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Departments of Reproductive Biology (J.P.K., A.V., M.J., L.P., P.M.C.) and Nutrition (J.P.K.), Case Western Reserve University School of Medicine, and Schwartz Center for Metabolism and Nutrition (J.P.K., P.M.C.), MetroHealth Medical Center, Cleveland, Ohio 44109; and Departments of Pediatrics, Biochemistry, and Molecular Genetics (J.S., J.E.F.), University of Colorado Health Sciences Center, Denver, Colorado 80262
Address all correspondence and requests for reprints to: Jacob E. Friedman, Ph.D., Departments of Pediatrics, Biochemistry, and Molecular Genetics, University of Colorado Health Sciences Center, 4200 East 9th Avenue, B-195, Denver, Colorado 80262. E-mail: jed.friedman{at}uchsc.edu.
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Abstract |
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regulatory subunit of phosphatidylinositol 3-kinase was markedly reduced by 55% (P < 0.02) postpartum. The change in insulin sensitivity from late pregnancy to postpartum correlated highly with the corresponding change in IRS-1 protein (r = 0.84; P < 0.007). Downstream signaling proteins, including total Akt and p70s6 kinase, and the glucose transporter protein GLUT-4, were similar at both time points. These data suggest that reduced IR tyrosine kinase activity is not a major factor in the IR of pregnancy in lean women with normal glucose tolerance. Rather, the reversal of insulin resistance 1 yr postpartum is accompanied by increased skeletal muscle IRS-1 along with a down-regulation of the p85 subunit of phosphatidylinositol 3-kinase. These changes may allow for greater p85/p110 binding to IRS-1 and play a significant physiological role in the underlying metabolic adaptation to normal human pregnancy and restoration of insulin sensitivity postpartum. |
Introduction |
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subunit of phosphatidylinositol (PI) 3-kinase in skeletal muscle from pregnant women at the time of delivery. Although these studies provide important insights into potential postreceptor insulin signaling mechanisms underlying the IR in late pregnancy, they were cross-sectional in design and included only obese women with substantial IR due to their preexisting obesity. The reversibility of these insulin signaling changes postpartum in women with normal glucose tolerance during pregnancy remain speculative given the lack of longitudinal studies in pregnancy. The restoration of maternal insulin sensitivity postpartum represents an important physiological and metabolic adaptation underlying a woman’s reproductive life. Clinical observations indicate that insulin sensitivity begins to increase shortly after delivery, and euglycemic-hyperinsulinemic clamp studies confirm that insulin sensitivity is comparable with that of nonpregnant controls within 3 d after delivery (5). It has also been shown that in obese women with normal glucose tolerance, insulin resistance is reversed within 15–16 wk after delivery (6). The only study that has examined the cellular changes in skeletal muscle postpartum found that in healthy pregnant women, insulin receptor binding and IRTK activity was unaltered compared with postpartum (7). However, the isolated IR preparation used in that study is not directly comparable with the intact tissue or the newer ELISA procedure that demonstrates reduced receptor function in relatively intact muscle IRs (3, 4). To date, there are no studies examining alterations in additional downstream insulin signaling proteins in skeletal muscle postpartum or the relationship between any changes that may manifest in muscle and the reversal of insulin resistance postpartum.
The present study was designed as a prospective longitudinal investigation of changes in maternal insulin sensitivity and insulin signaling from late pregnancy to 1 yr postpartum in healthy nonobese women. We hypothesized that insulin sensitivity would reverse postpartum and that this change would be accompanied by altered expression and/or activity of the IR and downstream signaling proteins.
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Subjects and Methods |
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A total of nine women with a mean age of 32 ± 2 yr volunteered to participate in the study (Table 1
). Glucose tolerance during pregnancy was established according to the criteria of Carpenter and Coustan (8). The subjects were instructed to maintain a carbohydrate and fat intake of 50–55% and 30–35%, respectively, for 2 wk before testing. Diet records were used to document adherence to the instructions, and the General Clinical Research Center nutritionist reviewed these records. The Minnesota Leisure Time Physical Activity questionnaire was used to document physical activity preceding each evaluation (9). For late pregnancy, physical activity was assessed from the last menstrual period, and for postpartum was from delivery up to a maximum of 12 months. The experimental protocol was approved by the Institutional Review Board at MetroHealth Medical Center (Cleveland, OH), and written informed consent was obtained from all subjects before enrollment into the study. All pregnancy data were collected between 30–36 wk gestation. Postpartum evaluations were conducted approximately 1 yr after delivery, when the women had stopped breast-feeding. All postpartum tests were conducted during the follicular phase of the menstrual cycle, and none of the women were using hormonal contraception.
