Original Article

A Study to Evaluate Surrogate Markers of Insulin

Resistance in Forty Euglycemic Healthy Subjects
AK Gupta*, SK Jain**

Abstract
Objective : Insulin resistance (IR) is increasingly being recognized as an important pathophysiological
determinant of not only diabetes but also a number of other clinical states. Methods for directly estimating
IR like euglycemic clamp technique and Insulin suppression test (IST) are experimentally demanding
and impractical tool for large scale epidemiological studies. We evaluated several surrogate markers of
IR in 40 healthy subjects.
Methods : Study included 40 euglycemic normal healthy north Indian subjects (33 males, 7 females) of
mean ± SD age 38.9 ± 8.6 yrs, BMI 20.5 ± 3.6 kg/m2 and WHR 0.87 ± 0.05. All subjects were tested for
fasting and postprandial (2 hr post 75 gm glucose) glucose and insulin. Then all the subjects underwent
IST by modified Harano’s method (simultaneous infusion of 20% dextrose @ 6mg/kg/min and plain
human insulin @ 50 mU/kg/hr). Metabolic clearance rate for glucose (MCR = glucose infusion rate/
steady state plasma glucose, ml/kg/min) was calculated for 120-150 min of infusion. Correlation of MCR
with various surrogate markers which included fasting glucose (FG), fasting insulin (FI), fasting glucose/
insulin ratio (FGIR), 120 min glucose (PPG), 120 min insulin (PPI), 120 min glucose/ insulin ratio (PPGIR),
homeostatic model assessment of insulin resistance (HOMA - IR), quantitative insulin sensitivity check
index (QUICKI), fasting glucose insulin product (FIGP), insulin sensitivity index (ISI), fasting insulin
resistance index (FIRI), insulin ratio (IRa) and insulinogenic index (II) were evaluated.
Results : MCR was found to be significantly (p <0.05) correlated with FI (r= -0.347), PPI (r= - 0.402),
PPG (r= - 0.317), PPGIR (r= 0.356), HOMA-IR (r= - 0.348), FIGP (r= - 0.348), and FIRI (r= - 0.348).
Conclusions : Among the surrogate markers which were significantly correlated to MCR, there was no
significant superiority of one marker over the other. We suggest that measuring insulin levels alone in a
single fasting sample can serve as a simple, cheap and convenient indirect qualitative index of IR. ©

