ABSTRACT Maternal undernutrition throughout pregnancy can have long-term effects on the health of adult offspring. Undernutrition around the time of conception alters growth, metabolism, and

endocrinology of the sheep fetus, but the impact on offspring after birth is largely unknown. We determined the effect of maternal periconceptional undernutrition in sheep on glucose

tolerance in the offspring before and after puberty. Undernourished (UN) ewes were fed individually to maintain weight loss of 10–15% bodyweight from 61 d before until 30 d after mating.

Offspring (24 UN, 30 control) underwent an i.v. glucose tolerance test at 4 and 10 mo of age. Glucose tolerance was similar in both groups at 4 mo. Insulin area under the curve increased by

(_p_ = 0.01). We conclude that maternal undernutrition around the time of conception results in impaired glucose tolerance in postpubertal offspring. SIMILAR CONTENT BEING VIEWED BY OTHERS

GUT DEVELOPMENT FOLLOWING INSULIN-LIKE GROWTH FACTOR-1 SUPPLEMENTATION TO PRETERM PIGS Article Open access 12 December 2023 MATERNAL CHOLINE SUPPLEMENTATION MITIGATES PREMATURE FOETAL WEIGHT

GAIN INDUCED BY AN OBESOGENIC DIET, POTENTIALLY LINKED TO INCREASED AMNIOTIC FLUID LEPTIN LEVELS IN RATS Article Open access 18 May 2024 SUPPLEMENTATION WITH A PREBIOTIC (POLYDEXTROSE) IN

OBESE MOUSE PREGNANCY IMPROVES MATERNAL GLUCOSE HOMEOSTASIS AND PROTECTS AGAINST OFFSPRING OBESITY Article 08 October 2020 MAIN It is generally accepted that a mother's diet during

pregnancy is important for the health of her offspring. Epidemiologic and animal studies have found associations between reduced size at birth and the development of cardiovascular disease

and hypertension in adult life (1,2). Impaired glucose tolerance and diabetes are also linked to small birth size (3–5). However, there is growing evidence that altered disease risk in adult

offspring may result from an adverse intrauterine environment independent of fetal size (6) or size at birth (7). Most studies of the relationship between maternal nutritional status during

pregnancy and impaired glucose homeostasis in offspring have looked at the effect of reduced maternal nutrition throughout pregnancy. Feeding rats a globally restricted diet, or one reduced

specifically in protein content throughout pregnancy, results in offspring with reduced birthweight and altered pancreatic development, including decreased pancreatic blood flow (8);

decreased β cell proliferation, islet size, and islet vascularization (9); reduced pancreatic insulin content and β cell mass (10) and hyperinsulinism (11); and also impaired activities of

key hepatic enzymes involved in glycolysis and gluconeogenesis (12). In sheep, impaired glucose homeostasis and insulin action was seen in 1-y-old male sheep that experienced placental

restriction _in utero_ (13). There is also evidence that disease risk in adulthood may be affected by maternal nutrition during more limited, but critical, periods of intrauterine growth and

development. Studies of the Dutch Hunger Winter showed that the consequences for the offspring depended upon the time of maternal exposure to famine (5,7). Most studies have suggested it is

the nutritional status of the mother during late gestation that influences glucose homeostasis in the offspring (5,14,15). However, offspring of rat dams fed a low-protein diet only for the

8 wk before pregnancy, showed increased levels of glucose as adults (16), suggesting that maternal nutritional status before conception may also be important. Fetuses of women with poor

nutritional status before or in early pregnancy are also more likely to be born small and preterm (17–19). In sheep, maternal nutrition during the periconceptional period is an important

determinant of fetal growth, metabolism, and endocrine status in late gestation. Mild maternal undernutrition during the first 70 d of gestation resulted in elevated blood pressure and

altered development of the hypothalamic-pituitary-adrenal (HPA) axis of late gestation fetuses and young lambs (20). Fetuses of ewes undernourished (UN) before until 7 d after mating also

showed altered development of the HPA axis (21) and altered fetoplacental growth (22). Late gestation twin fetuses of ewes UN only during the preattachment period (days 0–7) had altered

regulation of blood pressure (23). We have shown that maternal undernutrition from 61 d before until 30 d after mating resulted in extensive changes in the late gestation fetus, including

altered regulation of fetal growth (6,24) and the fetal somatotrophic axis (25), changes in placental function, and accelerated maturation of the HPA axis (26) resulting in preterm birth

