Związek pomiędzy otyłością, glikemią oraz stężeniem leptyny u chorych z cukrzycą typu 2 i zespołem metabolicznym

Oksana V. Marusyn

Endocrinology Department SHEI “Ivano-Frankivsk National Medical University”, Ivano-Frankivsk, Ukraine

 

ABSTRACT

The aim of the study was to establish the relationship between obesity, glucose and leptin level of 2 type diabetes mellitus patients with metabolic syndrome.

Materials and methods: 79 male patients were examined. They were divided into 2 groups. The first group included 48 patients who took Metformin and the second one – 31 persons taking Metformin, Glimepiride of one-day functioning and Thiazolidinediones. The patients were examined to determine their waistline, body mass index (BMI), level of glucose, glycohemoglobin, and leptin. The investigation was conducted at the hospitalization runtime, in 14 days, in 6 months and in 12 months.

Results: It was determined that after 12 months of therapy glycemia levels went significantly down, so the number of patients with glycemia level up to 7.0 mole per litre increased to 69.44% in the first group and to 55.56% in the second groupю It is also shown that positive dynamics in reducing glycohemoglobin levels has been achieved. These indices correlated clearly with the triglycerides level which decreased significantly from 1,53±0,17 mole per litre to 1,06±٠,٥٦ mole per litre in the first group of patients, but TG levels increased from 1,29±٠,١٩ mole per litre to 1,49±0,30 mole per litre in the second group of patients.

Conclusions: The survey examined leptin level and showed that leptin level increases alongside with the disease duration. Consequently, insulin resistance index HOMA is associated with leptin resistance and there is a direct correlation between them.

 

Wiad Lek 2018, 71, 6, -1168

 

Introduction

Today, obesity is one of the most common diseases in the world. Currently, more than 500 million people are suffering from obesity which is more than 7% of the world’s population, and 245 million people – from type 2 diabetes mellitus. Recently, this process has got a tendency to increase, especially in the economically developed countries. It can be said that type 2 diabetes mellitus is the most common obesity complication (85% of patients with type 2 diabetes mellitus are overweight).

In Ukraine, the problem of obesity is quite relevant. Thus, about 30% of the working Ukrainians suffer form obesity, and every fourth Ukrainian is overweight. This pathology is a serious medical problem connected with the decrease of life quality and duration, as it is accompanied by the development of type 2 diabetes mellitus as well as the emergence of such severe complications as dyslipidemia, atherosclerosis, arterial hypertension, night apnea, liver adipose disease and others, and also results in early disability, loss of working efficiency and mortality. Therefore, the country’s economic expenses for this pathology are equal expenses for treating cancer and make up 10% of annual health expenses [1,2,3]. WHO has recognized obesity as a non-infectious «the twenty-first century epidemy» and requires closer attention to this problem.

Over the past few years, more attention has been paid to the study of adipose tissue due to the obesity advance. It is proved that adipose tissue is not just a neutral fat excess but it is the largest endocrine gland of the human body that produces about 10 different hormones and interacts with almost all organs and systems of the organism. At present, the attention of many scholars is focused on establishing the relationship between these hormones and various obesity complications.

Leptin takes the leading position in the pathogenesis of insulin resistance development and type 2 diabetes mellitus. Therefore, the influence and interconnection of leptin level with tolerance disturbance to carbohydrates, abdominal obesity, arterial hypertension, and hypercortisolemia are now extensively studied. The functional value of this adipose tissue hormone in the physiological reactions of the body is very complicated.

Leptin is a multifunctional hormone of adipose tissue which intensifies glyconeogenesis processes of the liver and absorbing glucose by the skeletal muscles, as well as influencing speed of lipolysis, reducing the amount of triglycerides in white adipose tissue, and enhancing thermogenesis. Interestingly, it decreases the amount of triglycerides in the liver, pancreas and skeletal muscles without increasing the level of free fatty acids in the plasma. Leptin stimulates the central nervous system (regulates the saturation center), produces modulating effect on the development of atherosclerosis and arterial pressure [5, 6, 7].

Today, there are known environmental factors that influence the leptin level even more than the genetic component. In particular, scientific literature describes that smoking is accompanied by the development of hyperadrenergic state which contributes to lowering the level of leptin [3]. Thus, infectious diseases, endotoxins and cytokines lead to cause hyperleptinemia. Glucocorticoids, sex steroids (testosterone), and thyroid hormones play a significant role in the interaction between leptin and receptors, which correspondently contributes to the development of the resistance to leptin at the central nervous system level.

