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* The Lundberg Laboratory for Diabetes Research and
SOS Obesity Research Laboratory, Department of Internal Medicine, Sahlgrenska University Hospital, Göteborg, Sweden; and
Department of Endocrinology, Lund University, Malmö University Hospital, Malmö, Sweden
1Correspondence: The Lundberg Laboratory for Diabetes Research, Department of Internal Medicine, Sahlgrenska University Hospital, Grona Straket 8, SE-413 45 Göteborg, Sweden. E-mail ulf.smith{at}medicine.gu.se
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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50%
of the matched control group) was seen in 
30% of both groups and
these individuals were characterized by insulin resistance and its
hallmarks: higher levels of insulin, glucose, and triglycerides. Two
individuals with previously unknown NIDDM were diagnosed and both had
low IRS 1 expression. Low IRS 1 protein expression was associated with
low mRNA levels but not with the common Gly972Arg polymorphism of the
IRS 1 gene. Taken together, our present and previous findings show that
a low expression of IRS 1 in fat cells predicts insulin resistance and
NIDDM. Furthermore, they support the likelihood that an impaired
transcriptional activation may play a key role in the pathogenesis of
NIDDM.—Carvalho, E., Jansson, P.-A., Axelsen, M., Eriksson, J. W., Huang, X., Groop, L., Rondinone, C., Sjöström, L.,
Smith, U. Low cellular IRS 1 gene and protein expression predict
insulin resistance and NIDDM.
Key Words: diabetes • obesity • insulin receptor substrate 1 • insulin signaling • insulin action
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. Both genetic and
environmental factors play a role in the pathogenesis of NIDDM.
However, little progress has been made in unraveling the fundamental
molecular and genetic factors. Several environmental factors have been
defined including obesity, certain drugs, and smoking
(1
2
3)
. Genetic predisposition plays a key role since only
some individuals exposed to the environmental risk factors develop
NIDDM. Furthermore, healthy individuals who have two first-degree
relatives with NIDDM have a three- to fivefold greater risk of
developing the disease than those without a family history of diabetes
(4)
.
It is highly likely that NIDDM is a polygenic disorder involving
proteins related to insulin secretory capacity and/or insulin
sensitivity. Mutations have been identified in a few cases of NIDDM
involving the insulin receptor (5)
, other proteins in
insulin’s signaling cascade (6)
, or transcription factors
(7)
. However, no mutations of importance have been defined
in the ‘normal’ NIDDM phenotypes, i.e., in at least 90% of the
subjects.
A common polymorphism involving the important intracellular protein IRS
1 (insulin receptor substrate 1) has been reported (8)
.
IRS 1 is a docking protein that needs to become phosphorylated in order
to activate the enzyme phosphatidyl inositol 3-kinase (PI3-kinase), a
necessary step for the initiation of several effects of insulin such as
glucose transport (9)
. However, the IRS 1 polymorphism
seems to be important only in its rare homozygous form or may be
related to insulin resistance if combined with obesity
(8)
.
We have recently reported that fat cells from individuals with NIDDM
exhibit a marked reduction in cellular protein expression and function
of IRS 1 (10)
. The ‘backup’ protein IRS 2 was then found
to be the main docking protein for the intracellular propagation of the
insulin signal including the activation of PI3-kinase
(10)
. However, IRS 2 required a higher insulin
concentration for activation, the hallmark of insulin resistance. This
perturbation was not found in IDDM and thus is not related to
hyperglycemia per se (10)
.
We have now examined two groups of individuals with an increased
propensity for NIDDM: healthy individuals with a massive family
history, defined as two first-degree relatives with NIDDM; and
individuals with massive obesity. We found a marked reduction in IRS 1
protein content in ~30% of these two groups, which was associated
with insulin resistance and the presence of other markers of the
insulin resistance syndrome (11)
, including higher fasting
insulin and triglyceride levels.
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MATERIALS AND METHODS |
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The second group of individuals was recruited from the Obesity
Outpatient Unit. They all suffered from chronic massive obesity and
were under evaluation for potential surgery with gastric banding.
Clinical characteristics of the patient groups are shown in Tables 1
and 2
. Heredity for diabetes was common in the obese group but none had
two first-degree relatives with known NIDDM.
