The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 10 3221-3224
Copyright © 1997 by The Endocrine Society
Insulin Resistance Does Not Change the Ratio of Proinsulin to Insulin in Normal Volunteers1
Pei-Wen Wang,
Fahim Abbasi,
Marcello Carantoni,
Yii-Der I. Chen,
Salman Azhar and
Gerald M. Reaven
Stanford University School of Medicine, Stanford, California 94305;
Geriatric Research, Education, and Clinical Center, Veterans
Administration Palo Alto Health Care System, Palo Alto, California
94304; and Shaman Pharmaceuticals, 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.
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Abstract
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Plasma glucose, insulin, and proinsulin concentrations were measured
before and after an oral glucose challenge in 57 nondiabetic
individuals. In addition, insulin-mediated glucose disposal was
estimated by determining the steady state plasma glucose (SSPG)
concentration after a 180-min iv infusion of somatostatin, insulin, and
glucose. The plasma glucose concentration after oral glucose
administration was used to divide the population into those with normal
(n = 36) or impaired glucose tolerance (IGT; n = 21), and the
36 normal glucose-tolerant individuals were further subdivided into an
insulin-sensitive (SSPG, <9.0 mmol/L; n = 15) and an
insulin-resistant (SSPG, >10 mmol/L; n = 21) group. Fasting and
postglucose load insulin concentrations were similar in the normal
glucose-tolerant insulin-resistant and IGT groups, but were
significantly higher (P < 0.02-<0.001) than those
in normal glucose-tolerant insulin-sensitive individuals. Fasting
proinsulin concentrations were also higher (P <
0.002) in the normal glucose-tolerant insulin-resistant (15.1 ±
1.5 pmol/L) and IGT (15.8 ± 1.8 pmol/L) groups compared to those
in normal glucose-tolerant insulin-sensitive volunteers (9.3 ±
1.2 pmol/L). However, the ratio of fasting proinsulin to insulin was
identical in all three groups (0.12). When the three groups were
combined, significant relationships (P < 0.001)
existed between SSPG (degree of insulin resistance) and both fasting
proinsulin (r = 0.59) and insulin (r = 0.66) concentrations,
but not with the ratio of proinsulin to insulin (r = 0.03). These
results demonstrate that fasting proinsulin and insulin concentrations
are increased in insulin-resistant, nondiabetic subjects, and the more
insulin resistant, the greater the increase. In contrast, the ratio of
proinsulin to insulin did not vary as a function of insulin resistance.
Thus, neither insulin resistance nor the need to secrete more insulin
to maintain glucose tolerance necessarily leads to abnormal insulin
processing by the ß-cell.
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Introduction
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ALTHOUGH there is evidence that the plasma
proinsulin to insulin ratio is higher in patients with
noninsulin-dependent diabetes mellitus (NIDDM) and fasting
hyperglycemia (1, 2, 3, 4), the cause of this apparent abnormality in the
processing of insulin within the ß-cell is not clear. One obvious
explanation is that fasting hyperglycemia, or some metabolic defect
associated with it, is responsible for this phenomenon. As such, the
increase in the proinsulin to insulin ratio in plasma could be a
manifestation of glucotoxicity and could contribute to the progressive
decline in circulating insulin that is seen as glucose homeostasis
deteriorates in patients with NIDDM (5, 6, 7, 8, 9). Alternatively, the
increased proinsulin to insulin ratio could simply be a function of an
abnormal pancreatic ß-cell, stressed in its attempt to compensate for
the resistance to insulin-mediated glucose disposal characteristic of
patients with NIDDM (10, 11, 12). One way to distinguish between these
possibilities is to take advantage of the fact that a severe degree of
insulin resistance can also be seen in nondiabetic individuals (13, 14). By comparing the plasma proinsulin to insulin ratio in nondiabetic
individuals defined as insulin sensitive or insulin resistant, we
should be able to evaluate the effect of insulin resistance per
se on the proinsulin to insulin ratio. The study presented here
was initiated to address this issue.
