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,2
* The Center for the Study of Fetal Programming, Laramie, WY 82071;
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Department of Animal Science, University of Wyoming, Laramie, WY 82071;
and
Department of Obstetrics and Gynecology, University of Texas Health Sciences Center, San Antonio, TX 78229; and
and
Department of Animal and Range Sciences, Fargo, ND 58105
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Abstract |
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 Top Abstract INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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) between d 28 and 78 of gestation, and then all ewes were fed 100% of the NRC requirements from d 79 through lambing. Male lambs born to nutrient-restricted (n = 9) and control-fed (n = 9) ewes exhibited similar BW (5.8 vs. 6.0 ± 0.3 kg) and crown-rump lengths (53.8 vs. 55.4 ± 1.0 cm) at birth. At 63 and 250 d of postnatal age, wether lambs were subjected to a glucose tolerance test, in which a bolus of glucose was administered i.v. to evaluate changes in glucose and insulin concentrations. After i.v. glucose administration at 63 d of age, lambs from nutrient-restricted ewes exhibited a greater area under the curve for glucose (AUCg; 6,281 vs. 5,242 ± 429; P < 0.05) and insulin (AUCi; 21.0 vs. 8.6 ± 1.9; P < 0.001) than lambs from control-fed ewes. After glucose administration at 250 d of age, lambs from nutrient-restricted ewes had greater AUCg (7,147 vs. 5,823 ± 361; P < 0.01) but a lower AUCi (6.4 vs. 10.2 ± 1.9; P = 0.05) than lambs from control-fed ewes. Lambs from nutrient-restricted ewes were heavier (26.6 vs. 21.8 ± 2.3 kg; P < 0.05) and had more backfat (0.30 vs. 0.21 ± 0.03 cm, P < 0.05) by 4 mo of age than the lambs from control-fed ewes. At slaughter at 280 d of age, lambs from nutrient-restricted ewes remained heavier than lambs from control-fed ewes, had greater (P < 0.05) amounts of kidney and pelvic-area adipose tissue, and tended (P < 0.10) to have reduced LM and semitendinosus muscle weights as a percentage of HCW. These data demonstrate that a bout of maternal undernutrition during early to midgestation in sheep increased BW and fat deposition during adolescence and dysregulated glucose uptake in the absence of any change in birth weight.
Key Words: gestation • glucose tolerance • insulin resistance • maternal undernutrition • sheep
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INTRODUCTION |
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TopAbstractINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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; DelCurto et al., 1999). Gestating ewes on rangeland pastures often experience prolonged bouts of undernutrition (Thomas and Kott, 1995). Growth rates and carcass characteristics of young ruminants are known to vary considerably even when the genetics and nutritional management are constant (Owens et al., 1993; Thomas and Kott, 1995). Considerable epidemiological data have accrued in recent years indicating that maternal nutritional status during certain critical periods of gestation can have an impact on the offspring in later life (Barker and Clark, 1997; McMillen et al., 2001). More specifically, nutrient restriction during the first half of pregnancy in humans, rats, and sheep has been associated with postnatal metabolic and endocrine disorders, as well as cardiovascular disorders (Hales, 1997; Hawkins et al., 1997; Gilbert et al., 2005). Additionally, poor wool and carcass quality have been reported in offspring from undernourished ewes (Black, 1983; Bell, 1992; Kelley et al., 1996).
Insulin resistance has been documented in otherwise well prepubertal children born with intrauterine growth retardation, suggesting that this may be one of the earliest metabolic abnormalities present in these children (Hofman et al., 1997). In rats, uterine artery ligation during pregnancy or maternal nutrient restriction during pregnancy and lactation result in glucose intolerance or type 2 diabetes with aging, which is usually associated with reduced ß-cell mass and function (Garfano et al., 1998; Bertin et al., 1999).
The objective of this study was to evaluate the impacts of early to midgestational undernutrition in the ewe on postnatal growth rate, adiposity, and carcass characteristics, as well as glucose tolerance and insulin resistance of male offspring.
