ORIGINAL ARTICLE

Insulin Resistance Profile Among Siblings of Type 2

Diabetes Mellitus (Preliminary Study)
Dyah Purnamasari*, Sidartawan Soegondo*, Maryantoro Oemardi*, Iwang Gumiwang**

* Department of Internal Medicine, Faculty of Medicine, University of Indonesia - dr. Cipto Mangunkusumo Hospital.
Jl. Diponegoro no. 71, Jakarta Pusat 10430, Indonesia. ** Department of Internal Medicine, Faculty of Medicine,
University of Indonesia - dr. Cipto Mangunkusumo Hospital & Persahabatan Hospital, Jakarta, Indonesia.

Correspondence mail to: dyah_p_irawan@yahoo.com

ABSTRACT Conclusion: the prevalence of insulin resistance among

Aim: to obtain prevalence of insulin resistance among
siblings of subjects with type 2 DM and their metabolic
abnormality profiles as measured by their BMI, waist
circumference (WC), blood pressure, glucose intolerance,
concentration of triglyceride, HDL cholesterol, and uric
acid.
Methods: a preliminary, cross sectional study
conducted among 30 siblings from seven type 2 DM
subjects under medical treatment in Dr. Cipto
Mangunkusumo Hospital and other places where the
subjects lived. Those subjects underwent interviews,
physical examination including weight, height,
abdominal circumference, blood pressure and laboratory
examinations including glucose tolerance test, fasting
insulin, triglycerides, HDL cholesterol and uric acid level.
Data processed to obtain body mass index (BMI),
homeostasis model assessment of insulin resistance (HOMA-
IR) and HOMA-IR cut-off, which is determined based on 75
percentile. The criteria of hypertension, dyslipidemia,
central obesity and hyperglycemia are based on Asian
modification NCEP/ATP III criteria for metabolic
syndrome. Hyperuricemia is diagnosed based on uric acid
level >7mg/dl in men and >6 mg/dl in women.
Results: the prevalence of insulin resistance among
siblings of type 2 DM in this study is 26.67% with the
proportion in each family varies from 0% to 75%.
The most metabolic component found in this study is
central obesity (56.7%), followed by hypertension (46.7%),
decreased HDL cholesterol level (26.6%), hyper-
triglyceridemia (26.6%) and hyperglycemia (20%). As
many as three-quarters of subjects with insulin resistance
have BMI >25 kg/m 2 . Among subjects with insulin
resistance, all have central obesity, half of them have
hypertension, decreased HDL cholesterol level and
hyper-triglyceridemia. While hyperglycemia is found in
37.5% subjects.
siblings of type 2 DM in this study was 26.67% with the
proportion in each family varies between 0-75%. Central
obesity is the most metabolic component commonly found.
Key words: insulin resistance, the siblings of subjects with
type 2 DM.
INTRODUCTION
Diabetes mellitus (DM) is a chronic disease with
an increase in prevalence. 1-3 The most feared
complications of diabetes are the chronic complications
either macrovascular or microvascular complications.
In addition, DM itself is an independent risk factor for
coronary heart disease.1,3-6 The risk of cardiovascular
disease among DM subjets are greater than those
without DM. So far, there have been two hypotheses
regarding the occurrence of diabetes; beta cell failure
and insulin resistance.3,6,8-10 Insulin resistance occurs
several decades before the onset of type 2 diabetes
and is the best predictor for future occurrence of type
2 diabetes mellitus.3,4,6,8,9,11 Given the strong genetic
influence on the incidence of type 2 DM, it is predicted
that insulin resistance is also influenced by genetic
factors.8,12-15
Studies have reported the prevalence of insulin
resistance in the general population. Some studies in
white subjects showed that the prevalence of insulin
resistance ranged from 12-23%.16-17 Axelsen et al found
that healthy men with a family history of type 2 DM
have an increase of postprandial lipid level without
glucose intolerance which is estimated to most
probably due to insulin resistance.4 Haffner et al
discovered the hyperinsulinemia condition as a

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Vol 42 Number 4 October 2010 Insulin Resistance Profile Among Siblings of Type 2 Diabetes Mellitus

