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*Corresponding author: Mariya Marushchak, Department of 
Functional and Laboratory Diagnostics, I. Horbachevsky Ter-
nopil National Medical University, 1 Maidan Voli, 46001 Ter-
nopil, Ukraine. E-mail: marushchak@tdmu.edu.ua

International Journal of Medicine and Medical Research 
2020, Volume 6, Issue 2, p. 30-36
copyright © 2020, TNMU, All Rights Reserved

U.P. Hevko et al.

DOI 10.11603/Ijmmr.2413-6077.2020.2.11688

POLYMORPHISMS OF INSULIN RECEPTOR SUBSTRATE 1 AS A RISK 
FACTOR FOR TYPE 2 DIABETES MELLITUS, OBESITY AND CHRONIC 
PANCREATITIS AMONG POPULATION OF TERNOPIL REGION

U.P. Hevko, M.I. Marushchak
I. HORBACHEVSKY TERNOPIL NATIONAL MEDICAL UNIVERSITY, TERNOPIL, UKRAINE

Background. The course of type 2 diabetes mellitus (T2DM), obesity and chronic pancreatitis (CP) in most 
cases is not isolated, so it requires broadening the knowledge about the pathogenetic links at their combined 
course. Despite significant advances in genome research, most of the genetic factors that cause development of 
T2DM are still unclear.

Objective. The aim of the study was to establish the prevalence of IRS1 gene polymorphism in the patients 
with T2DM as well as obesity and CP. 

Methods. The study involved 33 patients with T2DM who were hospitalized in the endocrinology department 
of Ternopil University Hospital in 2019-2020 and 10 apparently healthy patients. Analysis of IRS1 gene 
polymorphism (SNP in the promoter region – rs2943640; gene localization 2q36.3) was performed on the basis 
of polymerase chain reaction data using specific primers. 

Results. It was found that the frequencies of the genotype responsible for C/A polymorphism of IRS1 gene 
in T2DM, T2DM with obesity and in the combined course of T2DM with obesity and CP did not deviate significantly 
from the Hardy-Weinberg equilibrium (p>0.05). The patients with combined course of T2DM, obesity and chronic 
pancreatitis experienced a probable influence of genotypes C/C and C/A of IRS1 gene on the development of the 
studied comorbidity (p<0.05), which is confirmed by a probable difference in the dominant model of IRS1 gene 
inheritance only when T2DM was combined with obesity and CP compared to the control group (p<0.001).

Conclusions. The presence of the C allele in both homozygous and heterozygous states may increase the 
risk of T2DM comorbidity, obesity and CP in the population of Ternopil region.

KEYWORDS: type 2 diabetes mellitus; obesity; chronic pancreatitis; insulin receptor substrate 1; 
genes polymorphism.

Introduction
Type 2 diabetes mellitus (T2DM) is a multi-

factorial genetic disease that causes significant 
morbidity and mortality worldwide [1]. Multi-
morbidity, the presence of two or more chronic 
diseases [2], is typical for patients with T2DM, 
which makes multimorbidity in this population 
a significant clinical issue. Nowakowska et al. 
found out that almost 75% of patients had at 
least one additional comorbidity at the time of 
T2DM diagnosis, and 44% – at least two co-
morbidities [3]. Other studies indicate diabetic 
complications in 90% [4], 91.4% [5], 84.6% [6], 
44% [7] of patients with T2DM, which probably 
depends on the age and gender coverage of 
the respondents in the study. 

The course of T2DM, obesity and chronic 
pancreatitis (CP) in most cases is not defined, 
so it requires broadening the knowledge about 
the pathogenetic links at their combined course 

[8-11]. It is obvious that T2DM is a poorly cont-
rolled epidemic that requires active research of 
the mechanisms of development, features of 
the course, methods of prevention, treatment 
and prevention of complications [12]. Despite 
significant advances in genome research, most 
of the genetic factors that cause development 
of T2DM are still unclear [13, 14]. The insulin 
receptor substrate (IRS) is a key central receptor 
in transmission of insulin signals. Several IRS 
polymorphisms have been identified, but the 
Gly to Arg 972 substitution of IRS1 probably is 
pathogenetically crucial in the development of 
T2DM [15]. 

Therefore, the aim of our study was to 
establish the prevalence of IRS1 gene poly-
morphism in the patients with type 2 diabetes 
mellitus as well as obesity and chronic pan-
creatitis.

Methods
The study involved 33 patients with T2DM 

who were hospitalized in the endocrinology 



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department of Ternopil University Hospital in 
2019-2020 and 10 apparently healthy patients. 
The distribution of groups is presented in 
Table 1.

