AJP - Regu Information on EB 2010
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Am J Physiol Regul Integr Comp Physiol 286: R554-R559, 2004. First published November 13, 2003; doi:10.1152/ajpregu.00076.2003
0363-6119/04 $5.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
286/3/R554    most recent
00076.2003v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (10)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Chen, L.
Right arrow Articles by Nyomba, B. L. G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Chen, L.
Right arrow Articles by Nyomba, B. L. G.

DEVELOPMENT AND TISSUE PLASTICITY

Insulin resistance of gluconeogenic pathways in neonatal rats after prenatal ethanol exposure

Li Chen, Tong Zhang, and B. L. G. Nyomba

Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada R3A1R9

Submitted 10 February 2003 ; accepted in final form 11 November 2003


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Alcohol exposure during pregnancy is associated with fetal growth restriction and programs the offspring to insulin resistance later in life. The underlying mechanisms are still uncertain, but a dysregulation of gluconeogenesis and adipose hormones may be contributory. Newborn rats from dams that had been given ethanol (EtOH) or water (controls) during pregnancy were studied. Adiponectin mRNA was determined in subcutaneous fat by RT-PCR, and serum adiponectin was measured by RIA. Subsets of rats were killed before and after intraperitoneal administration of insulin, to determine, by RT-PCR, the hepatic expression of gluconeogenic enzymes and that of the transcription factor peroxisome proliferator-activated receptor-coactivator (PGC)-1, which promotes gluconeogenesis. EtOH offspring had delayed hypoglycemic response to insulin but normal adiponectin mRNA and serum levels compared with controls. The inhibitory response of the gluconeogenic enzyme phosphoenol- pyruvate carboxykinase (PEPCK) and PGC-1 mRNAs to insulin was blunted in EtOH offspring compared with controls. The data suggest that intrauterine EtOH exposure causes insulin resistance of genes for PGC-1 and PEPCK early in life.

fetal growth restriction; adiponectin; gluconeogenesis; peroxisome proliferator-activated receptor-{gamma} coactivator-1

ADVERSE EVENTS DURING PREGNANCY may interfere with fetal physiology, metabolism, and development and may program the fetus to later develop insulin resistance and other metabolic and cardiovascular diseases in adulthood, as shown in epidemiological studies (2, 17, 32, 36). Animal models of intrauterine growth restriction (IUGR) employing malnutrition (13, 27, 30, 45), placental ischemia (37), glucocorticoid exposure (4), and diabetes (44) during pregnancy have confirmed these data. We and others have shown that ethanol (EtOH) ingestion during pregnancy leads to abnormal fetal development and is associated with glucose intolerance in the adult offspring (7-9, 15, 25, 46). Reported alcoholemia attained in the dams was ~30 nmol/l (8, 15), corresponding to human chronic drinking (50). These studies have suggested that EtOH-induced IUGR is associated with insulin resistance in later life.

Increased hepatic glucose production is a major component of insulin resistance (28), but the regulation of hepatic glucose production in EtOH-induced IUGR is currently unclear. Glucose is produced through glycogenolysis or gluconeogenesis. Both phenomena are inhibited by insulin and enhanced by a deficiency of insulin action (16, 38). Recent studies suggest that adipose hormones may be involved in the control of glucose metabolism in the liver. Indeed, the suppression of hepatic glucose production by insulin is enhanced by leptin and adiponectin (5, 10, 18) but impaired by resistin (34). There are currently limited data on the association of adipocyte hormones with IUGR. Leptin levels are relatively low in humans born with IUGR, and it has been suggested that this may explain obesity and insulin resistance in these individuals (22). Offspring of rats undernourished during pregnancy have decreased leptin levels early in life but elevated levels in adulthood in association with obesity (45). In a recent report (8), we have shown that prenatal EtOH exposure results in IUGR with impaired glucose homeostasis and increased resistin expression in both neonatal and adult rat offspring. The neonatal offspring had decreased leptin levels, whereas adult offspring had normal leptin levels. Adiponectin expression was not investigated in neonatal offspring. However, its expression was normal in the adult offspring, even after chronic feeding with saturated fat (9).