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MATERIALS AND METHODS |
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TopAbstractINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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). A mineral-vitamin mixture [51.4% sodium tri-phosphate, 47.6% potassium chloride, 0.39% zinc oxide, 0.06% cobalt acetate, and 0.50% ADE vitamin premix (17,000,000 IU of vitamin A; 1,700,000 IU of vitamin D3; and 900,000 IU of vitamin E per kg; the amount of vitamin premix was formulated to meet the vitamin A requirements)] was included with the beet pulp pellets.
On d 21 postmating, all ewes were placed in individual pens and fed the control diet (100% of NRC recommendations for the early gestational ewe). On d 28 post-mating, the ewes were randomly assigned to remain on the control diet at 100% of the NRC (1985) recommendations (control-fed; n = 20) or were fed the control diet at 50% of the NRC (1985) recommendations (nutrient-restricted; n = 20). On d 45 postmating, pregnancy was confirmed by ultrasonography (Ausonics Microimager 1000 sector scanning instrument, Ausonics Pty Ltd, Sydney, Australia). At weekly intervals from d 28 of gestation until parturition, all ewes were weighed and the daily rations were adjusted for BW gain for control-fed ewes or BW loss for nutrient-restricted ewes. We have reported previously that this level of feed restriction from d 28 to 78 of gestation in ewes of the same breeding and from the same flock as those reported here resulted in a fetal intrauterine growth restriction of 
30% by d 78 (Vonnahme et al., 2003). On d 79 of gestation, all nutrient-restricted ewes were realimented to the control ration (100% of NRC requirements for the early gestational ewe), and all of the ewes were fed to meet the NRC (1985) recommendations until d 104 of gestation. From d 105 of gestation until the day of parturition, the rations fed to all of the pregnant ewes were increased according to the NRC guidelines for late gestational ewes (NRC, 1985).
Blood samples were collected at weekly intervals between d 28 and 140 of gestation by jugular venipuncture into chilled, heparinized Vacutainer tubes containing 2.5 mg/mL of sodium fluoride (Sigma, St. Louis, MO) and that were maintained on ice. After collection, the blood tubes were centrifuged at 3,000 x g for 10 min. Plasma was collected and stored at –80°C for subsequent glucose analysis.
Parturition and Postnatal Procedures
Gestation length was similar for control-fed and nutrient-restricted realimented ewes and averaged 149 ± 2 d. Lambing occurred between 10 April and 28 April and was allowed to proceed naturally in all ewes, which were given free-choice access to good quality alfalfa hay thereafter. At birth, morphological data (birth weight, crown-rump length, abdominal and thoracic circumferences, biparietal diameter, femur length, humerus length) were collected and recorded for all lambs. There was no effect of dietary treatment on the percentages of ewes giving birth to singleton and twin lambs, which averaged 53 and 47%, respectively. Morphological data were also obtained from all lambs at 60 d of age. Before 2 wk of age, the lambs were tail-docked, and males were castrated by placement of rubber rings (FASS, 1999).
At 2 wk of age, a wether lamb born to each of 9 control-fed ewes (3 singleton and 6 twin lambs), and a wether lamb born to 9 nutrient-restricted ewes (7 singleton and 2 twin lambs) was selected at random for inclusion in the study to avoid potential sex differences in the data collected. Singleton lambs were reared as singletons, and twin lambs were reared as twins. Whether these animals were born and reared as singletons or twins was not part of the selection criteria for this study. All lambs were given free access to a standard, commercially available creep feed (Lamb Creep B30 w/Bovatec, Ranch-Way Feeds Inc., Ft. Collins, CO) from birth to weaning. At 120 ± 2 d of age, the 18 wether lambs previously selected were weaned, and pairs of lambs of the same treatment group were placed in pens containing a feeder and waterer. The lambs were weighed at weekly intervals thereafter and transitioned to a high-concentrate feed (All-American Show Lamb Grower, Ranch Way Feeds) with a partial diet of hay until the concentrate could be utilized as their sole diet. The lambs were fed the concentrate ad libitum until they were slaughtered at 280 ± 2 d of age.
