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Department of Diabetes and Metabolic Medicine, Division of General and Developmental Medicine, St. Bartholomew’s and the Royal London School of Medicine and Dentistry, Queen Mary, University of London, London, E1 4NS, United Kingdom
Address all correspondence and requests for reprints to: Mark Holness, University of London, Department of Diabetes and Metabolic Medicine, Medical Sciences Building, Queen Mary, Mile End Road, London E1 4NS, United Kingdom. E-mail: m.j.holness{at}qmw.ac.uk
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Abstract |
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Introduction |
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Dexamethasone stimulates leptin synthesis and secretion in rat adipocytes (14), and leptin has been shown to markedly impair glucose-stimulated insulin secretion (GSIS) (15, 16, 17). In addition, leptin has been proposed as a potential factor regulating fetal growth (reviewed in Ref. 18). The present study sought to establish whether low-dose dexamethasone administration leads to altered characteristics of GSIS or modified hepatic or peripheral insulin action during late pregnancy, and the extent to which modulation of plasma leptin levels may contribute to such effects.
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Materials and Methods |
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Animals
All studies were conducted in adherence to the regulations of
the United Kingdom Animal Scientific Procedures Act (1986). Female
Wistar rats (200–250 g) were purchased from Charles River Laboratories (Margate, Kent, UK). Rats were subjected to a
standard light-dark cycle (0800–2000 h dark, 2000–0800 h light) cycle
in a temperature-controlled room (21 ± 2 C). The rats were housed
in individual cages and were given free access to food and water. Rats
were maintained on standard, pelleted rodent diet purchased from
Special Diet Services (Witham, Essex, UK). This diet consisted of 52%
carbohydrate, 15% protein, 3% lipid, and 30% nondigestible residue
(by weight), and contained 2.61 kcal metabolisable energy/g. Rats were
time-mated by the appearance of sperm plugs (d 0 of pregnancy) and
randomly assigned to two groups. Dexamethasone was administered sc at a
low dose (100 µg/kg maternal body weight per d) via a chronically
implanted osmotic minipump to rats from d 14–19 of pregnancy
(term = 22–23 d) or, for an equivalent period, to age matched
unmated female rats. An initial priming dose (0.1 mg) of dexamethasone
was given by sc injection before minipump implantation. This procedure
led to almost total suppression of endogenous corticosterone levels
(results not shown). Pregnant rats with less than eight fetuses were
not included in the study. Sham operations involving incision and
manipulation under anesthesia identical to the procedure for
implantation of the osmotic minipump were undertaken on control
rats.
In vivo studies of glucose kinetics
Maternal glucose-insulin homeostasis was assessed on d 19 of
pregnancy in the postabsorptive state and during insulin infusion at
euglycemia. On the d of the experiment, food was withdrawn at the
end of the dark (feeding) phase and studies undertaken in the
postabsorptive state. For euglycemic-hyperinsulinemic clamp studies,
rats were fitted with chronic indwelling jugular cannulae for infusion
and sampling. Euglycemic-hyperinsulinemic clamp studies were conducted
at 5 d after cannulation to permit full recovery from surgery in
unstressed conscious rats as described in Refs. 19, 20 . A
constant infusion of human Actrapid insulin was given for up to
2 h. The insulin dose was standardized to 4 mU/kg per min. The
infusion of exogenous glucose was initiated at 1 min after the start of
insulin infusion. Blood was sampled from the right jugular vein at
5-min intervals. Adjustments in the exogenous glucose infusion rate
were made to maintain glycemia at approximately 4.2 mM.
Blood glucose concentrations during the clamp were determined using a
glucose analyzer (YSI, Inc., Yellow Springs, OH). A
plateau for the exogenous glucose infusion rate was reached after
60–90 min. The glucose infusion rate required to maintain euglycemia
during the plateau phase of the clamp is denoted as glucose infusion
rate (GIR).