The present study was performed in neonatal rats exposed to EtOH in utero to examine the insulin response of enzymes involved in hepatic glucose production and to determine the expression of adiponectin and its association with glucose homeostasis.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Animals and experimental design. Virgin Sprague-Dawley rats from Charles River Canada (Saint Constant, PQ) were treated as previously described (8, 9). Briefly, the rats were randomly divided into two weight-matched groups (n = 6/group), and after pregnancy was timed by the vaginal plug method, one group was given EtOH, 2 g/kg (36%), by gavage twice daily at 9:00 AM and 4:00 PM throughout gestation; the second group (control) was given the same volume of water instead of EtOH. The rats were otherwise allowed free access to tap water and commercial rat chow (Agway Prolab, Syracuse, NY). Body weight and food intake were recorded from day 14 of gestation to parturition. Daily food intake (23.5 ± 1.3 vs. 25.7 ± 0.9 g) and weight gain (140.0 ± 15.5 vs. 140.0 ± 11.2 g) during pregnancy were similar between the EtOH and control dams. The rats were allowed to deliver spontaneously, and the period of gestation was similar between EtOH (21.5 ± 0.3 days; range 20-22 days) and control dams (21.3 ± 0.3 days; range 21-22 days). Litter size was also similar between EtOH (14.5 ± 1.5) and controls (15.8 ± 0.9). On the first day of life, male pups from each litter were weighed, and their length was measured from the tail tip to the crown. The pups were subjected to an insulin tolerance test (ITT) and randomly assigned to be killed by decapitation at different time points (0, 10, 20, 30, 60, and 90 min) after an intraperitoneal injection of insulin (Humulin R, Eli Lilly, Indianapolis, IN) at a dose of 1.0 IU/kg body wt (1). A total of 48 pups per group was used. The pups were separated from their mothers for 2 h before the experiments. Trunk blood was collected in heparinized capillary tubes and used for the determination of glucose and insulin. Livers were rapidly dissected out, snap-frozen in liquid nitrogen, and stored at -70°C. In pups killed at time 0, subcutaneous fat and blood were also used to determine adiponectin mRNA and plasma concentration, respectively (8, 9). The protocol was approved by the Committee for Animal Use in Research and Teaching of the University of Manitoba.

PCR. Trizol, oligo(deoxythymidine) primers, SuperScript reverse transcriptase, Taq DNA polymerase, and cDNA primers were obtained from Invitrogen (Carlsbad, CA). RT-PCR assays were performed as previously described (8, 9). Total RNA was extracted from ~100 mg frozen tissue by the Trizol method, and the first-strand cDNAs were synthesized from 5 µg total RNA using SuperScript reverse transcriptase and oligo(deoxythymidine) primers. The reverse transcription products (5 µl) were amplified by PCR using Taq DNA polymerase and specific primers (Table 1). Another 5 µl of the reverse transcription product was amplified with GAPDH primers as an internal control. For each gene, the PCR program consisted of denaturation at 94°C for 5 min, followed by 30 cycles of 45 s at 94°C, 45 s at specific annealing temperatures (Table 1), 90 s at 72°C, and a final 7 min at 72°C. The expected RT-PCR products are shown in Table 1. RT-PCR products (10 µl) were electrophoresed in a 1.5% agarose gel, stained with ethidium bromide, and densitometrically analyzed using NIH Image software.


View this table:
[in this window]
[in a new window]
  		Table 1. Primer sequences

 

Glycogen phosphorylase. Glycogen phosphorylase activity in the liver was assayed in the direction of glycogen formation, based on the incorporation of D-[U-14C]glucose-1-phosphate (PerkinElmer Life Sciences, Boston, MA) into glycogen in the absence of AMP and the presence of caffeine (39). Briefly, 20 mg of tissue were homogenized in 0.2 ml of a buffer containing a final concentration of 50 mM potassium phosphate (pH 7.4), 20 mM sodium fluoride, 10 mM EDTA, 6% glycerol, 2 mM sodium vanadate, 10 mM disodium pyrophosphate, 1 µg/ml leupeptin, 10 µg/ml aprotinin, and 0.1 mM PMSF. All the chemicals were from Sigma (St. Louis, MO). The homogenate was centrifuged at 1,000 g at 4°C, and 10 µl of the supernatant were added to 50 µl of a reaction mixture consisting of a final concentration of 200 mM potassium fluoride, 100 mM [U-14C]glucose-1-phosphate (0.1 µCi/reaction), 10 mM caffeine, and 1% glycogen. The incubation was carried out for 15 min in a 30°C water bath, and the reaction was stopped by precipitating 50 µl of the reaction mixture onto Whatman paper immediately dropped in 66% cold ethanol. After several washes in 66% cold ethanol, the filters were washed briefly in acetone, allowed to dry, and placed in scintillation vials containing 10 ml scintillate for radioactivity counting. Glycogen phosphorylase activity is expressed as micromoles of glucosyl transferred onto glycogen per minute per gram protein.

Other assays. Serum adiponectin was measured with a mouse RIA kit (Linco Research, St. Charles, MO), as previously described (9). Serum insulin was measured with a sensitive rat RIA kit (Linco), which has 100% cross-reactivity with human insulin. Glucose was measured using a 2300 glucose analyzer (YSI, Yellow Springs, OH). Tissue protein was determined by the Bradford method using BSA as standard.