prediabetic state among individuals with a family RESULTS

history of type 2 DM, while Warram et al found that
individuals who have family history of type 2 DM have
a greater risk of metabolic abnormalities than those
without family history, and as many as 16% of these
individuals will progress to having type 2 DM after
being followed for 13 years.7
Previous study mentioned that intervention can be
started earlier since insulin resistance state in order to
delay the onset of type 2 DM. It is undoubtable that
lifestyle modification and weight loss are rational ways
to improve insulin resistance.3,5,6,10,18
There are no data about insulin resistance profile
among type 2 DM families in Indonesia. Since earlier
lifestyle modifications and provision of medicines,
especially during the insulin resistance state which is
still in normoglycemia state, will delay the onset of type
2 DM better than those with glucose intolerance,19,20 it
is needed to conduct a research about insulin
resistance profile among type 2 DM families, in this
case siblings of type 2 DM. This study will collect some
metabolic parameters such as anthropometric
examination, blood pressure, lipid profile, glycemia status
and uric acid level.
Subjects consisted of 15 men (50%) and 15
females (50%). The youngest and oldest subjects are
29 and 70 years old, respectively, while the age group
of 41-50 years old was the most. In this study, the
cut-off value of HOMA-IR was 2.04.
The prevalence of insulin resistance among
siblings of type 2 DM in this study is 26.67% with the
proportion in each family varies from 0% to 75%.
Insulin resistance is most widely in the age group of
41-50 years old (37.5%), compared to the age group
of 31-40 years old (25%), 51-60 years old (25%) and
61-70 years old (12.5%). The most metabolic
component found in this study is central obesity (56.7%),
followed by hypertension (46.7%), decreased HDL
cholesterol level (26.6%), hypertriglyceridemia (26.6%)
and hyperglycemia (20%). As many as three-quarters
of subjects with insulin resistance have BMI >25 kg/
m2. Among subjects with insulin resistance, all have
central obesity, half of them have hypertension,
decreased HDL cholesterol level and hyper-
triglyceridemia. While hyperglycemia is found in 37.5%
subjects.

METHODS Table 1. Subject characteristics

A preliminary, cross sectional study was conducted Characteristics Mean (SD) Median

among 30 siblings from seven type 2 DM subjects Age (year) 47 (11.34) 46

Weight (kg) 59.55 (13.70) 60.25
under medical treatment in Dr. Cipto Mangunkusumo Height (cm) 156.99 (7.75) 156.25
Hospital in Jakarta and other places where the BMI (kg/m2) 24.19 (5.21) 25.28
Abdominal circumference (cm) 83.1 (12.67) 84
subjects lived. Those subjects underwent interviews, Systolic blood pressure (mmHg) 127.5 (21.84) 122.5
physical examination including weight, height, Diastolic blood pressure (mmHg) 75.5 (8.13) 72.5
abdominal circumference, blood pressure and Fasting blood glucose (mg/dl) 92.73 (45.45) 83.5
2-hour PP blood glucose (mg/dl) 131.33 (92.20) 113
laboratory examinations including glucose tolerance test, Fasting blood insulin (IU/ml) 6.98 (4.67) 6.35
fasting insulin, triglycerides, HDL cholesterol and uric HOMA-IR 1.6 (1.23) 1.36
Triglyceride (mg/dl) 153.5 (161.23) 98
acid level. Blood sampling was conducted in the HDL cholesterol (mg/dl) 48.63 (10.68) 49
morning between the hours of 08:00 to 10:00 a.m. Uric acid (mg/dl) 4.62 (1.15) 4.5
local time, after the subjects underwent 12 hours of
fasting. Blood laboratory examinations were conducted
at the Prodia Laboratory, Kramat Street, Central
Table 2. The frequency of metabolic components based on
Jakarta. Data were processed to obtain body mass age group
index (BMI), homeostasis model assessment of insulin Components n 21-30 31-40 41-50 51-60 61-70
resistance (HOMA-IR) and HOMA-IR cut-off. Obesity 16 1 3 7 4 1
Cut-off value of HOMA-IR is determined based on Central obesity 17 1 3 6 4 3
Hypertension 14 0 1 5 4 4
75 percentile. The criteria of hypertension, dyslipidemia, Hypocholesterol HDL 10 0 3 4 3 0
Hypertriglyceridemia 8 0 2 2 2 2
central obesity and hyperglycemia were based on Asian Hyperglycemia 3 0 1 2 0 0
modification NCEP/ATP III criteria for metabolic Hyperuricemia 0 0 0 0 0 0

syndrome. Hyperuricemia was diagnosed based on uric

acid level >7mg/dl in men and >6 mg/dl in women.

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Dyah Purnamasari Acta Med Indones-Indones J Intern Med