There was no significant difference in age 
and gender between the patients of experi-
mental groups. All patients were informed of 
the purpose of the clinical trial and gave written 
informed consent to participate in it. The 
privacy of the patient’s identity and health has 
been maintained.

Verification of T2DM was performed in 
accordance with the recommendations of the 
American Diabetes Association (2019) [16]. The 
criteria for T2DM diagnosing were based on the 
rate of glycated hemoglobin (HbA1c) (≥6.5%), 
which was determined using the COBAS 6000 
automatic biochemical analyzer (Roche Hitachi, 
Germany).

Verification of chronic pancreatitis (CP) was 
based on the Unified Clinical Protocol of Pri­
mary, Secondary (Specialized) Medical Care and 
Medical Rehabilitation “Chronic Pancreatitis” 
and the recommendations of the American 
Pancreatic Association [15,16].

BMI was calculated by the BMI formula = 
body weight (kg) / height (m2). The data were 
interpreted according to the WHO recommen-
dations: normal weight in the range of 20.0-
24.9 kg/m2; overweight (pre-obesity) – 25.0-
29.9 kg/m2; class 1 obesity – 30.0-34.9 kg/m2; 
class 2 obesity – 35.0-39.9 kg/m2 and class 3  
obesity >40 kg/m2 [17].

Inclusion criteria were: clinical, laboratory 
and instrumental signs of T2DM, CP and obe-
sity, no severe increase (not more than in 3 
times from the upper of norm maximum) of 
alpha-amylase, lipase, ALT, AST, alkaline 
phosphatase, gamma-glutamyltranspeptidase 
in the blood.

Exclusion criteria from the study were: signs 
of clinically significant neurological, mental, 
renal, hepatic, immunological, gastrointestinal, 
urogenital disorders, musculoskeletal lesions, 
skin, sense organs, endocrine (except T2DM) 
or hematological diseases that were uncont-
rolled, acute pancreatitis, unstable or life-

threatening heart diseases, malignant neo-
plasms not in complete remission for at least 5 
years, medication (drug) dependence, alcohol 
dependence.

Analysis of IRS1 gene polymorphism (SNP 
in the promoter region – rs2943640; gene loca-
lization – 2q36.3) was performed on the basis 
of polymerase chain reaction data using specific 
primers. Genomic DNA was extracted from 
peripheral blood leukocytes using a commer-
cially available DNA isolation kit (QIAamp Blood 
DNA Mini Kit, QIAGEN, Germany). The rs2943640 
IRS1 gene polymorphism  was genotyped using 
the TaqMan real-time PCR method (Applied 
Biosystems, Foster City, CA, USA). Three geno-
types of IRS1 polymorphism (rs2943640) were 
defined (C/C, C/A and A/A).

Statistical analysis of the data was performed 
using the STATISTICA 7.0 software. The Hardy-
Weinberg equilibrium was used to verify the 
conformity of the genotypes of the selected 
samples to the general population. Comparison 
of the frequencies observed and expected, 
calculated according to the formula p2 + 2pq + 
q2 = 1 (the Hardy-Weinberg equilibrium), was 
performed using the Pearson’s chi­square χ2. 
In assessment of the reliability coefficient 
p>0.05, the null hypothesis of the samples 
equality was taken into the account, i.e. the 
correspondence of the selected sample to the 
general population.

Comparative analysis of frequency tables 
was performed using the Pearson’s chi-square 
χ2 and two-tailed p-value for Fisher’s exact test 
(in cases of the expected frequencies of indi-
vidual indicators not exceeding 5).

To evaluate the influence of the factor (the 
presence of a certain genotype or allele of the 
gene) on the disease incidence, calculation of the 
odds ratio (OR), its 95% confidence interval (CI) 
and the reliability coefficient p­value was used.

Results
Insulin receptor substrate (IRS) molecules 

are key mediators in transmission of insulin 
signals. Several polymorphisms have been 
defined in IRS genes, but only the Gly to Arg 

Table 1. Characteristic features of the study groups (n=44)

Group № Characteristics of the group n %
1 T2DM patients with normal body weight without chronic pancreatitis 9 22.7
2 T2DM patients with overweight / obesity without chronic pancreatitis 14 31.9

3 T2DM patients with overweight / obesity with concomitant chronic  pancreatitis 10 22.7

4 Apparently healthy patients (control) 10 22.7

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972 substitution of IRS-1 is pathogenically 
crucial in development of T2DM. However, 
other polymorphisms described in IRS-1 gene 
are associated with insulin resistance (IR) in 
T2DM. The frequency distribution of poly-
morphic genotypes of IRS1 gene (rs2943640) 
and verification of conformity with the Hardy­
Weinberg population equilibrium were perfor-
med in the experimental and control groups. It 
was found out that the frequencies of the 
genotype responsible for C/A poly morphism of 
IRS1 gene in T2DM, T2DM with obesity and at 
the combined course of T2DM with obesity and 
CP did not deviate significantly from the Hardy­
Weinberg equilibrium (p>0.05), while in the 
control group the selected sample did not 
correspond to the general population (Table 2).