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Subjects and Methods
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Fifty-seven healthy nondiabetic volunteers were selected for
this study. They were selected from a larger group that responded to a
newspaper advertisement indicating our interest in studying the
relationship between insulin secretion and action. To enter the study,
individuals had to be in good general health, with a body mass index
(BMI) between 20–35 kg/mg2, a normal medical history and
physical examination, normal values on a routine hematological survey
and chemical screening battery, and a nondiabetic glucose tolerance
test by National Diabetes Data Group criteria (15). On the basis of the
glucose tolerance test, they were divided into 36 subjects with normal
glucose tolerance and 21 subjects with impaired glucose tolerance
(IGT). The baseline characteristics of the three groups presented in
Table 1
demonstrate that they were
relatively similar in terms of age, gender distribution, and BMI.
However, fasting plasma glucose concentration was significantly
(P < 0.001) higher in those with IGT compared to
levels in the other two groups. All studies were performed at the
General Clinical Research Center of Stanford Medical Center and were
initiated after a 14-h overnight fast.
Plasma glucose (16) and insulin (17) concentrations were determined
before and 30, 60, 90, 120, and 180 min after oral administration of
75 g glucose. The ability of insulin to promote glucose uptake was
estimated by a modification (18) of the insulin suppression test as
validated by our laboratory (19). After an overnight fast, an iv
catheter was placed in each of the patient’s arms. Blood was sampled
from one arm for measurement of plasma glucose and insulin
concentrations, and the contralateral arm was used for administration
of test substances. Somatostatin was administered [250 µg/h in a
solution containing 2.5% (wt/vol) human serum albumin] to suppress
endogenous insulin secretion. Simultaneously, insulin and glucose were
infused at rates of 25 mU/m2·min and 240
mg/m2·min. Blood was sampled every 30 min until 150 min
into the study and then every 10 min until 180 min had elapsed. The
four values obtained from 150–180 min were averaged and considered to
represent the steady state plasma glucose (SSPG) and insulin (SSPI)
concentrations achieved during the infusion. Because SSPI
concentrations are comparable in all individuals, SSPG concentrations
provide a direct estimate of insulin-mediated glucose disposal in each
individual: the lower the SSPG, the more insulin-sensitive the
individual. Normal glucose-tolerant individuals were divided into an
insulin-sensitive (SSPG, <9 mmol/L; n = 15) and an
insulin-resistant (SSPG, >10 mmol/L; n = 21) group for subsequent
analysis. The latter cut-off point is based on our extensive database
and defines the upper 25% of a volunteer population on the basis of
their SSPG values.
The fasting blood samples obtained on the morning of both the oral
glucose tolerance test and the insulin suppression test were analyzed
for proinsulin and insulin. Plasma insulin concentrations were
determined by RIA (17) using a human-specific antibody (Linco Research,
St. Charles, MO). This antibody selectively measures human insulin with
practically no cross-reactivity (<0.2%) to proinsulin or the primary
circulating split form, (des31,32)-proinsulin. Proinsulin
was measured (20) by a RIA kit (Linco Research) This kit measures total
proinsulin in serum or plasma, and cross-reactivity is less than 0.1%
to insulin and C peptide. These values were used to determine the ratio
of proinsulin to insulin.
Results are expressed as the mean ± SEM. Differences
among the three groups were compared by one-way ANOVA, and Pearson
correlation coefficients between the variables were also
determined.
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Results
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SSPI and SSPG concentrations of the three experimental groups are
shown in Fig. 1. The results in the
left panel demonstrate that the SSPI concentrations were
somewhat lower in those with IGT, but the difference was not
statistically significant. Despite the similarity of the values for
SSPI in the three groups, it is obvious from the data in the
right panel that the mean SSPG concentration of the
insulin-sensitive group (6.1 ± 0.6 mmol/L) was approximately half
those of the insulin-resistant (12.9 ± 0.4 mmol/L) and IGT
(12.3 ± 0.4 mmol/L) groups, whereas the latter two groups were
equally insulin resistant.