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Procedures
After admission to the study all patients underwent the
following investigations. Body weight and length were recorded with
standard techniques. Waist and hip circumferences were registered and
the waist/hip ratio (WHR) was calculated (12)
. Body
composition was analyzed by bioimpedance in the relatives and their
control subjects, and lean body mass (LBM) and body fat were
calculated. All subjects then underwent a 75 g oral glucose
tolerance test (OGTT), with measurements of blood levels of glucose and
insulin at times 0 and 120 min. Fasting levels of triglycerides were
analyzed using routine hospital techniques. Biopsies of the abdominal
subcutaneous fat were obtained by the needle aspiration technique.
Relatives with a family history and their matched controls underwent
additional investigations. Degree of insulin sensitivity was measured
with the euglycemic, hyperinsulinemic clamp technique
(13)
, the ‘golden’ standard for measuring insulin
sensitivity, as previously reported in detail (14)
.
Briefly, insulin was infused into an intravenous cannula placed in the
antecubital vein at a rate of 60 mU/m2/min. Blood
glucose levels were maintained at 5.0 mmol/l by infusing glucose at a
variable rate. After reaching a plateau (~60–90 min), the average
rate of glucose infusion required to maintain euglycemia was calculated
over 30 min (90–120 min) and expressed per kilogram of LBM. Glucose
was analyzed in arterialized venous blood using an automatic glucose
analyzer (Yellow Springs Instrument, Yellow Springs, Ohio). Insulin was
analyzed with a standard radioimmunoassay (Pharmacia, Uppsala, Sweden).
The relatives and their controls also underwent a test for oral lipid
tolerance, as described previously (15)
. The subjects
consumed a mixed meal containing 51 g (49 E%) fat and 83 g
(36 E%) carbohydrates. Serum triglyceride levels were measured before,
during, and 6 h after food ingestion.
Fat cell analyses
The adipose specimens obtained from the needle biopsies were
digested with collagenase to obtain isolated fat cells
(16)
. The cells were then lysed in the presence of
protease inhibitors, followed by protein separation in 7.5% sodium
dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) as
previously reported (10)
. The protein content of IRS 1 was
analyzed by immunoblotting with a carboxyl-terminal antibody (UBI, Lake
Placid, NY) and the gels were scanned with a PhosphorImager.
Quantitation was also verified with 125I-protein
A (10)
. A protein reduction of 
50% as compared to
control subjects was required for the definition of a low IRS 1 protein
content.
Cell lysates were also analyzed for other key proteins in the intracellular signaling cascade for insulin such as the insulin receptor and the subunits of PI3-kinase. mRNA for IRS 1 was quantified on Northern blots using a cDNA probe against bases 1333–2335.
All evaluations of protein expression were performed by the same investigators (E.C. and U.S.), who were blinded to any information about the clinical and laboratory results of the subjects prior to the final analysis.
Screening for the Gly972Arg polymorphism
As the Gly972Arg polymorphism in IRS 1 creates a BstNI site, it
can be detected by polymerase chain reaction (PCR) -restriction
fragment length polymorphism. The PCR primers flanking this restriction
site were5'-CTTCTGTCAGGTGTCCATCC-3' (upstream) and
5-CTCTGCAGCAATGCCTGTTC-3' (downstream). Genomic DNA (20 ng) was used in
a 20 µl PCR reaction containing 1x PCR buffer, 150 µM dNTP, and
0.4 µM each of the primers, 1% (v/v) formamide and 0.5 U
Taq DNA polymerase (Perkin Elmer, Norwalk, Conn.).
The PCR was run at 94°C for 5 min, 30 cycles at 94°C for 30 s,
55°C for 30 s, 72°C for 30 s, and 72°C for 10 min. Ten
microliter PCR products were incubated with 1 unit of BstNI for 3 h at 60°C in a final volume of 15 µl. The samples were then run on
a 2% agarose gel, stained with ethidium bromide, and analyzed under
ultraviolet light.
Statistical methods
The Mann-Whitney test was used for comparisons between the
groups. P < 0.05 was considered statistically
significant. Conventional methods were used to calculate means
±SE and the X2 test was
used to test for differences in distribution of the protein levels
between the groups.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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shows the clinical and laboratory characteristics of the two groups.
They were of the same age, gender, BMI, and body fat. OGTT was normal
in all subjects, and although the relatives tended to have slightly
higher insulin levels at times 0 and 120 min, no significant
differences were observed. Furthermore, insulin sensitivity measured
with the euglycemic clamp was similar in both groups.
