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Original Articles |
INSERM, U-457 (D.J., P.C., C.L.-M.), and Clinical Investigation Unit (R.H.), Hôpital Robert Debré, 75019 Paris, France; and INSERM, U-449, and Genalys, Faculté de Médecine Laennec (H.V.), 69372 Lyon, France
Address all correspondence and requests for reprints to: Dr. D. Jaquet, INSERM, U-457, Hôpital Robert Debré, 75019 Paris, France. E-mail: djacquet{at}infobiogen.fr
Abstract
The aim of this study was to investigate whether insulin
resistance-associated in utero undernutrition was
related to changes in insulin action on gene expression of molecules
involved in the insulin signaling pathway and peripheral glucose
metabolism in muscle and adipose tissue. Thirteen insulin-resistant
subjects born with intrauterine growth retardation (IUGR) were matched
for age, gender, and body mass index to 13 controls. Gene expression of
insulin receptor, insulin receptor substrate-1, p85
phosphatidylinositol 3-kinase, glucose transporter-4 (GLUT4),
hexokinase II, and glycogen synthase was studied in skeletal muscle at
baseline and after a 3-h euglycemic insulin stimulation. Target
messenger ribonucleic acid (mRNA) levels were quantified using the
RT-competitive PCR method. Insulin-stimulated glucose uptake was
significantly lower in IUGR-born subjects than in controls (36.9
± 12, 7 vs. 53.9 ± 12.7 µmol/kg·min;
P = 0.007), affecting both the glucose oxidation
rate and the nonoxidative glucose disposal rate. At baseline, the
expression of the six genes in muscle did not significantly differ
between the two groups. The insulin-induced changes over baseline
were comparable in both groups for all mRNAs, except GLUT4. In contrast
to what observed in the control group (mean increment, 49 ± 23%;
P = 0.0009), GLUT4 expression was not stimulated by
insulin in the IUGR group (8 ± 8%; P =
0.42). Moreover, the magnitude of the defect in GLUT4 mRNA regulation
by insulin was correlated to the degree of insulin resistance (r =
0.73; P = 0.01). A similar lack of significant
GLUT4 mRNA stimulation by insulin was observed in the adipose tissue of
IUGR-born subjects. In conclusion, insulin resistance in IUGR-born
subjects is associated with an impaired regulation of GLUT4 expression
by insulin in muscle and adipose tissue. Our data provide additional
information about the mechanism of insulin resistance associated with
in utero undernutrition and strengthen the role of
glucose transport in the control of insulin sensitivity.
THE ASSOCIATION between in utero undernutrition and the later impairment of glucose tolerance or type 2 diabetes is now well established (1, 2). Several recent reports support the hypothesis that this association involves a prior step of insulin resistance as observed in common forms of type 2 diabetes (3, 4, 5). In a cohort of young adults (25 yr old) selected from birth data, we have shown that subjects born with intrauterine growth retardation (IUGR) demonstrated hyperinsulinemia and insulin resistance, with normal glucose tolerance (6, 7). However, the mechanisms by which in utero undernutrition leads to the development of insulin resistance in adulthood remain unknown.
To explain the high prevalence of type 2 diabetes in Western populations, Neel has hypothesized that genes that would favor survival at a time of famine would become detrimental when food supply is abundant. These genes build the thrifty genotype (8). Moreover, it has been recently proposed that genetic predisposition to insulin resistance might represent a selective survival advantage in low birth weight infants (9). We speculated that such a genetic predisposition could alter the control of gene expression of the molecules involved in insulin action.
The aim of the present study was therefore to investigate whether early
adult-onset insulin resistance associated with in utero
undernutrition would be related to an impaired expression and/or an
altered regulation of genes involved in the insulin signaling pathway
and the peripheral glucose utilization. For this purpose, gene
expression of insulin receptor, insulin receptor substrate-1 (IRS-1),
p85 regulatory subunit of the phosphatidylinositol 3-kinase
(p85PI-3K), glucose transporter-4 (GLUT4), hexokinase II, and
glycogen synthase were measured in the basal state and after insulin
infusion in muscle and adipose tissue biopsies from controls and
insulin-resistant IUGR-born subjects.