Glucose Tolerance Test
Wether lambs selected for this study (control-fed = 9; nutrient-restricted = 9) were removed from their mothers at 63 ± 1 d of lactation for a 12-h period, and then were weighed and their jugular veins were catheterized (SurFlash 18 ga. x 2.5 inches long, Terumo Medical, Ann Arbor, MI) without anesthesia and using aseptic procedures. The lambs were allowed approximately 60 min to recover from the catheterization before initiating a glucose tolerance test. To establish baseline values of glucose and insulin, blood samples (3 mL) were drawn from the jugular catheter and placed into tubes containing heparin and sodium fluoride (2.5 mg/mL; Sigma) at –15 and –5 min relative to administration of a bolus injection of glucose via the jugular catheter (0.25 g/kg of BW in 20 s, 50% dextrose solution; Vedco, St. Joseph, MO). Additional blood samples were collected at 2, 5, 10, 15, 30, 60, and 120 min after the glucose injection. The catheters were flushed with heparinized saline after the glucose infusion and after each blood sampling. Blood samples were placed on ice until they were centrifuged at 3,000 x g for 10 min, and the plasma was stored at –80°C until subsequent analysis.
A second glucose tolerance test was performed at 250 ± 1 d of age on 8 of the 9 selected wethers from each treatment group. One wether lamb from each treatment group (a twin from the control-fed group on d 221 and a singleton from the nutrient-restricted group on d 236) was injured before the second glucose tolerance test and was removed from the study. The second glucose tolerance test was accomplished using procedures outlined in the first glucose tolerance test with the following modifications. To reduce stress and for ease of catheter placement, the wethers were placed briefly under isoflurane anesthesia (4% induction, 2% maintenance), and a catheter was inserted (12 cm) into a jugular vein under aseptic conditions. The wethers were then allowed a minimum of 5 d of recovery before the glucose tolerance test.
Fat Measurements
After clipping the wool, subcutaneous backfat over the LM was measured at 100 and 140 d of age by real-time ultrasound using the method of Edwards et al. (2003). Animals were restrained, and the 12th- and 13th-rib vertebrae were located by palpating along the ribs. Vegetable oil was applied to the wool over the 12th and 13th vertebrae, and using a real-time ultrasound machine with a 5 MHz probe (Ausonics Micorimager 1000 sector scanning instrument, Ausonics Pty Ltd., Sydney, Australia), backfat measurements were obtained. The minimum detectable level of backfat for this method was approximately 0.1 mm.
Tissue Collection and Processing of Lambs at Slaughter
At 280 ± 2 d of age, all 16 wether lambs were slaughtered at the University of Wyoming abattoir. Kidney and pelvic fat was removed on the slaughter floor and weighed, and HCW was obtained within 10 min of slaughter. The LM, semitendinosus muscle, and left femur were weighed.
Glucose and Hormone Assays
Glucose was analyzed using the Infinity (Cat. # TR15498, ThermoTrace Ltd., Melbourne, Australia) colorimetric assay modified in the following manner. Plasma was diluted 1:5 in PBS, and 10 µL of diluted plasma was added to 300 µL of the reagent mixture. All samples were run in triplicate, and sample analysis was completed using multiple assays. The intraassay and interassay CV were 5 and 7%, respectively, and sensitivity was 10 mg/dL. Insulin was measured by RIA in accordance with the manufacturer’s recommendations (Coat-A-Count, Diagnostic Products Corp., Los Angeles, CA) and completed using 2 assays. The intraassay CV was < 10%, whereas the interassay CV was < 5% and sensitivity was 0.05 ng/mL. Fasted glucose and insulin baseline values were ascertained from the –15 and –5 min samples.
