Endocrine Journal 2013, 60 (3), 283-290

Original

Homeostasis model assessment of insulin resistance for

evaluating insulin sensitivity in patients with type 2 diabetes
on insulin therapy
Kohei Okita, Hiromi Iwahashi, Junji Kozawa, Yukiyoshi Okauchi, Tohru Funahashi, Akihisa Imagawa and
Iichiro Shimomura

Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita 565-0871, Japan

Abstract. Homeostasis model assessment of insulin resistance (HOMA-IR) is a simple and useful method for evaluating
insulin sensitivity. But it is difficult to apply to type2 diabetes patients treated with insulin. We have devised a method for
measuring HOMA-IR and investigated the validity of HOMA-IR for evaluating insulin sensitivity in patients with type 2
diabetes on insulin therapy. In the first arm of the study, 19 poorly controlled diabetic subjects were treated with insulin
and underwent euglycemic clamp study. Then the relationship between insulin resistance index assessed by the clamp test
(clamp-IR) and HOMA-IR was investigated in these subjects. Log transformed HOMA-IR correlated with log transformed
M/I values derived from the standard euglycemic clamp (r=-0.753, p=0.002). In the second arm of the study, we investigated
the relationship between HOMA-IR and various clinical parameters in 156 patients with poorly controlled diabetes after
glycemic control. Log transformed HOMA-IR correlated negatively with age (r=-0.292, p=0.0002), HDL-C (r=-0.342,
p<0.0001), log transformed serum adiponectin (r=-0.309, p=0.0006) and log transformed KITT (r=-0.264, p=0.0009), and
positively with body mass index (r=0.499, p<0.0001), waist circumstance (r=0.461, p<0.0001), visceral fat area (r=0.401,
p<0.0001), diastolic blood pressure (r=0.223, p=0.0054), log transformed triglyceride (r=0.497, p<0.0001), urinary CPR
(r=0.216, p=0.0099), ΔCPR of glucagon stimulation test (r=0.496, p<0.0001) and log transformed insulinogenic index
(r=0.325, p=0.0002). These results suggest that HOMA-IR is a useful test for the evaluation of insulin sensitivity even in
patients with type 2 diabetes treated with insulin.

Key words: Homeostasis model assessment of insulin resistance (HOMA-IR), Glucose clamp test, Insulin therapy