Subjects and Methods
Subjects
The study population consisted of 13 insulin-resistant subjects
born with IUGR and 13 controls recruited from the regional cohort of
the city of Haguenau in which subjects had been selected from birth
data (6). All subjects were of Caucasian origin. IUGR was
defined as a birth weight below the third percentile of the local
distribution for gender and gestational age (10). Control
subjects, selected for birth weight between the 25th and the 75th
percentiles of the same distribution, were matched for age, gender, and
body mass index at the time of the study to the IUGR-born subjects. The
clinical characteristics of the 2 groups at birth and at the time of
the study are summarized in Table 1
. As
expected, mean birth weight and ponderal index were significantly
reduced in the IUGR group. According to the selection criteria, there
were no significant differences between the 2 groups in terms of age,
gender distribution, ‘and anthropometric parameters at the time of the
study. Parental history of type 2 diabetes (P = 0.59),
dyslipidemia (P = 0.64), and hypertension
(P > 0.99) did not significantly differ between the 2
groups. All subjects had normal glucose tolerance during an oral
glucose tolerance test, according to American Diabetes Association
criteria (11). All subjects gave their written informed
consent, and the study protocol was reviewed and approved by the ethics
committee of the Paris/St. Louis School of Medicine.
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Assessment of total body fat mass. The percentage of total body fat mass was calculated after bioelectrical impedance analysis (RJL Systems, Clinton Township, NJ).
Euglycemic hyperinsulinemic clamp. Subjects were admitted to the Clinical Investigation Unit at Robert Debré Hospital (Paris, France). A 3-h euglycemic hyperinsulinemic clamp was performed after a 10-h fast as previously described (12). Insulin was infused throughout the test at 80 mU/m2·min. To maintain plasma glucose concentrations at 100 ± 10 mg/dL during the clamp, adjustment of glucose infusion was made from the results of plasma glucose measured every 5 min during the first hour and the two measurement periods. In between, adjustment was performed every 10 min.
Peripheral glucose uptake was calculated as the average glucose infusion rate during two consecutive 20-min periods (140–180 min) and was corrected for a target value of plasma glucose at 5.5 mmol/L. At steady state, mean plasma glucose concentrations were similar in the IUGR and control groups (5.44 ± 0.11 vs. 5.39 ± 0.11 mmol/L, respectively). Intraindividual coefficients of variations of plasma glucose during the first and the second periods were 1.9 ± 0.5% and 1.9 ± 0.6%, respectively. Serum insulin concentrations measured at steady state did not differ between IUGR-born subjects and controls (1224 ± 420 vs. 1244 ± 396 pmol/L; P = 0.85).
The glucose turnover rate was determined by the tracer dilution method. A priming dose (5 mg/kg) of [6,6-2H2]glucose (Eurisotop, St. Aubain, France) was given 90 min before the clamp was started, followed by a continuous infusion (5 mg/kg·h) throughout the basal and clamp periods. [6,6-2H2]Glucose isotopic enrichment was determined from blood samples drawn every 10 min during the last 30 min of the basal period and during the last 40 min of the euglycemic clamp. Endogenous glucose production was calculated at baseline and at the end of the euglycemic clamp using steady state equations (13). To calculate glucose oxidation rate, respiratory exchange measurements were taken during the final 30 min of both the basal and clamp periods using indirect calorimetry (GEN, Europa-Scientific, Crewe, UK). Steady state was obtained when the intraindividual coefficient of variation of the respiratory exchange measurements was less than 10% during at least 20 min.
The nonoxidative glucose disposal rate was calculated as the difference between the peripheral glucose uptake and the glucose oxidation rate.
Analytical methods
Plasma glucose concentrations during the clamp were measured by the glucose oxidase method with an on-site analyzer (Beckman Coulter, Inc., Fullerton, CA).
