WPŁYW CZYNNIKÓW RYZYKA NA INSULINOOPORNOŚĆ U PACJENTÓW Z NADWAGĄ I OTYŁOŚCIĄ

Tetiana Maksymets1, Natalia Karpyshyn2, Taras Gutor3, Helen Sklyarova4, Eugen Sklyarov1

1 Department of Therapy 1 and Medical Diagnostics, Faculty of postgraduate education, Danylo Halytsky Lviv
National Medical University, Lviv, Ukraine

2 Department of Family Medicine, Danylo Halytsky Lviv National Medical University, Lviv, Ukraine

3 Department of Public Health Management, Faculty of postgraduate education, Danylo Halytsky Lviv
National Medical University, Lviv, Ukraine

4 Department of Family Medicine, Faculty of postgraduate education,Danylo Halytsky Lviv National Medical University, Lviv, Ukraine

ABSTRACT

Introduction: Obesity is a multifactorial, heterogenic disease, associated with an increased risk of morbidity and mortality due to cardiovascular diseases, diabetes, cancer, chronic liver and kidney diseases. Excessive body weight and obesity are serious medical and social problems, since their incidence is constantly increasing and has reached global epidemic proportions.

The aim: Determining the influence of risk factors on insulin resistance level in patients with overweight and obesity.

Materials and methods: The study included 127 patients with overweight and obesity. Anthropometric measurement was performed for determination of the degree and type of obesity by WHO and IDF (2015) criteria. The levels of ALT, AST, uric acid, lipids, glucose, insulin, glycated hemoglobin in the blood were measured. HOMA-IR index was calculated and multiple regression method with inclusion of reliable signs was applied.

Results: By multiple regression method, we identified four signs which, in combined action, affect HOMA-IR index: AST, triglycerides, insulin level and atorvastatin dose. Value of determination coefficient indicates that the level of insulin resistance in overweight and obese patients is by 37% explained by the factors included in regressive model. However, we did not investigate the influence of behavioral risk factors and burdened family history of type 2 diabetes mellitus, which significantly affect insulin resistance level.

Conclusions: We assume that modification of lifestyle and individual approach to pharmacologic correction of dyslipidemia in overweight and obese patients help to avoid the development of insulin resistance, which is a predictor of type 2 diabetes mellitus.

Wiad Lek 2018, 71, 3 cz. I

Introduction

Obesity is a multifactorial disease, incidence of which is constantly increasing. The role of obesity problem is determined by a development of severe comorbid pathology and high mortality due to coronary artery disease, arterial hypertension, dyslipidemia, type 2 diabetes mellitus (T2D), oncological diseases, etc.

Factors, which determine the development of obesity, are genetic, demographic (age, gender, ethnicity), social and economic (education, occupation, marital status), psychological and behavioral (nutrition, physical activity, alcohol, smoking, stresses), and drug intake.

Unhealthy diet combined with hypodynamia of individuals with a hereditary tendency to obesity is a crucial factor.

An important component of the mechanisms of obesity pathogenesis is adipose tissue, which produces biologically active substances – adipokines that variously affect metabolic processes in the body.

A leading role in pathogenesis of cardiometabolic complications in overweight and patients belongs to hyperinsulinemia and insulin resistance (IR), which leads to oxidative stress, impairment of lipid metabolism, inflammation, and causes endothelial dysfunction with further development of atherosclerosis [1].

Drugs for the treatment of dyslipidemia, which is a pathogenic background of coronary artery disease (CAD), are inhibitors of HMG-CoA-reductase. Statins can reduce the level of pro-atherogenic lipid fractions and possess a range of pleiotropic effects, namely, anti-inflammatory, anti-ischemic, antithrombotic and antiproliferative effects. Statins reduce coronary and cerebrovascular events in primary and secondary prevention [2]. Type 2 diabetes mellitus is also an important independent risk factor of CAD. There are many clinical data, which confirm ability of statins to reduce the incidence of cardiovascular events and mortality among patients with and without T2D; however, they can increase the risk of type 2 diabetes mellitus [3].

Investigations of the recent years indicate an increase in type 2 diabetes mellitus morbidity during statin therapy in patients with high risk, in particular, with initial impairment of glucose metabolism, presence of concomitant obesity, burdened family history of T2D and post-menopause in women [4]. Concerning statin therapy, important factors are high dosage, long period of treatment, combination with other drugs that can influence insulin resistance, as well as lipophilicity of statin [5]. It should be emphasized that the course of statin-induced T2D, unlike a spontaneous one, is prognostically more favorable [6].