The two main causes of hyperglycemia in type 2
diabetes mellitus are impaired insulin secretion and
increased insulin resistance [1, 2]. Evaluation of insulin
resistance (or sensitivity) and β-cell function is impor-
tant for understanding the disease status and selection
of pharmacologic treatment. The gold standard of eval-
uation of insulin sensitivity is glucose clamp test [3].
However, the test is limited to research use and is diffi-
cult to perform at every medical institution. Although
there are also other tests, they are often complex or
inadequate [4, 5]. Homeostasis model assessment,
first described by Matthews et al., is a method for esti-
mating insulin sensitivity [6]. This model is based on
Submitted Aug. 24, 2012; Accepted Oct. 17, 2012 as EJ12-0320
Released online in J-STAGE as advance publication Nov. 10, 2012
Correspondence to: Kohei Okita, Department of Metabolic
Medicine, Graduate School of Medicine, Osaka University, 2-2-B5
Yamadaoka, Suita 565-0871, Japan.
E-mail: oki@endmet.med.osaka-u.ac.jp
Abbreviations: HOMA-IR : homeostasis model assessment of
©The Japan Endocrine Society
the theory of a feedback loop between β cells and the
liver [7]. The homeostasis model assessment of insulin
resistance (HOMA-IR), calculated from fasting plasma
glucose level and immunoreactive insulin (IRI), is a
simple method for evaluation of insulin sensitivity and
correlates with the results of glucose clamp test in sub-
jects with mild diabetes without significant hypergly-
cemia [8]. Neverthless it is difficult to apply to patients
with poor glycemic control [9], those with severe β cell
dysfunction [10] or those treated with insulin.
Chronic hyperglycemia is known to induce insu-
lin secretion defect and worsen insulin resistance [11].
This phenomenon, called glucotoxicity, is partly revers-
insulin resistance, IRI :immunoreactive insulin, BMI :body mass
index, FPG :fasting plasma glucose, BMI:body mass index,
eVFA: estimated visceral fat area, CPR:C-reactive protein,
ΔCPR: increment of CPR with the glucagon stimulation test, M/
I values: insulin sensitivity index estimated with the clamp test,
KITT: insulin sensitivity index estimated with the insulin tolerance
test, I.I.: insulinogenic index.
284 Okita et al.
ible [12, 13]. Glycemic control is required before eval-
uation of insulin sensitivity in patients with poor gly-
cemic control. In this regard, insulin sensitivity should
be evaluated after the control of blood glucose level in
diabetic subjects. HOMA-IR can be used for evalua-
tion of insulin resistance in patients on diet therapy or
sulfonylureas [14] but might be not suitable for those
on insulin therapy, because insulin treatment affects
serum insulin levels, which in turn influences the feed-
back system between the liver and β cells. While it is
necessary to evaluate insulin resistance in insulin users,
HOMA-IR can only be used to evaluate insulin resis-
tance in such patients after minimization of the effect
of subcutaneously injected insulin.
In this study, insulin resistance was evaluated with
HOMA-IR in patients on short acting insulin with or
without sulfonylureas. The aim of this study was to
validate HOMA-IR in patients with insulin-induced
glycemic control. First, we treated patients with poor
glycemic control with insulin. Then, we evaluated
the agreement between HOMA-IR and clamp-IR of