Plasma insulin concentrations were measured using a double antibody RIA (ERIA Diagnostics Pasteur, Paris, France). Cross-reactivity with proinsulin and derived metabolites was less than 1%. Assay sensitivity was 1.2 pmol/L, and intra- and interassays coefficients of variations were 3.8% and 8% at 48 pmol/L, respectively, and 2.4% and 4.8% at 300 pmol/L, respectively.
Plasma isotopic enrichment of [6,6-2H2]glucose was determined by gas chromatography-mass spectrometry (5971 MSD, Hewlett-Packard Co., Palo Alto, CA). Mean values of the intraindividual coefficients of variation of the plasma isotopic enrichment of [6,6-2H2] glucose at steady state were 4.9 ± 2.1% and 7.2 ± 2.2% at baseline and during the hyperinsulinemic clamp, respectively.
Muscle and adipose tissue biopsies
Muscle and adipose tissue biopsies were performed under local anesthesia (2% lidocaine) at baseline and after the 3-h insulin infusion, as previously described (13, 14, 15). Muscle biopsies were obtained percutaneously from the vastus lateralis using a Weil Blakesley plier (wet weight, 58 ± 4 mg, with no significant difference in sample sizes between the IUGR and control subjects). Abdominal sc adipose tissue was aspirated from the periombilical area through a 15-gauge needle (wet weight, 259 ± 16 mg, with no significant difference in sample sizes between IUGR and control subjects). Tissue samples were immediately frozen in liquid nitrogen and stored at -80 C for further analysis.
Total RNA preparation
Tissue samples were pulverized in liquid nitrogen. Total RNAs were isolated from muscle biopsies using the TRIzol reagent (Life Technologies, Inc., Cergy-Pontoise, France). The yield in total RNA was 25.7 ± 2.5 µg/100 mg muscle tissue (wet weight). For adipose tissue, total RNAs were prepared using the RNeasy total RNA kit (QIAGEN, Courtaboeuf, France). The recovery was 1.4 ± 0.1 µg/100 mg tissue (wet weight). The 260–280 nm absorbance ratio was between 1.8–2 for all preparations. Total messenger RNA (mRNA) solutions were stored at -80 C until quantification of the target mRNAs.
Quantification of target mRNAs
The absolute mRNA concentrations of the six selected genes were
measured by RT-competitive PCR (RT-cPCR), a method that relies on the
use of a competitor DNA molecule during the amplification process,
after a specific RT reaction (13, 14). The conditions of
the RT have been defined to warrant maximal efficiency of first strand
complementary DNA synthesis (14), and the competitive PCR
has been clearly demonstrated to be a real quantitative method to
determine the steady state expression levels of specific mRNAs
(14). Insulin receptor, IRS-1, and glycogen synthase mRNAs
were quantified using a multispecific competitor DNA that was
constructed and validated previously (13). For the assays
of the mRNAs encoding GLUT4, p85PI-3K and hexokinase II, we used
another competitor DNA molecule that was recently developed and
validated (16). The sequences of the primers used for the
RT-cPCR assays are indicated in the previous publications (13, 16).
The conditions of the RT-cPCR reactions have been described in details previously (13, 14). For each mRNA, the specific first strand complementary DNA was synthesized from 0.1 µg of total RNA added in the RT reaction. During the PCR, we used sense primers that were 5'-end labeled with Cy-5 fluorescent dye (Eurogentec, Seraing, Belgium). The PCR products were then analyzed with an automated laser fluorescence DNA sequencer (ALFexpress, Pharmacia, Upsala, Sweden) in denaturating 4% polyacrylamide gels (15, 16). The amounts of PCR products (competitor and target) were calculated by integrating peak areas using Pharmacia Fragment Manager software from. To determine the initial concentration of the target mRNA, the logarithm of the peak surface ratio of competitor to target was plotted against the logarithm of the amount of competitor added into the PCR medium. The initial concentration of the target was determined at the competition equivalence point as previously described (14). Coefficients of variation range from 5 to 17% according to the mRNA tested (14).