According to the scientific data, patients with de novo type 1 diabetes mellitus possess low leptin level, but it gradually increases after insulin therapy prescritpion. However, patients with type 2 diabetes mellitus and signs of insulin resistance are marked with the elevated leptin level in fasting state. Consequently, the lower the insulin sensitivity, the higher the leptin level, and this is the main criterion of hyperleptinemia being an integral part of the metabolic syndrome.

Due to present-day beliefs, obesity is accompanied by a high endogenous leptin level and exogenous leptin resistance. Many scientific studies prove that the lipotoxic effects of free fatty acids and the adipocytes imbalance may be caused by obesity and insulin resistance progression. It is also known that cortisol stimulates the synthesis of cortisol-dependent lipoprotein lipase produced on the upper body adipocytes capillaries, anterior abdominal wall and visceral adipose tissue which leads to the abdominal obesity progression [1, 2]. As a result, leptin resistance is one of the leading etiopathogenetic factors in the development and progression of metabolic syndrome.

By this time, the study of the leptin effect on arterial hypertension and insulin resistance of adults has been carrying on.

The aim

To investigate the relationship between the leptin level and the degree of obesity and insulin resistance of type 2 diabetes mellitus patients with metabolic syndrome.

Materials and methods

79 males with type 2 diabetes mellitus and metabolic syndrom were examined. They were divided into 2 groups. The first group included 48 patients who took Metformin and the second one – 31 persons taking Metformin, Glimepiride of one-day functioning and Thiazolidinediones (pioglitazone). The age of patients was 40-69 years and older. The control group consisted of 23 overweight patients without diabetes mellitus and metabolic syndrome.

The selection of patients with metabolic syndrome was based no the criteria proposed in the National Cholesterol Education Program (NCEP, 2001) of the American Heart Association and the National Institute of Heart, Lungs and Blood published in the Circulation Magazine in 2005 and certified by the IDF. The criteria include male waistline >= 102 cm, female waistline >= 88 cm; triglyceride level increase >= 1.7 mole per litre or specific treatment for lipid abnormality; HDL cholesterol level decrease for males < 1.03 mole per litre, for females < 1.3 mole per litre or a specific treatment for lipid abnormality; blood pressure increase >= 130/85 mmHg or treatment for previously diagnosed arterial hypertension; and glucose levels increase >= 5.6 mole per litre or taking medications for treating diabetes mellitus. Three out of five indicators make it possible to diagnose metabolic syndrome.

According to the protocol, the patients were examined for their waistline, body mass index (BMI), glucose level, and glycohemoglobin. Triglycerides and leptin level were additionalyy determined in blood serum. The content of triglycerides was studied using «LACHEMA» sets (the Czech Republic), and the leptin level – with the help of the immune enzyme method using the standard LEPTIN set produced by DRG (USA).

The study has been conducted in dynamics: at the time of hospitalization, in 14 days, in 6 months and in 12 months.

All patients were recommended to modify their lifestyle: hypocaloric diet (up to 1800 kcal per day) and metered physical activity (10,000 steps per day with pedometer registration) [8, 9, 10].

Results and discussion

All patients have been overweight (BMI > 30) and waistline – more than 102 cm.

In determining glycemia levels, it has been found out that in the first group, the average glycemic index at the primary examination was 8.0 ± 0.2 mole per litre. Moreover, in this group, the level of glycemia to 7.0 mole per litre was observed in 30.83% of patients, in 50.53% of patients blood glucose level ranged from 7.1 to 10.0 mole per litre, and in 15.79% of patients blood glucose level was higher than 10.0 mole per litre.

At the primary examination of the second group, it has been found out that glycemia level to 7.0 mole per litre was only in 12.0% of patients, from 7.1 to 10.0 mole per litre – in 56.0% of patients and more than 10.0 mole per litre – in 32.0% of patients.

Following the prescription of the above-mentioned GLD (Glucose-Lowering Drugs) in each group of respondents, a study on lifestyle modification in 6 months resulted in a significant increase in the number of patients with glycemia to 7.0 mole per lirte in the first group (64.71%), but in the second one this indicator decreased to 9.09% of patients. From 7,1 to 10,0 mole per litre, the glucose level was in 29.41% of patients in the first group and 63.64% of patients in the second group. These data give the evidence that the greatest number of patients with the above-mentioned index was found in the second group. Blood glucose level higher than 10.0 mole per litre was determined in the second group in 27.27% of patients, and in the first group, this figure was lower and was 5.88%.