(27). There was also altered regulation of the glucose-insulin axis, with evidence of accelerated pancreatic maturation and reduced glucose area under the curve (AUC) during a glucose

tolerance test (GTT) (28,29). There are limited data in sheep regarding the consequences of maternal undernutrition in early gestation on the offspring after birth. Male offspring of ewes

undernourished from day 1–31 showed evidence of insulin resistance at 1.5 y of age (30). Impaired glucose tolerance and insulin resistance were reported in 1-y-old offspring of ewes

undernourished in late but not early gestation (15). Undernutrition of ewes during mid gestation (days 28–79) altered insulin responses to GTT in male offspring pre- and postweaning (31).

Offspring of ewes with a low body condition score before and during pregnancy showed mild glucose intolerance and impaired insulin secretion at 18 mo (32). However, there are few data in

animals or humans regarding the possible long-term implications of altered maternal nutrition around the time of conception independent of size at birth and, in particular, whether the

observed changes in the late gestation fetus in response to periconceptional undernutrition have any implications for the postnatal health and disease risk of offspring. We therefore studied

the effect of moderate maternal undernutrition around the time of conception in sheep, on glucose tolerance of the postnatal offspring before and after puberty. MATERIALS AND METHODS

ANIMALS. Four- to 5-y-old Romney ewes were acclimatized for 10 d to indoor conditions and a pelleted diet (65% lucerne, 30% barley, with limestone, molasses, and trace element supplements;

Camtech Nutrition Ltd., Hamilton, New Zealand). Sixty-one days before mating ewes were weighed, then randomly assigned to maintenance feeding (“N,” concentrates at 3–4% of bodyweight/d) or

low plane feeding (“UN,” fasted for 2 d then fed concentrates at 1–2% of bodyweight/d). Ewes were weighed twice weekly and rations for UN ewes were adjusted individually to reduce bodyweight

by 10–15% over the first month (_i.e._ by 1 mo before mating), and then maintain this weight (6,33). A fortnight before mating oestrous was synchronized with a progesterone containing

intravaginal device (34). The feed restriction of UN ewes continued until 30 d after mating and thereafter all ewes were fed _ad libitum_ for the remainder of the experiment. Ewes were

housed indoors in a photoperiod controlled feedlot from 71 d before mating until 2 wk after lambing. They were kept in individual pens with open mesh sides to ensure visual contact with

other ewes during the undernutrition period (UN ewes only), and from 3 wk before expected lambing until 2 wk after lambing. At other times all animals were housed in group pens. After birth

lambs were weighed and remained with their mothers indoors for the first 2 wk of life. All animals were then returned to pasture outdoors and managed as part of a single flock. Lambs were

weighed again at weaning (12 wk). While on pasture, animals were kept acquainted with concentrate feeds and handled to allow better acclimatization on reentry to the feedlot for metabolic

and endocrine tests. At 4 and 10 mo of age, offspring were again brought indoors, housed in individual pens and fed concentrates. After a 2-d acclimatization period, animals were weighed,

and indwelling catheters (internal diameter 0.04 inch, Critchley Electrical, Auburn, Australia) were inserted percutaneously into both jugular veins under local anesthetic, while the animals

were standing in their pens. This procedure takes 5–10 min. Food was removed at 17:00 h and animals underwent an i.v. GTT the following day. After a 3 mL baseline blood sample, a bolus of

0.5 g/kg of glucose was given i.v. within 1 min (29). Blood samples (3 mL) were taken from the second catheter at 2, 5, 10, 15, 20, 30, 40, 50, 60, and 120 min for the measurement of glucose

and insulin concentrations. Catheters were later removed and the animals returned to pasture. Ethical approval was obtained from the University of Auckland Animal Ethics Committee.

