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 important for understanding the disease status and selection
of pharmacologic treatment. The gold standard of evaluation of insulin sensitivity is glucose clamp test [3].
However, the test is limited to research use and is difficult 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 estimating insulin sensitivity [6]. This model is based on
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 subjects with mild diabetes without significant hyperglycemia [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 insulin secretion defect and worsen insulin resistance [11].
This phenomenon, called glucotoxicity, is partly revers-
Submitted Aug. 24, 2012; Accepted Oct. 17, 2012 as EJ12-0320
Released online in J-STAGE as advance publication Nov. 10, 2012
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.
Correspondence to: Kohei Okita, Department of Metabolic
Medicine, Graduate School of Medicine, Osaka University, 2-2-B5
Yamadaoka, Suita 565-0871, Japan.
E-mail: [email protected]
Abbreviations: HOMA-IR : homeostasis model assessment of
©The Japan Endocrine Society
Okita et al.
284
ible [12, 13]. Glycemic control is required before evaluation of insulin sensitivity in patients with poor glycemic 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 evaluation 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 feedback 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 resistance 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 confirming the validity of HOMA-IR in representing insulin
resistance, we investigated the relationship between
HOMA-IR and various clinical and biological parameters 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 diabetics [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 insulin before each meal) for at least 2 weeks until fasting plasma glucose (FPG) fell to less than 140 mg/
dL. NPH insulin was added before sleep in 10 subjects 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 formula: HOMA-IR = FPG (mg/dL) × fasting IRI (μU/
mL)/405. Before HOMA-IR was calculated, patients
were switched to treatment with sulfonylurea (glibenclamide 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 performed according to the method of DeFronzo et al.
[3] with a little modification using an artificial pancreas (model STG-22, Nikkiso, Tokyo, Japan). Briefly,
the test consisted of a 120-min euglycemic hyperinsulinemic 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 steadystate 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 clinical 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)
Insulin dose (U/day)
HOMA-IR
8.2±7.6
27.2±27.9
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
standing position. Visceral fat area was estimated by
bioelectrical impedance analysis (BIA), as described
previously [15]. On admission, patients were being
treated with diet alone (n=29, 18.6%), diet and hypoglycemic agents (n=103, 66.0%), or diet and insulin
(n=24, 15.4%). After admission, oral hypoglycemic
agents were withdrawn in all but 9 patients, 24 subjects
were treated with diet (25-30 kcal/ kg standard body
weight / day) alone, 9 were treated with diet and sulfonylureas, and 123 with insulin. Only regular or ultrarapid insulin was used before each meal for at least
2 weeks until FPG decreased to less than 140 mg/dL.
When FPG was more than 140 mg/dL while plasma
glucose before going to bed was less than 140 mg/dL,
NPH insulin was added before sleep.
HOMA-IR was calculated as study1. Then we investigated the relationship between HOMA-IR and various parameters (age, BMI, waist circumstance, eVFA,
systolic blood pressure, diastolic blood pressure, log
transformed triglycerides, LDL-cholesterol, HDLcholesterol, HbA1c, urinary CPR, ΔCPR, log transformed insulinogenic index, log transformed serum
adiponectin and log transformed KITT).
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.
These agents were continued until improvement of
glycemic control.
Insulin tolerance test was carried out before breakfast after an overnight fast. Patients on NPH insulin
were switched to sulfonylurea (glibenclamide 1.25 or
2.5 mg) at the night of the day before the test. Venous
blood samples were collected for measurement of
plasma glucose before and at 3, 6, 9, 12, 15 minutes
after an intravenous bolus injection of regular insulin (Novorin R 0.1 U/kg body weight). Fifteen minutes after insulin injection, the test was terminated by
injection of glucose. Insulin sensitivity (KITT) was
calculated from the linear slope of the plasma glucose
concentration from 3 to 15 minutes, as described previously [16].
The glucagon stimulation test was performed by
intravenous infusion of 1 mg glucagon (Novo Nordisk
Pharma, Tokyo) after an overnight fast. Blood samples
were collected at 0 and 6 min for measurement of CPR.