Rates of endogenous glucose production (Ra) and peripheral glucose disposal (Rd) were estimated in the basal state and during a euglycemic-hyperinsulinemic clamp using primed (0.5 µCi)-continuous (0.2 µCi/min per rat) iv infusion of [3-3H]glucose (19, 20). A steady-state of glucose specific activity in the basal state was achieved by 60 min. Blood samples (0.1 ml) were obtained at 60, 75, and 90 min after the commencement of the tracer infusion for determination of basal plasma glucose specific activity. From 90 min, rats were infused with insulin, while blood glucose levels were maintained at euglycemia for a further 120 min. The [3-3H] glucose infusion was continued for a further 120 min. Plasma insulin concentration, GIR and glucose specific activity all reached steady-state by 90 min after the start of the clamp, after which three blood samples (0.1 ml) were obtained at 15-min intervals for measurements of glucose specific activity. Mean coefficients of variation (± SEM) of glucose specific activity for the control and dexamethasone-treated pregnant groups were 6.7 ± 2.0% and 9.6 ± 1.6%, respectively, in the basal state and 8.4 ± 1.8% and 10.1 ± 1.8%, respectively, during the hyperinsulinemic clamp. Ra and Rd were calculated as described in Refs. 19, 20 . Glucose clearance rate (GCR) was calculated as Rd divided by the blood glucose concentration.
Iv glucose challenge
Glucose was administered as an iv bolus (0.5 g glucose/kg; 150
µl per 100 g body weight) to conscious, unrestrained rats (see
Refs. 19, 20). Glucose was injected via a chronic
indwelling jugular cannula and blood samples (100 µl) were withdrawn
at intervals from the indwelling cannula, which was flushed with saline
after the injection of glucose to remove residual glucose. Samples of
whole blood (50 µl) were deproteinized with
ZnSO4/Ba(OH)2, centrifuged
(10,000 x g) at 4 C, and the supernatant retained for
subsequent assay of blood glucose. The remaining sample was immediately
centrifuged (10,000 x g) at 4 C, and plasma was stored
at -20 C until assayed for insulin.
Biochemical and physiological determinations
Plasma insulin concentrations were measured by RIA using rat
insulin standards (Phadeseph Pharmacia). Plasma leptin concentrations
were determined by a commercially available RIA using rat leptin
standards (Linco Research, Inc.).
Statistical analyses
Statistical comparisons were made with StatView (Abacus
Concepts, Berkeley, CA). Multiple comparisons were made by ANOVA and
individual comparisons by Fisher post hoc tests. Comparisons between
just two sets of data were performed with the unpaired t
test. All data are presented as the means ±
SEM.
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Results |
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. The body weight of control dams
increased steadily from d 0–19 of gestation (Fig. 1). This was
accompanied by an increase in food intake in control dams from d 1–17
of gestation compared with d 0 of gestation, but food intake
subsequently declined thereafter before parturition (Fig. 1).
Dexamethasone treatment led to a modest, but statistically significant
decline in food intake compared with that of control dams on d 15
(16%; P < 0.01), 16 (19%, P <
0.001), and 17 (12%; P < 0.05) of pregnancy. This was
associated with a significant decline in body weight in
dexamethasone-treated dams compared with control dams on d
17 (9%; P < 0.05), 18 (9%; P <
0.001), and 19 (11%; P < 0.001) of pregnancy (Fig. 1). Glucocorticoid administration did not compromise pregnancy to term
and fetal numbers per dam were unchanged (control, 12.3 ± 0.5;
dexamethasone-treated, 12.0 ± 0.7 [8–13 litters]; N.S.).
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). This relative
hyperinsulinaemia was accompanied by higher postabsorptive blood
glucose concentrations (20%; P < 0.05) in the
dexamethasone-treated pregnant group (Table 1). The insulin: glucose
ratio, which is an index of the relative response of insulin to fasting
glycaemia, was significantly higher (43%, P < 0.05)
in the dexamethasone-treated pregnant group compared with controls. We
assessed to what extent these responses to dexamethasone were
specifically related to the pregnant state by treating age-matched
nonpregnant female rats with dexamethasone for 5 d. Dexamethasone
treatment of nonpregnant rats also resulted in elevated postabsorptive
insulin concentrations compared with those found in nonpregnant control
rats (control, 10 ± 1 µU/ml; dexamethasone-treated, 29 ±
5 µU/ml; P < 0.01), but did not alter postabsorptive
glycaemia.
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). Basal
blood GCR, an index of glucose disposal taking into account differences
in prevailing glucose concentrations, was also significantly increased
(by 17%; P < 0.01) in the dexamethasone-treated
pregnant group (Fig. 2).