BIOCHEMICAL ANALYSIS. Blood samples were collected on ice, centrifuged at 3000 rpm for 10 min at 4°C, and the plasma stored at −20°C. Plasma glucose concentrations were measured by an

enzymatic colorimetric assay (Roche Diagnostics, Mannheim, Germany) on a Roche/Hitachi 902 Automatic Analyser (Hitachi High-Technologies Corporation, Tokyo, Japan). Plasma insulin

concentrations were analyzed by radioimmunoassay (35) with ovine insulin as the standard (batch No. I9254; Sigma Chemical Co., St. Louis, MO). The limit of detection was 0.03 ng/mL. Inter-

and intraassay coefficients of variation were 11.6 and 12.6%, respectively. STATISTICAL ANALYSIS. Insulin data were log transformed to more closely approximate a normal distribution. Total

insulin and glucose AUC were calculated from baseline. Where a single data point was missing (because of practical difficulties of sampling or assay, or inadequate plasma volume), the

missing value was estimated by extrapolation for the purposes of calculating AUC. If more than one point was missing, the data were excluded from this calculation. Differences between ages

in AUC of glucose and insulin were compared using analysis of variance (ANOVA). Bodyweight, plasma concentrations of glucose and insulin, and AUC parameters at each age were analyzed using

factorial ANOVA, with nutritional group, sex and single/twin status as independent variables, and Tukey correction for multiple comparisons. The time courses of the plasma glucose and

insulin concentrations during the GTT were analyzed using repeated measures ANOVA with group, sex, and single/twin status as the covariates. The independent effects of nutritional group,

sex, single/twin status, birth weight and current weight were analyzed using multiple regression. All analyses were performed using JMP 5.1 (SAS Institute Inc., Cary, NC). Data are presented

as mean ± SEM. RESULTS A total of 54 offspring of 38 ewes were used in the study; 30 offspring of 20 N ewes (7 singles, 23 twins) and 24 offspring of 18 UN ewes (11 singles, 13 twins, Table

1). Mean birth weight was 5.5 ± 0.1 kg. Males were heavier than females at all ages (Table 1, _p_ = 0.05). There was no significant effect of nutritional group or single/twin status on

weight at birth or at 4 mo. However, at 10 mo there was an interaction between nutritional group and single/twin status, with singleton offspring of UN ewes heavier than those of N ewes (kg;

UN single: 50.5 ± 2.6, N single: 45.5 ± 3.0, UN twin: 44.5 ± 1.9, N twin: 47.3 ± 1.4; _p_ = 0.004). Baseline plasma glucose and insulin concentrations were similar in all animals at 4 and

10 mo (Table 2). In response to the i.v. glucose bolus, plasma glucose concentrations increased sevenfold in the first 2 min, then declined to just above baseline over the 2-h study period

(Fig. 1_A_). Mean glucose AUC did not change between 4 and 10 mo, but mean insulin AUC increased by approximately 33% (Table 2). At 4 mo, plasma glucose AUC, insulin AUC, and the ratio of

insulin:glucose AUC were similar in all animals (Table 2). At 10 mo, offspring of UN ewes had higher plasma glucose concentrations during the GTT than those of N ewes (_p_ = 0.006; Fig.

1_A_), with approximately 10% greater glucose AUC (Table 2). Offspring of UN ewes also had a lesser rise in plasma insulin concentrations (group × time interaction _p_ = 0.003), particularly

in the first 20 min after the glucose bolus (Fig. 1_B_) and a lower insulin:glucose AUC ratio (_p_ = 0.01; Table 2). The smaller rise in plasma insulin concentrations was most apparent in

females (ng · min · mL−1; UN female: 109 ± 10, N female: 178 ± 32, UN male: 184 ± 28, N male: 148 ± 10; sex effect _p_ = 0.007, group × sex interaction _p_ = 0.003) and in singletons (ng ·

min · mL−1; UN single: 122 ± 21, N single 202 ± 70, UN twins: 155 ± 20, N twin: 153 ± 10; group × single/twin interaction _p_ = 0.02). At 4 mo, glucose and insulin AUC both increased with

increasing current weight, (glucose: 9.25 ± 4.24 mM · min · kg−1, _p_ = 0.04; insulin: 0.03 ± 0.01 ng · min · mL−1 · kg−1, _p_ = 0.001). At 10 mo, glucose AUC was affected only by

nutritional group (UN _versus_ N: 46.0 ± 15.7 mM · min; _p_ = 0.005) and current weight (5.66 ± 2.86 mM · min · kg−1, _p_ = 0.05). None of the other parameters had a significant effect on

glucose or insulin AUC at either age. DISCUSSION We have demonstrated that moderate maternal undernutrition from 61 d before until 30 d after conception impairs glucose tolerance in the

adult offspring. The increased glucose AUC was associated with a decreased insulin response, particularly in females. We have previously demonstrated that periconceptional undernutrition in

sheep alters growth, metabolism, and endocrinology in the late gestation fetus, without altering size at birth (6,26) and can lead to preterm birth (27). However, this is the first