ΔCPR were expressed as increment of CPR. We also
calculated the insulinogenic index(I.I.), defined as the
ratio of increment in insulin to that in plasma glucose
285
Table 2 Characteristics of the subjects of Study 2
Males/females
156 (79 / 77)
Age (years)
60.1±11.5
Body mass index (kg/m2)
23.9±4.3
Waist circumference (cm)
89.6±12.2 (n=136)
Estimated visceral fat area (cm2 )
107.6±53.1 (n=102)
Systolic blood pressure (mmHg)
127.7±17.5
Diastolic blood pressure (mmHg)
73.2± 10.8
LDL-C (mg/dL)
113.2±26.0
HDL-C (mg/dL)
48.8±14.0
Triglycerides (mg/dL)
102.3±45.7
HbA1c (%)
9.4±1.7
Fasting plasma glucose (mg/dL) after treatment
114± 18
Fasting immunoreactive insulin (μU/mL)
7.1± 5.1
HOMA-IR
2.0±1.3
Urinary C-peptide (μg/day)
65.4±44.6 (n=142)
ΔCPR (ng/mL)
2.2±1.2 (n=126)
Insulinogenic Index
0.20±0.25 (n=140)
adiponectin (μg/mL)
5.4±3.3
KITT (%/min)
1.92±1.22
Data are collected after glycemic control, except for HbA1c, and
expressed means±SD.
HOMA-IR: homeostasis model assessment of insulin resistance,
ΔCPR: increment of C-peptide from the glucagon stimulation test,
KITT: K value from insulin tolerance test.
at 30 minutes after the 75g glucose load (Δinsulin 0-30
min / ΔPG 0-30 min).
Daily urine samples were collected for measurements of urinary CPR. Venous blood sample were
collected before breakfast for measurements of LDLcholesterol, HDL-cholesterol, triglyceride and adiponectin. Plasma adiponectin levels were determined
with an adiponectin ELISA kit (Otsuka Pharmaceutical
Co., Tokushima, Japan), as described previously [17].
The cases with insulin antibody that might have
influence on glucose homeostasis were excluded from
the studies.
Written informed consent was obtained from all subjects, and the study was approved by the ethics committee of Osaka University.
Statistical analysis
Data are expressed as mean±standard deviation
(SD). Pearson’s correlation coefficient analysis was
used to assess the relationship between HOMA-IR and
various variables. A p value less than 0.05 was considered significant. All analyses were performed using the
Statview 5.5 software (SAS Institute, Cary, NC).
Okita et al.
286
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 sulfonylurea 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 diabetic 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:
0.0067-0.0976).
The correlation between log transformed HOMA-IR
and log transformed M/I values derived from the standard euglycemic clamp was significant (r=-0.753,
p=0.002, Fig. 1).
Study 2
After treatment, the mean fasting plasma glucose
of 156 subjects improved from 178±51 to 114±18 mg/
dL. The insulin dose used for glycemic control was
19.1±13.1 U/day. NPH insulin was used in 51 patients
for glycemic control, sulfonylurea 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 glycemic control, fasting IRI was
7.1±5.1 μU/mL and HOMA-IR was 2.0±1.3. In all
of these patients, age (r=-0.292, p=0.0002), HDL-C
(r=-0.342, p<0.0001), log transformed KITT (r=-0.264,
p=0.0009), log transformed adiponectin (r=-0.309,
p=0.0006) correlated negatively with log transformed
HOMA-IR after glycemic control. On the other hand,
BMI (r=0.499, p<0.0001), waist circumstance (r=0.461,
p<0.0001), eVFA (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 (r=0.496, p<0.0001) and log transformed insulinogenic index (r=0.325, p=0.0002) correlated positively with the log transformed HOMA-IR
(Fig. 2). Log transformed HOMA-IR did not correlate with systolic blood pressure, LDL-cholesterol or
HbA1c (Table 3).