Statistical analyses
All data were entered and analyzed on the StatView 5.0
statistical package. (SAS Institute, Inc., Cary, NC).
Nonparametric tests were used for continuous variables because of the
small sample size and the skewed distributions of the data. The
Mann-Whitney U test was used for the comparison between the IUGR and
control groups. The paired Wilcoxon test was used in each group for the
comparisons of gene expression changes under insulin stimulation
vs. baseline. The relationship between changes in gene
expression after insulin stimulation and the peripheral glucose uptake
values were analyzed using a linear regression model. P
0.05 was considered significant.
Results
Metabolic parameters
At baseline, mean values of fasting plasma glucose were comparable between the IUGR and control groups (4.90 ± 0.44 vs. 4.79 ± 0.39 mmol/L; P = 0.68). Endogenous glucose production did not significantly differ between the two groups (11.6 ± 2.2 vs. 12.1 ± 1.1 µmol/kg·min; P = 0.52). The glucose oxidation rate was slightly lower in the IUGR group, but the difference did not reach statistical significance (8.8 ± 2.2 vs. 10.5 ± 2.8 µmol/kg·min; P = 0.06). Serum fasting triglycerides (1.47 ± 0.87 vs. 1.21 ± 1.15 mmol/L; P = 0.34), total cholesterol (4.73 ± 0.59 vs. 4.45 ± 0.74 mmol/L; P = 0.45) and high density lipoprotein cholesterol (1.62 ± 0.63 vs. 1.41 ± 0.42 mmol/L; P = 0.44) did not significantly differ between IUGR-born and control subjects.
As shown in Fig. 1, at steady state under
insulin stimulation, peripheral glucose uptake, the glucose oxidation
rate, and the nonoxidative glucose disposal rate were reduced in the
IUGR-born subjects. The relative specific contributions of glucose
oxidation rate (45 ± 13% vs. 40 ± 6%), on the
one hand, and the nonoxidative glucose disposal rate (55 ± 13%
vs. 60 ± 6%), on the other hand, to the peripheral
glucose uptake under insulin stimulation did not significantly differ
between the IUGR and control groups (P = 0.17). This
suggests that both components of peripheral glucose uptake were equally
affected in the IUGR group. Endogenous glucose production was similarly
suppressed in the two groups under insulin stimulation (-7.2 ±
7.7 vs. 7.7 ± 6.1 µmol/kg·min; P =
0.58).
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The mRNA levels (expressed as attomoles per µg total RNA) for
genes encoding key proteins of the insulin signaling pathway, namely
insulin receptor, IRS-1, and p85PI-3K, or key proteins involved in
peripheral glucose utilization (GLUT4, hexokinase II, and glycogen
synthase) were determined in skeletal muscle by RT-cPCR. The mean
concentrations of these transcripts in the basal state in the two
groups are given in Table 2A. There were
no statistically significant differences between the IUGR and control
groups in basal mRNA expression of the six target genes.
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PI-3K mRNA expression in the IUGR and control groups was
observed. Conversely, a significant reduction of IRS-1 mRNA expression
was noted in both groups (values expressed as the percent change over
baseline are given in Table 2
B). Insulin infusion did not significantly
affect the mRNA level of insulin receptor in either IUGR-born subjects
or controls (Table 2B). When compared between the two study groups, the
mean percent changes over baseline of expression of these three genes
did not show any statistically significant differences.
With respect to the molecules involved in peripheral glucose
utilization, insulin infusion had no statistically significant effect
on glycogen synthase mRNA expression in both IUGR and control groups
(Table 2). Conversely, hyperinsulinemia significantly increased
hexokinase II mRNA expression compared with baseline in both IUGR-born
and control subjects (Table 2). When the two study groups were
compared, the magnitude of the insulin-induced changes over baseline in
the mRNA expression of these two genes did not significantly differ
(Table 2B). GLUT4 mRNA expression was significantly increased during
insulin infusion in the control group and the relative increment over
baseline (+49 ± 23%) was statistically significant (Fig. 2). By contrast, as illustrated in Fig. 2, insulin infusion had no significant effect on GLUT4 mRNA expression
in the IUGR group (relative increment over baseline, +8 ± 8%;
P = 0.85).