subjects on insulin therapy (Study 1). After confirm-
ing the validity of HOMA-IR in representing insulin
resistance, we investigated the relationship between
HOMA-IR and various clinical and biological param-
eters that are associated with diabetes to determine the
clinical usefulness of HOMA-IR (Study 2).
Materials and Methods
Study 1
The study subjects were 19 Japanese type 2 diabet-
ics [12 men and 7 women, aged 53.6±14.9 years, body
mass index (BMI) 23.3±5.5 kg/m2, hemoglobin A1c
(HbA1c) 8.7±1.2 %] who had been admitted to Osaka
University Hospital for glycemic control between 2001
and 2006. The clinical characteristics of the patients
are summarized in Table 1. On admission, all oral
hypoglycemic agents were withdrawn, and all subjects
were treated with diet(25-30 kcal/ kg standard body
weight / day) and insulin (regular or ultrarapid insu-
lin before each meal) for at least 2 weeks until fast-
ing plasma glucose (FPG) fell to less than 140 mg/
dL. NPH insulin was added before sleep in 10 sub-
jects because their fasting plasma glucose was more
than 140 mg/dL, though plasma glucose before sleep
was less than 140 mg/dL. When FPG decreased to less
than 140 mg/dL after treatment, insulin sensitivity was
evaluated with HOMA-IR and clamp-IR. The correla-
tion between HOMA-IR and M/I values derived from
the standard euglycemic clamp was investigated.
HOMA-IR was calculated using the following for-
mula: HOMA-IR = FPG (mg/dL) × fasting IRI (μU/
mL)/405. Before HOMA-IR was calculated, patients
were switched to treatment with sulfonylurea (gliben-
clamide 1.25 or 2.5 mg) instead of NPH insulin at the
night of the day before the measurement to minimize
the influence of insulin injected subcutaneously.
The euglycemic-hyperinsulinemic clamp was per-
formed according to the method of DeFronzo et al.
[3] with a little modification using an artificial pan-
creas (model STG-22, Nikkiso, Tokyo, Japan). Briefly,
the test consisted of a 120-min euglycemic hyperinsu-
linemic clamp period. During the clamp test, subjects
received primed-constant infusion of regular insulin
(1.45 mU/kg min, Eli Lilly, Indianapolis, IN) and an
exogenous glucose infusion to maintain blood glucose
levels at 100 mg/dL and to achieve the desired steady-
state serum insulin level (100 μU/mL). When the rate
of exogenous glucose infusion reached a steady-state
level, we evaluated insulin sensitivity as the average
glucose infusion rate during the last 30 minutes divided
by the average serum insulin level during the last 30
minutes (M/I).
Study 2
The study subjects were 156 Japanese with poorly
controlled type 2 diabetes (79 men and 77 women)
who had been admitted to Osaka University Hospital
for glycemic control between 2001 and 2008. The clin-
ical characteristics of the patients are listed in Table
2. Height and waist circumstance were measured in
Table 1 Characteristics of the subjects of Study 1
Males/females 19 (12 / 7)
Age (years) 53.6 ±14.9
Body weight (kg) 60.0±19.1
Body mass index (kg/m2 ) 23.3±5.5
HbA1c (%) 8.7±1.2
Fasting plasma glucose (mg/dL) 120.0±15.1
Fasting C-peptide (ng/mL) 1.77±0.81
Fasting immunoreactive insulin (μU/mL) 8.2±7.6
Insulin dose (U/day) 27.2±27.9
HOMA-IR 2.45±2.38
Data were collected after glycemic control, except for HbA1c, and
expressed means±SD.
HOMA-IR: homeostasis model assessment of insulin resistance
 HOMA-IR in insulin-treated diabetics 285