The aim

Determining the influence of risk factors on insulin resistance level in patients with overweight and obesity.

Materials and methods

During screening, 127 patients with overweight and obesity were selected for the investigation. Among them, there were 86 (67.7%) men and 41 (32.3%) women.

For investigation of influence of various factors on insulin resistance, the examined group included three cohorts of patients: those who were obese and did not receive atorvastatin, and patients who along with obesity had CAD and received atorvastatin in the dose of 20 or 40 mg daily, respectively.

The criteria for exclusion were the presence of T2D, obesity due to endocrine pathology, severe heart, kidney, liver failure, acute conditions and oncologic diseases.

Anthropometric measurement was performed, which involved the calculation of body mass index, measurement of waist circumference as well as determination of the degree and type of obesity by WHO and IDF (2015) criteria.

The level of glycated hemoglobin (HbA1C) in the whole blood was determined by turbidimetric assay method, using test system “Hemoglobin A1c-direct” BioSystems (Spain).

Insulin in blood serum was determined on chemiluminescent immunoassay analyzer “Immulite 2000” (Siemens, Germany) using a proper reagent (Immulite 2000 Insulin, USA ).

Insulin resistance index was calculated by the formula:

НОМA-IR=fasting insulin (µIU/mL)*fasting blood glucose (mmol/l) /22.5. Patients with НОМA-IR>1.7 by ATPIII were considered insulin resistant.

Biochemical indices and lipids were performed by generally accepted methods on automatic analyzer “BioSystems” (Spain) using original set of reagents.

Multiple regression method with inclusion of reliable signs was used for statistic processing of investigation results.

Results and discussion

We used multiple regression method with systematic inclusion of signs to determine the influence of risk factors on insulin resistance level in overweight and obese patients.

According to literature data and own observations, we selected 16 signs which could affect the level of insulin resistance. These signs included age, BMI, waist circumference, ALT, AST, level of uric acid, low-density lipoproteins, high-density lipoproteins, total cholesterol, triglycerides (TG), glycated hemoglobin, glucose, insulin, period of treatment and dose of atorvastatin.

Mean age of patients who were involved in the research was 58.7 ±9.6 years. Mean BMI constituted 31.1±4.8 kg / м 2.

By multiple regression method, we identified four signs, which, in combined action, affect НОМА-IR index: AST, triglycerides, insulin level and dose of atorvastatin. Values of their coefficients and reliability are given in table I.

The obtained regression equation is the following:

НОМА = -6.55757-0.10622* AST + 4.63733* TG+ 0.25885* insulin + 0.10118* dose of atorvastatin.

The obtained regression equation is characterized by the following parameters: coefficient of determination (R2) constitutes 0.37; Fischer criterion = 17.7, which for this number of degrees of freedom is p<0.001. Value of coefficient of determination indicates that the level of insulin resistance in overweight and obese patients is by 37% explained by the factors included in regression model; while by 63% it depends on the signs not included in regression model (for example, family history, unhealthy diet, hypodynamia, smoking, intake of other drugs). As it is indicated in table 1, two factors have a higher level of unmistakable prognosis than 0.05. However, they are included in regression model based on analysis of residuals, which were the lowest in the presented model among all the possible combinations.

Lifestyle (in particular, nutrition and physical activity) and condition of insulin resistance have a strong influence on the level of triglycerides, since it is a balance between TG synthesis and their utilization. Elevation of TG level, especially in combination with increased level of low-density lipoproteins is a surrogate marker of insulin resistance and a predictor of occurrence of type 2 diabetes mellitus. Moreover, a high level of free fatty acids, potential derivatives of TG, further deteriorates sensitivity of tissues to insulin, causing vicious circle between the levels of insulin and triglycerides. [7]

Our results concerning the influence of hypertriglyceridemia on occurrence of insulin resistance and type 2 diabetes mellitus also coincide with the data, obtained by other researchers who point out its influence on clinical characteristics and function of β-cells in patients with type 2 diabetes mellitus diagnosed for the first time [8].