Statistics. Statistical analyses were conducted with SPSS software (version 11.0 for Windows; SPSS, Chicago, IL). To detect changes in glucose and insulin concentrations after insulin injection, we performed for each group a one-way ANOVA followed by post hoc pairwise comparisons by Tukey's test after ANOVA established significant differences. Data were otherwise analyzed using a two-factor ANOVA for the main effects of group (EtOH vs. control) and insulin treatment, as well as for group x insulin interaction followed by unpaired t-test for post hoc comparisons between groups or treatments. Insulin concentrations were log-transformed before analysis. Values are expressed as means ± SE. P < 0.05 was considered significant.


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
Animal characteristics. Neonatal rats exposed to EtOH in utero were shorter (4.9 ± 0.08 vs. 5.3 ± 0.05 cm, P < 0.0001) and weighed significantly less than controls (5.5 ± 0.1 vs. 6.4 ± 0.1 g, n = 48/group, P < 0.0001). Baseline plasma glucose (4.7 ± 0.6 vs. 3.5 ± 0.3 mmol/l, n = 8/group, P = 0.07) and insulin (0.67 ± 0.09 vs. 0.51 ± 0.11 ng/ml, P = 0.3) levels were similar between EtOH offspring and controls.

Insulin sensitivity. To investigate differences in insulin sensitivity, we performed an ITT using littermates at different time points (Fig. 1). Insulin was given intraperitoneally before neonatal rats were decapitated and blood was collected for the measurement of glucose and insulin. In control pups, glucose concentrations declined rapidly after insulin administration, and the decrease became significant by 30 min. In pups exposed to EtOH in utero, however, a decline in glucose concentrations did not become significant until 90 min after insulin injection. In control pups, the insulin concentrations after intraperitoneal insulin administration reached a maximum at ~30 min and then declined. In EtOH pups, insulin concentrations continued to rise (Fig. 1). Overall the insulin levels were similar between the two groups, except at 90 min, when it was higher in EtOH vs. control rats (P < 0.05). By two-way ANOVA, there was a significant main effect of insulin treatment on both glucose (P < 0.0001) and insulin (P < 0.01), but the effect of group was significant on glucose only (P < 0.0001), and there was no group x time interaction on either glucose or insulin concentrations.



View larger version (37K):
[in this window]
[in a new window]
  		Fig. 1. Plasma glucose (A) and insulin (B) during insulin tolerance test (ITT) in ethanol (EtOH) and control neonatal rats. Data shown are means ± SE (n = 7-10 rats/group per time point). *P < 0.05, ***P < 0.001, EtOH vs. control, by t-test; #P < 0.05, ##P < 0.01, time point vs. 0 min by Tukey's test. Significance of 2-way ANOVA: glucose concentrations (main effect of EtOH or insulin treatment, P < 0.0001); insulin levels (main effect of insulin treatment, P < 0.01).

 

Liver enzymes and peroxisome proliferator-activated receptor-{gamma} coactivator-1. To investigate whether liver enzymes could contribute to the hyperglycemia observed in EtOH-exposed pups, we measured phosphoenolpyruvate carboxykinase (PEPCK), glucose-6-phosphatase (G6Pase), and glucokinase (GK) mRNA as well as glycogen phosphorylase activity in liver extracts before and 30 min after insulin injection. The latter time point was chosen because 1) insulin levels had peaked in control pups and 2) insulin concentrations were comparable between groups, and, therefore, the groups were being submitted to a similar insulin stimulus. The expression of the gluconeogenic enzymes at baseline was not different between EtOH-exposed pups and controls. After insulin administration, PEPCK mRNA decreased by 39% in controls and 25% in the EtOH group (Fig. 2). G6Pase mRNA did not change in either group. GK mRNA was similar between the two groups at baseline and did not significantly change (P = 0.08) after insulin injection in either group taken individually. By two-factor ANOVA, the main effect of group was not significant on any of the mRNAs, consistent with the lack of baseline mRNA differences between groups. However, there was a significant main effect of insulin on PEPCK (P < 0.0001) and GK (P < 0.01). Most importantly, there was a significant group x insulin interaction on PEPCK (P < 0.05) but not on GK (P = NS). This was consistent with a significant group difference in the response of PEPCK mRNA to insulin and a lack of group difference in the response of GK mRNA to insulin. Glycogen phosphorylase activity was not different between the control and EtOH groups either before (47.4 ± 2.9 vs. 41.5 ± 4.7 µmol·g protein-1·min-1) or after (44.1 ± 6.0 vs. 41.2 ± 8.7 µmol·g protein-1·min-1) insulin injection.



View larger version (56K):
[in this window]
[in a new window]
  		Fig. 2. Hepatic mRNA of gluconeogenic enzymes and peroxisome proliferator-activated receptor-{gamma} coactivator-1 (PGC-1) before and 30 min after insulin (Ins) injection in EtOH and control (CON) neonatal rats (n = 8 rats/group). The mRNA level for each gene was determined in a separate experiment in parallel with GAPDH mRNA to control for load. A: representative PCR blots are shown. B: data shown are means ± SE. PEPCK, phosphoenolpyruvate carboxykinase; G6Pase, glucose-6-phosphatase; GK, glucokinase. aP < 0.01, bP < 0.0001, postinsulin vs. preinsulin; #P < 0.05, ##P < 0.01, insulin-treated EtOH vs. insulin-treated controls.