standing position. Visceral fat area was estimated by Table 2 Characteristics of the subjects of Study 2
bioelectrical impedance analysis (BIA), as described Males/females 156 (79 / 77)
previously [15]. On admission, patients were being Age (years) 60.1±11.5
treated with diet alone (n=29, 18.6%), diet and hypo- Body mass index (kg/m2) 23.9±4.3
glycemic agents (n=103, 66.0%), or diet and insulin Waist circumference (cm) 89.6±12.2 (n=136)
(n=24, 15.4%). After admission, oral hypoglycemic Estimated visceral fat area (cm2 ) 107.6±53.1 (n=102)
agents were withdrawn in all but 9 patients, 24 subjects Systolic blood pressure (mmHg) 127.7±17.5
were treated with diet (25-30 kcal/ kg standard body Diastolic blood pressure (mmHg) 73.2± 10.8
weight / day) alone, 9 were treated with diet and sul- LDL-C (mg/dL) 113.2±26.0
fonylureas, and 123 with insulin. Only regular or ultr- HDL-C (mg/dL) 48.8±14.0
arapid insulin was used before each meal for at least Triglycerides (mg/dL) 102.3±45.7
HbA1c (%) 9.4±1.7
2 weeks until FPG decreased to less than 140 mg/dL.
Fasting plasma glucose (mg/dL) after treatment 114± 18
When FPG was more than 140 mg/dL while plasma
Fasting immunoreactive insulin (μU/mL) 7.1± 5.1
glucose before going to bed was less than 140 mg/dL,
HOMA-IR 2.0±1.3
NPH insulin was added before sleep.
Urinary C-peptide (μg/day) 65.4±44.6 (n=142)
HOMA-IR was calculated as study1. Then we inves-
ΔCPR (ng/mL) 2.2±1.2 (n=126)
tigated the relationship between HOMA-IR and vari-
Insulinogenic Index 0.20±0.25 (n=140)
ous parameters (age, BMI, waist circumstance, eVFA,
adiponectin (μg/mL) 5.4±3.3
systolic blood pressure, diastolic blood pressure, log KITT (%/min) 1.92±1.22
transformed triglycerides, LDL-cholesterol, HDL- Data are collected after glycemic control, except for HbA1c, and
cholesterol, HbA1c, urinary CPR, ΔCPR, log trans- expressed means±SD.
formed insulinogenic index, log transformed serum HOMA-IR: homeostasis model assessment of insulin resistance,
adiponectin and log transformed KITT). ΔCPR: increment of C-peptide from the glucagon stimulation test,
KITT: K value from insulin tolerance test.
With regard to antihypertensive and hypolipidemic
medications used at admission, 51.1% of subjects
were treated with antihypertensive agents and 36.0%
of subjects were treated with hypolipidemic agents. at 30 minutes after the 75g glucose load (Δinsulin 0-30
These agents were continued until improvement of min / ΔPG 0-30 min).
glycemic control. Daily urine samples were collected for measure-
Insulin tolerance test was carried out before break- ments of urinary CPR. Venous blood sample were
fast after an overnight fast. Patients on NPH insulin collected before breakfast for measurements of LDL-
were switched to sulfonylurea (glibenclamide 1.25 or cholesterol, HDL-cholesterol, triglyceride and adi-
2.5 mg) at the night of the day before the test. Venous ponectin. Plasma adiponectin levels were determined
blood samples were collected for measurement of with an adiponectin ELISA kit (Otsuka Pharmaceutical
plasma glucose before and at 3, 6, 9, 12, 15 minutes Co., Tokushima, Japan), as described previously [17].
after an intravenous bolus injection of regular insu- The cases with insulin antibody that might have
lin (Novorin R 0.1 U/kg body weight). Fifteen min- influence on glucose homeostasis were excluded from
utes after insulin injection, the test was terminated by the studies.
injection of glucose. Insulin sensitivity (KITT) was Written informed consent was obtained from all sub-
calculated from the linear slope of the plasma glucose jects, and the study was approved by the ethics com-
concentration from 3 to 15 minutes, as described pre- mittee of Osaka University.
viously [16].
The glucagon stimulation test was performed by Statistical analysis
intravenous infusion of 1 mg glucagon (Novo Nordisk Data are expressed as mean±standard deviation
Pharma, Tokyo) after an overnight fast. Blood samples (SD). Pearson’s correlation coefficient analysis was
were collected at 0 and 6 min for measurement of CPR. used to assess the relationship between HOMA-IR and
ΔCPR were expressed as increment of CPR. We also various variables. A p value less than 0.05 was consid-
calculated the insulinogenic index(I.I.), defined as the ered significant. All analyses were performed using the
ratio of increment in insulin to that in plasma glucose Statview 5.5 software (SAS Institute, Cary, NC).
286 Okita et al.