Leptin was measured in plasma samples from fasted lambs at the time of the backfat measurements at 140 d of age in a single assay according to the manufacturer’s recommendations (MultiSpecies Leptin RIA kit, Cat. # XL-85K, LINCO Research Inc., St. Charles, MO). The intraassay CV for leptin was 10.3%, and sensitivity was 0.5 ng/mL.
Calculations and Statistics
All data are presented as means ± SEM, and significance was accepted when P < 0.05, with P < 0.10 considered a trend. For comparisons between twin and singleton lambs within a group, a mean without the SEM was presented when less than 3 observations were present. Area under the curve (AUC) was determined for insulin and glucose using the trapezoidal rule with Sigma Plot software (SPSS Inc., Chicago, IL). The first-phase insulin response was calculated in a manner described by Soto et al. (2003) as the sum of the 2- and 5-min insulin values minus the average of the baseline (–5 and –15 min) values. Lamb weight increases were compared using PROC MIXED (SAS Inst. Inc., Cary, NC) as 2 x 2 factorial arrangement in split-plot design, with lamb within treatment x lamb status as the error term. Weight gain was calculated as the change in BW between 2 consecutive measurements. Statistical comparisons between groups (nutrient-restricted vs. control-fed, or twin vs. single) were completed using independent t-tests, factorial ANOVA, or PROC MIXED for repeated measures where appropriate. Post hoc analysis was performed with a Tukey’s HSD test as indicated.
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RESULTS |
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TopAbstractINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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). Rate of gain was similar for both dietary groups after realimentation, with nutrient-restricted ewes remaining lighter (P < 0.05) than control-fed ewes at lambing. Plasma glucose concentrations were similar on d 28 between ewes assigned to control-fed and nutrient-restricted diets (Figure 2). From d 35 to 78, however, in association with the 50% decrease in NRC requirements, plasma glucose concentrations of nutrient-restricted ewes were reduced (P < 0.05) compared with those of control-fed ewes. Plasma glucose concentrations of nutrient-restricted ewes had rebounded to those exhibited by control-fed ewes by d 85, 1 wk after realimentation of nutrient-restricted ewes to NRC requirements. No differences in plasma glucose concentrations were observed between control-fed ewes and nutrient-restricted ewes from d 85 through 140 of gestation (data not shown).
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). When comparisons were made for morphometric measurements such as crown-rump length, biparietal diameter, thoracic girth, abdominal girth, and humerus length, a factorial AN-OVA revealed no differences between singles and twins within or between dietary groups (Table 1).
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). However, by 4 mo of age the lambs from nutrient-restricted ewes were heavier than the lambs from control-fed ewes (26.6 vs. 21.8 ± 1.4 kg; P < 0.04), and they remained heavier thereafter (P < 0.02) regardless of birth status (singleton vs. twin). Further, there was no significant interaction of treatment x birth status (P > 0.27). The total weight gain between 60 and 120 d of age was greater (P < 0.05) in lambs from nutrient-restricted ewes than lambs from control-fed ewes (14.2 vs. 11.0 ± 1.0 kg), but total weight gain between birth and 60 d or beyond 120 d was not different between the 2 groups.
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Glucose Tolerance Test
Clear and distinct differences were observed in the responses of the 2 groups (control-fed vs. nutrient-restricted) of offspring to the first (63 ± 1 d) and second (250 ± 1 d) glucose challenges, whereas no effect of birth type (singles vs. twins) was detected for any measure during either glucose challenge (P > 0.10). During the first glucose challenge, wether lambs from nutrient-restricted ewes demonstrated greater (P < 0.05) baseline glucose levels at both –15 min (88.7 vs. 66.5 ± 7.4 mg/dL; Figure 4) and at –5 min (86.9 vs. 70.9 ± 5.4 mg/dL; Figure 4), whereas baseline insulin was not different between the 2 groups (Figure 5). Lambs from nutrient-restricted ewes also had greater AUCg (6,282 vs. 5,242 ± 429; P < 0.05; Figure 4) and insulin (21.0 vs. 8.6 ± 1.9; P < 0.001; Figure 5) when compared with the lambs from control-fed ewes.