Table 3. The frequency of metabolic components in insulin
resistance group
Metabolic components Number of insulin Percentage
in insulin resistance resistance (n=8) (%)
Central obesity
- Yes 8 100.0
- No 0 0
Hypertension
- Yes 4 50.0
- No 4 50.0
Hypocholesterol HDL
- Yes 4 50.0
- No 4 50.0
Hypertriglyceridemia
- Yes 4 50.0
- No 4 50.0
Hyperglycemia
- Yes 3 37.5
- No 5 62.5
DISCUSSION
In this study, we examined siblings of diabetic
patients aged were 45-55 years old. The average age
of the siblings was 47 years old, despite finding a 38-
years-old diabetic patient who has siblings aged 29-34
years old. Thus, the results achieved in this study are
limited to the population or in families with the same
age range.
In this study, the cut-off value of HOMA-IR is 2.04.
Cut-off values of HOMA-IR ever reported vary
widely, but for the high risk population as in this study
have not been reported. Differences in cut-off value
of HOMA-IR in previous studies reinforce the
perception that insulin resistance is different from one
population to another population that is likely determined
by other inter-gender, the difference of body fat
distribution between men and women, ethnic and age.21
In this study, the cut-off value of HOMA-IR is
relatively low compared to previous studies (in the
general population). It is very likely due to the number
of subjects that is relatively small.36-38
Tripathy and Vaag (EGIR study) reported that
individuals with a family history of diabetes (first
degree relative) have a higher insulin resistance
(represented by the average value of HOMA-IR, not
a cut-off HOMA-IR) than individuals without a
history of DM.23 The average value of HOMA-IR in
the group with a family history of DM on a study by
Tripathy is 1.21, whereas in this study is 1.60. In this
study, the frequency of insulin resistance varies within
families between 0-75%. If the effect of genetic
factors being equal on all subjects of the study,
significant variations can indicate the strong influence
of environment on insulin resistance. While in this study,
there are several environmental factors which are not
analyzed, such as diet and exercise habits. Influence
206
of a history of type 2 DM in the father or mother or
both at the incidence of insulin resistance can not be
viewed because it is not performed genetic analysis.
In this research note that in type 2 diabetic
subjects with decreased HDL cholesterol, tend to have
siblings with decreased HDL cholesterol as well.
Although the significance is not determined yet, this
possibility supports the findings of De Fronzo that the
phenotype picture of insulin resistance is influenced by
several genes that form the background of gene D
(Diabetic gene), genes of L (lipid gene), gene H
(hypertension gene), and gene A (atherosclerotic
gene).19,24 Individuals who are insulin resistance, with
the influence of the dominant gene D will be type 2
DM, with the dominant influence of the L gene would
have dyslipidemia (hypertriglyceridemia or decreased
of HDL level), as well as for hypertension and that of
atherosclerosis.15,19
In addition, although it is not significant, siblings of
type 2 DM who relatively have younger onset of type
2 DM (<40 years old) tend to have an average value
of HOMA-IR higher than those with older onset of
type 2 DM. This was previously reported by Tripathy
et al that siblings of type 2 DM whose age is relatively
younger (<44 years) will have siblings with an average
value of HOMA-IR higher than those with older onset
of type 2 DM (p <0.005).23
The frequency of insulin resistance in all subjects
as a group is 26.67%. In this study, incidence of insulin
resistance increases with age and is highly found in
the age group 41-50 years and then decreases with
increasing age most probably caused by the prevalence
of bias. Among three quarters of subjects with insulin
resistance had a BMI >25 kg/m2. This finding is in line
with Nasution (2005) who reported the relationship
between BMI with insulin resistance (p = 0.017). With
different approaches, the relationship between IMT,
insulin resistance can be seen from the report by Choi
et al, which involved 1314 subjects with age >60 years,
and Thomas et al involving 225 Chinese subjects aged
65-74 years. Two studies showed increased BMI with
HOMA-IR degrees which are grouped into quartiles.25
In this study, central obesity is highest among the
other metabolic components. Pranoto et al in Surabaya
and Adam et al in Makassar also reported that central
obesity component of metabolic syndrome is most
commonly found.22,26 However, several other studies
showed different results. Nasution reported
hypertension is a component of the metabolic syndrome
that most often found in the elderly group (>60 years).
These differences are likely influenced by the age range
studied. In Bali and Pekalongan, a prominent
Vol 42 Number 4 October 2010 Insulin Resistance Profile Among Siblings of Type 2 Diabetes Mellitus
component of the metabolic syndrome is a decrease in
HDL cholesterol level and hypertension.27,28
Central obesity was also found in all subjects with
normal glucose tolerance and insulin resistance. This
is in line with research conducted by Carr et al who
reported that abdominal circumference is very good
for identifying insulin resistance in subjects with nor-
mal glucose tolerance (p<0.001).29 As explained in the
literature review, the central role of obesity on meta-
bolic syndrome considering its function as a source of
FFA, adipokin, adinopektin, TNF and IL-6 that
affect the emergence of insulin resistance.19,29,30
Increased uric acid was not found on the subject
of this research, so this parameter is very insensitive
to predict the incidence of insulin resistance.
Meanwhile, hypertension, increased triglyceride
concentrations, decreased HDL cholesterol concen-
trations and hyperglycemia (fasting blood glucose >110
mg/dl) can be used to predict insulin resistance,
although not as good as central obesity.
Limitations in this study were (1) This study is a
preliminary study with a sample of only 30 people
(seven families) that can not be used to analyze the
relationship (2) the results of this study can not be used
to represent high-risk groups in Indonesia, due to the
strong influence of ethnic factors on the incidence of
insulin resistance (3) genetic analysis can not be done
so that the genetic role is not clearly visible, and (4)
this study did not use a control group (individuals who
had no family history of DM) as a comparator so that
the difference between high risk groups and low risk is
not visible.
CONCLUSION
The prevalence of insulin resistance among
siblings of type 2 DM in this study was 26.67% with
the proportion in each family varied between 0-75%.
Central obesity was the most metabolic component
commonly found.
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