Plasma glucose and insulin concentrations in the three groups before
and after the oral glucose challenge are shown in Fig. 2. The total integrated glucose area was
higher (P < 0.001) in subjects with IGT (26.4 ±
0.8 mmol/L·h) than in either the insulin-resistant or
insulin-sensitive groups (20.1 ± 0.6 and 17.6 ± 0.6
mmol/L·h, respectively). Furthermore, although the difference was not
quantitatively striking, the glucose response area was also higher
(P < 0.05) in the insulin-resistant compared to the
insulin-sensitive group. The total integrated plasma insulin response
was essentially identical in the IGT (1680 ± 204 pmol/L·h) and
insulin resistant (1590 ± 210 pmol/L·h) groups, and was higher
(P < 0.001) in both than in the insulin-sensitive
individuals (816 ± 108 pmol/L·h).
Fasting plasma proinsulin and insulin concentrations and the ratio of
proinsulin to insulin are presented in Table 2. As can be seen from these data, both
proinsulin and insulin concentrations were significantly higher
(P < 0.001) in the insulin-resistant and IGT groups
than in the insulin-sensitive subjects. However, the ratio of
proinsulin to insulin was similar in all three experimental groups.
Figure 3 displays the relationship within
all 57 subjects between SSPG and fasting plasma proinsulin and insulin
concentrations and the ratio of proinsulin to insulin. It is obvious
from these data that the more insulin resistant an individual (the
higher the SSPG), the higher the proinsulin (r = 0.59;
P < 0.001) and insulin (r = 0.66;
P < 0.001) concentrations. In contrast, there was no
relationship between SSPG and the ratio of proinsulin to insulin
(r = 0.03; P < = NS). There was also a
significant (r = 0.65; P < 0.01) relationship
between fasting proinsulin and insulin concentrations (data not shown).
All of these relationships were essentially unchanged when corrected
for differences in age, gender distribution, and BMI.
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Figure 3. Relationship between SSPG and fasting
insulin concentration (top panel), fasting proinsulin
concentration (middle panel), and the ratio of fasting
proinsulin to insulin concentrations (bottom panel) in
all 57 volunteers.
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Discussion
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In this paper we have defined for the first time the relationship
between a specific measure of resistance to insulin-mediated glucose
disposal and fasting insulin and proinsulin concentrations in healthy
nondiabetic volunteers. The results of our study can be summarized as
follows: 1) both plasma proinsulin and insulin concentrations are
higher in insulin-resistant than in insulin-sensitive individuals with
normal oral glucose tolerance; 2) the relative increases in the
concentrations of proinsulin and insulin are similar; and 3) the
increases in proinsulin and insulin concentrations are proportionate to
the degree of insulin resistance. Given these findings it seems
reasonable to conclude that insulin resistance per se does
not affect the processing of insulin by the pancreatic ß-cell in
normal individuals. In support of this view is the report that the
molar ratio of proinsulin to insulin was not increased in obese
individuals with normal glucose tolerance (21). On the other hand,
Haffner and associates (22) have published evidence that the ratio of
fasting proinsulin to insulin concentration was increased in
individuals diagnosed as having the insulin resistance syndrome,
i.e. higher plasma triglyceride and lower high density
lipoprotein cholesterol concentrations, IGT, and mild hypertension.
These data were interpreted to signify that insulin resistance
per se was associated with an increase in the ratio of
fasting proinsulin to insulin concentrations. Obviously, this
conclusion is in marked contrast to our data showing that the ratios of
fasting proinsulin to insulin were similar in insulin-resistant and
insulin-sensitive normal volunteers. One obvious difference is that we
actually measured insulin-mediated glucose disposal, whereas its
presence was inferred by Haffner et al. (22). Furthermore,
their population was quite different from ours, in being heavier (BMI,
30 kg/m2) and predominately Mexican-American (70%),
and approximately 25% of their population had either IGT or
hypertension. The role played by any of these factors in accounting for
the disparity in results remains to be seen, but it seems reasonable to
conclude at this time that insulin resistance, per se does
not necessarily lead to an increase in the ratio of fasting proinsulin
to insulin concentrations.