Results

Study 1
The mean insulin dose used to induce glycemic
control was 27.2±27.9 U/day and FPG improved
from 181.1±45.0 to 120.0±15.1 mg/dL. Ten subjects
required NPH insulin for glycemic control, and sulfo-
nylurea instead of NPH insulin was used at the night
of the day before measurement of IRI and to calculate
HOMA-IR. After treatment of patients with poor dia-
betic control with insulin, fasting IRI was 8.2±7.6 μU/
mL and HOMA-IR was 2.45±2.38 (range: 0.77-9.01).
M/I value derived from the standard euglycemic clamp
test was 0.0464±0.0219 mg/kg/min/μU/mL (range: Fig. 1 Study 1. Relation between insulin sensitivity represented
0.0067-0.0976). by HOMA-IR and that derived from euglycemic
hyperinsulinemic clamp (M/I)
The correlation between log transformed HOMA-IR
and log transformed M/I values derived from the stan-
dard euglycemic clamp was significant (r=-0.753, Table 3 Correlation analysis of log transformed HOMA-IR
p=0.002, Fig. 1). and various clinical parameters
r p
Study 2 Age (years) -0.292 0.0002
After treatment, the mean fasting plasma glucose Body mass index (kg/m2 ) 0.499 <0.0001
of 156 subjects improved from 178±51 to 114±18 mg/ Waist circumference (cm) 0.461 <0.0001
dL. The insulin dose used for glycemic control was Estimated visceral fat area (cm2 ) 0.401 <0.0001
19.1±13.1 U/day. NPH insulin was used in 51 patients Systolic blood pressure (mmHg) 0.121 0.1338
for glycemic control, sulfonylurea instead of NPH insu- Diastolic blood pressure (mmHg) 0.223 0.0054
lin was used at the night of the day before measurement Log triglyceride (mg/dL) 0.497 <0.0001
of IRI and to calculate HOMA-IR. After treatment of LDL-C (mg/dL) 0.006 0.9451
patients with poor glycemic control, fasting IRI was HDL-C (mg/dL) -0.342 <0.0001
7.1±5.1 μU/mL and HOMA-IR was 2.0±1.3. In all HbA1c (%) 0.027 0.41
of these patients, age (r=-0.292, p=0.0002), HDL-C Urinary C-peptide (μg/day) 0.216 0.0099
(r=-0.342, p<0.0001), log transformed KITT (r=-0.264, ΔCPR (ng/mL) 0.496 <0.0001
p=0.0009), log transformed adiponectin (r=-0.309, Log insulinogenic index 0.325 0.0002
Log adiponectin (μg/mL) -0.309 0.0006
p=0.0006) correlated negatively with log transformed
Log KITT (%/min) -0.264 0.0009
HOMA-IR after glycemic control. On the other hand,
ΔCPR: increment of C-peptide from the glucagon stimulation
BMI (r=0.499, p<0.0001), waist circumstance (r=0.461, test, KITT: K value from insulin tolerance test, HOMA-IR:
p<0.0001), eVFA (r=0.401, p<0.0001), diastolic blood homeostasis model assessment of insulin resistance.
pressure (r=0.223, p=0.0054), log transformed trig-
lyceride (r=0.497, p<0.0001), urinary CPR (r=0.216,
p=0.0099), ΔCPR (r=0.496, p<0.0001) and log trans- inantly regulated by feedback loop between the liver
formed insulinogenic index (r=0.325, p=0.0002) cor- and β cells [7]. Increased insulin resistance in the liver
related positively with the log transformed HOMA-IR increases insulin secretion to stabilize hepatic glucose
(Fig. 2). Log transformed HOMA-IR did not corre- efflux. When the ability of β cells to secrete insulin is
late with systolic blood pressure, LDL-cholesterol or appropriate against insulin tolerance, plasma glucose
HbA1c (Table 3). level remains normal. However, defective β cell func-
tion results in increased hepatic glucose efflux and con-
Discussion sequently leads to hyperglycemia. A rise in FPG from
80 to 140 mg/dL results in an increase in fasting plasma
FPG and serum insulin concentration are predom- insulin, and increases in FPG beyond 140 mg/dL are
 HOMA-IR in insulin-treated diabetics 287

