The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 5 1567-1569
Copyright © 1999 by The Endocrine Society
From the Clinical Research Centers |
Measurements of Insulin-Mediated Glucose Disposal Are Stable Over Time1
Francesco Facchini,
Michael H. Humphreys,
Jorgen Jeppesen and
Gerald M. Reaven
Departments of Medicine (J.J., G.M.R.), Stanford University School
of Medicine, Stanford, California 94305; San Francisco General Hospital
and University of California San Francisco (F.F., M.H.H.), San
Francisco, California 94110; and Shaman Pharmaceuticals (G.M.R.), Inc.,
South San Francisco, California 94080
Address all correspondence and requests for reprints to: G. M. Reaven, M.D., Shaman Pharmaceuticals, Inc., 213 East Grand Avenue, South San Francisco, California 94080-4812. E-mail:
greaven{at}shaman.com
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Abstract
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To evaluate the stability of insulin-mediated glucose disposal,
over time, we measured the steady-state plasma insulin (SSPI) and
steady-state plasma glucose (SSPG) concentrations in response to a
continuous infusion of SRIF (5 µg/min), insulin (25
µU/m2·min), and dextrose (240
µg/m2·min). These measurements were made in 15 healthy
volunteers, studied before and after a mean (±SEM)
interval of 48 ± 2 months. The mean (±SEM) weight of
the volunteers did not increase with time (75.4 ± 3.1
vs. 76.6 ± 3.2 kg), and there was no significant
variation between the 2 mean (±SEM) values of either SSPI
(324 ± 18 vs. 372 ± 24 pmol/L) or SSPG
(8.4 ± 1.0 vs. 8.2 ± 1.0 mmol/L). Given the
similarity of both SSPI and SSPG concentrations at baseline and
follow-up, it can be concluded that insulin-mediated glucose disposal
was stable in these 15 individuals over an interval of approximately 4
yr.
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Introduction
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WE HAVE recently shown, in a prospective
study, that resistance to insulin-mediated glucose disposal at baseline
predicted the development of cardiovascular disease in a group of
healthy volunteers, followed over an average of 5.3 yr (1). Based on
the data in this paper, we concluded that insulin resistance was an
independent risk factor for cardiovascular disease. Implicit in this
conclusion was the premise that insulin-mediated glucose disposal was a
relatively stable characteristic and would persist relatively
unchanged, over time, in any given individual. This assumption may well
be the case, but the reproducibility of measures of insulin resistance
have only been evaluated over relatively short time periods (2, 3).
Given the importance of establishing the fact that insulin action is
relatively stable over time, the present study was initiated, in which
we recruited 15 healthy volunteers from our original study for repeat
assessment of insulin-mediated glucose disposal.
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Subjects and Methods
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Fifteen healthy individuals (6 females, 9 males), with a mean
(±SEM) age at baseline of 46 ± 3 yr, participated in
this study. Subjects were judged to be in good general health, at both
evaluations, on the basis of a medical history and physical
examination, normal routine blood chemistries and cell counts, and
glucose tolerance test criteria that indicated them to be
nondiabetic (4). They were weighed in light clothing, without
shoes, on an electronic scale. After obtaining written, informed
consent, subjects were admitted to the Stanford General clinical
Research Center, where insulin resistance was quantified after an
overnight fast. Baseline studies were repeated again, in similar
fashion, after a mean (±SEM) of 48 ± 2 months
(range, 31–72 months). Resistance to insulin-mediated glucose
disposal, on both occasions, was determined by a modification of the
insulin suppression test, as initially described by our research group
(5, 6). Briefly, each subject received an iv infusion of SRIF (5
µg/min), insulin (25 mU/m2·min), and glucose (240
mg/m2·min). The infusion was given via an indwelling
teflon catheter in a superficial antecubital vein. Venous blood samples
were obtained from a similar catheter inserted in a contralateral
antecubital vein, kept open with a 0.9% NaCl infusion containing 20
meq/L KCl. The continuous infusion was given for 180 min, and
blood was obtained before and 30, 60, 90, 120, 150, 160, 170, and 180
min after starting the infusion, for measurement of plasma glucose (7)
and insulin (8) concentrations. The mean value of the four measurements
made during the last 30 min of the test was used to calculate the
steady-state plasma insulin (SSPI) concentration and steady-state
plasma glucose (SSPG) concentration. Given the similarity of the SSPI
levels in all individuals, the SSPG concentration provides a measure of
insulin-mediated glucose disposal, i.e. the higher the SSPG,
the more insulin resistant the research subject; the lower the SSPG,
the more insulin sensitive the subject.
Data are expressed as mean ± SE. Mean values for
SSPG, SSPI, and weight at baseline were compared with corresponding
values at follow-up, by two-tailed paired Student’s t test.
Calculations were performed with a commercial statistical
software for the Macintosh, and statistical significance was
defined as P < 0.05.