demonstration that these changes may have important implications for health of the adult offspring. The period of undernutrition was chosen to incorporate critical periods of development,

encompassing development of the oocyte, through early embryonic development and placentation. Most previous studies of the relationship between maternal nutrition during pregnancy and

glucose tolerance of the offspring have examined undernutrition throughout pregnancy and/or lactation (30,36) but have not included the period before conception. Low body condition score

before and throughout gestation in sheep resulted in mild glucose intolerance in 18-mo-old male offspring (32), but this experiment did not allow any conclusions about the critical time

window. Studies in rats (14), sheep (15), and humans (5,7) have reported impaired glucose tolerance in the offspring after undernutrition late, but not early in pregnancy, suggesting that

late gestation is a critical period for the development of fetal pancreatic function. There are, however, some data suggesting the periconceptional period may also be important. We have

previously shown that fetuses of periconceptionally UN ewes had evidence of accelerated pancreatic maturation, and a smaller glucose AUC in response to GTT (28,29). In rats, maternal

undernutrition for 8 wk before conception resulted in hyperglycemia in adulthood (16). A low-protein diet confined to the preimplantation period (0–4 d after mating) in rat dams resulted in

increased hepatic phosphoenolpyruvate gene expression by late gestation (37). Our study now demonstrates that maternal nutrition around the time of conception has postnatal consequences for

glucose homeostasis, and thus potentially for the lifetime of the offspring. Offspring of UN mothers had a greater plasma glucose AUC at 10 mo, indicating that they were less efficient at

clearing glucose. This clearance is determined largely by the capacity to secrete insulin, and insulin sensitivity. The smaller insulin AUC and reduced insulin:glucose AUC ratio strongly

suggest impaired insulin secretion. Insulin deficiency may result from inadequate production and/or secretion of insulin, and both may result from maternal undernutrition during pregnancy.

Rats born to dams fed a low-protein diet showed a relative deficiency of pancreatic β-cells (38), decreased β-cell proliferation, islet size, and vascularization as newborns (9), and

impaired insulin secretion during fetal and young adult life (39). Global feed restriction during late pregnancy resulted in reduced β-cell proliferation and lower pancreatic insulin content

in the offspring (40). Similarly, insulin secretion requires glucose metabolism in the β-cell, and activities of the enzymes involved are reduced in offspring of diabetic rats (41), and

those fed a low-protein diet (12). There is also evidence that insulin production and secretion may be influenced by prenatal events in sheep. Lambs subjected to undernutrition during late

fetal life showed decreased insulin secretion at 19 wk (42). Similarly, placental restriction resulted in impaired glucose-stimulated insulin secretion in young lambs, although peripheral

insulin sensitivity was increased (43). We have previously shown that periconceptional undernutrition resulted in increased fetal insulin response to i.v. challenge with glucose but not

arginine at 119 d gestation (29), suggesting accelerated maturation of the fetal pancreas. Thus, we hypothesized that the adult pancreas would have fewer mature β-cells, potentially leading

to impaired insulin secretory capacity in later life. The current study provides the first evidence that this may be the case. However, we cannot rule out the possibility that insulin

resistance may also contribute to the decreased glucose tolerance observed in UN animals. Insulin AUC increased by 33% between 4 (prepuberty) and 10 mo (young adulthood), perhaps reflecting

the development of insulin resistance with age as seen in other species such as humans (44) and rats (12,45). In sheep, glucose tolerance, insulin secretion, insulin sensitivity, and insulin

action all decreased with age, predominantly between weaning and adolescence (42). In UN animals, there was a lower peak of plasma insulin 15 min after the glucose bolus, suggesting the

major effect is on the initial phase of insulin secretion. A similar decrease in initial insulin secretory response was also seen in 18-mo offspring of ewes of low body condition score (32)

and in lambs exposed to undernutrition during early to mid gestation (31). In most species, the response of insulin to a rapidly changing glucose concentration is biphasic (46–48). The first

phase insulin response plays a critical role in maintaining glucose homeostasis, primarily by inhibiting hepatic glucose production (47,48). If early phase insulin release is impaired,

increasing glucose concentrations require continued insulin release, placing increased stress on the β-cell, resulting in hyperglycemia and hyperinsulinemia (47). In humans, loss of the

early phase insulin response has been associated with progressive impairment of glucose tolerance leading to diabetes (49–51). Therefore, the loss of β-cell function that facilitates the

early phase insulin release may play a critical role in the impaired glucose tolerance we observed in the 10 mo UN animals. We found that periconceptional undernutrition has a more profound

effect on female than male offspring at 10 mo, indicated by much lower insulin concentrations despite similar glucose tolerance, perhaps as a result of improved insulin sensitivity.