Fig. 2 Study 2. Relation between insulin sensitivity measured by HOMA-IR and various clinical parameters

associated with reduced insulin secretion and increased
hepatic glucose output [18].
To evaluate insulin resistance with HOMA-IR, FPG
should be less than 140 mg/d and the feedback system
between the liver and β cells should be reconstructed.
Injection of a high dose of insulin could affect fast-
ing IRI and HOMA-IR. Regular or ultrarapid insu-
lin injected before supper is almost cleared in the next
morning, although the action of NPH insulin may last
until the morning. To diminish the effect of exogenous
insulin, NPH insulin was substituted with sulfonylurea
at the night before the day of estimation of HOMA-IR.
Treatment with sulfonylurea is considered to protect
against damage of the feedback system between the
liver and β cells. Indeed, Emoto et al. demonstrated that
log transformed HOMA-IR correlated well with clamp
288 Okita et al.
IR in type 2 diabetics treated with sulfonylureas [14].
Insulin treatment may stimulate immunity, and anti-
bodies to insulin may be produced in subjects treated
with insulin. Therefore insulin users might have anti-
bodies to insulin and these might have influence on
glucose homeostasis. In this case, we cannot evaluate
insulin sensitivity exactly. Before evaluating insulin
sensitivity, we must consider whether insulin antibody
is negative or not. The cases with insulin antibody that
might have influence on glucose homeostasis should
be excluded.
Study 1 showed significant correlation between
log transformed HOMA-IR and log transformed M/I
derived from the standard euglycemic clamp even in
poorly controlled diabetic patients after treated with
insulin. HOMA-IR correlated well with log trans-
formed M/I in both highly insulin resistant subjects
and low insulin resistant subjects. Furthermore, there
was no difference in such relationship between patients
who did not need and patients who needed NPH insu-
lin for glycemic control. These results suggest that
HOMA-IR appropriately expresses insulin sensitivity
in type 2 diabetic patients under glycemic control with
insulin when insulin regimen was optimized to evalu-
ate the insulin sensitivity.
Insulin resistance correlates with obesity (especially
visceral fat obesity)[19], hypertension [20], dyslipi-
demia [21] or hypoadiponectinemia [22, 23]. In Study
2, we have clarified the relationship between log trans-
formed HOMA-IR or HOMA-IR and various clinical
parameters. The same result was obtained when the
subjects were restricted to insulin users. These param-
eters except HbA1c were evaluated after glycemic con-
trol, because it was presumed that the original state can
be evaluated after correction of glucotoxicity.
Log transformed HOMA-IR correlated well with
log transformed KITT. KITT is another method used
to evaluate insulin sensitivity [16]. KITT is reported to
be safe and reproducible method, and the values cor-
relate well with M/I values derived from the euglyce-
mic hyperinsulinemic clamp test [24, 25]. It should be
emphasized that both KITT and HOMA-IR represent
insulin sensitivity well even in poorly controlled dia-
betics after insulin treatment.
In this study, log transformed HOMA-IR correlated
with various clinical parameters associated with obe-
sity. BMI, waist circumstance and eVFA are parame-
ters of body composition, HDL-C, diastolic blood pres-
sure, TG and adiponectin are parameters associated
with obesity. These results suggest that insulin resis-
tance, expressed by HOMA-IR, is also associated with
obesity in poorly controlled type 2 diabetic patients
after insulin therapy. Although 51.1% of the patients
were being treated with antihypertensive agents and
36.0% of the same subjects were being treated with
hypolipidemic agents at study entry, HOMA-IR cor-
related with diastolic blood pressure, HDL-C and TG.
These results emphasize the validity of HOMA-IR to
reflect insulin resistance even after insulin treatment.
Log transformed HOMA-IR also correlated with
various clinical parameters associated with insu-
lin secretion. Urinary CPR, ΔCPR and insulinogenic
index are parameters that express insulin secretion
capacity. Increased insulin secretion seems to be also
associated with obesity. Insulin can increase adipos-
ity since it is a key hormone in adipogenesis. Age is
also thought to correlate with insulin secretion capac-
ity since insulin secretion ability is known to decrease
with age [26]. This phenomenon is attributed in part to
decreased β cell sensitivity to glucose-dependent insu-
linotropic polypeptide [27] and reduced β2-adrenergic
receptor expression [28].
In non-diabetic subjects, increased insulin resistance
increases insulin secretion to maintain plasma glucose
level within the normal range. Increased insulin secre-
tion might lead to increased adiposity, which enhances
the likelihood of development of insulin resistance. In
this regard, insulin secretion is reported to correlate with
insulin sensitivity in a hyperbolic function in unrelated
nondiabetic subjects [29]. However, when β cell fails
to maintain insulin secretion against insulin resistance,
relative insulin deficiency leads to impaired glucose tol-
erance or diabetes [1]. Diabetic subjects do not have
adequate insulin secretion capacity to keep blood glu-
cose within the normal range, but have insulin secretion
capacity enough to enhance fat cell growth and body
composition. This means that insulin secretion capacity
relates to insulin resistance even in type 2 diabetic sub-
jects. In this study, we showed that insulin resistance
estimated by HOMA-IR correlated with insulin secre-
tion ability estimated by urinary CPR, ΔCPR and insu-
linogenic index. This means that insulin secretion cor-
relates with insulin sensitivity not only in nondiabetic
subjects, but also in type 2 diabetic patients.
In diabetic patients with β cell dysfunction,
HOMA-IR may not be accurate [10]. In the present
study, insulin secretion ability expressed by ΔCPR of
glucagon loading test was 2.1±1.0 ng/mL (range: 0.4-
 HOMA-IR in insulin-treated diabetics
4.8) in Study 1, and 2.2 ±1.2 (range: 0.4-5.6) in Study
2. FPG was controlled in all subjects within 140 mg/
dL by insulin therapy with or without sulfonylureas.
These findings suggest that we can evaluate insulin
resistance with HOMA-IR in patients whose ΔCPR of
glucagon loading test is more than 0.4 ng/mL and FPG
was well controlled without long-acting insulin.
The insulin secretion capacity of Japanese subjects is
lower than that of Caucasian subjects [30]. In Japanese
subjects, the point of FPG beyond that insulin secretion
reduces seems to be lower than that in Caucasian sub-
jects. Reduced insulin secretion and increased hepatic
glucose output may begin at the point of FPG lower
than 140mg/dL. Further examination about the level of
FPG on calculating HOMA-IR is expected.
In summary, the present study suggested a method
of measuring HOMA-IR and confirmed the validity
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