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Body composition was determined by hydrostatic weighing according to the method described by Catalano et al. (10). Height was measured to the nearest 1.0 cm without shoes, and body weight was measured to the nearest 0.1 kg.
Euglycemic-hyperinsulinemic clamps
A single-stage 2-h euglycemic-hyperinsulinemic clamp with [6,6-2H]glucose kinetics (5 mM glucose, 40 mU/m2·min) was performed during late pregnancy (30–36 wk) and was repeated approximately 1 yr after delivery, as previously described (11). Insulin sensitivity was computed from the glucose infusion rate that was required to maintain blood glucose at 90 mg/dL, plus residual endogenous glucose output based on [6,6-2H]glucose kinetics.
Muscle biopsy
Muscle biopsies were performed using the Bergstrom needle biopsy procedure as previously described (12). Approximately 100 mg tissue was obtained from the vastus lateralis muscle during late pregnancy and again approximately 1 yr postpartum. Both biopsies were performed under basal conditions after an overnight fast. The muscle sample was immediately frozen in liquid nitrogen and stored at –70 C for subsequent analysis.
IR content
IR content was measured as described previously (4, 13). Approximately 20 mg muscle tissue was homogenized in cold homogenization buffer [50 mM HEPES (pH 7.5), 10 mM Na4P2O7, 2 mM Na3VO4, 5 mM EDTA, 10 mM NaF, 1 tablet/ml proteinase inhibitor cocktail, and 1% Triton X-100]. After solubilization and centrifugation at 20,000 x g, the supernatant was collected and assayed for protein concentration with crystalline BSA as a standard, as previously described (4). A 96-well plate was coated with anti-IR antibody (LabVision, Fremont, CA) [0.2 µg/well in 50 mM Na2CO3 (pH 9.0)] at 22 C for 4 h. The plates were washed with Tris-buffered saline, Tween 20 [TBST; 20 mM Tris (pH 7.6), 150 mM NaCl, and 0.05% Tween 20] and blocked with 100 µl blocking buffer (1% BSA in TBST) for 90 min at 56 C. After washing, the samples (200 ng protein/well) or standards were loaded on the plate in binding buffer [50 mM HEPES (pH 7.6), 150 mM NaCl, 0.1% Triton X-100, 0.1% BSA, 1 mg/ml Bacitracin, 1 mM phenylmethylsulfonylfluoride, 2 mM Na3VO4, 2 µM Pepstatin A, and 2 µM leupeptin] and incubated overnight at 4 C. The plates were then washed and incubated with biotinylated anti-IR antibody in buffer B [50 mM HEPES (pH 7.6), 150 mM NaCl, 0.05% Tween 20, 1% BSA, 1 mg/ml Bacitracin, 1 mM phenylmethylsulfonylfluoride, and 2 mM Na3VO4]. Color was developed with peroxidase-conjugated streptavidin (1:1000) in buffer B and ELISA amplification reagents. The absorption was read at an OD of 450 nm on a Microplate Reader (Bio-Rad Model 3550, Bio-Rad, Hercules, CA). The concentration of IR in each muscle sample was calculated from a standard curve derived using 10–100 pg purified human IRs from placenta (4).
IR tyrosine phosphorylation assay
A 96-well plate was coated with IR antibody, washed, and blocked as described above. An identical concentration of IR (0.622 pg/ml) was used for each sample. The samples were diluted in 100 µl/well binding buffer and incubated at 4 C overnight. The plates were washed and incubated with or without insulin (100 nmol) in kinase buffer at 22 C for 15 min. The reaction was started by adding ATP (50 µM) to the kinase buffer (20 µl/well), and the plates were incubated for 1 h at 22 C. The plates were then washed briefly and incubated with antiphosphotyrosine antibody-horseradish peroxidase (1:2000) in buffer B described above for 2 h at 37 C. The color reaction was quantified on a Microplate Reader as above and compared with basal phosphorylation in the absence of insulin.