Sex-specific effects of prenatal events on postnatal physiology have been widely recognized but are not always consistent. Aged rats born to dams fed a low-protein diet are glucose

intolerant, due more to insulin resistance in males and insulin deficiency in females (12). In offspring born to rats fed a low-protein diet, females were also more susceptible to the insult

in mid gestation and males to late gestation (38). In contrast, placental restriction in sheep resulted in greater impairment of insulin sensitivity, insulin secretion, and glucose

homeostasis in males than in females (13). The effect of maternal periconceptional undernutrition was also greater in singles than twins. We have previously shown in sheep that fetal twins

show a greater insulin response to i.v. glucose but not arginine challenge than singletons (28), suggesting accelerated pancreatic development similar to that seen in UN singleton fetuses

(29). This would be expected to result in a greater reduction in insulin secretion in twins than singletons; the opposite of our findings. However, periconceptional undernutrition abolished

the difference in insulin responses between singletons and twins (28), and others have postulated that the effects of intrauterine insults are greater on fetuses that are growing rapidly

(1,24). Thus, it is possible that twins, who grow more slowly than singletons, are relatively protected from the effects of periconceptional undernutrition, although the mechanisms by which

this occurs remain obscure. In conclusion, we have shown that maternal periconceptional undernutrition impairs glucose tolerance in postpubertal offspring. Maternal nutrition around the time

of conception may have important implications for glycaemic regulation in the next generation. ABBREVIATIONS * AUC: area under the curve * GTT: glucose tolerance test * HPA:

hypothalamic-pituitary-adrenal * N: nourished (control group) * UN: undernourished (treatment group) REFERENCES * Barker D 1998 Mothers, Babies and Health in Later Life. Edinburgh: Churchill

Livingstone * Bertram CE, Hanson MA 2001 Animal models and programming of the metabolic syndrome. _Br Med Bull_ 60: 103–121 Article  CAS  Google Scholar  * Newsome CA, Shiell AW, Fall CH,

Phillips DI, Shier R, Law CM 2003 Is birth weight related to later glucose and insulin metabolism?—a systematic review. _Diabet Med_ 20: 339–348 Article  CAS  Google Scholar  * Hales CN,

Barker DJ, Clark PM, Cox LJ, Fall C, Osmond C, Winter PD 1991 Fetal and infant growth and impaired glucose tolerance at age 64. _BMJ_ 303: 1019–1022 Article  CAS  Google Scholar  * Ravelli

AC, van der Meulen JH, Michels RP, Osmond C, Barker DJ, Hales CN, Bleker OP 1998 Glucose tolerance in adults after prenatal exposure to famine. _Lancet_ 351: 173–177 Article  CAS  Google

Scholar  * Oliver MH, Hawkins P, Harding JE 2005 Periconceptional undernutrition alters growth trajectory and metabolic and endocrine responses to fasting in late-gestation fetal sheep.

_Pediatr Res_ 57: 591–598 Article  Google Scholar  * Roseboom TJ, van der Meulen JH, Ravelli AC, Osmond C, Barker DJ, Bleker OP 2001 Effects of prenatal exposure to the Dutch famine on adult

disease in later life: an overview. _Twin Res_ 4: 293–298 Article  CAS  Google Scholar  * Iglesias-Barreira V, Ahn MT, Reusens B, Dahri S, Hoet JJ, Remacle C 1996 Pre- and postnatal low

protein diet affect pancreatic islet blood flow and insulin release in adult rats. _Endocrinology_ 137: 3797–3801 Article  CAS  Google Scholar  * Snoeck A, Remacle C, Reusens B, Hoet JJ 1990

Effect of a low protein diet during pregnancy on the fetal rat endocrine pancreas. _Biol Neonate_ 57: 107–118 Article  CAS  Google Scholar  * Bertin E, Gangnerau MN, Bailbe D, Portha B 1999

Glucose metabolism and beta-cell mass in adult offspring of rats protein and/or energy restricted during the last week of pregnancy. _Am J Physiol Endocrinol Metab_ 277: E11–E17 Article 