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Results
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There were no significant changes, over time, as compared with
baseline, in the mean (±SEM) values for weight (75.4
± 3.1 vs. 76.6 ± 3.2 kg), SSPG (8.4 ± 1.0
vs. 8.2 ± 1.0 mmol/L), or SSPI (324 ± 18
vs. 372 ± 24 pmol/L). The results in Figs. 1
and 2
present the individual data for all 15 volunteers, as both the absolute
(Fig. 1) and the per cent (Fig. 2) change, as compared with the
baseline. It can be seen from these data that, although the values for
the three variables both increased and decreased over the period of
observation, they were relatively stable, over time, in any individual.
In the case of the measurements of SSPG, the mean (±SEM)
coefficient of variation, over time, for the 15 volunteers was 7.9
± 0.9%. The mean (±SEM) absolute change in SSPG was
0.19 ± 0.34 (ranging from +1.8 to -1.9 mmol/L). Similar
calculations for the per cent change in SSPG revealed a mean
(±SEM) change of 11.8 ± 3.8%, ranging from -37%
to +19%.
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Figure 1. Individual values at baseline (1 ) and
follow-up (2 ) for weight (left panel), SSPG
(middle panel), and SSPI (right panel).
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Figure 2. Per cent changes in weight
(left panel), SSPG (middle panel), and
SSPI (right panel), comparing values at baseline (1 ) and
follow-up (2 ).
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Baseline SSPG values varied more than 4-fold in the 15 volunteers
studied (3.6–16.2 mmol/L), and the results in Figs. 1
and 2
demonstrate that the magnitude of the change in SSPG, over time, do not
seem to be related to the initial degree of insulin resistance. For
example, SSPG concentration in the individual with the greatest
relative change (-37%) was 5.4 mmol/L at baseline and 3.4 mmol/L at
the end of the study. The only other individual with a change in SSPG
concentration of more than 20% during the period of observation had an
initial SSPG concentration of 10.3 mmol/L, with a final value of 7.4
mmol/L. This individual is of particular interest in that this
represents the only instance in which the change, over time,
represented a significant change in physiological status. Specifically,
based upon our database, an individual with an SSPG concentration
10 mmol/L would be considered to be insulin resistant, whereas a
value of 7.4 mmol/L would certainly not merit that designation. With
this one exception, it is apparent that SSPG concentrations that were
high at baseline stayed high, and insulin-sensitive individuals with
lower SSPG values at baseline had low values at follow-up. In other
words, varying SSPG concentration from 5.4–3.4 mmol/L does not
confound that fact that the individual in question is insulin
sensitive.
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Discussion
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In conclusion, the data presented provide substantial evidence in
support of the view that the ability of insulin to mediate glucose
disposal is reasonably stable over time. As such, this suggests that
results of prospective studies aimed at assessing the effects of
insulin resistance on clinical outcome will not be confounded by
significant variability in this physiological characteristic (if only
measured at baseline ?). It should be emphasized that these
results were obtained in relatively few volunteers, and it is certainly
possible that the findings might not be applicable to the general
population, in whom changes in age, physical activity, or weight might
have more profound effects on insulin sensitivity. On the other hand,
the results were not confounded by any efforts on our part to modify
life-style behavior known to affect insulin sensitivity. Thus, there is
no a priori reason to assume that our findings in these 15
volunteers are not generalizable to larger populations.
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Footnotes
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1 This work was supported by Research Grants HL-08506 and RR-00070
from the National Institutes of Health. 
Received October 21, 1998.
Revised January 26, 1999.
Accepted January 28, 1999.
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References
|
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-
Yip J, Facchini FS, Reaven GM. 1998 Resistance
to insulin-mediated glucose disposal as a predictor of cardiovascular
disease. J Clin Endocrinol Metab. 83:2773–2776.[Abstract/Free Full Text]
-
Greenfield MS, Doberne L, Kraemer FB, Tobey TA, Reaven
GM. 1981 Assessment of insulin resistance with the insulin
suppression test and the euglycemic clamp. Diabetes. 30:387–392.[Abstract]
-
Bogardus C, Lillioja S, Mott DM, Hollenbeck C, Reaven
GM. 1985 Relationship between degree of obesity and in
vivo insulin action in man. Am J Physiol.
248:E286–E291.
-
National Diabetes Data Group. 1979 Classification
and diagnosis of diabetes mellitus and other categories of glucose
intolerance. Diabetes. 28:1039–1057.[Medline]
-
Shen S-W, Reaven GM, Farquhar JW. 1970 Comparison
of impedance to insulin mediated glucose uptake in normal and diabetic
subjects. J Clin Invest. 49:2151–2160.
-
Pei D, Jones CNO, Bhargava R, Chen Y-DI, Reaven
GM. 1994 Evaluation of octreotide to assess insulin-mediated
glucose disposal by the insulin suppression test. Diabetologia. 37:843–845.[CrossRef][Medline]
-
Kadish AH, Little RL, Sterberg JC. 1968 A new
rapid method for determination of glucose by measurement of rate of
oxygen consumption. Clin Chem. 14:116–131.[Abstract]
-
Hales CN, Randle PJ. 1968 Immunoassay of insulin
with insulin antibody precipitate. Biochem J. 88:137–139.
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Top
Abstract
Introduction