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and 7). The lambs from nutrient-restricted ewes continued to exhibit a greater AUCg (7,147 vs. 5,823 ± 361; P < 0.01; Figure 6) than lambs from control-fed ewes. However, the nutrient-restricted progeny demonstrated a lower insulin AUC (6.36 vs. 10.17 ± 1.85; P = 0.05; Figure 7) and insulin to glucose ratio (0.9 x 10–3 ± 0.2 x 10–3 vs. 1.8 x 10–3 ± 0.2 x 10–3 ng/mL, mg/dL; P < 0.03). Further, the first-phase insulin response [the sum of the 2 and 5 min insulin values minus the base-line value (Soto et al., 2003)] to the glucose tolerance test was less (P < 0.03) in the lambs from nutrient-restricted ewes compared with the lambs from control-fed ewes (3.92 vs. 7.05 ± 1.13).
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). At slaughter, HCW tended to be greater (P = 0.06) for lambs from nutrient-restricted ewes than lambs from control-fed ewes. The weight of kidney-pelvic fat and the ratio of kidney-pelvic fat to HCW were greater (P < 0.05) for lambs from nutrient-restricted ewes than lambs from control-fed ewes. In contrast, LM and semitendinosus muscle weights were similar for lambs from nutrient-restricted ewes and lambs from control-fed ewes, but the ratio of LM and semitendinosus muscle weights to HCW tended to be lower (P < 0.08) in lambs from nutrient-restricted ewes than lambs from control-fed ewes due to the tendency for increased HCW of the lambs from nutrient-restricted ewes. Left femur weights were greater (P < 0.05) for lambs from nutrient-restricted ewes than lambs from control-fed ewes, but this weight difference disappeared when left femur weight was evaluated as a percentage of HCW (Table 2). Further, there was no significant interaction of treatment x birth status for any of the carcass measurements taken (P > 0.20).
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DISCUSSION |
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TopAbstractINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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recently reported that undernutrition (50% of requirements) of pregnant ewes during the last 37 d of gestation, but not during the first 30 d, resulted in glucose intolerance in the resulting offspring at 12 mo of age. The impacts of periconceptional undernutrition on ovine fetal pancreatic function have been demonstrated previously, as Oliver et al. (2001) reported that feeding 60% of requirements from 60 d before to 30 d of gestation magnified fetal insulin release to a glucose challenge in late gestation. Further, the postnatal disruption of glucose metabolism in the current study presents as a biphasic phenomenon, with different insulin responses to glucose infusion pre- and postweaning. Importantly, although our model of early to midgestational global undernutrition has been demonstrated to elicit a marked intrauterine growth restriction (30%) at midgestation in association with fetal hypoglycemia and decreased concentrations of amino acids and polyamines in fetal blood (Vonnahme et al., 2003; Kwon et al., 2004), birth weight of the singleton and twin lambs to nutrient-restricted realimented ewes are similar to singleton and twin lambs born to control-fed ewes. These data are consistent with a late gestational acceleration of fetal growth in nutrient-restricted realimented ewes when compared with control-fed ewes from mid to late gestation. Epidemiological studies of the offspring of the Dutch famine survivors showed that exposure to famine during early gestation was at least as important as exposure in late gestation in predisposing offspring to metabolic and cardiovascular disorders in adult life, despite having no significant effect on birth weight (Ravelli et al., 1998; Roseboom et al., 2000a,b). Similarly, maternal nutrient restriction from early to midgestation in ewes has been shown to affect the hypothalamic-pituitary-adrenal axis and cardiovascular function of their lambs in the absence of altered singleton or twin birth weight (Hawkins et al., 2000; Gilbert et al., 2005). This is also the first report of an increased postnatal weight gain, adiposity, and plasma leptin concentrations in the normal birth weight offspring of ewes under-nourished from early to midgestation. Further, the lambs from nutrient-restricted ewes were heavier than lambs from control-fed ewes at necropsy, but their carcasses exhibited a greater fat to lean ratio than lambs from control-fed ewes.