CAS  Google Scholar  * Vickers MH, Breier BH, Cutfield WS, Hofman PL, Gluckman PD 2000 Fetal origins of hyperphagia, obesity, and hypertension and postnatal amplification by hypercaloric

nutrition. _Am J Physiol Endocrinol Metab_ 279: E83–E87 Article  CAS  Google Scholar  * Hales CN, Desai M, Ozanne SE, Crowther NJ 1996 Fishing in the stream of diabetes: from measuring

insulin to the control of fetal organogenesis. _Biochem Soc Trans_ 24: 341–350 Article  CAS  Google Scholar  * Owens JA, Thavaneswaran P, De Blasio MJ, McMillen IC, Robinson JS, Gatford KL

2007 Sex-specific effects of placental restriction on components of the metabolic syndrome in young adult sheep. _Am J Physiol Endocrinol Metab_ 292: E1879–E1889 Article  CAS  Google Scholar

  * Alvarez C, Martin MA, Goya L, Bertin E, Portha B, Pascual-Leone AM 1997 Contrasted impact of maternal rat food restriction on the fetal endocrine pancreas. _Endocrinology_ 138: 2267–2273

Article  CAS  Google Scholar  * Gardner DS, Tingey K, Van Bon BW, Ozanne SE, Wilson V, Dandrea J, Keisler DH, Stephenson T, Symonds ME 2005 Programming of glucose-insulin metabolism in

adult sheep after maternal undernutrition. _Am J Physiol Regul Integr Comp Physiol_ 289: R947–R954 Article  CAS  Google Scholar  * Joshi S, Garole V, Daware M, Girigosavi S, Rao S 2003

Maternal protein restriction before pregnancy affects vital organs of offspring in Wistar rats. _Metabolism_ 52: 13–18 Article  CAS  Google Scholar  * Godfrey K, Robinson S, Barker DJ,

Osmond C, Cox V 1996 Maternal nutrition in early and late pregnancy in relation to placental and fetal growth. _BMJ_ 312: 410–414 Article  CAS  Google Scholar  * Moore VM, Davies MJ, Willson

KJ, Worsley A, Robinson JS 2004 Dietary composition of pregnant women is related to size of the baby at birth. _J Nutr_ 134: 1820–1826 Article  CAS  Google Scholar  * King JC 2003 The risk

of maternal nutritional depletion and poor outcomes increases in early or closely spaced pregnancies. _J Nutr_ 133: 1732S–1736S Article  CAS  Google Scholar  * Hawkins P, Steyn C, McGarrigle

HH, Calder NA, Saito T, Stratford LL, Noakes DE, Hansona MA 2000 Cardiovascular and hypothalamic-pituitary-adrenal axis development in late gestation fetal sheep and young lambs following

modest maternal nutrient restriction in early gestation. _Reprod Fertil Dev_ 12: 443–456 Article  CAS  Google Scholar  * Edwards LJ, McMillen IC 2002 Impact of maternal undernutrition during

the periconceptional period, fetal number, and fetal sex on the development of the hypothalamo-pituitary adrenal axis in sheep during late gestation. _Biol Reprod_ 66: 1562–1569 Article 

CAS  Google Scholar  * MacLaughlin SM, Walker SK, Roberts CT, Kleemann DO, McMillen IC 2005 Periconceptional nutrition and the relationship between maternal body weight changes in the

periconceptional period and feto-placental growth in the sheep. _J Physiol_ 565: 111–124 Article  CAS  Google Scholar  * Edwards LJ, McMillen IC 2002 Periconceptional nutrition programs

development of the cardiovascular system in the fetal sheep. _Am J Physiol Regul Integr Comp Physiol_ 283: R669–R679 Article  CAS  Google Scholar  * Harding JE 1997 Periconceptual nutrition

determines the fetal growth response to acute maternal undernutrition in fetal sheep of late gestation. _Prenat Neonatal Med_ 2: 310–319 Google Scholar  * Gallaher BW, Breier BH, Keven CL,

Harding JE, Gluckman PD 1998 Fetal programming of insulin-like growth factor (IGF)-I and IGF-binding protein-3: evidence for an altered response to undernutrition in late gestation following

exposure to periconceptual undernutrition in the sheep. _J Endocrinol_ 159: 501–508 Article  CAS  Google Scholar  * Bloomfield FH, Oliver MH, Hawkins P, Holloway AC, Campbell M, Gluckman