INTRODUCTION have continued to increase and now include enhanced

B erson and Yalow1 defined insulin resistance (IR) as a
state (of a cell, tissue, system, or body) in which greater
than normal amount of insulin is required to elicit a
quantitatively normal response. Insulin is a key regulator of
glucose homeostasis and insulin resistance is determined by
both genetic and environmental factors and plays an important
pathophysiological role in diabetes. 2 The abnormalities
initially associated with insulin resistance in nondiabetic
individuals included hyperinsulinemia, borderline glucose
tolerance, dyslipidemia (in the form of increased triglycerides
and decreased HDL cholesterol) and hypertension.3 The
pathophysiological states associated with insulin resistance
*Senior Resident; **Professor of Medicine, Department of Medicine,
Lady Hardinge Medical College and Associated Hospitals, New Delhi.
Received : 27.7.2002; Revised : 18.6.2003; Accepted : 26.4.2004
© JAPI • VOL. 52 • JULY 2004 www.japi.org
postprandial lipemia,4 small dense LDL particle,5 high uric
acid levels,6 enhanced renal sodium retention and decreased
urinary uric acid clearance,6 higher resting heart rate,7
dysfibrinolysis,8 and polycystic ovarian syndrome.9 Thus,
the concept of insulin resistance has evolved from its role in
pathogenesis of type 2 diabetes to attain a greater role.
The hyperinsulinemic euglycemic clamp technique is the
gold standard method for measuring insulin sensitivity.10 The
clamp technique is experimentally demanding and costly and
has proven to be impractical tool particularly for conducting
large scale crosssectional or longitudinal studies. Insulin
suppression test (IST) by modified Harano’s method used in
this study is another method for assessing insulin resistance.11
It has excellent correlation with euglycemic clamp technique
(r= 0.83).11 This method is much easier to perform, reliable
and well tolerated and requires much simpler experimental
setup. However, its application to a large number of subjects
549
is also problematic because of necessity of frequent blood Table 1 : Various surrogate markers calculated
sampling and analysis. Thus there is a pressing need to evolve 1. Fasting glucose (FG) mg/dl
indirect or surrogate markers of insulin resistance which are 2. Fasting insulin (FI) µU/ml (18,19)
more applicable for large population-based epidemiological 3. Fasting glucose/insulin ratio [FGIR = FG/FI mg/10-4U (13,19)]
investigations. Several such markers have been proposed.12- 4. 120 min glucose (PPG) mg/dl
18
The utility and significance of these surrogate estimates of 5. 120 min insulin (PPI) µU/ml (19)
insulin resistance depend on the degree to which they 6. 120 min glucose/insulin ratio
correlate with the direct estimate of this variable. Due to [PPGIR = PPG/PPI mg/10-4U (13)]
7. Homeostatic model assessment of insulin resistance
extreme importance of this issue, we attempted to define the
[HOMA-IR = FI x FG/22.5 (µU/mol/l3 (12)].
degree of correlation between a quantitative measure of 8. Quantitative insulin sensitivity check index
insulin resistance i.e. metabolic clearance rate for glucose [QUICKI = 1/Log(FI)+ Log (FG) (16)].
(MCR) determined by modified Harano’s method11 and various 9. Fasting insulin glucose product (FIGP) (17).
surrogate markers in 40 euglycemic subjects. 10. Insulin sensitivity index [ISI = 104/FIxFG (18)]
11. Fasting insulin resistance index [FIRI = FGxFI/25 (14)].
MATERIALS AND METHODS 12. Insulin ratio [IRa = PPI/FI (18)]
13. Insulinogenic index [II = (PPI-FI)/(PPG-FG) (18)].