Discussion
FPG and serum insulin concentration are predom-
Fig. 1 Study 1. Relation between insulin sensitivity represented
by HOMA-IR and that derived from euglycemic
hyperinsulinemic clamp (M/I)
Table 3 Correlation analysis of log transformed HOMA-IR
and various clinical parameters
r
p
Age (years)
-0.292
0.0002
0.499
<0.0001
Body mass index (kg/m2 )
Waist circumference (cm)
0.461
<0.0001
Estimated visceral fat area (cm2 )
0.401
<0.0001
Systolic blood pressure (mmHg)
0.121
0.1338
Diastolic blood pressure (mmHg)
0.223
0.0054
Log triglyceride (mg/dL)
0.497
<0.0001
LDL-C (mg/dL)
0.006
0.9451
HDL-C (mg/dL)
-0.342
<0.0001
HbA1c (%)
0.027
0.41
Urinary C-peptide (μg/day)
0.216
0.0099
ΔCPR (ng/mL)
0.496
<0.0001
Log insulinogenic index
0.325
0.0002
Log adiponectin (μg/mL)
-0.309
0.0006
Log KITT (%/min)
-0.264
0.0009
ΔCPR: increment of C-peptide from the glucagon stimulation
test, KITT: K value from insulin tolerance test, HOMA-IR:
homeostasis model assessment of insulin resistance.
inantly regulated by feedback loop between the liver
and β cells [7]. Increased insulin resistance in the liver
increases insulin secretion to stabilize hepatic glucose
efflux. When the ability of β cells to secrete insulin is
appropriate against insulin tolerance, plasma glucose
level remains normal. However, defective β cell function results in increased hepatic glucose efflux and consequently leads to hyperglycemia. A rise in FPG from
80 to 140 mg/dL results in an increase in fasting plasma
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 fasting IRI and HOMA-IR. Regular or ultrarapid insulin 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 antibodies to insulin may be produced in subjects treated
with insulin. Therefore insulin users might have antibodies 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 transformed 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 insulin 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 evaluate the insulin sensitivity.
Insulin resistance correlates with obesity (especially
visceral fat obesity)[19], hypertension [20], dyslipidemia [21] or hypoadiponectinemia [22, 23]. In Study
2, we have clarified the relationship between log transformed HOMA-IR or HOMA-IR and various clinical
parameters. The same result was obtained when the
subjects were restricted to insulin users. These parameters except HbA1c were evaluated after glycemic control, 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 correlate well with M/I values derived from the euglycemic hyperinsulinemic clamp test [24, 25]. It should be
emphasized that both KITT and HOMA-IR represent
insulin sensitivity well even in poorly controlled diabetics after insulin treatment.
In this study, log transformed HOMA-IR correlated
with various clinical parameters associated with obesity. BMI, waist circumstance and eVFA are parameters of body composition, HDL-C, diastolic blood pressure, TG and adiponectin are parameters associated
with obesity. These results suggest that insulin resistance, 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 correlated 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 insulin 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 adiposity since it is a key hormone in adipogenesis. Age is
also thought to correlate with insulin secretion capacity 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 insulinotropic 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 secretion 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 tolerance or diabetes [1]. Diabetic subjects do not have
adequate insulin secretion capacity to keep blood glucose 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 subjects. In this study, we showed that insulin resistance
estimated by HOMA-IR correlated with insulin secretion ability estimated by urinary CPR, ΔCPR and insulinogenic index. This means that insulin secretion correlates 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-
289
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 subjects. 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
of HOMA-IR for the evaluation of insulin sensitivity
in patients with poorly controlled type 2 diabetes after
insulin therapy. The results also showed a close correlation between log HOMA-IR and log M/I values derived
from the standard euglycemic clamp. Furthermore,
HOMA-IR correlated with various clinical parameters
even in patients with poorly controlled type2 diabetes
after glycemic control with insulin. These results suggest that HOMA-IR is a reliable and useful parameter
for the evaluation of insulin sensitivity in patients with
type 2 diabetes treated with insulin. Further examination is expected.
Appendix
We do not have any potential conflicts of interest relevant to this article.
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