Several studies have proposed a strong connection between intrauterine growth restriction, postnatal catch-up growth and the incidence of obesity and type 2 diabetes mellitus (Desai and Hales, 1997; Bertin et al., 1999; Hales and Ozanne, 2003). Results from a prospective report in 1-yr-old human babies demonstrate a strong relationship between early catch-up growth and insulin resistance (Soto et al., 2003). The increased plasma leptin concentration at 140 d of postnatal age in concert with the observed increase in backfat thickness and increased BW in the lambs from nutrient-restricted ewes may be a direct consequence of programmed hyperphagia in these animals. This concept is in agreement with Vickers et al. (2000) who reported a rat model of programmed obesity, hyperphagia and hyperleptinemia in offspring of undernourished mothers.
A strong relationship between leptin concentrations and percentage of body fat has been reported previously in the sheep (Caprio et al., 1996; Ostlund et al., 1996; Ehrhardt et al., 2003). A report has shown a strong relationship between nutrient intake and plasma leptin concentrations in growing sheep (Ehrhardt et al., 2003). The increased backfat thickness in lambs from nutrient-restricted vs. control-fed ewes on d 140 of age in this study, are consistent with a previous report demonstrating an increased adipose deposition in the fetus as early as 140 d of gestation in ewes that were undernourished from d 28 to d 80 of gestation (Bispham et al., 2003). The present data viewed in concert with the aforementioned reports strongly suggest the occurrence of programmed increases in adiposity in the present model.
As previously mentioned, the present data were evaluated to examine the possibility that the differing numbers of twin vs. singleton lambs in the control-fed and nutrient-restricted groups confounded the results. While our animal numbers are relatively low, we found no significant impact of birth type on glucose or insulin responses to i.v. glucose administration at 63 or 250 d of age. Our observation that twinning did not independently impose an effect on glucose-insulin homeostasis in the offspring at 2 or 8 mo of age is in agreement with the Birmingham twin study (Baird et al., 2001) and the Danish Twin Registry (Christensen et al., 1995, 2001). Further, Gardner et al. (2005) reported that offspring of ewes undernourished from d 110 to term experienced glucose intolerance at 12 mo of age, but their glucose-insulin homeostasis was unaffected by fetal number (singleton vs. twin pregnancies).
It is generally accepted that single born lambs grow more quickly than multiple-born lambs (Dickerson et al., 1972; Kempster et al., 1987). While singleton lambs in this study were heavier at birth than twin lambs, no differences in BW were noted between singleton and twin lambs thereafter, regardless of their mother’s dietary treatment. Additionally, there was no impact of birth type on carcass measurements obtained at slaughter. The lack of effect of birth type on these measurements may result from the low and uneven numbers of singleton and twin lambs in this study, and needs further investigation in a larger study.
The present observations show that a significant divergence in BW occurred between the lambs born to control-fed and nutrient-restricted ewes between 60 and 120 d of age. This period includes the time at which the animals were suckling and allowed free access to creep feed. Although we have no measurements of actual feed consumption during this interval, it is possible that consumption of milk and or consumption of creep feed may have differed between the lambs from nutrient-restricted and control-fed ewes. During this period the lambs from nutrient-restricted ewes also demonstrated an increased insulin response measured as AUC to a glucose tolerance test. In response to this initial glucose tolerance test at 63 d of age (preweaning), the lambs from nutrient-restricted ewes exhibited a greater glucose elevation in the face of a hyper-secretion of insulin when compared with the lambs from control-fed ewes. These data demonstrate that fetal nutrient restriction during early to midgestation amplifies the effects of an ad libitum feeding regimen in early postnatal life, and triggers a hyper-responsive pancreatic insulin secretion during the preweaning period in response to a glucose tolerance test. Additionally, the augmented insulin secretion that we observed during this time period may underlie the divergence in postnatal growth rate observed as it has been demonstrated previously that insulin is a potent anabolic hormone in the growing lamb (Wolff et al., 1989).
