The interaction of intrauterine environment and diet on the pathogenesis of Type 2 Diabetes

Abstract

Introduction: Prenatal environmental factors such as intrauterine growth retardation (IDGR), as well as postnatal factors such as over-nutrition and sedentary lifestyle contribute to the development of type 2 diabetes (T2D) in predisposed individuals. The aim of this study was to determine in a rat model whether IDGR and high fat lipogenic diet interact in T2D pathogenesis. Methods: A previously described surgical model ((bilateral uterine artery ligation (BDAL)) of IDGR Sprague-Dawley rats with sham-operated controls was used. Male and female IDGR and sham pups were fed high fat or chow-diets from weaning. Serial measurements of body weight and serum variables including blood glucose, free fatty acids and triglyceride were taken. Intraperitoneal glucose tolerance tests including insulin response measurements were performed at 13 and 23 weeks of age. At 24 weeks of age, the rats were euthanased and pancreases were harvested. Pancreases were assessed histologically with haematoxylin and eosin staining for islet morphology, perl staining for iron, trichrome staining for collagen. Sections were also immunostained for insulin. Results: The BDAL surgery resulted in IDGR pup weights that were approximately 25% less that the sham pup weights. Thus, the BDAL procedure was effective in producing moderately severe intrauterine growth restriction. The chow-fed IDGR rats developed an abnormal metabolic phenotype, but this was mild compared to the previously reported IDGR model. The chow-fed IDGR rats did not develop overweight or diabetes, but did develop fed-state hypertriglyceridaemia (female only) and fasting hyperlipacidaemia (male only) as well as hyperinsulinaemia (evident at 23 weeks of age in male rats with a trend for this evident in female rats). Control sham rats on high fat-diet developed hyperglycaemia, fed-state hyperlipacidaemia, fasting and fed-state hypertriglyceridaemia and mildly impaired glucose tolerance with evidence of marked post-glucose load hyperinsulinaemia. Unexpectedly, the high fat-fed IUGR rats were protected against excessive weight gain (most evident in female rats), nonfasting hyperglycaemia and glucose intolerance (evident in female rats only). IUGR rats on the HF diets, however, had higher non-fasting triglyceride levels and had accentuated hyperinsulinaemia in response to a glucose load at 23 weeks of age. Thus, IUGR and high fat-diet most likely caused a greater degree of hyperinsulinaemia. Despite mild effects of IUGR on the metabolic phenotype of the rats, the histological analyses of the pancreases showed major changes in male rats. Two of four chow-fed IUGR had evidence of multiple large disorganized islets; where four of five high fat fed IUGR rats had these disorganized islets. No sham rat pancreases had any of these abnormal islets. Staining for iron showed marked peri-islet iron accumulation associated with these abnormal islets and staining for collagen showed marked islet fibrosis. The insulin immunohistochemistry confirmed the abnormal islet architecture. Conclusion: IUGR chow-fed rats did not develop T2D, which is at variance from previously reported studies. IUGR did alter the effects of high fat-diet on the metabolic phenotype causing more severe hypertriglyceridaemia and insulin resistance, but again diabetes did not develop. The Canberra IUGR rat, as opposed to the one previously reported, is capable of successful islet beta cell compensation. However, islet morphology was severely disturbed in the Canberra male IUGR rats that appeared worse with high fat feeding. The presence of increased iron staining associated with these abnormal islets may have pathophysiological significance. We postulate that genetic background and its effect on islet susceptibility to insults (intrauterine and post-natal) is an essential component in pathogenesis of T2D, explaining the differences between IUGR models.