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). A trend toward higher
glucose levels was evident in the dexamethasone-treated pregnant group
after 15 min and the rate of glucose disappearance (K value) calculated
over the first 15 min was significantly lower (by 39%;
P < 0.05) for the dexamethasone-treated pregnant group
than for the controls (control pregnant, 3.1 ± 0.4%/min;
dexamethasone-treated pregnant, 1.9 ± 0.2%/min). Dexamethasone
treatment of nonpregnant rats resulted in a trend toward a lower K
value (a 21% decrease, but this did not achieve statistical
significance) compared with control nonpregnant rats (control
nonpregnant, 2.9 ± 0.2%/min; dexamethasone-treated nonpregnant,
2.3 ± 0.2%/min). Thus, the impact of dexamethasone
treatment on rates of glucose clearance after an iv glucose
challenge is more pronounced in pregnant than in nonpregnant rats.
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).
Insulin concentrations in rats of the dexamethasone-treated pregnant
group remained significantly lower (by 36%; P <
0.05) than those of the control pregnant group at 5 min after iv
glucose administration (82 ± 11 µU/ml and 52 ± 8 µU/ml,
respectively) (Fig. 3). The incremental area under the curve for insulin (IAUC-insulin) was, as expected, significantly higher in late pregnant control rats than in age-matched unmated control rats (control nonpregnant, 149 ± 8 µU/min per liter; control pregnant, 215 ± 27 µU/min per liter; a 44% increase, P < 0.05). Dexamethasone treatment did not significantly affect IAUC-insulin values for nonpregnant rats (dexamethasone-treated nonpregnant, 121 ± 34 µU/min per liter). Thus, dexamethasone treatment specifically impairs the enhancement of insulin secretion that is normally observed in response to pregnancy and IAUC-insulin values for nonpregnant and late-pregnant rats after dexamethasone treatment do not differ significantly (dexamethasone-treated nonpregnant, 121 ± 34 µU/min per liter; dexamethasone-treated pregnant, 121 ± 20 µU/min per liter; NS).
Effect of maternal dexamethasone treatment during pregnancy on
whole body insulin action and glucose disposal during
hyperinsulinaemia
Previous studies have demonstrated that an insulin infusion rate
of approximately 4 mU/kg per min leads to plasma insulin concentrations
in the upper physiological range (approximately 75 µU/ml) during
clamp (19, 21). In the present study, steady-state plasma
insulin concentrations attained during clamp were similar in the
control and dexamethasone-treated pregnant groups (control, 69 ±
7 µU/ml [n = 10]; dexamethasone-treated, 74 ± 5 µU/ml
[n = 4]). The standardization of blood glucose concentrations
during insulin infusion enables direct comparison of whole-body insulin
action between the two pregnant groups. Steady-state blood glucose
concentrations during hyperinsulinemia did not differ significantly
between the two groups of pregnant rats (control, 4.1 ± 0.2
mM [n = 10]; dexamethasone-treated, 4.2 ± 0.1
mM [n = 4]). The coefficients of variance for blood
glucose concentrations were <15% for both groups.
At similar steady-state insulin and glucose concentrations, the GIRs
required to maintain glycemia at approx. 4.2 mM during
insulin stimulation (insulin infusion rate of 4 mU/kg per min) were
24.7 ± 1.0 mg/min per kg and 27.5 ± 1.2 mg/min per kg
respectively in the control and dexamethasone-treated pregnant groups.
Rd increased significantly in response to insulin infusion in both
control and dexamethasone-treated pregnant groups (by 218%;
P < 0.001 and by 54%; P < 0.001,
respectively) (Fig. 2). Rd estimated during steady-state
hyperinsulinaemia and expressed relative to body mass was not
significantly affected by dexamethasone treatment in late pregnancy
(Fig. 2); however, Rd expressed on a whole animal basis was
significantly lower in the dexamethasone-treated pregnant group than in
the control pregnant group (control, 9.2 ± 0.5 mg/min;
dexamethasone-treated, 7.6 ± 0.3 mg/min; P <
0.05). Clamp GCR values are plotted against prevailing steady-state
insulin levels in Fig. 2, clearly demonstrating a specific impairment
of the effect of insulin to promote glucose clearance in the
dexamethasone-treated pregnant group as demonstrated by the lower
gradient of the plasma insulin-GCR relationship.
