Fetal programming, fructose, and insulin resistance

Despite continuous improvements in health of the US population, some chronic diseases, including diabetes, are persistant concerns for human health and well-being (Center for Disease Control and Prevention, 2009). The development of diabetes and other metabolic disorders involves two key factors, the impact of maternal malnutrition during the prenatal phase of life and postnatal progression caused by unbalanced food choice patterns, particularly those associated with excessive carbohydrate and fat intake (Yajnik, 2004). Both maternal undernutrition and over-nutrition have been related to increased incidence of the cluster of diseases known as the metabolic syndrome, with symptoms including dyslipidemia, hypertension, hyperphagia, hyperleptinemia and hyperinsulinemia (Wu et al, 2004). Furthermore changes occurring during the fetal period predispose offspring to early onset of metabolic diseases. Given the risk imposed by compromised prenatal nutrition, an unbalanced postnatal diet can exacerbate the situation. Excess consumption of fat and sugar has been closely associated with an increased incidence of chronic diseases, such as cardiovascular diseases and metabolic syndrome (Howard & Wylie-Rosset, 2002). Therefore it is reasonable to assume that the increase in fructose consumption over time is also true for pregnant women, which leads to concerns of the impact of fructose during pregnancy and the diseases in the offspring. Chapter 1 of this thesis reviews the literature on the current findings of fetal programming, fructose and type 2 diabetes and the connecting relationships. Chapter 2 investigates metabolic events that occur during pregnancy and lactation and accompany the consumption of diets containing high fructose or low protein and how these metabolic events could potentiate the fetal programming process. Rat dams fed a fructose diet during pregnancy and lactation develop gestational diabetes and fatty liver. Chapter 3 follows the offspring from the dams fed control or experimental diets described in Chapter 2 and characterizes the metabolic changes in these offspring. Offspring from dams fed the fructose diet during pregnancy and lactation showed impaired growth and were protected from post-weaning fat-induced insulin resistance. Compromised glucose tolerance predisposed by maternal low protein and amplified by post-weaning fructose was prevented for offspring from fructose-fed dams. Chapter 4 separates the fetal programming effects originating from two periods, pregnancy and lactation. The impaired growth observed in offspring from fructose-fed dams in Chapter 4 was due to suckling on fructose-fed dams. Over-expression of PPARα, G6Pase, PEPCK-C and CPT-1a induced by maternal fructose feeding during pregnancy was ameliorated by suckling on fructose-fed dams. Chapter 5 summarizes the results and concludes the major findings. The main findings from this work indicate that fructose consumption during pregnancy and lactation leads to glucose intolerance and fatty liver. Offspring from these dams exhibit elevated gluconeogenesis capacity and altered metabolic responses to postnatal diet challenge. Suckling on fructose-fed dams impairs neonatal growth and ameliorates the metabolic aberrations induced by fetal exposure to fructose. The protective effects are likely the benefits of matched prenatal and postnatal environment, the key element that explains the pathogenesis of fetal programming