The corresponding frequencies for the 
genotypes of IRS1 gene were as follows: 66.7% 
for C/A and 33.3% for A/A in the experimental 

group 1; 21.4% for C/A, 64.3% for C/A and 14.3% 
for A/A in the group 2; 70.0% for C/A, 10.0% for 
C/A and 20.0% for A/A in the group 3 and 100.0% 
for C/A in the control group (Table 3).

The frequencies of alleles of IRS1 gene in 
the patients involved in the study are presented 
in Table 2. In the patients with T2DM the allele 
C predominated, in the patients with T2DM + 
obesity + CP – allele A, while in the patients with 
T2DM + obesity and in the control group, the C 
allele and the A allele were almost equal.

The obtained results, presented in Table 4, 
indicate the absence of a statistically significant 
relationship between the factor (presence of 
alleles C or A) and the disease incidence 
(p>0.05).

Evaluation of the reliability coefficient in the 
analysis of odds ratio showed probable in flu­
ence of the genotypes C/C and C/A of the IRS1 
gene on development of T2DM combined with 

Table 2. Polymorphism of IRS1 genes (rs2943640) according to the Hardy-Weinberg  
equilibrium in T2DM and its comorbidity

Genotypes
T2DM

(Group 1)
T2DM+obesity

(Group 2)
T2DM+obesity+СР

(Group 3) Control

Expected Present Expected Present Expected Present Expected Present
Polymorphism of IRS1 gene (rs2943640)
Homozygotes 
that are common

С/С 1 0 4,0 3 6.4 7 2.5 0

Heterozygotes С/А 4 6 7.0 9 3.2 1 5 10
Homozygotes 
that are rare

А/А 4 3 3.0 2 0.4 2 2.5 0

χ2, р χ2=2.25; р>0.05 χ2=1.20; р>0.05 χ2=2.45; р>0.05 χ2=10.00; р<0.01*

Table 3. Frequency of the alleles of the IRS1 genes (rs2943640) in T2DM and its comorbidity

Frequency of alleles
T2DM 

(group 1)
T2DM+obesity

(group 2)
T2DM+obesity+СР

(group 3) Control

n % n % n % n %
Polymorphism of IRS1 gene (rs2943640)
Allele C 6 33.33 15 53.57 16 80.00 10 50.00
Allele A 12 66.67 13 46.43 4 20.00 10 50.00
 pF (patients/control) рF=0.342 рF=0.999 рF=0.096 –

Table 4. The odds ratio for alleles in different study groups in T2DM and its comorbidity

Group
IRS1 gene (rs2943640)

Allele C Allele A
OR 95 % CI p OR 95 % CI p

T2DM 
(Group 1)

0.50 0.13-1.86 >0.05 2.00 0.54-7.45 >0.05

T2DM+obesity
(Group 2)

1.15 0.37-3.64 >0.05 0.87 0.27-2.73 >0.05

T2DM+obesity+СР
(Group 3)

4.00 0.98-16.27 >0.05 0.25 0.06-1.02 >0.05

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obesity and CP (p<0.05) (Table 5). This is con­
firmed by a probable difference in the dominant 
model of IRS1 gene inheritance only in the 
group with combination of T2DM as well as 
obesity and CP compared with the control 
group (reliability coefficient for the chi­square 
p<0.001). Thus, the presence of the C allele in 
both homozygous and heterozygous states 
may increase the risk of T2DM comorbidity, 
obesity and CP (Table 6).

It should be noted that in recessive models 
of IRS1 gene inheritance in T2DM, T2DM + 

obesity and T2DM + obesity + CP no significant 
differences were established compared with 
the control group, but there was also a tendency 
to increase in the probability of development 
of these diseases in the presence of C allele 
(Table 7). 

