovascular disease by 5,4% [31].

Not only initiated by insulin resistance glycopenia and atherogenic hyperlipoproteinemia, but also activation of processes of free radical oxidation, contribute to disorders of energy formation in tissues of pregnant women with obesity. According to our data, there is an activation of proteins oxidative modification in cases of pregnant women with obesity as a result of increased formation of active oxygen forms. The level of oxidative proteins modification in serum was 35.8% higher compared to the control group of pregnant women (5,99±0,34 IU/ml vs 4,41±0,19 IU/ml; р<0,001). Proteins oxidation destruction is considered as a possible factor of enzymes inactivation and violation of the integral protein-receptors structural organization. It should be noted that increased production of active forms of oxygen is considered to be one of the early manifestations of mitochondrial dysfunction. The author argues that disturbance of the mitochondrial pathways, which regulates the balance between accumulation and energy utilization, reduces the insulin sensitivity of tissues and contributes to the progression of pathology [32]. Thus, proteins oxidative modification, which leads to the formation of modified proteins, can play a significant role in the development of insulin resistance in cases of pregnant women with obesity.

The adipose tissue is hormonally active and under condition of insulin resistance produces a large number of adipocytokines, among which the tumor necrosis factor alpha (TNFα) and leptin are recognized as insulin resistance inductors [33, 34]. We found that content of TNFα in the blood of pregnant women with obesity of varying degrees, was 1,7 times higher than that in the control (6,44±0,46 pg / ml versus 3,73±0,52 pg/ml; p<0,05). TNFα affects negatively the energy supply of cells, breaking glucose transport to the skeletal muscle [35, 36]. Besides, TNFα mediates the symptoms of toxemia and endothelial cells damage by inhibiting the production of nitric oxide [37]. According to our data, obesity is accompanied by a significant increase the level of leptin in serum of pregnant women with I degree obesity in 1,7 times, in serum of pregnant women with II degree obesity in 2,0 times and in serum of pregnant women with III degree obesity in 1,8 times compared with the control group (32,23±7,20 ng/ml). Consequently, a pregnancy complicated by obesity runs past the background of hyperleptinemia, which means the development of leptin resistance. It is believed that leptin inhibits insulin production by affecting on the hypothalamic centers and pancreas β-cells [38].

Pathogenetic interrelationship with atherogenic hyperlipoproteinemia, increasing oxidative modification of proteins, and adipocytic dysfunction, which initiates an enhanced synthesis of TNFα and leptin, play a significant role in the mechanism of insulin resistance development, which is already realized in the early pregnancy stages in obese women.

The general pathogenic consequence of the insulin resistance progression during pregnancy in obese women is an energy deficiency increase, which causes a threatening obstetric and perinatal complications frequency increase, reflected in the table IV. So, the frequency of late gestosis has increased with the increase of obesity severity. Late gestosis is observed in every second woman with obesity of the III degree.

CONCLUSIONS

Thus, the progression of insulin resistance during pregnancy of women with varying degrees of obesity is the pathogenetic basis of energy insufficiency and the reduction of adaptive mechanisms of pregnant women with obesity, as evidenced by the increase in obstetric and perinatal complications frequency.

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Conflict of interest:

The Authors declare no conflict of interest

ADDRESS FOR CORRESPONDENCE

Kostiantyn Tarasenko

Higher State Educational Establishment of Ukraine,

Ukrainian Medical Stomatological Academy,

Street Shevchenko, 23, 36011, Poltava, Ukraine

tel.: +380999496745

e-mail.: tarasenko.konstantin50@gmail.com

Received: 26.01.2018

Accepted: 29.04.2018

Table І. Indices of pregnant women insulin resistance depending on the degree of obesity in the early and late gestation periods (M ± m)

Indexes

Pregnant with I degree obesity

Pregnant with II degree obesity

Pregnant with III degree obesity

Pregnant women with I-III degree obesity in general

Control group of pregnant women

HOMA-IR index in early gestation period

4,14±0,51*

(n=78)

3,74±0,44*

(n=35)

4,10±1,68*

(n=9)

4,02±0,37*

(n=122)

1,70±0,23

(n=31)

HOMA-IR index in late gestation period

4,22±1,48

(n=16)

6,98±1,52*

(n=13)

4,63±0,68*

(n=16)

5,18±0,75*

(n=45)

2,57±0,42

(n=21)

Note: * – the reliability of differences in the indices of pregnant with obesity group and the control group, р<0,05.