Our observation that the lambs from nutrient-restricted ewes were hyperglycemic before the first glucose challenge on d 63, but that their glucose levels returned to a level similar to the lambs from control-fed ewes at 120 min after the glucose tolerance test, may reflect augmented calorie consumption in the lambs from nutrient-restricted ewes. This notion is supported by a report by Greenwood et al. (2002) showing elevated glucose concentrations in growing lambs fed on a high plane of nutrition. The elevated glucose levels may indicate a programmed increase in appetite in the lambs from nutrient-restricted ewes that contributed to the accelerated growth observed between 2 and 4 mo of age. This possibility is supported by a study in the rat demonstrating hyperphagia and obesity in offspring of undernourished mothers (Vickers et al., 2000) but remains to be confirmed in our model.
Hyperinsulinemia of infancy in humans usually continues into childhood, followed by a progressive decline in insulin secretion and increased glucose intolerance in later life (Kassem et al., 2000). Evidence indicates that hyperinsulinaemia of infancy is caused by dysregulation of the apoptotic wave in ß cells that matures the neonatal pancreas (Kassem et al., 2000). The observed hypersinsulinemia in lambs of nutrient-restricted ewes may also reflect dysregulation of pancreatic development caused by maternal undernutrition. Final maturation of the ovine pancreas occurs near 2 mo of postnatal age (Titlbach et al., 1985), and our first glucose tolerance test occurred at 63 d of age. The mechanism responsible for the glucose intolerance observed at the same time point remains unclear.
In response to the glucose tolerance test at 250 d of age, the lambs from nutrient-restricted ewes continued to demonstrate an increased AUCg when compared with lambs from control-fed ewes. However, the lambs from nutrient-restricted ewes were hypoinsulinemic (lower AUCi) when compared with lambs from control-fed ewes. This dramatic change in insulin secretion in comparison to the lambs from control-fed ewes represents a second phase of glucose intolerance indicating pancreatic ß-cell dysfunction; possibly as a result of a reduced complement of ß-cells following the early hyper-responsive phase exhibited preweaning. Our data agree with a report in the rat, which demonstrates a progressive deterioration in insulin secretion to a glucose tolerance test in offspring of undernourished dams (Simmons et al., 2001).
Although the mechanisms underlying a predisposition to types 1 and 2 diabetes mellitus remain unclear, epidemiologic and experimental evidence indicate a strong relationship to prenatal and early postnatal events (Gale, 2002; Virtanen and Knip, 2003). Moreover, significant controversy remains as to the importance of insulin resistance vs. insulin deficiency in the etiology of noninsulin dependent diabetes mellitus (Ferrannini, 1998). Deterioration of the acute insulin response or the first-phase insulin response, both measured as the sum of or a portion of the peripheral insulin concentrations during the initial 10 min of a glucose tolerance test, is thought to reflect the secretion of pre-formed insulin in response to a maximal stimulus (Ferrannini, 1998). Human clinical studies have shown that a decreased first-phase insulin response to a glucose challenge in children is a strong correlate of later pancreatic dysfunction and subsequent onset of insulin dependent diabetes mellitus (Ferrannini, 1998). Further, a decreased first-phase insulin response to a glucose tolerance test in children is highly correlated with risk factors for insulin dependent diabetes mellitus (Chase et al., 2001). Thus, our observation indicating a decreased first-phase insulin response following the second glucose tolerance test in lambs exposed to undernutrition during gestation is consistent with reports describing the onset of diabetes mellitus in humans (Efendic et al., 1988; Kassem et al., 2000; Virtanen and Knip, 2003).
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Footnotes |
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2 Corresponding author: spford{at}uwyo.edu
Received for publication October 28, 2005. Accepted for publication January 8, 2007.
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TopAbstractINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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, n = 20). Values are percentage weight change (means ± SEM).