Study was conducted in 40 normal and healthy north Indian
subjects. There were 33 males and seven females subjects
with mean ± SD age of 38.9 ± 8.6 years (range 22-57), BMI of Table 2 : Measured values of MCR, fasting and 120 min
20.5 ± 3.0 kg/m2 (range 16.0-27.7) and WHR of 0.87 ± 0.05 glucose and insulin
(range 0.76-0.96). The study was conducted at the Department MCR (ml/kg/min) 8.6 ± 0.3 (5.7-11.6)
of Medicine, Lady Hardinge Medical College and Dr. RML FG (mg/dl) 87.0 ± 1.6 (62.0-110.0)
Hospital and Radioimmunoassay Lab, INMAS, Delhi. All FI ((µU/ml) 10.1 ± 1.5 (2.1-38.9)
subjects had a normal medical history, and routine clinical PPG (mg/dl) 104.1 ± 3.8 (50.0-138.0)
laboratory tests. Written informed consent of each subject PPI (µU/ml) 25.2 ± 2.5 (7.4-60.8)
was taken before undertaking the procedure. Data are mean ± SEM (range)
All subjects were tested for plasma glucose and serum
insulin which were measured before (fasting) and 120 min Table 3 : Correlations (r) of MCR with various surrogate
after the ingestion of 75 g oral glucose challenge. On a markers of insulin resistance
separate admission, all subjects underwent IST. After an Pearson’s correlation (r value) p value
overnight fast insulin (regular, Human Actrapid, Novo
Nordisk) @ 50 mU/kg/hr, and glucose as 20% dextrose @ 6 Fasting glucose (FG) 0.150 0.355
[(-) 0.162 to 0.462]
mg/kg/min were infused through an I/V catheter placed on
Fasting insulin (FI) - 0.347 0.028*
one arm by a syringe infusion pump (Model Pilot A2, [(-) 0.628 to (-) 0.066]
Fresenius, Germany) and a volumetric infusion pump (Cure Fasting glucose/insulin 0.209 0.195
Mate Model SM 2100, Jong Sang Techno Co. Ltd, Korea) ratio (FGIR) [(-) 0.097 to 0.575]
respectively. Blood samples were collected at every five 120 min glucose - 0.317 0.046*
minutes interval between 120 to 150 min of infusion through (PPG) [(-) 0.601 to (-) 0.030]
another I/V catheter placed on the other arm. Insulin levels 120 min insulin 0.402 0.010*
(PPI) [(-) 0.670 to (-) 0.134]
were measured by radioimmunoassay (Coat-A-Count Insulin
120 min glucose/insulin 0.356 0.024*
kits of Diagnostic Products Corporation, US) and glucose by ratio (PPGIR) [0.077 to 0.635]
autoanalyser (glucose oxidase method). The mean Homeostatic model assessment - 0.348 0.028*
concentration of glucose in the seven samples (120-150 min) of insulin resistance [(-) 0.639 to (-) 0.067]
was calculated representing steady state plasma glucose (HOMA-IR)
(SSPG). Metabolic clearance rate for glucose (MCR) was Quantitative Insulin sensitivity 0.149 0.360
calculated as rate of glucose infusion/SSPG. During the check index (QUICKI) [(-) 0.163 to 0.461]
procedure each subject was closely observed for signs and Fasting insulin glucose - 0.348 0.028*
product (FIGP) [(-) 0.629 to (-) 0.067]
symptoms of hypoglycemia and other complications of
Insulin sensitivity 0.209 0.195
intravenous infusion. index (ISI) [(-) 0.097 to 0.575)
Various surrogate markers of insulin resistance as reported Fasting insulin resistance - 0.348 0.028*
by different authors were calculated and then correlated with index (FIRI) [(-) 0.629 to (-) 0.067]
MCR (Table 1). All data are expressed as mean ± SEM or Insulin ratio - 0.106 0.514
(IR) [(-) 0.422 to 0.210]
mean ± SD, and all analysis were performed using the SPSS
Insulinogenic - 0.251 0.118
10.0 package for windows. Pearson’s correlation (r) between index (II) [(-) 0.550 to 0.048]
MCR and all surrogate measures of insulin resistance were
calculated. P <0.05 was considered to indicate statistical *p <0.05. Confidence interval given in parentheses.
significance.