 

We next determined peroxisome proliferator-activated receptor-{gamma} coactivator-1 (PGC-1) expression to explain differences in PEPCK expression. Before insulin injection, PGC-1 mRNA was not different between the two groups. After insulin administration, however, PGC-1 mRNA decreased by ~25% in controls but did not decrease in EtOH-exposed rats (Fig. 2). By two-way ANOVA, there was a significant main effect of insulin (P < 0.05) and a significant group x insulin interaction (P < 0.01) on PGC-1 mRNA.

Adiponectin. Because of the role played by adiponectin in the regulation of glucose homeostasis, we determined its mRNA in subcutaneous adipose tissue and its peptide level in serum from newborn rats. Both adiponectin mRNA (0.70 ± 0.03 vs. 0.72 ± 0.03 U, P = NS) and peptide levels (1.1 ± 0.1 vs. 1.3 ± 0.1 mg/l, P = NS) were similar between the two groups.


   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
We have recently shown that EtOH ingestion by the mother during pregnancy results in IUGR with impaired glucose homeostasis in the offspring (8, 9). Adult offspring were glucose intolerant despite hyperinsulinemia, an indication that they were insulin resistant. We now show that insulin resistance is already present early in the life of these offspring, as documented by a delayed hypoglycemic response to insulin. We also investigated whether the gluconeogenic pathway in this IUGR model is insulin resistant at this early age.

Increased hepatic glucose production due to glycogenolysis and gluconeogenesis is an important component of insulin resistance in type 2 diabetes (28). Glycogenolysis is regulated by glycogen phosphorylase, but in this study, glycogen phosphorylase activity was not different between EtOH-exposed offspring and controls. A lack of difference in glycogen phosphorylase activity has been reported between insulin-resistant and insulin-sensitive neonatal animals (42). In gluconeogenesis, the regulation of the rate-limiting (PEPCK) and the last committed (G6Pase) enzymes occurs mainly at the transcription level (26). However, the insulin response sequences in these enzymes are functionally different and their response to insulin is not identical (30). In the current study, G6Pase mRNA levels were not different between groups. PEPCK mRNA levels were suppressed by 25% in the EtOH offspring and by ~40% in controls after insulin administration. This represents ~35% reduction in insulin action on PEPCK in the EtOH group. Alterations of gluconeogenic enzymes have been reported in adult rat offspring born with IUGR due to protein malnutrition, placental ischemia, or glucocorticoid exposure (14, 24, 29, 33). In the malnutrition model, the adult offspring had increased liver PEPCK activity with a concomitant decrease in GK activity (14, 33). In the placental ischemia IUGR model, where newborn rats were also studied, hepatic PEPCK and G6Pase mRNA were both increased and GK mRNA was decreased (24). These results suggested that IUGR programs both an increase of gluconeogenesis and a reduction of glycolysis, resulting in an increased hepatic glucose output. However, an increase of PEPCK only, without an alteration of G6Pase or GK expression, was reported in rat offspring with glucocorticoid-induced IUGR (29). Although these results were intriguing, the authors suggested that the increase in PEPCK, the rate-limiting enzyme in the gluconeogenesis pathway, may promote hepatic glucose production, even though G6Pase and GK are unaltered. Similarly, Sun et al. (40) have reported in transgenic mice that a modest increase in PEPCK gene expression is sufficient to increase hepatic glucose production despite an increased GK expression. Our results are in line with these conclusions.

The mechanisms regulating PEPCK response to insulin in EtOH-IUGR are still unknown. Gluconeogenic enzymes, including PEPCK, are increased by chronic EtOH ingestion in rats, but this effect is due to reduced carbohydrate intake rather than EtOH per se (35). Fetuses of rats exposed to EtOH are hypoglycemic (41), which may increase gluconeogenic enzymes. In the adult rat liver, PEPCK gene transcription is upregulated by glucagon, glucocorticoids, and epinephrine and downregulated by insulin, which exerts a dominant effect (26). It is unlikely that hypoglycemia or hypoinsulinemia in utero or an increase in epinephrine, corticosterone, or glucagon after delivery was the explanation for the difference in PEPCK mRNA in the current study, because this was not different at baseline. Our results suggest that PEPCK mRNA response to insulin exposure is impaired by ~35% in the EtOH rat offspring, but it is unclear whether these changes are biologically important, because we did not measure hepatic glucose production. However, a suppression of PEPCK of this magnitude has been reported by Rossetti and colleagues (3) to be associated with enhanced hepatic insulin sensitivity after removal of visceral fat in rats.