Effect of maternal dexamethasone treatment during pregnancy on
endogenous glucose production during hyperinsulinaemia
Although Ra was suppressed by hyperinsulinemia in both groups,
suppression of Ra was greater in the dexamethasone-treated pregnant
group (P < 0.05) under hyperinsulinaemic conditions
(Fig. 2). Furthermore, whereas GIR was greater than Rd for each member
of the dexamethasone-treated pregnant group, which is typically
interpreted to indicate that endogenous glucose production has been
suppressed completely, GIR was less than Rd for the control pregnant
group, indicating that incomplete suppression of endogenous production
of glucose had been obtained.
Maternal leptin levels are increased by dexamethasone
administration
Maternal plasma leptin levels at d 19 of gestation, measured in
the postabsorptive state, were significantly higher (by 2.2-fold:
P < 0.05) in the pregnant group treated with
dexamethasone compared with the control group. Insulin infusion (2 h)
significantly increased (2-fold; P < 0.001) plasma
leptin levels in the control pregnant group, but increases in plasma
leptin levels did not achieve significance in the dexamethasone-treated
pregnant group. Basal and clamp leptin levels are plotted against
prevailing steady-state insulin levels in Fig. 4. The plasma insulin-plasma leptin
relationships (slopes of the lines) provide indices of the
response of plasma leptin levels to 2-h hyperinsulinaemia at
euglycaemia. There was no indication that the elevated postabsorptive
leptin levels observed in the dexamethasone-treated pregnant group
could be solely attributed to relative hyperinsulinaemia, and it
appeared that the leptin response to a rise in insulin was unimpaired
by dexamethasone treatment in late pregnancy (Fig. 4).
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Discussion |
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The liver is a major target tissue for the glucocorticoids (reviewed in Ref. 22). In the nonpregnant state, glucocorticoids increase hepatic glucose production by stimulating gluconeogenesis (23). The expression of the gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK) has been identified as a key target. Hepatic PEPCK expression is also regulated by insulin, and the effect of insulin is dominant over that of the glucocorticoids (24). Ra in the postabsorptive state was increased in late-pregnant dams treated with dexamethasone, compared with the controls. This effect was not associated with changes in liver weight as a consequence of dexamethasone treatment (control, 14.5 ± 0.3 g; dexamethasone-treated, 13.9 ± 0.4 g). Postabsorptive GCR was also increased by dexamethasone administration in late pregnancy, and thus the modest increase in postabsorptive glycaemia observed in this group can be entirely attributed to increased glucose production. The observation of increased Ra in the postabsorptive state in late pregnant dams treated with dexamethasone compared with the controls pregnant dams suggests that hepatic sensitivity to glucocorticoids with respect to glucose production is retained in late pregnancy.
It is established that gestation is characterized by adaptations of carbohydrate metabolism, including a progressive state of maternal insulin resistance, that impede maternal glucose utilization (1, 2, 3, 4). The development of maternal insulin resistance confers a competitive advantage to the developing fetus because uterine uptake and the placental transport of glucose appear to be relatively unaffected by changes in the maternal insulin status (5, 6). It is also well known that stress hormones, such as the glucocorticoids, induce insulin resistance (12, 22, 25), and can precipitate glucose intolerance when they are in excess. However, since late pregnancy is already a state of insulin resistance, a key question addressed in the present study was whether the administration of dexamethasone during late pregnancy would further depress insulin action. Whole-body insulin action, as assessed by the rate of glucose infusion required to maintain euglycaemia during steady-state hyperinsulinaemia (GIR), was unaffected by maternal dexamethasone treatment during late pregnancy. However, kinetic analysis revealed a shift in insulin sensitivity, with augmented insulin resistance of peripheral tissues but enhanced hepatic insulin sensitivity. The identification of peripheral insulin resistance as a component of the maternal response to excess glucocorticoids during late pregnancy is supported by the finding of a lower rate of glucose disappearance (K value) during the iv glucose tolerance test in the dexamethasone-treated pregnant group. Importantly, the impact of dexamethasone treatment on rates of glucose disappearance was more pronounced in pregnant than in nonpregnant rats. The question remains as to why the increased Ra in the postabsorptive state is not associated with an impaired response of Ra to hyperinsulinaemia. It appears that hyperinsulinaemia can effectively counter the effect of dexamethasone treatment to increase Ra. Overall, our findings suggest that increased postabsorptive Ra in the dexamethasone-treated pregnant group reflects a direct effect of dexamethasone to increase hepatic glucose production which is not due to an action to impair hepatic insulin sensitivity. Thus, our results are consistent with the previously demonstrated dominance of insulin over dexamethasone with respect to regulation of PEPCK expression (24).