We identified 8/44 individuals, all males, with a marked reduction
(50%) in adipocyte IRS 1 content: two control subjects (2/22=9%)
and six relatives (6/22=27%). Figure 1
shows the IRS 1 protein expression in representative individuals. On
average, it was reduced by ~70% in this group as compared to cells
from the other subjects. This reduction in protein expression was
probably due to a reduced transcription since IRS 1 gene expression
(mRNA levels) was also markedly reduced when measured with Northern
blots (Fig. 2
) and RT-PCR (data not shown). We also investigated whether
abnormalities in the expression of other key insulin signaling proteins
could be detected, i.e., the insulin receptor and PI3 kinase subunits
(p 85 and p 110), but this was not found. However, PI3-kinase activity
associated with IRS 1 was reduced, as expected (data not shown).
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We then compared the clinical characteristics of the group with low IRS
1 expression with the remaining 36 individuals. As shown in Table 1
,
the group with low IRS 1 was differentiated from the other individuals
by having insulin resistance and other markers of the insulin
resistance syndrome. Although these groups had similar age, BMI, amount
of body fat, and glucose levels, the group with low IRS 1 expression
had significantly higher fasting insulin levels, a well-known marker of
insulin resistance. The presence of insulin resistance was also
verified by the euglycemic clamp results and calculation of the Insulin
Sensitivity Index; both analyses showed ~30% lower levels in the
group with low IRS 1 expression. Furthermore, this group had higher
fasting triglyceride levels whereas the postprandial lipid tolerance
was not significantly different. The group with low IRS 1 expression
also had a significantly larger WHR than the other subjects despite
similar BMI and amount of body fat (Table 1)
. Since the group with low
IRS 1 consisted of males only, WHR was also compared to that of males
in the control group. However, the difference was still significant
(P<0.02)
DNA analyses for IRS 1 polymorphism
Polymorphism of the Gly 972 Gly Site for IRS 1 was examined in the
eight individuals with low IRS 1 gene and protein expression as well as
in eight control subjects without this abnormality. Only one individual
with a low IRS 1 expression was found to have the Gly 972 Arg genotype,
and all the rest were normal (Gly 972 Gly).
Obese group
The clinical and laboratory data of the obese individuals are
shown in Table 2
. Compared with relatives and their control subjects (Table 1)
, the
obese group was older and had ~fivefold greater amount of body fat.
Their fasting insulin levels were higher but similar to the group of
relatives and control subjects with low IRS 1 expression (Table 1)
.
Unfortunately, the obese group did not undergo a euglycemic clamp, but
the degree of insulin resistance is indicated by the fasting insulin
levels.
We identified 6/20 (30%) obese individuals with low IRS 1 expression.
The characteristics of this group are shown in Table 2
. They were of
similar age and BMI as the group with normal IRS 1 expression. Their
fasting insulin and glucose levels at 120 min during the OGTT were
significantly higher (Table 2)
, suggesting they were more insulin
resistant. Furthermore, their fasting triglyceride levels tended to be
higher. Two individuals with low IRS 1 expression were found during the
OGTT to have previously undiagnosed NIDDM and an additional two had
impaired glucose tolerance (IGT). No diabetes was detected in the group
with normal IRS 1 expression, but five had IGT.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. Taken together, our findings show that low IRS 1
expression in fat cells is related to insulin resistance but is not
secondary to hyperglycemia, obesity, or hyperinsulinemia per se. This
latter point is important (17)
and is documented by the
finding that several obese individuals had insulin levels at least as
high as the insulin-resistant lean group, but a normal expression of
IRS 1 protein.
Impaired protein expression was more frequently found in young, lean
individuals with a genetic predisposition for NIDDM than in the matched
control subjects (27% vs. 9%), although this difference was not
statistically significant (X2 test,
P<0.2) in this small group of individuals. Furthermore, low
IRS 1 expression was common in the obese group (30%). One reason for
this finding could be a common genetic predisposition for diabetes in
the obese group. Such a possibility is supported by our previous
finding in a prospective population study that a family history of
diabetes was positively associated with overweight and weight gain over
a 12 year follow-up period (18)
.