IRTK activity assay
A 96-well plate was coated, washed, and blocked as described above. An equivalent amount of IR from each muscle sample (0.622 pg/ml) was added to each well, the plates extensively washed, and insulin (100 nM) added to the kinase buffer. The reaction was initiated by adding 10 µl kinase reaction mixture (50 µM ATP, 0.2 µCi/well [
-32P]ATP, and 50 µg/well Poly Glu to Tyr), and the samples were incubated for 60 min at 22 C. The reaction was stopped by blotting 25 µl reaction mixture onto Whatman 3MM paper (Whatman, Maidstone, UK). Filter papers were washed extensively with 10% trichloroacetic acid with 10 mM Na4P2O4 for 15 min at 4 C, 15 min at 20 C, and 2 x 5 min boiling followed by a short rinse with acetone. Incorporation of 32P was determined by liquid scintillation counting.
Western blot analysis
The level of IRß, IRS-1, IRS-1 Ser312 phosphorylation, p85, Akt, p70S6 kinase, and GLUT-4 protein was determined in the muscle biopsy samples. Approximately 50 mg of muscle tissue was homogenized in ice-cold buffer [50 mM HEPES (pH 7.5), 10 mM NaF, 5 mM EDTA, 10 mM Na4P2O7, and 2 mM Na3VO4]. Homogenates were kept on ice, sonicated for 15 sec, and centrifuged for 30 min at 14,000 rpm. Protein concentration of the resulting supernatant was quantified using a commercial kit (Sigma, St. Louis, MO). Approximately 60 g protein extract was mixed with Laemmli sample buffer, and proteins were separated by SDS-PAGE. After electrophoresis, the proteins were electrotransferred to a nitrocellulose membrane (Amersham Biosciences, Piscataway, NJ). Membranes were blocked in TBST (10 mmol/liter Tris, 100 mmol/liter NaCl, and 0.02% Tween 20) containing 5% nonfat milk for 2 h at room temperature, washed with TBST for 15 min, and incubated with primary antibody (IR, 1:200; IRS-1, 1:200; p85, 1:1000; Akt, 1:200; and p70S6K, 1:200) overnight at 4 C (Santa Cruz Biotechnology, Inc., Santa Cruz, CA). The membranes were washed several times with TBST before incubation with a secondary antirabbit IgG antibody (1:10,000) (Amersham Biosciences) for 1 h at room temperature. The membranes were washed with TBST again and subjected to enhanced chemiluminescence according to the manufacturer’s instructions (Pierce Chemical, Rockford, IL). Results were quantified by scanning densitometry (GS-710, Imaging Densitometer, Bio-Rad).
Statistical analysis
All values are presented as means ± SE. Differences between dependent variables were examined using a paired Student’s t test. The relationship between insulin sensitivity measured during the clamp and insulin signaling proteins was based on univariate correlation analysis. The data were analyzed using the Statview II statistical package (Abacus Concepts, Berkeley, CA). The -level for statistical significance was set at 0.05.
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Results |
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Mean age and parity at entry to the study was 32 ± 2 yr and 
1, respectively. As expected, body weight postpartum was reduced compared with late pregnancy, although percentage body fat was unchanged (Table 1
). Fasting plasma glucose was lower during pregnancy compared with postpartum (P < 0.05), whereas fasting plasma insulin levels were increased by 41% (P < 0.05) during late pregnancy, reflecting the insulin resistance of late gestation.
Insulin sensitivity
During late pregnancy, glucose infusion was 5.5 ± 0.4 mg/kg fat-free mass (FFM)·min1 and increased to 9.6 ± 0.9 mg/kg FFM·min postpartum. Thus, on average, insulin sensitivity increased by approximately 74% postpartum (Fig. 1).
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To evaluate possible mechanisms associated with improved insulin sensitivity postpartum, we measured IR content and receptor activation in skeletal muscle biopsies obtained from the same women during pregnancy and approximately 1 yr after delivery. The IR protein concentration was determined in muscle protein extracts measured by ELISA. The IR concentration increased 42% postpartum compared with late pregnancy (P < 0.05) (Table 2). A similar increase (46%) was observed in total IRß protein expression as measured by Western blot analysis (P < 0.001) (Fig. 2A).