One year after the examination, an increase in the number of patients with a glycemic level was noted up to 7.0 mole per litre in comparison with the data at admission in all groups of respondents. In the second group, the number of such patients increased to 55.56%, and in the first – to 69.44%. The glycemic index ranged from 7.1 to 10.0 mole per litre in 25% of patients in the first group and 44.44% in the second group. Blood glucose level above 10.0 mole per litre was in 5.56% of patients in the first group, but there was no patient with this indicator in the second group.

In the control group of patients with no signs of a metabolic syndrome, the average glycemic index was 5.12±1.99 mole per litre at the primary examination, in 6 months – 5.19±2.0 mole per litre, and in one year – 5.29 ± 2.02 mole per litre.

The above data point to a clear picture of the achievement of positive dynamics in reducing the level of glycemia in patients in the first group, but the achievement of subcompensated levels of glycemia in 6 months was noted in patients of the second group, and only a year later, the glycemic index greater than 10.0 mole per litre was not in any of the patients from this group. This is probably due to a well-chosen combination of GLD and the modified lifestyle of patients. In the control group, which did not have signs of a metabolic syndrome, an increase in the average index of glycemia was observed at 0.17% during a year.

All patients had a triglyceride level (TG) checked. Thus, in the first group, the TG level at admission was 1,53±0,17 mole per litre, in 6 months this figure decreased to 1,46±0,28 mole per litre, and one year later from the time of the first examination – to 1,06±0.56 mole per litre.

In patients of the second group, at the first examination, triglycerides level was equal to 1.29±0.19 mole per litre, in 6 months this figure remained almost unchanged and was 1.25±0.18 mole per litre, however, a year later, even an increase in the TG level to 1.49±0.30 mole per litre (N to 1.7 mole per litre) was determined.

In the control group without MS and type 2 diabetes mellitus at the primary examination, this figure was 1.74±0.18 mole per litre, in 6 months – 1.92±0.24 mole per litre, and in a year, it slightly decreased to 1,81±0.20 mole per litre.

So, comparing the results of the average TG in the study groups and the control group without metabolic syndrome, a positive gradual decrease in the average figures of TG level has been noted in the first group due to changes of a lifestyle, the chosen dose of TPD, keeping to a proper diet, while in the second group this result has not been achieved, on the contrary, the level of TG even increased.

In the study of the HOMA index as an indirect index of insulin resistance (N <= 2.77), it was found out that in the second group, the average index of HOMA at the primary examination was 2.55±0.37, in 6 months – 2.56±0.56 and a year later – 2.57±0.33, while in the first group at the primary examination, the average HOMA index was 3.55±0.43; in 6 months it even increased to 4.18±0, 92, and a year later the level of the above mentioned indicator decreased to 3.52±0.62.

Thus, all the indicators in the second group corresponded to the norm, while in the first group they were above the norm during the year. 6 months later, the average index of HOMA grew in two groups, and in a year the above mentioned indicator was getting lower though it did not reach a level lower than at the initial survey.

Analysing the results of leptin levels in patients of the first group who received metformin, it was found out that at the primary examination, the lowest level of leptin (1.90±0.40 ng/ml) was in patients with diabetes mellitus during 15 to 19 years, but in 6 months it has grown to 3.10±0.60 ng/ml, and a year later to 4.90±0.60 ng/ml. Its initial index (6.20±0.70 ng/ml) was noted in patients with the duration of the disease from 5 to 9 years, but in 6 months it decreased to 5.50±0.50 ng/ml, but after one year it increased to 11.2±0.20 ng/ml. In patients with diabetes mellitus up to 4 years, the average leptin level was 5.70±0.10 ng/ml, in one year decreased to 3.50±0.40 ng/ml and a year later increased to 7.10±0.90 ng/ml. The same situation was observed in patients with a duration of illness from 10 to 14 years. It is interesting that in patients with a 20-year disease or more, the first level of leptin was 2.90±0.09 ng/ml, in 6 months it dropped to 2.40±0.11 ng/ml, and a year later – up to 2.20±0.60 ng/ml. The average level of leptin in this group at the primary examination was 4.18±0.81 ng/ml. In 6 months, this figure decreased to 3.64±0.52 ng/ml, but in one year it increased to 6.30±1.47 ng/ml.