A recent study has shown that the transcription factor PGC-1 modulates hepatic gluconeogenesis through an increase of PEPCK transcription (49). PGC-1 is a coactivator-like protein that interacts with PPAR-{gamma}, an orphan receptor found in the nucleus of fat cells that has been the target of diabetes treatment with thiazolidinediones. PGC-1 is not significantly expressed in the liver in the feeding state but is readily detectable after fasting and in states of diminished insulin action where gluconeogenesis is increased (49). PGC-1 overexpression increases glucose production and the transcription of genes encoding gluconeogenic enzymes, including PEPCK and G6Pase. PGC-1 is upregulated by cAMP-dependent mechanisms and glucocorticoids and downregulated by insulin. However, PGC-1 is not the sole regulator of these enzymes. PGC-1 interacts with the hepatic nuclear factor-4{alpha} and the glucocorticoid receptor for fully activating PEPCK expression. It is unclear, however, whether this explains the observed differences in the effects of insulin on PEPCK between the EtOH pups and controls. It is also unclear whether the 25% suppression of PGC-1 mRNA by insulin in the current study has any biological significance. However, mRNA changes of this magnitude have been reported to be important for hepatic glucose metabolism. For example, a 25% increase in hepatic glucocorticoid receptor expression has been reported to be a mechanism for increased PEPCK expression and gluconeogenesis in rats exposed to dexamethasone in utero (29). Furthermore, a recent report of elevated PGC-1 mRNA levels in newborn and adult rat offspring with IUGR due to placental ischemia lends support to the suggestion that programming of gluconeogenesis by IUGR may be mediated through PGC-1 (24).

The response of GK mRNA to insulin was normal in EtOH offspring. As mentioned above, studies of GK expression in IUGR models have yielded variable results, with reports of decreased (14, 24, 33) or normal (29) levels, depending on models and experimental conditions. GK expression would be expected to be decreased in this study because it is usually low in newborn rat liver (43) and because EtOH has an inhibitory effect on this enzyme (48). An increase of GK expression can be triggered by hyperglycemia (6), as a compensatory antihyperglycemic mechanism to promote glucose disposal. An increase in glucose transporter-1, which also promotes glucose disposal, has been found in the liver of newborn rats in the placental ischemia model in association with an upregulation of gluconeogenesis (23, 24). Similarly, parallel increases of G6Pase and GK activity have been reported after feeding rats a high-sucrose diet, which is known to cause insulin resistance (12). Sun et al. (40) have suggested that liver insulin resistance may be selective to gluconeogenesis while sparing glycolysis.

Adiponectin has been implicated as a factor that suppresses hepatic glucose production and plays a major role in the regulation of insulin action (19). Adiponectin expression is reduced in insulin-resistant states (21), increased with caloric restriction and thiazolidinedione treatment (11), and correlates with insulin sensitivity determined by euglycemic clamps (20, 47). Administration of this hormone increases insulin sensitivity, inhibits hepatic glucose production, and reduces glycemia in mice (5, 10). In the current study, however, we found no effect of prenatal EtOH exposure on adiponectin expression. In adult rat offspring exposed to EtOH in utero, adiponectin expression was also normal despite glucose intolerance and hyperinsulinemia (9). These results suggest that the insulin resistance associated with EtOH-induced IUGR is not explained by changes in adiponectin levels.

In summary, the gluconeogenic enzyme PEPCK and the transcription factor PGC-1, which regulates the expression of this enzyme, had an impaired response to insulin in rat newborns exposed to EtOH in utero. The data suggest that intrauterine EtOH exposure causes insulin resistance of genes for PGC-1 and PEPCK early in life. Further studies are required to investigate the presence of these abnormalities in the adult offspring exposed to EtOH during pregnancy to confirm the suspicion that insulin resistance of hepatic PGC-1 is an early defect programming the liver to enhanced gluconeogenesis later in life.


   GRANTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This study was supported by grants from the Canadian Institutes of Health Research and the Manitoba Health Research Council.


   FOOTNOTES
 

Address for reprint requests and other correspondence: B. L. G. Nyomba, Health Sciences Centre, Univ. of Manitoba, 820 Sherbrook St., Rm. GG449, Winnipeg, Manitoba, Canada R3A1R9 (E-mail: bnyomba{at}cc.umanitoba.ca).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 