During normal pregnancy, pancreatic islets undergo a number of adaptive changes to meet the increased demand for insulin secretion imposed by maternal insulin resistance (reviewed in Ref. 7). These include increased GSIS, a reduction in the glucose-stimulated threshold, and ß cell proliferation. The lowering of the threshold for GSIS is thought to be the primary mechanism by which the ß cells can release significantly more insulin under normal blood glucose concentrations (7). In the present experiments, in which the administration of dexamethasone exaggerated the physiological peripheral insulin resistance of late pregnancy, the higher insulin:glucose concentration ratio observed in the dexamethasone-treated pregnant group in the postabsorptive state suggests that insulin secretion may occur at a lower level of glycaemia. It therefore appears that the leftward shift in the insulin secretory response curve typical of late pregnancy is not only retained, but augmented. The adaptation in ß cell function observed in dexamethasone-treated pregnant rats in the present study parallels the apparent enhancement of insulin sensitivity with respect to suppression of Ra observed in this group, suggesting that there may be a common underlying signal/mechanism. Enhanced basal insulin secretion was, however, accompanied by a marked impairment in GSIS as a consequence of dexamethasone administration, suggesting a dissociation between enhanced glucose sensing and augmented glucose responsiveness in vivo.
It has emerged that lactogenic hormones—the placental lactogens (PL-I and PL-II) and PRL—may be important for mediating some of the adaptations of the endocrine pancreas to pregnancy (see e.g. Refs. 8, 9, 10, 11), in particular the increase in islet proliferation and islet cell hypertrophy. In rodents, PL-I is normally made in the trophoblast giant cells of the placenta (26, 27, 28) and the PLs interact on islet cells with the PRL receptor, a member of the cytokine family of receptors (29, 30). In the present study, dexamethasone treatment during pregnancy led to decreased placental weights (results not shown) and thus placental PL-I production may be impaired. Perhaps even more importantly, recent work has shown that glucocorticoids, whose concentrations normally increase in late pregnancy to assist maturation of fetal tissue function (31), counteract the effect of lactogens on insulin secretion and ß cell proliferation (13), presumably to curtail insulin hypersecretion postpartum. In vitro, dexamethasone at a concentration equivalent to the plasma glucocorticoid concentration found during late pregnancy was shown to exert a significant inhibitory effect on insulin secretion by islets previously cultured with PRL to mimic the islet adaptive response to pregnancy (13). Of major importance was the finding that dexamethasone inhibited ß-cell proliferation induced by PRL and promoted ß cell apoptosis (13). Studies of the effects of long-term high-dose dexamethasone treatment (2 mg/kg daily for 12 d) on GSIS in isolated islets from male rats demonstrated a marked leftward shift in the glucose dose-response relationship after dexamethasone treatment, but no difference in insulin secretion at 20 mM glucose (32). Our data therefore provide direct in vivo support for the concept that compensatory insulin hypersecretion in pregnancy is opposed by excessive exposure of the ß cell to glucocorticoids, probably by an effect to impair ß cell proliferation and islet mass augmentation in response to PL-I, but that the lowered GSIS threshold occurs via a different mechanism that is not adversely affected (and may even be enhanced) by glucocorticoids. It is possible that high basal insulin secretion but substantially reduced GSIS in the dexamethasone-treated dams may reflect sustained exposure of the ß cells to a relatively elevated glucose concentration as rats made hyperglycaemic by chronic (48 h) glucose infusions develop ß-cell glucose unresponsiveness despite high basal insulin secretion (33, 34).