Calculating the Spirman linear correlation coefficient, a reliable (p<0.001) feedback was determined between glycated hemoglobin and leptin levels – rx, y = -0,61±0,07, p<0.05.

The lowest level of average leptin in the second group of patients was observed in persons with a duration of the disease from 10 to 14 years and from 15 to 19 years and was 2,10±0,80 ng/ml at the primary examination in the first category and 2,10±0,30 ng/ml in the second. Similarly, in these two groups, the above mentioned indicator initially increased to 3.70±0.70 ng/ml and 2.40±0.20 ng/ml, respectively, and then decreased. However, in the category of patients with diabetes mellitus for 10 to 14 years, it was 1.90±0.40 ng/ml, which is lower than the primary index, and in the third category (from 15 to 19 years) to 2,20±0,50 ng/ml, which is greater than the first indicator.

In patients with a period of disease from 0 to 4 years, the average level of leptin at the first examination was 2.70±0.70 ng/ml, in 6 months increased to 3.50±0.50 ng/ml, but one year later it decreased twice to 1.70±0.20 ng/ml. In the group with diabetes mellitus from 5 to 9 years, the first average leptin was 3.40±0.60 ng/ml, in 6 months it decreased to 2.70±0.90 ng/ml, and a year later – to 2,50±0,80 ng/ml. Patients with a disease duration of 20 years or more had a primary average leptin level of 3.60±0.70 ng/ml, in 6 months decreased to 2.20±0.30 ng/ml and in a year they were 2,50±0,90 ng/ml.

Summing up, it is noted that, for the first survey, the average leptin index in patients of the second group was 2.78±0.32 ng/ml, in 6 months it increased to 2,90±0.30 ng/ml and in a year it was 2,16±0,16 ng/ml which is less than the first indicator. However, with the probability of an error-free prediction (p>0.05), the absence of mutual influence of leptin indices on the specified levels of BMI, testosterone, TG, and others has been established. Such a dynamics of the average level of leptin is different from the control group and the first group.

Conclusions

1. There is a reverse strong correlation between the level of glycosylated hemoglobin and leptin in patients with type 2 diabetes mellitus.

2. The level of leptin gets higher with an increase in the disease duration.

3. Insulin resistance in patients with type 2 diabetes mellitus is associated with leptin resistance and there is a direct correlation between them.

Prospects for further research: In the future, the relationship between leptin and other adipose tissue hormones in type 2 diabetes mellitus associated with metabolic syndrome will be studied.

References

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2. Ametov A.S., Demydova T.Y., Tselikovska A.L., Leptin Influence on Body Mass Regulation, Moscow: 2002.

3. Gunter W., Sheldon C., Han D. et al. Leptin and Renal Diseases. Am. J. Kidney Dis., 2002. 39:1–11.

4. P.M. Bodnar, L.O. Kononenko, H.P. Mykhalchyshyn et al. Metabolic Syndrome, Journal of the Academy of Medical Sciences of Ukraine. 2000.4: 677-685.

5. Weyer C., Funahashi T., Tanaka S. et al. Hypoadiponectinemia in Obesity and Type 2 Diabetes: Close Association with Insulin Resistance and Hyperinsulinemia. J. Clin. Endocrinol Metabol., 2001.86:1930–1935.

6. Hloba Y.W. Contemporary Representation of Adipose Tissue Hormones and Other Bioactive Substances as a Factor of the Development of High Body Mass and Type 2 Diabetes Mellitus. Endocrinology. 2004.1:78– 88.

7. Tereshchenko I.V. Leptin and Its Role in the Human Body. Endocrinology Issues. 2001. 4:40–47.

8. A. Kaminskii, A. Kovalenko, O. Hirina, I. Kiseliova. Drug obesity therapy. Rational pharmacotherapy. 2008. 1:53– 63.

Conflict of interest:

The Authors declare no conflict of interest.

CORRESPONDING AUTHOR

Oksana V. Marusyn

Endocrinology Department SHEI

“Ivano-Frankivsk National Medical University”

Halycka str., 2, 76018, Ivano-Frankivsk, Ukraine

тел: +380342528001; +380950890369

e-mail: mov_oksana@ukr.net

Received: 12.03.2018

Accepted: 01.07.2018