Authors state that correction of dyslipidemia pharmacologically or by changing lifestyle can reduce, to a certain extent, lipotoxicity effect, improving homeostasis of glucose, sensitivity to insulin and reducing the risk of type 2 diabetes mellitus [9].

Сonclusions

In patients with excessive body weight and obesity, an increased level of НОМА-IR index is by 37% explained by the factors included in regression model, namely, levels of AST, triglycerides, insulin and atorvastatin dose, while it largely depends on behavioral factors, which were not included in the analysis. Thus, we suggest, that modification of lifestyle and individual approach to statin therapy will enable patients to avoid insulin resistance that is a predictor of type 2 diabetes mellitus.

References

1. E. Dale Abel, Karen M. O’Shea and Ravichandran Ramasamy. Insulin Resistance: Metabolic mechanisms and consequences in the heart. Arterioscler Thromb Vasc Biol. 2012;32(9):2068-2076. doi.10.1161/ATVBAHA.111.241984

2. Payal Kohli , David D.Waters, Rita Nemr et al. Risk of New-Onset Diabetes and Cardiovascular Risk Reduction From High-Dose Statin Therapy in Pre-Diabetics and Non–Pre-Diabetics: An Analysis From TNT and IDEAL. J Am Coll Cardiol. 2015; 65( 4): 402-404. doi.10.1016/j.jacc.2014.10.053

3. Kwang Kon Koh, Michael J.Quon, Seung Hwan Han et al. Atorvastatin Causes Insulin Resistance and Increases Ambient Glycemia in Hypercholesterolemic Patients. J Am Coll Cardiol. 2010;55(12):1209-1216. doi. 10.1016/j.jacc.2009.10.053

4. David D.Waters, Jennifer E.Ho, S.Matthijs Boekholdt at al. Cardiovascular Event Reduction Versus New-Onset Diabetes During Atorvastatin Therapy: Effect of Baseline Risk Factors for Diabetes. J Am Coll Cardiol. 2013;61(2):148-152. doi. 10.1016/j.jacc.2012.09.042

5. Eliano Pio Navarese, Anna Szczesniak, Michalina Kolodziejczak et al. Statins and Risk of New-Onset Diabetes Mellitus: is there a Rationale for Individualized Statin Therapy? Am J Cardiovasc Drugs. 2014;14:79-87. doi.10.1007/s40256-013-0053-0

6. Giovanni Corrao, Matteo Monzio Compagnoni, Federico Rea et al. Clinical significance of diabetes likely induced by statins: Evidence from a large population-based cohort. Diabetes Res Clin Pract 2017;133:60-68. doi.10.1016/j.diabres.2017.08.008

7. Amir Tirosh, Iris Shai, Rafael Bitzur et al. Changes in Triglyceride Levels Over Time and Risk of Type 2 Diabetes in Young Men. Diabetes Care 2008;31(10): 2032-2037 doi.10.2337/dc08-0825

8. Zheng S, Zhou H, Han T, et al. Clinical characteristics and beta cell function in Chinese patients with newly diagnosed type 2 diabetes mellitus with different levels of serum triglyceride. BMC Endocr Disord. 2015;15:21. doi.10.1186/s12902-015-0018-1

9. Vidar HjellvikSolveig SakshaugHanne Strøm. Body mass index, triglycerides, glucose, and blood pressure as predictors of type 2 diabetes in a middle-aged Norwegian cohort of men and women. Clin Epidemiol. 2012; 4: 213–224. doi.10.2147/CLEP.S31830

This article is a fragment of scientific research work of Department of Therapy №1 and Medical Diagnostics, Faculty of postgraduate education Danylo Halytsky Lviv National Medical University, Lviv, Ukraine: “Features of the respiratory, cardiovascular, digestive system in patients with diabetes mellitus and obesity: features of pathogenesis, clinic, diagnostics “

ADDRESS FOR CORRESPONDENCE

Tetiana A. Maksymets

Hrinchenka Str 6/101, 79037, Lviv, Ukraine

tel: +380977471613

e-mail: maksymets.t@gmail.com

Received: 11.03.2018

Accepted: 10.05.2018

Table I. Role of coefficients for risk factors of increased level of insulin resistance in patients with overweight and obesity were selected for the investigation.

B

p value

Absolute term of an equation

-6.55757

0.02

AST

-0.10622

0.21

TG

4.63733

<0.001

Insulin

0.25885

0.01

Dose of atorvastatin

0.10118

0.15