  1. Arai M and Widmaier EP. Activation of the pituitary-adrenocortical axis in day-old rats by insulin-induced hypoglycemia. Endocrinology 129: 1505-1512, 1991.[Abstract/Free Full Text]
  2. Barker DJ, Hales CN, Fall CH, Osmond C, Phillips K, and Clark PM. Type 2 (non-insulin-dependent) diabetes mellitus, hypertension and hyperlipidemia (syndrome X): relation to reduced fetal growth. Diabetologia 36: 62-67, 1993.[CrossRef][Web of Science][Medline]
  3. Barzilai N, She L, Liu BQ, Vuguin P, Cohen P, Wang J, and Rossetti L. Surgical removal of visceral fat reverses hepatic insulin resistance. Diabetes 48: 94-98, 1999.[Abstract]
  4. Benediktsson R, Lindsay RS, Noble J, Seckl JR, and Edwards CR. Glucocorticoid exposure in utero: a new model for adult hypertension. Lancet 341: 339-341, 1993.[CrossRef][Web of Science][Medline]
  5. Berg AH, Combs TP, Du X, Brownlee M, and Scherer PE. The adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nat Med 7: 947-953, 2001.[CrossRef][Web of Science][Medline]
  6. Bossard P, Parsa R, Decaux JF, Iynedjian P, and Girard J. Glucose administration induces the premature expression of liver glucokinase gene in newborn rats. Relation with DNase-I-hypersensitive sites. Eur J Biochem 215: 883-892, 1993.[Web of Science][Medline]
  7. Castells S, Mark E, Abaci F, and Schwartz E. Growth retardation in fetal alcohol syndrome. Unresponsiveness to growth-promoting hormones. Dev Pharmacol Ther 3: 232-241, 1981.[Web of Science][Medline]
  8. Chen L and Nyomba BLG. Effects of prenatal alcohol exposure on glucose tolerance in the rat offspring. Metabolism 52: 454-462, 2003.[CrossRef][Web of Science][Medline]
  9. Chen L and Nyomba BLG. Glucose intolerance and resistin expression in rat offspring exposed to ethanol in utero: modulation by postnatal high fat diet. Endocrinology 144: 500-508, 2003.[Abstract/Free Full Text]
  10. Combs TP, Berg AH, Obici S, Scherer PE, and Rossetti L. Endogenous glucose production is inhibited by the adipose-derived protein Acrp30. J Clin Invest 108: 1875-1881, 2001.[CrossRef][Web of Science][Medline]
  11. Combs TP, Wagner JA, Berger J, Doebber T, Wang WJ, Zhang BB, Tanen M, Berg AH, O'Rahilly S, Savage DB, Chatterjee K, Weiss S, Larson PJ, Gottesdiener KM, Gertz BJ, Charron MJ, Scherer PE, and Moller DE. Induction of adipocyte complement-related protein of 30 kilodaltons by PPAR{gamma} agonists: a potential mechanism of insulin sensitization. Endocrinology 143: 998-1007, 2002.[Abstract/Free Full Text]
  12. Commerford SR, Ferniza JB, Bizeau ME, Thresher JS, Willis WT, and Pagliassotti MJ. Diets enriched in sucrose or fat increase gluconeogenesis and G-6-Pase but not basal glucose production in rats. Am J Physiol Endocrinol Metab 283: E545-E555, 2002.[Abstract/Free Full Text]
  13. Dahri S, Snoeck A, Reusens-Billen B, Remacle C, and Hoet JJ. Islet function in offspring of mothers on low-protein diet during gestation. Diabetes 40, Suppl 2: 115-120, 1991.
  14. Desai M, Byrne CD, Zhang J, Petry CJ, Lucas A, and Hales CN. Programming of hepatic insulin-sensitive enzymes in offspring of rat dams fed an isocaloric protein-restricted diet. Am J Physiol Gastrointest Liver Physiol 272: G1083-G1090, 1997.[Abstract/Free Full Text]
  15. Elton CW, Pennington JS, Lynch SA, Carver FM, and Pennington SN. Insulin resistance in adult rat offspring associated with maternal dietary fat and alcohol consumption. J Endocrinol 173: 63-71, 2002.[Abstract]
  16. Exton JH. Gluconeogenesis. Metabolism 21: 945-990, 1972.[CrossRef][Web of Science][Medline]
  17. Freinkel N. Banting lecture 1980: of pregnancy and progeny. Diabetes 29: 1023-1035, 1980.[Abstract]
  18. Fruhbeck G and Salvador J. Relation between leptin and the regulation of glucose metabolism. Diabetologia 43: 3-12, 2000.[CrossRef][Web of Science][Medline]
  19. Havel PJ. Control of energy homeostasis and insulin action by adipocyte hormones: leptin, acylation stimulating protein, and adiponectin. Curr Opin Lipidol 13: 51-59, 2002.[CrossRef][Web of Science][Medline]
  20. Hotta K, Funahashi T, Bodkin NL, Ortmeyer HK, Arita Y, Hansen BC, and Matsuzawa Y. Circulating concentrations of the adipocyte protein adiponectin are decreased in parallel with reduced insulin sensitivity during the progression to type 2 diabetes in rhesus monkeys. Diabetes 50: 1126-1133, 2001.[Abstract/Free Full Text]
  21. Hu E, Liang P, and Spiegelman BM. AdipoQ is a novel adipose-specific gene dysregulated in obesity. J Biol Chem 271: 10697-10703, 1996.[Abstract/Free Full Text]
  22. Jaquet D, Gaboriau A, Czernichow P, and Levy-Marchal C. Relatively low serum leptin levels in adults born with intra-uterine growth retardation. Int J Obes Relat Metab Disord 25: 491-495, 2001.[CrossRef][Web of Science][Medline]
  23. Lane RH, Crawford SE, Flozak AS, and Simmons RA. Localization and quantification of glucose transporters in liver of growth-retarded fetal and neonatal rats. Am J Physiol Endocrinol Metab 276: E135-E142, 1999.[Abstract/Free Full Text]
  24. Lane RH, MacLennan NK, Hsu JL, Janke SM, and Pham TD. Increased hepatic peroxisome proliferator-activated receptor-{gamma} coactivator-1 gene expression in a rat model of intrauterine growth retardation and subsequent insulin resistance. Endocrinology 143: 2486-2490, 2002.[Abstract/Free Full Text]
  25. Lopez-Tejero D, Llobera M, and Herrera E. Permanent abnormal response to glucose load after prenatal ethanol exposure in rats. Alcohol 6: 469-473, 1989.[CrossRef][Web of Science][Medline]