Leptin has been proposed as a potential factor in fetal growth. In the nonpregnant state, leptin expression in adipose tissue of lean rodents changes in parallel with the changes in insulin concentrations associated with feeding and fasting (reviewed in Ref. 18). In starved rats, circulating leptin levels are increased with insulin infusion at euglycemia (35, 36, 37). In the present experiments with late pregnant rats, insulin infusion at euglycamia significantly elevated leptin levels. Leptin levels were already elevated in the postabsorptive state in the dexamethasone-treated dams and further elevated by hyperinsulinaemia in the treated group. Given that leptin has been reported to influence hepatic and peripheral actions of insulin (38, 39, 40, 41) and to impair GSIS (15, 16, 17), we cannot exclude a role for leptin in modulating or mediating altered maternal insulin-glucose interactions invoked by inappropriately high glucocortioid concentrations during late pregnancy.
Intrauterine growth retardation (IUGR) (assessed as low birth weight) in humans has been identified as a risk factor for the development of disorders in adult life, including glucose intolerance and insulin resistance (reviewed in Ref. 42). However, the mechanisms underlying IUGR remains to fully elucidated. The fetus is normally protected from maternal glucocorticoids by the placental enzyme 11ß-hydroxysteroid dehydrogenase type-2 (11ß-HSD2), which catalyzes the rapid conversion of active glucocorticoids to inert 11-keto derivatives (43). The synthetic glucocorticoid dexamethasone is a poor substrate for 11ß-HSD2 (43) and, in the rat, dexamethasone administration during the last third of pregnancy leads to fetal growth retardation (44, 45). Early growth retardation induced by maternal dexamethasone treatment in the rat produces fasting and postglucose hyperinsulinaemia (46) in the adult offspring. The administration of carbenoxolone, an inhibitor of placental 11ß-HSD2, to pregnant rats prevents the normal degradation of maternal glucocorticoids exposing the fetus to elevated levels of maternal glucocorticoids. This treatment also leads to a significant reduction in birth weight (47). Although these data provided strong evidence that excessive exposure to glucocorticoids affects fetal growth directly, the possibility nevertheless existed that an adverse impact of dexamethasone treatment on maternal glucose handling or insulin sensitivity might additionally impair nutrient provision to the developing fetus and thereby contribute to IUGR. We observed significant (15% P < 0.001) fetal growth retardation at d 19 of gestation in response to maternal dexamethasone treatment in the present study (mean fetal weight (g): control, 2.62 ± 0.07 [6 litters]; dexamethasone-treated, 2.22 ± 0.03 [13 litters]). However, the data obtained in the present study indicate that maternal peripheral insulin-dependent glucose utilization is impaired by dexamethasone treatment, and therefore it would be predicted that even more glucose would be made available for fetal use. Thus, fetal IUGR in response to dexamethasone treatment is unlikely to reflect a maternal metabolic defect with respect to inadequate suppression of insulin-dependent glucose disposal. Leptin has been proposed as a potential factor in fetal growth and, therefore, dexamethasone-induced IUGR could reflect, in part, an inappropriately low plasma leptin level. However, the present study demonstrates an effect of dexamethasone treatment to enhance leptin levels during pregnancy, indicating that an inappropriately low plasma leptin level is unlikely to contribute to IUGR.
In summary, dexamethasone treatment during late pregnancy elicited fasting hyperinsulinaemia and hyperglycaemia and significantly enhanced endogenous glucose production. Insulin secretion after iv glucose challenge and insulin’s ability to promote glucose clearance were impaired, whereas suppression of endogenous glucose production by hyperinsulinemia was enhanced by dexamethasone treatment. The data indicate that elevated maternal glucocorticoids impair adaptations of the endocrine pancreas to pregnancy in that hypersecretion of insulin in response to deteriorating peripheral insulin action is no longer apparent leading to impaired glucose tolerance. Increased glucose production in the basal state is likely to underlie fasting hyperglycaemia; however, the response of Ra to insulin is sensitized supporting the concept that impaired glucose tolerance is due to impaired peripheral glucose disposal.
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Acknowledgments |
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Footnotes |
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Abbreviations: 11ß-HSD2, 11ß-Hydroxysteroid dehydrogenase type-2; GCR, glucose clearance rate; GIR, glucose infusion rate; GSIS, glucose-stimulated insulin secretion; IAUC, incremental area under the curve; IUGR, intrauterine growth retardation; K, rate of glucose disappearance after an iv glucose load; PEPCK, phosphoenolpyruvate carboxykinase; Ra, endogenous glucose production; Rd, glucose disposal.
Received February 12, 2001.
Accepted for publication May 16, 2001.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, P < 0.05; 
,
P < 0.01; *, P < 0.001.