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).
No significant correlation was found in the control group (r =
0.006; P = 0.98).
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Effect of insulin infusion on GLUT4 mRNA expression in adipose tissue
The lack of significant stimulation of GLUT4 mRNA expression by
insulin in muscle led us to investigate whether the same impairment
would also prevail in the adipose tissue of IUGR-born subjects. In sc
abdominal adipose tissue, GLUT4 mRNA expression at baseline did not
significantly differ between IUGR and control subjects (45.8 ±
8.6 vs. 57.3 ± 8.6 attomoles/µg total mRNA;
P = 0.57). Figure 2 shows that, as in skeletal muscle,
insulin infusion for 3 h failed to have a significant effect in
IUGR subjects; the relative increment in GLUT4 expression over baseline
was +32 ± 19%, and the comparison was not statistically
significant vs. baseline (P = 0.25).
Conversely, GLUT4 mRNA levels were significantly increased in adipose
tissue of the control subjects (+94 ± 27%; P =
0.01). When the two study groups were compared, the insulin-induced
relative changes in GLUT4 mRNA expression in the adipose tissue reached
the same level of significance as those in muscle (8 ± 8%
vs. 49 ± 23%; P = 0.09).
Discussion
The main finding of our study is that insulin resistance is associated with an impaired regulation of GLUT4 gene expression by insulin in IUGR-born subjects that is observed in both skeletal muscle and adipose tissue. All subjects included in the present study had been precisely selected on birth data, and both groups were carefully matched for age, gender, and body mass index. Additionally, the two groups were comparable in terms of parental history of type 2 diabetes, dyslipidemia, or hypertension. Therefore, the insulin resistance observed in the IUGR group is probably related to in utero undernutrition itself and not to other confounding factors.
Interestingly, in the IUGR group, the magnitude of the defect in GLUT4 mRNA regulation by insulin in muscle was correlated to the degree of insulin resistance assessed by the insulin-stimulated glucose uptake. No such a correlation was found when changes in hexokinase II or glycogen synthase mRNA expression under insulin stimulation were analyzed. In addition, mRNA expression of these two genes did not significantly differ between the IUGR and control groups either at baseline or under insulin stimulation. These observations are consistent with the metabolic abnormalities observed in the IUGR-born subjects. Indeed, our data show that under insulin stimulation, both the glucose oxidation rate and the nonoxidative glucose disposal rate are affected in IUGR-born subjects, suggesting that these two components account for the decreased insulin sensitivity.
Taken together, our data suggest that an impaired regulation of GLUT4 gene expression might contribute to the insulin resistance associated with in utero undernutrition, strengthening the role of glucose transport in the control of insulin sensitivity. Nevertheless, further studies investigating the consequences of this abnormality at the protein level are necessary, and the mechanism by which GLUT4 might be involved in this case of insulin resistance should be examined.
The question of whether the impaired regulation by insulin of GLUT4 gene expression observed in insulin-resistant IUGR-born subjects is a consequence of the insulin resistance itself or whether it is rather related to in utero undernutrition remains to be elucidated. GLUT4 expression at baseline was comparable in muscle of IUGR-born and control subjects. This observation is in keeping with reports of normal GLUT4 mRNA levels in muscle from diabetic patients (16, 17, 18, 19, 20, 21, 22). The acute regulation by insulin of GLUT4 gene expression in normal subjects and patients with insulin resistance has not been fully investigated in humans. Using a slot blot analysis, Andersen et al. previously reported that GLUT4 gene expression in muscle was acutely stimulated by short-term insulin stimulation in healthy subjects (21). By contrast, GLUT4 mRNA expression failed to increase under insulin infusion in type 2 diabetic patients and insulin-resistant first degree relatives (21, 23). Together, these data favor the idea that an impaired acute insulin stimulation of GLUT4 gene expression would reflect insulin resistance itself. Further investigations of GLUT4 gene expression and its regulation under other pathological conditions associated with insulin resistance will help clarify the proper role of in utero undernutrition on the impaired regulation by insulin of GLUT4 gene expression observed in IUGR-born adults.
