IUGR in the Absence of Postnatal “Catch-Up” Growth Leads to Improved Whole Body Insulin Sensitivity in Rat Offspring

Abstract

A suboptimal in utero environment leads to fetal adaptations to ensure short-term survival but in the long-term may lead to disease when the postnatal growth does not reflect that in utero. This study examined the effect of IUGR on whole body insulin sensitivity and metabolic activity in adult rats. Female Wistar-Kyoto rats were fed either a normal protein diet (NPD 20% casein) or a low protein diet (LPD; 8.7% casein) during pregnancy and 2 wk of lactation. In offspring at 32 wk of age, indirect calorimetry and dual energy x-ray absorptiometry (DEXA) were performed to assess metabolic activity and body composition. Insulin sensitivity was assessed using a euglycemic-hyperinsulinemic clamp. At 3 d of age, male and female LPD offspring were 23 and 27% smaller than controls, respectively. They remained significantly smaller throughout the experimental period (ϳ10% smaller at 32 wk). Importantly, there was increased insulin sensitivity in LPD offspring (47% increase in males and 38% increase in females); pancreatic insulin content was normal. Body composition, O 2 consumption, respiratory exchange ratio (RER), and locomotor activity were not different to controls. These findings suggest that in the absence of "catch-up" growth IUGR programs for improved insulin sensitivity. O ver recent years, there has been an escalation in the incidence of metabolic syndrome and type 2 diabetes within the community, and this has been linked to a mismatch in prenatal and postnatal growth (1-3). In this regard, many epidemiological and experimental studies support the hypothesis that a suboptimal in utero environment leads to fetal adaptations to ensure short-term survival but, in turn, lead to long-term disease risk when the postnatal environment does not reflect that in utero (2-4). In addition, IUGR leads to a reduction in prenatal growth and altered ontogeny of major organs, which may also contribute to long-term disease risk (5-8). For example, IUGR, because of maternal protein restriction in rats has been shown to lead to a reduced number of cardiomyocytes in the heart (6), reduced nephron endowment in the kidney (7), and reduced ␤-cell proliferation and islet size in the pancreas (8).Hence, it is likely that altered programming of glucose metabolism coupled with direct reductions in pancreatic islet ␤ cells contribute to the development of metabolic syndrome and type 2 diabetes in infants that were growth restricted in utero, particularly when the postnatal growth trajectory is inappropriately higher than that in utero (9). Although there is substantial evidence to support this hypothesis, whether IUGR can program for improved postnatal glucose metabolism in the absence of "catch-up" growth has been relatively unexplored, and it is imperative that this alternative be rigorously tested. Importantly, in this regard, in our laboratory, we have a model of maternal protein restriction in Wistar Kyoto (WKY) rats where the IUGR offspring remain smaller throughout life when compared with nongrowth restricted offspring; thes...

Transgenerational programming of fetal nephron deficits and sex-specific adult hypertension in rats

“…The mechanisms underlying altered drinking behaviour in 12-month-old F2 Restricted males, as well as their physiological relevance, warrant further investigation. It is also worth noting that, relative to bodyweight, females consumed more food than male counterparts, which may be attributed to greater energy expenditure (Lim et al 2011).…”

When early life growth restriction in rats is followed by attenuated postnatal growth: effects on cardiac function in adulthood

“…Although the ponderal index was significantly increased in the LPD offspring compared to controls, we have previously shown using dual-energy x-ray analysis (DEXA) that overall body composition (including percentage body fat) is not altered in LPD offspring [17]. In this regard, it is important to note that the ponderal index in the LPD offspring remained unchanged throughout life (from postnatal day 4 until 18 weeks of age); thus, there was no evidence of a mismatch in growth (and levels of 'leanness') after birth, with body weights also remaining significantly lower throughout life.…”

“…Abdominal girth, head width and length, crown-rump length and tibia length were measured at postnatal day 4, at weaning (4 weeks) and at the experimental endpoint (18 weeks of age) using electronic digital callipers (range from 0-150 mm) [17]. Ponderal index was calculated as (body weight; g) 9 100/ (crown-rump length; cm) 3 , which incorporates weight and length of the rat [24].…”

“…The offspring are growth-restricted at birth and maintain a lower growth trajectory postnatally with body weight significantly attenuated compared to nongrowth-restricted offspring through adulthood [17][18][19][20][21]. These growthrestricted offspring have a developmental nephron deficit [20], but no evidence of renal dysfunction or elevation in blood pressure in early adulthood, and they exhibit improved insulin sensitivity [17,18]. Interestingly, although there were no effects on blood pressure, there were significant differences in the biochemical composition of the myocardium of female IUGR rats at 18 weeks of age [22].…”

A Model of Intrauterine Growth Restriction Was Induced by Bilateral Uterine Vessel Clamping in Pregnant Rats

“…Because rat has several advantages: short gestation, large litters and large enough for complex surgical intervention, so most of these studies have been performed in rats (12,13). Experimental IUGR model induced by uterine vessel ligation was first described by Wigglesworth (14), other common models include maternal diabetes, stress, hypoxia, nutrient restriction, protein restriction (11,12,15). Compared with exposing pregnant animals to surgical interventions, it is inconvenient to alter maternal nutritional and hypoxic conditions during pregnancy.…”