Table ІІ. Indicators of lipid metabolism of pregnant women with obesity of varying degrees and with physiological body mass in early gestation periods (M ± m)

Indexes

Pregnant

with I degree obesity

(n=77)

Pregnant

with II degree obesity

(n=35)

Pregnant with III degree
obesity

(n=9)

Pregnant women with I-III degree obesity in general (n=121)

Control group of pregnant
women

(n=30)

Body weight

80,93±0,94*

91,87±1,96*

103,17±4,75*

85,71±1,09*

62,15±1,42

Total cholesterol, mmol/l

5,70±0,15

5,64±0,25

5,58±0,19

5,68±0,12

5,29±0,20

Triglycerides, mmol/l

1,62±0,09*

1,81±0,14*

1,49±0,10*

1,66±0,07*

1,16±0,11

VLDL Cholesterol, mmol/l

0,74±0,04*

0,82±0,06*

0,67±0,04*

0,76±0,03*

0,52±0,05

LDL Cholesterol, mmol/l

3,47±0,12

3,30±0,24

3,24±0,22

3,41±0,11

3,25±0,17

HDL Cholesterol, mmol/l

1,49±0,03*

1,52±0,06

1,64±0,08

1,51±0,03

1,62±0,05

Atherogenic coefficient by Klimov A.N

2,94±0,13*

2,86±0,26

2,49±0,26

2,88±0,11

2,41±0,18

Note: * – the reliability of differences in the indices of pregnant with obesity group and the control group, р<0,05.

Table ІІІ. Characteristics of pregnant women with obesity of varying degrees and with physiological body weight lipid metabolism indicators in late gestation period (М±m)

Indexes

Pregnant with I degree obesity (n=31)

Pregnant with II degree obesity (n=23)

Pregnant with III degree
(n=29)

Pregnant women with I-III degree obesity in general (n=82)

Control group of pregnant women (n=32)

Triglycerides, mmol/l

1,90±0,19*

2,46±0,31*

2,23±0,14*

2,17±0,12*

1,15±0,08

VLDL Cholesterol, mmol/l

0,57±0,07*

0,78±0,16*

0,71±0,08*

0,68±0,06*

0,30±0,02

Total cholesterol, mmol/l

6,36±0,27

6,15±0,45

5,89±0,25

6,13±0,18

5,63±0,27

Note: * – the reliability of differences in the indices of pregnant with obesity group and the control group, р<0,05.

Table IV. The frequency of obstetric complications during pregnancy in surveyed groups of women

Сomplications

I degree obesity
(n=149)

II degree obesity
(n=73)

III degree obesity
(n=46)

Control group
(n=101)

Absolut number

%

Absolut number

%

Absolut number

%

Absolut number

%

Miscarriage threat

28

18,8*

19

26,0*

11

23,9*

9

8,9

Stillbirth threat

33

22,2

16

21,9

11

23,9

16

15,8

Preterm birth threat

34

22,8

14

19,2

11

23,9

14

13,9

Placental dysfunction

56

37,6*

39

53,4*

24

52,2*

30

29,7

Infant respiratory distress syndrome

8

5,4

7

9,6

8

17,4*, #

4

4,0

Intrauterine growth retardation

2

1,3

0

0

3

6,5*, #,##

0

0

Early gestosis

7

4,7

4

5,5

5

10,9

6

5,9

Late gestosis

37

24,8*

33

45,2*,#

23

50,0*,#

7

6,9

Preterm birth

7

4,7

3

4,1

3

6,5

3

3,0

Pathology of amniotic fluid: polyhydramnios

21

14,1*

15

20,6*

12

26,1*

7

6,9

Pathology of amniotic fluid: oligohydramnios

20

13,4

12

16,4

5

10,9

15

14,9

Anemia of pregnancy

52

34,9

23

31,5

11

23,9

23

22,8

Аsymptomatic bacteriuria

34

22,8

12

16,4

9

19,6

14

13,9

Disorder of the birth canal biocenosis

66

44,3

35

47,9

20

43,5

40

39,6

TORCH infection

57

38,5

33

45,2

21

46,7

48

47,5

Vertically transmitted infection

30

20,1*

15

20,6*

6

13,0

11

10,9

Obstetric bleeding during pregnancy

0

0

2

2,7#

1

2,2

0

0

Notes: * – compared to the control group (р<0,05);

# – compared to the I degree obesity;

## – compared to the II degree obesity.