  26. Lucas PC and Granner DK. Hormone response domains in gene transcription. Annu Rev Biochem 61: 1131-1173, 1992.[CrossRef][Web of Science][Medline]
  27. Martin MA, Alvarez C, Goya L, Portha B, and Pascual-Leone AM. Insulin secretion in adult rats that had experienced different underfeeding patterns during their development. Am J Physiol Endocrinol Metab 272: E634-E640, 1997.[Abstract/Free Full Text]
  28. Mitrakou A, Kelley D, Mokan M, Veneman T, Pangburn T, Reilly J, and Gerich J. Role of reduced suppression of glucose production and diminished early insulin release in impaired glucose tolerance. N Engl J Med 326: 22-29, 1992.[Abstract]
  29. Nyirenda MJ, Lindsay RS, Kenyon CJ, Burchell A, and Seckl JR. Glucocorticoid exposure in late gestation permanently programs rat hepatic phosphoenolpyruvate carboxykinase and glucocorticoid receptor expression and causes glucose intolerance in adult offspring. J Clin Invest 101: 2174-2181, 1998.[Web of Science][Medline]
  30. O'Brien RM, Streeper RS, Ayala JE, Stadelmaier BT, and Hornbuckle LA. Insulin-regulating gene expression. Biochem Soc Trans 29: 552-558, 2001.[CrossRef][Web of Science][Medline]
  31. Ozanne SE, Wang CL, Coleman N, and Smith GD. Altered muscle insulin sensitivity in the male offspring of protein-malnourished rats. Am J Physiol Endocrinol Metab 271: E1128-E1134, 1996.[Abstract/Free Full Text]
  32. Pettitt DJ, Bennett PH, Saad MF, Charles MA, Nelson RG, and Knowler WC. Abnormal glucose tolerance during pregnancy in Pima Indian women: long-term effects on offspring. Diabetes 40, Suppl 2: 126-130, 1991.
  33. Pollak A, Susa JB, Stonestreet BS, Schwartz R, and Oh W. Phosphoenolpyruvate carboxykinase in experimental intrauterine growth retardation in rats. Pediatr Res 13: 175-177, 1979.[Web of Science][Medline]
  34. Rajala MW, Obici S, Scherer PE, and Rossetti L. Adipose-derived resistin and gut-derived resistin-like molecule-{beta} selectively impair insulin action on glucose production. J Clin Invest 111: 225-230, 2003.[CrossRef][Web of Science][Medline]
  35. Rao GA and Larkin EC. Nutritional factors required for alcoholic liver disease in rats. Alcohol Alcohol 21: 369-373, 1997.
  36. Ravelli ACJ, van der Meulen JHP, Michels RPJ, Osmond C, Barker DJP, Hales CN, and Bleker OP. Glucose tolerance in adults after prenatal exposure to famine. Lancet 351: 173-177, 1998.[CrossRef][Web of Science][Medline]
  37. Simmons RA, Templeton LJ, and Gertz SJ. Intrauterine growth retardation leads to the development of type 2 diabetes in the rat. Diabetes 50: 2279-2286, 2001.[Abstract/Free Full Text]
  38. Skurat AV and Roach PJ. Regulation of glycogen synthesis. In: Diabetes Mellitus: A Fundamental and Clinical Text, edited by LeRoith D, Taylor SI, and Olefsky JM. Philadelphia, PA: Lippincott-Raven, 2000, p. 251-264.
  39. Stalmans W and Hers HG. The stimulation of liver phosphorylase b by AMP, fluoride and sulfate. A technical note on the specific determination of the a and b forms of liver glycogen phosphorylase. Eur J Biochem 54: 341-350, 1975.[Web of Science][Medline]
  40. Sun Y, Liu S, Ferguson S, Wang L, Klepcyk P, Yun JS, and Friedman JE. Phosphoenolpyruvate carboxykinase overexpression selectively attenuates insulin signaling and hepatic insulin sensitivity in transgenic mice. J Biol Chem 277: 23301-23307, 2002.[Abstract/Free Full Text]
  41. Tanaka H, Suzuki N, and Arima M. Hypoglycemia in the fetal alcohol syndrome in rat. Brain Dev 4: 97-103, 1982.[Web of Science][Medline]
  42. Thorburn A, Andrikopoulos S, and Proietto J. Defects in liver and muscle glycogen metabolism in neonatal and adult New Zealand obese mice. Metabolism 44: 1298-1302, 1995.[CrossRef][Web of Science][Medline]
  43. Toyoda Y, Miwa I, Kamiya M, Ogiso S, Okuda J, and Nonogaki T. Changes in subcellular and zonal distribution of glucokinase in rat liver during postnatal development. FEBS Lett 359: 81-84, 1995.[CrossRef][Web of Science][Medline]
  44. Van Assche FA, Holemans K, and Aerts L. Fetal growth and consequences for later life. J Perinat Med 26: 337-346, 1998.[Web of Science][Medline]
  45. Vickers MH, Breier BH, Cutfield WS, Hofman PL, and Gluckman PD. Fetal origins of hyperphagia, obesity, and hypertension and postnatal amplification by hypercaloric nutrition. Am J Physiol Endocrinol Metab 279: E83-E87, 2000.[Abstract/Free Full Text]
  46. Villaroya F and Mampel T. Glucose tolerance and insulin response in offspring of ethanol-treated pregnant rats. Gen Pharmacol 16: 415-418, 1985.[Web of Science][Medline]
  47. Weyer C, Funahashi T, Tanaka S, Hotta K, Matsuzawa Y, Pratley RE, and Tataranni PA. Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia. J Clin Endocrinol Metab 86: 1930-1935, 2001.[Abstract/Free Full Text]
  48. Wimhurst JM and Harris EJ. The actions of avenaciolide and ethanol on glucose metabolism and on related enzyme activities in the isolated perfused rat liver. Biochim Biophys Acta 437: 51-61, 1976.[Medline]
  49. Yoon JC, Puigserver P, Chen G, Donovan J, Wu Z, Rhee J, Adelmant G, Stafford J, Kahn CR, Granner DK, Newgard CB, and Spiegelman BM. Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1. Nature 413: 131-138, 2001.[CrossRef][Medline]
  50. Zhang M, Gong Y, Corbin I, Mellon A, Choy P, Uhanova J, and Minuk GY. Light ethanol consumption enhances liver regeneration after partial hepatectomy in rats. Gastroenterology 119: 1333-1339, 2000.[CrossRef][Web of Science][Medline]