Discussion 
It is established that genes are crucial in 

development of T2DM. Researchers have 
suggested the interaction between many ge-
netic factors and environmental factors that 

Table 5. The odds ratio for genotypes in different study groups in T2DM and its comorbidity

Group
Genotype

Polymorphism of IRS1 gene (rs2943640)
CC CА АА

OR 95 % CI OR 95 % CI OR 95% CI
T2DM 
(Group 1)

1.11 0.02-61.38 0.09 0.01-2.00 11.31 0.50-256.21

T2DM+obesity
(Group 2)

6.39 0.29-138.94 1.73 0.03-99.96 4.20 0.18-97.55

T2DM+obesity+СР
(Group 3)

71.40* 3.00-1696.84 0.002* 0.001-0.13 6.18 0.26-146.79

Note. * ‒ р<0.05.

Table 6. Dominant model of IRS1 gene inheritance (rs2943640) in T2DM and its comorbidity

Genotypes
Experimental group Control

pF OR 95% CI p% %
T2DM (Group 1)

С/С 0 0 ‒ 1.11 0.02‒61.38 >0.05
С/А+А/А 100.00 100.00 0.90 0.02‒50.25 >0.05

T2DM+obesity (Group 2)
С/С 21.43 0 0.239 6.39 0.29‒138.94 >0.05
С/А+А/А 78.57 100.00 0.16 0.01‒3.40 >0.05

T2DM+obesity+СР (Group 3)
С/С 80.00 0 <0.001* 71.40 3.00‒1696.84 0.008*
С/А+А/А 20.00 100.00 0.01 0.001‒0.33 0.008*

Note. * – statistically significant results.

Table 7. Recessive model of IRS1 inheritance (rs2943640) in T2DM and its comorbidity

Genotypes
Experimental group Control

pF OR 95 % CI p% %
T2DM (Group 1)

С/С+С/А 66.67 100.00 0.087 0.09 0.01‒2.00 >0.05
А/А 33.33 0 11.31 0.50‒256.21 >0.05

T2DM+obesity (Group 2)
С/С+С/А 85.71 100.00 0.493 0.24 0.01‒5.53 >0.05
А/А 14.29 0 6.18 0.26‒146.79 >0.05

T2DM+obesity+СР (Group 3)
С/С+С/А 80.00 100.00 0.474 0.16 0.01‒3.85 >0.05
А/А 20.00 0 6.18 0.26‒146.79 >0.05

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contribute to the disease development [20]. 
However, there are only isolated data in the 
literature on the role of IRS1 polymorphism 
(rs2943640) in increased susceptibility to T2DM. 
Thus, Langenberg C et al. presented the results 
of the InterAct study, which proved the effect 
of C allele of IRS1 gen e p olymorphism 
(rs2943640) on the risk of T2DM development 
[21]. In the study prepared by Liu J and et al. 8 
SNPs associated with T2DM were found, 
including rs2943640 variant of IRS1 gene, which 
was also associated with body mass index [22].

A study of the physical activity genetics 
made by Loos RJ et al., which included IRS1 
(rs2943640) among the studied genes, showed 
an increased interaction of the gene with the 
risk of diabetes, in particular, a dependence on 
genetic susceptibility to insulin resistance [23]. 
Another interesting result of this study is the 
established data on the higher genetic risk of 
T2DM in individuals with the highest level of 
physical activity that is consistent with the 
large-scale study of Langenberg et al. (24), in 
which the predicted effect of T2DM genetic risk 
was the strongest among young, lean, and 
physically active individuals [21]. It should be 
noted that according to Karaderi T. et al., 
rs2943640 variant of IRS1 gene is associated 
with decreased BMI [24]. Our results prove the 
effect of C allele of IRS1 gene (rs2943640) on 
the increased susceptibility to the combination 
of T2DM+obesity+CP, but there is no probable 
effect of the factor (alleles C and A) on deve-
lopment of only T2DM and T2DM+obesity. 
There are no data in the literature on the role 
of IRS1 gene (variant rs2943640) in increased 
susceptibility to CP.

There are some limitations in this study that 
need to be considered when interpreting its 
results: the sample size is too small, so it is 
difficult to find significant relationships between 

the data; inclusion into the experimental 
groups only of patients with comorbidity 
T2DM+obesity and T2DM+obesity+CP; patients 
were not randomly selected generating a 
potential selection bias. Therefore, we cannot 
exclude the hypothesis that the evaluated 
patients do not represent the whole population 
of the patients with comorbid T2DM, but these 
results are the first step in finding genes for 
increased susceptibility to the studied patho-
logy, they reflect a more heterogeneous real­
world population characteristic in clinical 
practice.

Conclusions
The patients with combined course of 

T2DM, obesity and chronic pancreatitis have a 
probable influence of genotypes C/C and C/A 
of IRS1 gene on development of the studied 
comorbidity (p<0.05) that is confirmed by a 
probable difference in the dominant model of 
IRS1 gene inheritance only when T2DM is 
combined with obesity and CP compare to the 
control group (p<0.001). Thus, the presence of 
the C allele in both homozygous and hete-
rozygous states may increase the risk of T2DM 
comorbidity, obesity and CP in the population 
of Ternopil region.