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). Insulin-stimulated IR tyrosine phosphorylation increased 3- to 4-fold above basal levels; however, there was no significant difference in maximal insulin-stimulated tyrosine phosphorylation in IR postpartum compared with late pregnancy. The basal and maximal insulin-stimulated IRTK activity against an artificial tyrosine substrate (Poly Glu to Tyr) was also unchanged from late pregnancy to postpartum. Downstream signaling protein expression and phosphorylation
Upon insulin stimulation, the IR binds and phosphorylates the IRS family of proteins including IRS-1, the major IR substrate in adult human skeletal muscle. In the present study, IRS-1 protein expression increased 69% (P < 0.05) postpartum compared with late pregnancy (Fig. 2B). Phosphorylation on serine 312 of IRS-1 is a negative regulator of IRS-1 tyrosine phosphorylation (14) and has been implicated as a cause of IR in response to increased fatty acid concentration (15). We measured the abundance of IRS-1 phospho Ser312 in the basal state using a phospho-specific antibody and found the levels were significantly increased postpartum (P < 0.05). However, after adjusting for increased IRS-1 expression, there was no significant change in basal IRS-1 Ser312 after pregnancy.
As shown in Fig. 2C, compared with late pregnancy, the abundance of the p85 regulatory subunit of PI 3-kinase was significantly reduced by 55% (P < 0.01) postpartum. There was no difference in the expression of downstream signaling proteins Akt, p70S6K, or the skeletal muscle glucose transporter, GLUT-4, from late pregnancy to postpartum (data not shown).
When the increase in IRS-1 protein was expressed as the change from late pregnancy to postpartum, the improvement was positively correlated with insulin sensitivity (Fig. 3; r = 0.84; P < 0.007). One subject was excluded from the analysis due to a technical problem measuring IRS-1 postpartum. There was no significant correlation between the change in p85 and change in insulin sensitivity (P = 0.59).
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Discussion |
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subunit of PI 3-kinase in skeletal muscle. These changes confirm that defects in the insulin signaling pathway noted previously in skeletal muscle from obese pregnant patients with normal glucose tolerance contribute to the altered effect of insulin on glucose uptake (3). It is also notable that there is a strong positive association between IRS-1 protein expression measured in muscle during the basal state and insulin sensitivity measured during in vivo hyperinsulinemia. Enhanced insulin sensitivity postpartum was also accompanied by an increase in IR concentration and protein expression. The change in IR expression experienced in the lean subjects studied here was not found previously in our cross-sectional studies (3, 4). This difference could be due to the fact that our previous cross-sectional data were based on comparisons between obese pregnant subjects with obese nonpregnant controls with significant IR (3, 4). It is known from in vitro cell culture experiments that hyperinsulinemia reduces IR mRNA abundance (20), and this is consistent with previous reports of decreased IR content in skeletal muscle of obese humans and animals with insulin resistance (21, 22). The increase in IR from late pregnancy to postpartum found here suggests that the improvement in insulin sensitivity postpartum in lean women could be partially due to up-regulation of the IR. However, we did not find a significant association between a change in IR and fasting insulin or the change in IR and insulin sensitivity in these women. Regarding the role of reduced IR in insulin sensitivity, studies in human adipocytes have shown that the total numbers of IRs do not predict the maximal effect of insulin to stimulate glucose transport (23), and most studies suggest that postreceptor changes in insulin signaling underlie skeletal muscle insulin resistance (for review, see Ref. 24).
The present study also documents that the return of insulin sensitivity postpartum in lean subjects is accompanied by a small (11%), nonsignificant increase in the intrinsic IRTK activity in IR from skeletal muscle. Having adjusted for IR content in each analysis, these changes in IRTK were not due to differences in IR expression in the muscle. Similar data showing no significant change in IRTK activity postpartum were reported in lean women by Damm et al. (7) using isolated purified IRs. Together, these data confirm that reduced IRTK activity is not a major factor in the IR of pregnancy in lean women with normal glucose tolerance. This is in contrast to obese pregnant subjects in which there is a modest but significant 21% lower maximal IRTK activity in skeletal muscle compared with obese nonpregnant controls (3). Most studies of human skeletal muscle have found impaired IRTK activity in type 2 diabetes and in subpopulations of obese insulin-resistant subjects (25, 26, 27, 28). However, our findings indicate that not all pregnant women have a reduction in IR activation and suggest that there are additional factors associated with obesity, such as TNF or free fatty acids, that may modify the IR phenotype expressed during pregnancy.