550 www.japi.org © JAPI • VOL. 52 • JULY 2004

 (A)
(C)
Fig. 1 : Relationship of MCR glucose with (A) 120 min glucose, (B) fasting insulin, (C) 120 min insulin, (D) 120 min glucose/insulin ratio, and (E)
RESULTS
Values of MCR and various surrogate markers of insulin
resistance for the 40 subjects are shown in Table 2. Pearson’s
correlation (r) of MCR with these surrogate markers of insulin
resistance calculated are shown in Table 3. These results
demonstrated that simple Pearson’s correlation coefficients
between MCR, and fasting insulin, 120 min insulin, 120 min
glucose, 120 min glucose/insulin ratio, HOMA-IR, FIGP and
FIRI were statistically significant (p <0.05) (Fig. 1). The 120
© JAPI • VOL. 52 • JULY 2004
(B)
(D)
(E)
HOMA-IR.
min insulin was found to be most closely related to MCR (p=
0.01). No significant correlations of MCR were achieved with
fasting glucose, fasting glucose/insulin ratio, QUICKI, ISI,
insulin ratio, and insulinogenic index. Out of the various
surrogate measures which are variations of a formula that
involves fasting insulin and fasting glucose i.e. HOMA-IR,
FGIR, QUICKI, FIGP, FIRI and ISI, only HOMA-IR, FIGP and
FIRI achieved statistically significant (p <0.05) correlations
with MCR glucose. The r value was similar for all of these
variables (r= -0.348). Also all of these measures, based on
www.japi.org 551
fasting glucose and insulin were found to be highly
significantly correlated with each other (p < 0.001).
Large majority of the healthy subjects had FI less than 10
µU/ ml However, five subjects had extremely high FI more
than 20 µU/ ml. Furthermore, these five subjects had higher
levels of PPI (Fig. 1C) and HOMA-IR (Fig. 1E), and lower
values of both fasting and PP glucose/ insulin ratio (Fig. 1D),
when compared to rest of the group.
DISCUSSION
We studied correlations of presently available surrogate
markers of IR12-18 with MCR and also compared these markers
with each others. Metabolic clearance rate for glucose (MCR)
was found to be statistically significantly correlated with
fasting insulin, 120 min insulin, 120 min glucose, 120 min
glucose/insulin ratio, HOMA-IR, FIGP and FIRI (p <0.05).
The highest degree of correlation of MCR was achieved with
120 min insulin (r= -0.402) closely followed by fasting insulin
(r= 0.347). Thus both fasting and post-glucose load insulin
were found to be significantly related to direct estimate of
insulin resistance (MCR) with no significant difference in
their correlations with MCR. Since it is very convenient to
take a single fasting sample, fasting insulin as a surrogate
marker of insulin resistance can serve as convenient, simple
and cheap index of insulin resistance particularly suited for
large scale population based studies.
Fasting insulin is one of the most commonly studied
surrogate marker of insulin resistance. Yeni - Komshian et
al19 studied 490 healthy non-diabetic volunteers. They derived
steady state plasma glucose (SSPG) from insulin suppression
test and correlated it with various surrogate measures. They
reported significant correlations of SSPG with fasting insulin,
120 min insulin, insulin area under the curve, fasting glucose/
insulin ratio and HOMA-IR. Although they described total
insulin response during an OGTT as the best surrogate
measure, they also suggested that determination of fasting
insulin can provide a qualitative estimate of insulin resistance.
Similarly Markku Laakso15 measured insulin response to an
oral glucose load and quantitated insulin resistance using
the euglycemic hyperinsulinemic clamp technique to evaluate
the correlation between fasting and postprandial insulin
levels, and the degree of insulin resistance in individuals
with varying degrees of glucose tolerance. They reported
that although correlations of direct estimates of insulin
resistance with fasting or post-glucose load insulin levels
were consistent in subjects with normoglycemia, in subjects
with impaired glucose tolerance and diabetes, only the fasting
insulin correlated significantly with insulin resistance. They
suggested that in population studies, only the fasting insulin
level should be used as a marker of insulin resistance. Similarly
Hanson RL et al18 achieved high degree of correlation of
fasting and post-glucose load insulin with direct measure of
insulin resistance as determined by hyperinsulinemia
euglycemic clamp.
Also in our study, fasting insulin was found to be highly
significantly (p <0.001) correlated with other markers e.g. post
552 www.japi.org
glucose load insulin (r= 0.564), fasting glucose/ insulin ratio
(r= 0.728), 120 min glucose/insulin ratio (r= 0.419), HOMA-IR
(r= 0.988), QUICKI (r= 0.712), ISI (r= 0.728), FIGP (r=0.988),
FIRI (r=0.988) and IRa (r= 0.428, p <0.01). No significant
correlation was observed between MCR and fasting glucose/
insulin ratio although significant correlation was achieved
with 120 min post glucose load glucose/insulin ratio (p <0.05).
Yeni - Komshian et al19 and Legro RS et al13 described
significant correlations with both fasting and post-glucose
load glucose/insulin ratio though the correlations with the
latter were much significant. We also observed statistically
significant correlations (p <0.05) of MCR with different
markers based on fasting glucose and insulin e.g. HOMA-IR,
FIGP and FIRI. Correlation coefficients (r value) were exactly
similar for all of them (r= - 0.348). It can be explained on the
basis that all of these markers are based on product of fasting
glucose and insulin, and thus are no different or superior to
each other. This is in variance with what has been reported
by different authors.14,17 In fact HOMA-IR, FIGP and FIRI