Although it was not the primary goal of this study, these results are
relevant to the more general question as to what insights into the
pathogenesis of NIDDM can be gained by determining the fasting
proinsulin to insulin ratio. The earlier an increase in the ratio of
proinsulin to insulin can be seen in the natural history of NIDDM, the
more fundamental to the pathogenesis of the syndrome would appear to be
the role of abnormal processing of insulin by the ß-cell. In this
context, published data are ambiguous. The results of our study as well
as those of three others (2, 3, 23) have found no significant increase
in the proinsulin to insulin ratio in patients with IGT. Furthermore,
Clark and associates (24) have shown that the ratio of proinsulin to
insulin remains normal in diet-treated patients with NIDDM. In
contrast, Davies et al. (25), reported that the fasting
percentage of proinsulin to insulin was higher (15.3% vs.
11.6%) in patients with IGT, and Haffner and associates (26) also
found the ratio to be somewhat higher in patients with IGT (0.09
vs. 0.07).
The situation appears equally controversial in the case of women with
gestational diabetes (27, 28). Thus, Byrne et al. (27)
reported that the molar ratio of proinsulin to insulin was unchanged in
insulin-resistant women with a history of gestational diabetes, whereas
Hanson et al., in a much larger series of subjects, found
the ratio to be elevated (28). However, even in this latter case, the
researchers concluded that an increase in the ratio of proinsulin to
insulin was not a marker for the development of either IGT or
NIDDM.
If we focus on normal glucose-tolerant individuals, the results are
also mixed. Insulin resistance and/or hyperinsulinemia are recognized
as risk factors for the development of NIDDM in subjects with normal
glucose tolerance (6, 7, 8, 9), and we found the ratio of proinsulin to be
similar in insulin-resistant and hyperinsulinemic normal volunteers
compared to that in a matched group of insulin-sensitive individuals.
Furthermore, Haffner et al. (5) published data indicating
that nondiabetic individuals from a population at high risk to develop
NIDDM (Mexican-Americans) had higher fasting concentrations of both
proinsulin and insulin than did a population at low risk for NIDDM
(non-Hispanic whites), but similar ratios of proinsulin to insulin. On
the other hand, as discussed earlier, the same research group found the
proinsulin to insulin ratio to be increased in subjects with
manifestations of the insulin-resistant syndrome (22) as well as in
normal glucose-tolerant individuals of Mexican-American ancestry who
had a positive history of NIDDM compared to that in Mexican-Americans
without a positive family history (29). However, the impact of a family
history of NIDDM on the ratio of proinsulin to insulin was not observed
in studies carried out in either Pima Indians (3) or Finnish subjects
(23). Finally, although normal glucose-tolerant older individuals were
shown to have an increased molar ratio of proinsulin to insulin (21),
the researchers concluded that this was more likely to "reflect
intrinsic age-related ß-cell dysfunction." Obviously, consensus has
not emerged as to whether an increase in proinsulin disproportionate to
the increase in insulin concentration antedates the development of
NIDDM.
In conclusion, we demonstrated a higher fasting plasma concentration of
both proinsulin and insulin in nondiabetic insulin-resistant subjects,
and the more insulin resistant the individual, the greater the
increase. On the other hand, the fasting proinsulin to insulin ratio
bore no relationship to the degree of insulin resistance. Thus, insulin
resistance and the need to secrete more insulin to maintain glucose
tolerance do not necessarily lead to abnormal insulin processing by the
ß-cell.
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Footnotes
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1 This work was supported by grants from the NIH (RR-00070 and
HL-80506), the American Diabetes Association (Mentor Award), and the
office of Research and Development: Medical Research Service,
Department of Veteran Affairs. 
Received May 1, 1997.
Revised June 18, 1997.
Accepted June 19, 1997.
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Top
Abstract
Introduction