In previously published cross-sectional studies, we found that IRS-1 tyrosine phosphorylation and expression were reduced in pregnant subjects with normal glucose tolerance, and more so in GDM subjects compared with obese nonpregnant subjects (3). Our observations here show that IRS-1 protein expression increases from the third trimester of pregnancy to postpartum in lean women and is consistent with the hypothesis that IRS-1 levels play a pivotal role in the insulin resistance of pregnancy. Reduced IRS-1 protein was also noted in sc abdominal adipose tissue in GDM patients during the third trimester of pregnancy (29). A similar down-regulation of IRS-1 protein expression in skeletal muscle and adipose tissue was reported for insulin-resistant obese adults and patients with type 2 diabetes (21, 30, 31). Although these data point to the importance of IRS-1 in regulating insulin sensitivity, an increasing body of evidence indicates that serine/threonine phosphorylation of IRS-1 can reduce insulin’s effect on tyrosine phosphorylation, thereby regulating its interaction with PI 3-kinase. Rui et al. (32) have identified serine307 as a specific residue responsible for this effect in skeletal muscle in the mouse. Ser307 in mouse muscle cor-responds to Ser312 in human muscle. In the present study, there was no change in constitutive IRS-1 Ser312 phosphorylation from late pregnancy to postpartum when adjusted for increased total IRS-1 content. Whether other known serine/threonine sites on IRS-1 are affected by pregnancy is unknown but warrants further investigation.
IRS-1 tyrosine phosphorylation is required to fully activate PI 3-kinase, a necessary but not sufficient step for glucose transport (21, 33). Most available data support the hypothesis that activation of the p85/p110-type PI 3-kinase occurs through its recruitment of p85 subunit to specific phosphotyrosine sites on IRS-1 (34, 35). There is strong evidence from human, animal, and cell culture studies that changes in p85 expression can regulate insulin sensitivity (36, 37, 38, 39). Several splice variants of p85 exist, and there is competition between the p85 monomer and the p85-p110 heterodimer complex of PI 3-kinase for binding to IRS-1. Mice with reduced protein expression of the full-length p85 isoform by a heterozygous deletion of the gene have enhanced insulin signaling (38), suggesting that p85 expression is negatively correlated with insulin sensitivity. We previously reported a 1.5- to 2-fold increase in p85 expression in skeletal muscle from insulin-resistant pregnant women (3). Data from the present study indicate that after pregnancy p85 expression is normalized, and this may provide an important mechanism allowing IRS-1 to dock with PI 3-kinase in skeletal muscle. A recent report by Barbour et al. (39) provides some explanation for the increase in p85 expression during pregnancy and links the change to human placental growth hormone (hPGH). It was shown that overexpression of hPGH in mice caused insulin resistance by increasing the p85 monomer and inhibiting the association of the p85-p110 heterodimer with IRS-1. This finding may help to explain the reversal of IR postpartum because maternal hPGH levels decrease after delivery of the placenta.
We did not detect any change in Akt, p70S6K, or GLUT4 expression in skeletal muscle from women postpartum, despite the clear improvement in insulin sensitivity. However, we measured total Akt protein rather than distinguishing between the Akt-1 and Akt-2 isoforms. It is possible that we may have missed a shift in isoform expression. Alternatively, changes in activity or function may be more relevant to the reversal of IR in these proteins, rather than changes in expression.
In summary, we demonstrate that reversal of the insulin resistance of normal human pregnancy postpartum is accompanied by increased skeletal muscle expression of IR and IRS-1 with a down-regulation of p85 subunit of PI 3-kinase. Our current data suggest changes in insulin sensitivity correlates highly with expression of IRS-1. In addition, we speculate that reduction of previously high levels of the p85 monomers may play a role in increased insulin sensitivity postpartum by allowing for greater p85/p110 binding to IRS-1. The present results suggest these changes play an important physiological role in the underlying metabolic adaptation to pregnancy and reversal of insulin resistance postpartum.
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Acknowledgments |
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Footnotes |
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Abbreviations: FFM, Fat-free mass; hPGH, human placental growth hormone; IR, insulin receptor; IRS-1, IR substrate-1; IRTK, IR tyrosine kinase; PI, phosphatidylinositol.
Received April 21, 2004.
Accepted June 2, 2004.
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References |
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is a predictor of insulin resistance in human pregnancy. Diabetes 51:2207–2213 in obese women with gestational diabetes: relationship to FFA during pregnancy. Am J Physiol 282:E522–E533
stimulate phosphorylation of IRS-1 at inhibitory Ser307 via distinct pathways. J Clin Invest 107:181–189[CrossRef][Medline]
subunit of phosphoinositide 3-kinase. Nat Genet 21:230–235[CrossRef][Medline]
subunit of phosphoinositide 3-kinase improves insulin signaling and ameliorates diabetes. J Clin Invest 109:141–149[CrossRef][Medline]
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