PD, Harding JE, Challis JR 2004 Periconceptional undernutrition in sheep accelerates maturation of the fetal hypothalamic-pituitary-adrenal axis in late gestation. _Endocrinology_ 145:

4278–4285 Article  CAS  Google Scholar  * Bloomfield FH, Oliver MH, Hawkins P, Campbell M, Phillips DJ, Gluckman PD, Challis JR, Harding JE 2003 A periconceptional nutritional origin for

noninfectious preterm birth. _Science_ 300: 606 Article  Google Scholar  * Rumball CW, Harding JE, Oliver MH, Bloomfield FH 2008 Effects of twin pregnancy and periconceptional undernutrition

on maternal metabolism, fetal growth and glucose-insulin axis function in ovine pregnancy. _J Physiol_ 586: 1399–1411 Article  CAS  Google Scholar  * Oliver MH, Hawkins P, Breier BH, Van

Zijl PL, Sargison SA, Harding JE 2001 Maternal undernutrition during the periconceptual period increases plasma taurine levels and insulin response to glucose but not arginine in the late

gestational fetal sheep. _Endocrinology_ 142: 4576–4579 Article  CAS  Google Scholar  * Poore KR, Cleal JK, Newman JP, Boullin JP, Noakes D, Hanson MA, Green LR 2007 Nutritional challenges

during development induce sex-specific changes in glucose homeostasis in the adult sheep. _Am J Physiol Endocrinol Metab_ 292: E32–E39 Article  CAS  Google Scholar  * Ford SP, Hess BW,

Schwope MM, Nijland MJ, Gilbert JS, Vonnahme KA, Means WJ, Han H, Nathanielsz PW 2007 Maternal undernutrition during early to mid-gestation in the ewe results in altered growth, adiposity,

and glucose tolerance in male offspring. _J Anim Sci_ 85: 1285–1294 Article  CAS  Google Scholar  * Cripps RL, Green LR, Thompson J, Martin-Gronert MS, Monk M, Sheldon I, Hanson MA, Hales

CN, Ozanne SE 2008 The effect of maternal body condition score before and during pregnancy on the glucose tolerance of adult sheep offspring. _Reprod Sci_ 15: 448–456 Article  CAS  Google

Scholar  * Jaquiery AL, Oliver MH, Bloomfield FH, Connor KL, Challis JR, Harding JE 2006 Fetal exposure to excess glucocorticoid is unlikely to explain the effects of periconceptional

undernutrition in sheep. _J Physiol_ 572: 109–118 Article  CAS  Google Scholar  * Wheaton JE, Carlson KM, Windels HF, Johnston LJ 1993 CIDR: a new progesterone-releasing intravaginal device

for the induction of estrus and cycle control in sheep and goats. _Anim Reprod Sci_ 33: 127–141 Article  Google Scholar  * Oliver MH, Harding JE, Breier BH, Evans PC, Gluckman PD 1993

Glucose but not a mixed amino acid infusion regulates plasma insulin-like growth factor-I concentrations in fetal sheep. _Pediatr Res_ 34: 62–65 Article  CAS  Google Scholar  * Rees WD, Hay

SM, Cruickshank M, Reusens B, Remacle C, Antipatis C, Grant G 2006 Maternal protein intake in the pregnant rat programs the insulin axis and body composition in the offspring. _Metabolism_

55: 642–649 Article  CAS  Google Scholar  * Kwong WY, Miller DJ, Wilkins AP, Dear MS, Wright JN, Osmond C, Zhang J, Fleming TP 2007 Maternal low protein diet restricted to the

preimplantation period induces a gender-specific change on hepatic gene expression in rat fetuses. _Mol Reprod Dev_ 74: 48–56 Article  CAS  Google Scholar  * Chamson-Reig A, Thyssen SM,

Arany E, Hill DJ 2006 Altered pancreatic morphology in the offspring of pregnant rats given reduced dietary protein is time and gender specific. _J Endocrinol_ 191: 83–92 Article  CAS 

Google Scholar  * Dahri S, Snoeck A, Reusens-Billen B, Remacle C, Hoet JJ 1991 Islet function in offspring of mothers on low-protein diet during gestation. _Diabetes_ 40( Suppl 2): 115–120

Article  CAS  Google Scholar  * Garofano A, Czernichow P, Breant B 1997 In utero undernutrition impairs rat beta-cell development. _Diabetologia_ 40: 1231–1234 Article  CAS  Google Scholar 