Funding
This research received no external funding.
Conflict of Interest
The authors declare no conflict of interest.
Author Contributions
Hevko U.P. – methodology, software, vali-

dation, formal analysis, investigation, resources, 
data curation, visualization, writing – original 
draft, writing – reviewing and editing. 

Marushchak M.I. – conceptualization, visua-
lization, supervision, writing – reviewing and 
editing.

ПОЛІМОРФІЗМ СУБСТРАТУ ІНСУЛІНОВИХ РЕЦЕПТОРІВ 1 ТИПУ  
ЯК ФАКТОР РИЗИКУ РОЗВИТКУ ЦУКРОВОГО ДІАБЕТУ 2 ТИПУ,  
ПОЄДНАНОГО З ОЖИРІННЯМ ТА ХРОНІЧНИМ ПАНКРЕАТИТОМ  
У НАСЕЛЕННЯ ТЕРНОПІЛЬСЬКОЇ ОБЛАСТІ

У.П. Гевко, М.І. Марущак
ТЕРНОПІЛЬСЬКИЙ НАЦІОНАЛЬНИЙ МЕДИЧНИЙ УНІВЕРСИТЕТ ІМЕНІ І.Я. ГОРБАЧЕВСЬКОГО МОЗ УКРАЇНИ, 

ТЕРНОПІЛЬ, УКРАЇНА

Вступ. Перебіг цукрового діабету 2 типу (T2DM), ожиріння та хронічного панкреатиту (CP) в 
більшості випадків не є ізольованим, тому потребує поглиблення знань стосовно патогенетичних 

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ланок при їх поєднаному перебігу. Незважаючи на значні успіхи у дослідженнях геному, більшість 
генетичних факторів, що спричинюють розвиток T2DM, залишаються невизначеними.

Мета дослідження  – встановити поширення поліморфізму гена субстрату інсулінових рецепторів 
1 типу (IRS1) у хворих на T2DM у поєднанні з ожирінням та СР. 

Методи дослідження. У дослідження було включено 33 хворих на T2DM, які перебували на 
стаціонарному лікуванні в ендокринологічному відділенні Тернопільської університетської лікарні у 
2019-2020 рр. та 10 практично здорових осіб. Аналіз поліморфізму гена IRS1 (SNP у промоторному 
регіоні – rs2943640; генна локалізація 2q36.3) проведено на підставі даних полімерної ланцюгової реакції 
з використанням специфічних праймерів.

Результати. Встановлено, що частоти генотипу, що відповідає за С/А поліморфізм гена IRS1 при 
T2DM, T2DM з ожирінням та при поєднаному перебігу T2DM з ожирінням та СР суттєво не відхилялися 
від рівноваги Харді–Вайнберга (p>0,05). У хворих на поєднаний перебіг цукрового діабету 2 типу, ожиріння 
та хронічного панкреатиту виявляється вірогідний вплив генотипів С/С та С/А гена IRS1 на розвиток 
досліджуваної коморбідності (р<0,05), що підтверджується вірогідною відмінністю у домінантній 
моделі успадкування IRS1 гену тільки при поєднанні T2DM з ожирінням та СР порівняно з групою 
контролю (р<0,001).

Висновки. Наявність алелі С як в гомозиготному, так і в гетерозиготному станах може під-
вищувати ризик виникнення коморбідності T2DM, ожиріння та СР.

КЛЮЧОВІ СЛОВА: цукровий діабет 2 типу; ожиріння; хронічний панкреатит; субстрат 
інсулінових рецепторів 1 типу; поліморфізм гена.

Information about the authors
Hevko U.P. – PhD student, Department of Functional and Laboratory Diagnostics, I. Horbachevsky 

Ternopil National Medical University, Ternopil, Ukraine.
ORCID 0000-0001-5265-2842, e-mail: gevkoup@tdmu.edu.ua
Marushchak M.I. – professor, Department of Functional and Laboratory Diagnostics, I. Horbachevsky 

Ternopil National Medical University, Ternopil, Ukraine.
ORCID 0000-0001-6754-0026, e-mail: marushchak@tdmu.edu.ua

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Received 30 Nov 2020; revised 20 Dec 2020;  
accepted 23 Dec 2020.

This is open access article distributed under the Creative Com-
mons Attribution License, which permits unrestricted use, 
distribution, and reproduction in any medium, provided the 
original work is properly cited.

U.P. Hevko et al.