This article has been cited by other articles:


Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
X.-H. Yao and B. L. G. Nyomba
Hepatic insulin resistance induced by prenatal alcohol exposure is associated with reduced PTEN and TRB3 acetylation in adult rat offspring
Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2008; 294(6): R1797 - R1806.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
X.-H. Yao and B. L. Gregoire Nyomba
Abnormal glucose homeostasis in adult female rat offspring after intrauterine ethanol exposure
Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2007; 292(5): R1926 - R1933.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
S. Nammi, K. Dembele, and B. L. G. Nyomba
Increased 11beta-hydroxysteroid dehydrogenase type-1 and hexose-6-phosphate dehydrogenase in liver and adipose tissue of rat offspring exposed to alcohol in utero
Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2007; 292(3): R1101 - R1109.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
K. Dembele, X.-H. Yao, L. Chen, and B. L. G. Nyomba
Intrauterine ethanol exposure results in hypothalamic oxidative stress and neuroendocrine alterations in adult rat offspring
Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2006; 291(3): R796 - R802.
[Abstract] [Full Text] [PDF]

Home page
 J. Appl. Physiol.Home page
X.-H. Yao, L. Chen, and B. L. G. Nyomba
Adult rats prenatally exposed to ethanol have increased gluconeogenesis and impaired insulin response of hepatic gluconeogenic genes
J Appl Physiol, February 1, 2006; 100(2): 642 - 648.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
P. B. Persson
From clinical insights to new therapies
Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2006; 290(1): R124 - R125.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
286/3/R554    most recent
00076.2003v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (10)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Chen, L.
Right arrow Articles by Nyomba, B. L. G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Chen, L.
Right arrow Articles by Nyomba, B. L. G.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online
Copyright © 2004 by the American Physiological Society.