* Han J, Xu J, Long YS, Epstein PN, Liu YQ 2007 Rat maternal diabetes impairs pancreatic beta-cell function in the offspring. _Am J Physiol Endocrinol Metab_ 293: E228–E236 Article  CAS 

Google Scholar  * Gatford KL, De Blasio MJ, Thavaneswaran P, Robinson JS, McMillen IC, Owens JA 2004 Postnatal ontogeny of glucose homeostasis and insulin action in sheep. _Am J Physiol

Endocrinol Metab_ 286: E1050–E1059 Article  CAS  Google Scholar  * De Blasio MJ, Gatford KL, McMillen IC, Robinson JS, Owens JA 2007 Placental restriction of fetal growth increases insulin

action, growth, and adiposity in the young lamb. _Endocrinology_ 148: 1350–1358 Article  CAS  Google Scholar  * Dechenes CJ, Verchere CB, Andrikopoulos S, Kahn SE 1998 Human aging is

associated with parallel reductions in insulin and amylin release. _Am J Physiol_ 275: E785–E791 CAS  PubMed  Google Scholar  * Bracho-Romero E, Reaven GM 1977 Effect of age and weight on

plasma glucose and insulin responses in the rat. _J Am Geriatr Soc_ 25: 299–302 Article  CAS  Google Scholar  * Cherrington AD, Sindelar D, Edgerton D, Steiner K, McGuinness OP 2002

Physiological consequences of phasic insulin release in the normal animal. _Diabetes_ 51: S103–S108 Article  CAS  Google Scholar  * Del Prato S 2003 Loss of early insulin secretion leads to

postprandial hyperglycaemia. _Diabetologia_ 46: M2–M8 Article  CAS  Google Scholar  * Caumo A, Luzi L 2004 First-phase insulin secretion: does it exist in real life? Considerations on shape

and function. _Am J Physiol Endocrinol Metab_ 287: E371–E385 Article  CAS  Google Scholar  * Davies MJ, Rayman G, Grenfell A, Gray IP, Day JL, Hales CN 1994 Loss of the first phase insulin

response to intravenous glucose in subjects with persistent impaired glucose tolerance. _Diabet Med_ 11: 432–436 Article  CAS  Google Scholar  * Haffner SM, Miettinen H, Gaskill SP, Stern MP

1996 Decreased insulin action and insulin secretion predict the development of impaired glucose tolerance. _Diabetologia_ 39: 1201–1207 Article  CAS  Google Scholar  * Weyer C, Tataranni P,

Bogardus C, Pratley R 2001 Insulin resistance and insulin secretory dysfunction are independent predictors of worsening of glucose tolerance during each stage of type 2 diabetes

development. _Diabetes Care_ 24: 89–97 Article  CAS  Google Scholar  Download references ACKNOWLEDGEMENTS The authors thank Bridget Clark, Samantha Rossenrode, Eric Thorstensen, and Sulee

Kuy for their technical assistance. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Liggins Institute, University of Auckland, Private Bag 92019, Auckland, 1023, New Zealand Sarah E Todd, Mark

H Oliver, Anne L Jaquiery, Frank H Bloomfield & Jane E Harding Authors * Sarah E Todd View author publications You can also search for this author inPubMed Google Scholar * Mark H

Oliver View author publications You can also search for this author inPubMed Google Scholar * Anne L Jaquiery View author publications You can also search for this author inPubMed Google

Scholar * Frank H Bloomfield View author publications You can also search for this author inPubMed Google Scholar * Jane E Harding View author publications You can also search for this

author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Jane E Harding. ADDITIONAL INFORMATION Supported by the Health Research Council of New Zealand and The National Research

Centre for Growth and Development. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Todd, S., Oliver, M., Jaquiery, A. _et al._ Periconceptional

Undernutrition of Ewes Impairs Glucose Tolerance in Their Adult Offspring. _Pediatr Res_ 65, 409–413 (2009). https://doi.org/10.1203/PDR.0b013e3181975efa Download citation * Received: 24

July 2008 * Accepted: 31 October 2008 * Issue Date: April 2009 * DOI: https://doi.org/10.1203/PDR.0b013e3181975efa SHARE THIS ARTICLE Anyone you share the following link with will be able to

read this content: Get shareable link Sorry, a shareable link is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing

initiative