Unlike the blunted insulin stimulation of p85PI-3K gene expression
reported in type 2 diabetic patients (15), we failed to
observe any impairment in the expression and regulation by insulin of
the major genes involved in the insulin signaling pathway (insulin
receptor, IRS-1, and p85PI-3K) in the IUGR-born subjects. The
insulin resistance observed in these subjects was not associated with
an impaired expression of hexokinase II (16, 24) or
glycogen synthase (16, 25), as previously shown in
skeletal muscle of type 2 diabetic subjects. Together, these data
suggest that the molecular mechanisms responsible for insulin
resistance associated with type 2 diabetes mellitus or with in
utero undernutrition may be different. Alternatively, the
different pattern of expression of the key genes involved in insulin
sensitivity could represent different degrees of progression of the
disease. The comparison between IUGR-born adults with insulin
resistance or overt diabetes would be extremely useful to distinguish
between the two options.
IUGR is known to severely alter the fetal development of adipose tissue (26), and we have previously reported that IUGR-born subjects selected within the same cohort showed traits of insulin resistance in the adipose tissue (7). In the present study insulin-resistant IUGR-born subjects demonstrated an impaired regulation by insulin of GLUT4 gene expression in the sc adipose tissue as opposed to the positive effect of insulin in the control subjects and previously reported in healthy young adults during a hyperinsulinemic clamp (27). Our results constitute the first observation of a defective regulation of GLUT4 gene expression in adipose tissue of insulin-resistant subjects, strengthening the hypothesis that adipose tissue could be a key component of the metabolic complications associated with in utero undernutrition.
In conclusion, we have demonstrated that both the glucose oxidation rate and the nonoxidative disposal rate were affected by the insulin resistance associated with in utero undernutrition. These metabolic abnormalities are consistent with the impaired regulation by insulin of GLUT4 mRNA expression observed in both muscle and adipose tissue of insulin-resistant IUGR-born subjects. Although the consequences of such an impaired regulation of GLUT4 gene expression remain to be studied at the protein level, our results demonstrate that molecular abnormalities are already present in the insulin resistance observed in young, normoglycemic, IUGR-born adults. Moreover, our data provide an additional example of the contribution of glucose transport abnormalities to the pathophysiology of insulin resistance.
Acknowledgments
We acknowledge N. Vega for her excellent technical assistance. The authors thank Dr. D. Chevenne for his supervision of laboratory analyses. We also acknowledge the contributions of C.Traband, Dr. C. Collin, Dr. Boehrer, the laboratory staff at the Hospital of the City of Haguenau, and the nursing staff of the Clinical Investigation Unit of the Hospital R. Debré in supervising subjects.
Footnotes
1 This work was supported in part by Pharmacia-Upjohn (St.
Quentin-en-Yveunes, France) and a grant from La Fondation de
France. 
2 Supported by a fellowship from INSERM sponsored by Bayer Corp.-France.
Received November 10, 2000.
Revised February 5, 2001.
Revised March 21, 2001.
Accepted March 23, 2001.
References
phosphatidylinositol 3-kinase mRNA in
skeletal muscle of patients with type II (non-insulin-dependant)
diabetes mellitus. Diabetologia. 43:356–363.[CrossRef][Medline]
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) and
control (
) groups. Values were obtained after a 3-h insulin infusion
(80 mU/m2·min) at steady state of a euglycemic
hyperinsulinemic clamp. Results are given as the mean ±
SD. Satistical significance is given for the comparison
between the two study groups using a nonparametric Mann-Whitney U test.
PGU, Peripheral glucose uptake; NOXGDR, nonoxidative glucose disposal
rate; GOXR, glucose oxidation rate.
