Insulin resistance in adult rat offspring associated with maternal dietary fat and alcohol consumption

Abstract

Maternal diet during pregnancy has been reported to alter the offspring's ability to respond to a glucose challenge. The current studies report changes in basal and insulinstimulated, in vitro glucose uptake in red (soleus) and white (extensor digitorum longus) muscle fiber types, as well as whole body insulin responsiveness of adult rat offspring associated with their mother's dietary fat and alcohol content during pregnancy.The offspring of Harlan-derived Sprague-Dawley female rats, dosed during pregnancy with ethanol (ETOH) via a liquid diet (35% of calories as ETOH) with either 12% or 35% of calories as fat, were compared with offspring from litters whose mothers were pair-fed an isocaloric amount of the liquid diet without ETOH. Maternal access to the liquid diets was terminated on day 20 of the pregnancies (sperm plug=day 0). The offspring were surrogate fostered within 48 h of birth to mothers which had consumed commercial chow throughout their pregnancy. Following weaning at 21 days of age, the offspring consumed only commercial rat chow and they were examined over the next 14 months for changes in glucose homeostasis as a consequence of in utero exposure to maternal dietary fat and/or alcohol.The 35% maternal fat diet resulted in both in vivo and in vitro decreases in insulin sensitivity. Thus, compared with adults whose mother's diet contained 12% fat, significant, in vitro muscle and in vivo whole body insulin resistance (measured by hyperinsulinemiceuglycemic clamping) was observed in adult rats whose mothers consumed 35% of dietary calories as fat. The addition of ethanol to the maternal 35% fat diet further reduced the offspring's red muscle tissues in vitro response to insulin, but did not affect whole body insulin sensitivity. Muscle basal and insulin-stimulated receptor tyrosine kinase activity were significantly decreased (] 50%) by the 35% fat maternal diet but there was no compensatory increase in serum insulin or glucose levels.Based upon both in vivo and in vitro data, these studies suggested that in utero exposure to 35% fat has a sustained effect on the adult offspring's glucose uptake/insulin sensitivity and that the effect is paralleled, at least in part, by decreased insulin receptor tyrosine kinase activity. In utero ETOH exposure resulted in the loss of basal and insulin-stimulated, in vitro glucose uptake in red muscle fibers but maternal dietary ETOH had no detectable effect on either in vivo insulin sensitivity or muscle tyrosine kinase activity.

Increased 11β-hydroxysteroid dehydrogenase type-1 and hexose-6-phosphate dehydrogenase in liver and adipose tissue of rat offspring exposed to alcohol in utero

“…As found in other IUGR studies (41,53), alcohol-exposed rat offspring have increased expression of the hepatic ratelimiting gluconeogenic enzyme phosphoenolpyruvate carboxykinase (19,68). Thus, an increase in corticosterone levels in alcohol-exposed offspring could provide an explanation for anomalies of glucose homeostasis that we (16 -18) and others (22,46) have previously reported. Collectively, these studies have shown that rat offspring prenatally exposed to alcohol may be born small, but undergo a period of catch-up growth in association with insulin resistance, dyslipidemia, and hyperglycemia.…”

“…Aliquots of serum were stored at Ϫ20°C until analysis. Only male offspring were used because in the vast majority of studies of IUGR rats, abnormalities of glucose metabolism were found only in males (22,57). All of the animal studies were approved by the Committee for Animal Care and Use in Research and Teaching of the University of Manitoba.…”

Intrauterine ethanol exposure results in hypothalamic oxidative stress and neuroendocrine alterations in adult rat offspring

“…Feed intake of EtOH-treated dams was Ͻ 10% that of controls, but weight gain during pregnancy, litter size, and perinatal mortality were similar to controls. Our model differs from the model used by Pennington and colleagues (23,48) in that they administered EtOH in a liquid diet, and pups were surrogate fostered to nontreated dams. Cross-fostering is used to prevent a delay in pups' weight gain while suckling from their own undernourished mothers or to study the effects of chronic alcoholism during pregnancy or lactation separately (67).…”

“…In this study, three out of seven prepubertal children with FAS had abnormal oral glucose tolerance tests with increased plasma insulin response. We and others have shown that EtOH ingestion during pregnancy in amounts corresponding to human chronic drinking (63,69) can lead to IUGR and is associated with insulin resistance, hyperlipidemia, and glucose intolerance in adult rat offspring (12,13,23,40,48). At the cellular level, these rats have increased intramuscular and intrahepatic triglycerides (14); impaired insulin signaling with reduced muscle protein kinase C activation (15), glucose transporter-4 translocation (12,13), and glucose uptake (23); and increased liver expression of gluconeogenic genes (16,68).…”

Role of Triglyceride/Fatty Acid Cycle in Development of Type 2 Diabetes

“…To investigate the impact of maternal overnutrtion on the fetus, several studies have used the high-fat diet during pregnancy /lactation. They have shown that exposure to the high fat diet during pregnancy results in altered metabolism in the newborn can also lead to the development of metabolic diseases, including insulin resistance and dysfunction of pancreatic -cells, in the offspring (Elton, Pennington et al 2002;Buckley, Keseru et al 2005;Taylor, McConnell et al 2005). Thus, maternal nutrition directly impacts the developing -islet cells and can program the fetus for insulin resistance as adults.…”