were found to be highly correlated (r= 1.0) with each other.
Katz et al16 defined a quantitative insulin sensitivity index
(QUICKI) which is also based on fasting glucose and insulin
but transforms the data by taking both the logarithm and
reciprocal of the glucose insulin product. They claimed that
QUICKI holds good correlation with direct measures of insulin
sensitivity derived from two different methods i.e., euglycemic
hyperinsulinemic clamp and frequently sampled intravenous
glucose tolerance test (FSIVGTT). However, this variable
correlated poorly and insignificantly with MCR in our study.
We could not demonstrate any significant correlation with
measures like insulin sensitivity index, insulin ratio and
insulinogenic index which is in variance with the work of
Hanson RL et al.16
Also in an interesting observation, five subjects had
extremely high FI ( >20 (µU/ ml ) associated with higher PPI,
higher HOMA-IR, and low levels of both fasting and PP
glucose/insulin ratio as compared to rest of the subjects.
These subjects are otherwise normal and healthy. They may
belong to syndrome X. Other manifestations of the syndrome
like hypertension, diabetes, coronary artery disease,
dyslipidemia which although are not apparent at present may
appear later in the life.
In summary, we evaluated almost all of the presently
reported surrogate markers of insulin resistance in a single
study and could demonstrate significant correlations of quite
a few of them with direct measure of insulin resistance i.e.,
MCR derived from modified Harano’s method. We conclude
that simply measuring fasting insulin levels may serve as a
simple, cheap and reliable qualitative marker of insulin
resistance, and measuring other variables do not offer any
significant advantage.
REFERENCES
1. Berson SA, Yalow RS. In: Ellenberg M, Rifkin H (eds) Diabetes
Mellitus : Theory and Practice, New York: McGraw-Hill,
1970;388-423.
2. DeFronzo RA, Bonadanna RC, Ferrannini F. Pathogenesis of
© JAPI • VOL. 52 • JULY 2004
 NIDDM. A balanced overview. Diabetes Care 1992;15:318-
68.
3. Reaven GM. Role of insulin resistance in human disease.
Diabetes 1988;37:1595-1607.
4. Jeppesen J, Hollenbeck CB, Zhou M-Y, et al. Relationship
between insulin resistance, hyperinsulinemia, post heparin
plasma lipoprotein lipase activity, and postprandial lipemia.
Arterioscler Thromb Vasc Biol 1995;15:320-24.
5. Reaven GM, Chen Y-DI, Jeppesen J, Maheux P, Krauss RM.
Insulin resistance and hyperinsulinemia in individuals with
small, dense, low density lipoprotein particles. J Clin Invest
1993;92:141-46.
6. Facchini F, Chen YD-I, Hollenbeck C, Reaven GM.
Relationship between resistance to insulin mediated glucose
uptake, urinary uric acid clearance, and plasma uric acid
concentration. JAMA 1991;266:3008-11.
7. Facchini FS, Riccardo A, Stooh’s A, Reaven GM. Enhanced
sympathetic nervous system activity : the linchpin between
insulin resistance, hyperinsulinemia, and heart rate. Am J
Hypertens 1996;9:1013-17.
8. Juhan-Vague I, Thompson SG, Jespersen J, on behalf of the
ECAT Angina Pectoris Study Group; Involvement of the
hemostatic system in the insulin resistance syndrome.
Arterioscler Thromb 1993;13:1865-73.
9. Barbicri RI, Ryan KJ. Hyperandrogenism, insulin resistance
and acanthosis nigricans syndrome : a common
endocrinopathy with distinct pathophysiology features. Am J
Obstet Gynecol 1983;147:90-101.
10. DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique
: a method for quantifying insulin secretion and resistance.
Am J Physiol 1979;273:E 214-23.
11. Heine RJ, Home PD, Poncher M, et al. A comparison of 3
methods for assessing insulin sensitivity in subjects with
normal and abnormal glucose tolerance. Diabetes Res 1985;2:
113-20.
12. Mathews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher
BA, Turner RC. Homeostasis model assessment : Insulin
resistance and β-cell function from fasting plasma glucose
and insulin concentrations in man. Diabetologia 1985;28:412-
19.
13. Legro RS, Fine Good D, Dunaif A. A fasting glucose to insulin
ratio is a useful measure of insulin sensitivity in women with
polycystic ovary syndrome. J Clin Endocrinol Metab
1998;83:2694-98.
14. Duncan MH, Singh BM, Wise PH, Carter G, Alaghband ZJ. A
simple measure of insulin resistance. Lancet 1995;346:120-
21.
15. Laakso M. How good a marker is insulin level for insulin
resistance? Am J Epidemiol 1993;137: 959-65.
16. Katz A, Nambi SS, Mather K, et al. Quantitative insulin
sensitivity check index: A simple, accurate method for
assessing insulin sensitivity in humans. J Clin Endocrinol Metab
2000;85:2402-10.
17. Thomas GN, Critchley J, Tomlinson B, Anderson PJ, Lee ZS,
Chan JC. Obesity, independent of insulin resistance, is a major
determinant of blood pressure in normoglycemic Hong Kong
Chinese. Metabolism 2000;49:1523-8.
18. Hanson RL, Pratley RE, Bogardus C, et al. Evaluation of simple
indices of insulin sensitivity and insulin secretion for use in
epidemiologic studies. Am J Epidemiol 2000;151:190-8.
19. Yeni - Kom Shian H, Carantoni M, Abbasi F, Reaven GM.
Relationship between several surrogate estimates of insulin
resistance and quatification of insulin mediated glucose
disposal in 490 healthy non-diabetic volunteers. Diabetes Care
2000;23:171-75.

Announcement
XXIV Annual Conference of Association of Physicians of India, Orissa Chapter - 2004 will be
held on 13th and 14th November, 2004 at IMA House - Berhamper, Orissa.
For further details, please contact : Dr. LM Meher, Organising Secretary, Conference Secretariat of
Medicine Dept. MKCG Medical College, Berhampur, Orissa 760 004.
Tel. 0680-2281760; Email : lkmeher@yahoo.com

© JAPI • VOL. 52 • JULY 2004 www.japi.org 553