In the obese group with reduced IRS 1 expression, we also found two
individuals with previously unknown diabetes. However, not all
individuals with an IGT exhibited this abnormality. It is
well-established that IGT comprises a heterogeneous group where
~one-third progresses toward NIDDM, one-third remains as IGT, and
one-third reverses to normal glucose tolerance (19)
. Thus,
on balance, these results show that a reduced IRS 1 expression is
related to insulin resistance in healthy, normoglycemic individuals and
is also seen in NIDDM. An impaired effect of insulin can be expected
when IRS 1 expression is low, since this docking protein is critical
for the normal activation of PI3-kinase in response to insulin and,
consequently, glucose transport and uptake (9)
.
We have been able to use the adipocyte IRS 1 expression as a diagnostic procedure to characterize type of diabetes. Some individuals, presenting themselves with a typical clinical NIDDM phenotype but with normal IRS 1 expression, were found on the basis of subsequent analyses of insulin secretory capacity and presence of autoantibodies to be classified more precisely as IDDM (unpublished data).
Thus, this cross-sectional study suggests that low IRS 1 mRNA and protein expression in fat cells can identify individuals with NIDDM as well as those at risk (i.e., with insulin resistance). Larger studies are obviously required to corroborate this. This will also require a simpler assay since the system currently used is much too time-consuming and cumbersome.
An intriguing question is why low IRS 1 mRNA and protein expression in
fat cells is associated with NIDDM and insulin resistance. It has been
documented that the muscles, rather than fat tissue, are quantitatively
important for glucose disposal (1)
. However, it may well
be that adipose tissue produces or initiates factor(s) that in turn
regulate insulin sensitivity and body glucose homeostasis. This is
supported by recent findings in an animal model where ablation of
adipose tissue development caused the animals to become diabetic
(20)
.
Adipose tissue is the main storage organ in the body for lipids, but it
is highly unlikely that increased free fatty acid (FFA) levels can
account for the present findings. This is also supported by the fact
that fasting FFA levels were not significantly different among
relatives and their controls (data not shown). The endocrine aspects of
the adipose tissue seem much more probable. The fat cells produce
leptin (21)
, which seems to play an important role for
hypothalamic functions and hormone release. However, leptin does not
seem to produce insulin resistance (22)
in the few
short-term experiments that have been performed.
Another possibility is related to the production of cytokines, such as
the interleukins and tumor necrosis factor 
(TNF-), by the
adipose tissue. This is increased in obesity and immunoneutralization
of TNF- in obese animal models improves insulin resistance
(23)
. TNF- has been shown to impair gene transcription
for IRS 1 (24)
. Thus, one possibility is that individuals
with low IRS 1 gene and protein expression have an increased production
of TNF- and/or other cytokines by the adipose cells. This could, in
turn, reduce insulin-stimulated glucose uptake by peripheral tissues.
Furthermore, IRS 1 expression in the muscles may also be reduced,
similar to what was seen in the fat cells. Although it has been
reported that muscle IRS 1 protein expression does not appear to be
reduced in NIDDM, impaired phosphorylation and PI3-kinase activation in
response to insulin have been reported (25)
.
How could a genetic predisposition become apparent in this
scenario? It could be related to the activation of the gene(s)
regulating the production rate and/or the cellular sensitivity to
cytokines. In this scenario, the low IRS 1 protein expression would be
a marker of the underlying defect. Another possibility is that the low
IRS 1 protein reflects an impaired activation of transcription factors
important for this and possibly other proteins. Mutations of the HNF
transcription factors have been reported in subjects with
maturity-onset diabetes in the young (MODY) (7)
.
It is clear that the common polymorphism for the IRS 1 gene (Gly 972
Arg) cannot explain the present findings, since we found no
relationship between genotypes and low IRS 1 protein expression.
However, the WHR, a well-established marker of risk for NIDDM
(26)
, was significantly elevated in the group with low IRS
1 protein expression. Thus, the presence of this perturbation in the
fat cells also seems to be linked to other established risk factors for
NIDDM.
In summary, the present results show that low IRS 1 gene and protein expression is common in individuals with both genetic and environmental (obesity) risk for NIDDM, suggesting that this abnormality is located at a common pathogenetic pathway. Furthermore, the data support the concept that impaired transcriptional activation may play a key role in the development of insulin resistance and NIDDM.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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REFERENCES |
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