Acciones y consecuencias biológicas y moleculares de los RL.

Metabolic diseases such as obesity, type 2 diabetes (T2D) and cardiovascular disease are characterized by alterations in nutrient metabolism. It is recognized that an individuals’ dietary patterns can assist in preventing or delaying the onset of metabolic disease or, in contrast, can directly contribute to disease development and progression. Whole eggs are a nutrient-dense food, providing high-quality protein and an array of vitamins and minerals, and can play both nutritional and functional roles in the diet (1,2). Potential benefits of egg consumption during the progression of metabolic disease include body weight management and the maintenance of micronutrient balance, including vitamin D and methyl groups (2–4). However, there remains controversy surrounding the potential adverse effects of egg consumption, such as impaired blood glucose regulation and cardiovascular disease risk, in individuals with metabolic disease (5–9). The studies presented in this dissertation, utilizing rat models of metabolic disease, demonstrate that egg consumption may contribute to the maintenance of body weight and micronutrient balance, but may also impair insulin sensitivity.

The first two studies described in this dissertation examined whole egg as a naturally occurring dietary source of the micronutrient vitamin D. Suboptimal vitamin D status is highly prevalent in individuals with T2D (10–12), and is exacerbated by the presence of diabetic nephropathy owing to urinary loss of vitamin D (13,14). Results from the studies described in this dissertation demonstrate that the consumption of whole eggs was effective at maintaining vitamin D status in T2D rats. Notably, a diet containing 20% (w/w) protein from whole egg maintained vitamin D balance more effectively than a diet containing an equivalent amount of supplemental cholecalciferol. However, consumption of lower doses of whole egg, at 10, 5 and

2.5% protein from whole egg, translating to approximately 7, 3.5 and 1.75 eggs/day in humans, did not prevent vitamin D insufficiency in T2D rats. These data suggest that consumption of 1-2 eggs/day, without additional measures to improve vitamin D status, may not be an effective means to prevent insufficiency in individuals with T2D. However, accumulating evidence suggests that vitamin D-fortified eggs may be protective against declining concentrations of circulating 25(OH)D (15–17). Thus, studies evaluating the effect of fortified egg consumption on vitamin D homeostasis in T2D are warranted.

An interesting outcome of the vitamin D studies was a significant reduction in weight gain in obese, T2D rats fed a diet containing 20% protein from whole egg. This attenuation of weight gain was, in part, due to a reduction in body fat percentage. Furthermore, a dose- dependent attenuation of weight gain was observed in T2D rats fed diets containing 20, 10, 5 and 2.5% protein from whole egg. Despite reduced weight gain in T2D rats fed varying concentrations of dietary whole egg, we did not observe a corresponding reduction in food intake, indicating that the observed reduction in weight gain was not related to measures of satiety.

Obesity and excessive weight gain are major risk factors in the development of insulin resistance and T2D (18–21); thus, we investigated whether the attenuation of weight gain in T2D rats consuming a diet containing 20% protein from whole egg was related to measures of insulin sensitivity and skeletal muscle insulin signaling. Insulin sensitivity was impaired in T2D rats fed a whole egg-based diet; however, no differences in skeletal muscle insulin signaling were observed between T2D rats fed casein- and whole egg-based diets. In addition, fasting serum glucose was increased, whereas fasting serum insulin and the homeostatic model assessment of !-cell function were decreased in T2D rats fed a whole egg-based diet.

The final study described in this dissertation focused on other components of whole egg that may modulate the metabolic disorder hyperhomocysteinemia, which is associated with cardiovascular disease risk. Eggs contain choline, B vitamins and sulfur amino acids, nutrients which play important roles in the regulation of methyl group metabolism. Our results indicate that dietary egg protein may help prevent elevations in circulating homocysteine in a rodent model of hyperhomocysteinemia, due to upregulation of hepatic betaine-homocysteine S- methyltransferase activity, an enzyme important in the maintenance of homocysteine balance.

The findings from these studies suggest that inclusion of whole eggs in the diet may assist in body weight maintenance in individuals at risk for the development of obesity and T2D. Future studies will aim to elucidate the mechanism underlying the observed reduction in weight gain. Additionally, whole eggs are an important source of nutrients, such as B vitamins, choline and vitamin D, and, in combination with a healthy eating pattern, may contribute to vitamin D and homocysteine balance in individuals with metabolic disease. However, egg consumption may impair insulin sensitivity and blood glucose regulation in individuals with pre-existing T2D, though future studies are warranted to determine the impact of lower concentrations of dietary whole egg on metabolic biomarkers of insulin sensitivity.

References

1. United States Department of Agriculture Agricultural Research Service. Food

Composition Databases Show Foods -- Egg, whole, raw, fresh [Internet]. [cited 2018 Sep 13]. Available from: https://ndb.nal.usda.gov/ndb/foods/

2. Applegate E. Nutritional and functional roles of eggs in the diet. J Am Coll Nutr.;

2000;19:495S-498S.

3. Vander Wal JS, Gupta A, Khosla P, Dhurandhar N V. Egg breakfast enhances weight

4. Wang S, Yang L, Lu J, Mu Y. High-protein breakfast promotes weight loss by suppressing subsequent food intake and regulating appetite hormones in obese Chinese adolescents. Horm Res Paediatr.; 2015;83:19–25.

5. Griffin BA. Eggs: good or bad? Proc Nutr Soc.; 2016;75:259–64.

6. Djousse L, Gaziano JM, Buring JE, Lee I-M. Egg consumption and risk of type 2

diabetes in men and women. Diabetes Care.; 2009;32:295–300.

7. Guo J, Hobbs DA, Cockcroft JR, Elwood PC, Pickering JE, Lovegrove JA, Givens DI.

Association between egg consumption and cardiovascular disease events, diabetes and all-cause mortality. Eur J Nutr.; 2018;57:2943–52.

8. Shin JY, Xun P, Nakamura Y, He K. Egg consumption in relation to risk of

cardiovascular disease and diabetes: a systematic review and meta-analysis. Am J Clin Nutr.; 2013;98:146–59.

9. Tran NL, Barraj LM, Heilman JM, Scrafford CG. Egg consumption and cardiovascular

disease among diabetic individuals: a systematic review of the literature. Diabetes Metab Syndr Obes.; 2014;7:121–37.

10. Hirani V, Cumming RG, Le Couteur DG, Naganathan V, Blyth F, Handelsman DJ,

Waite LM, Seibel MJ. Low levels of 25-hydroxy vitamin D and active 1,25- dihydroxyvitamin D independently associated with type 2 diabetes mellitus in older Australian men: the Concord Health and Ageing in Men Project. J Am Geriatr Soc.; 2014;62:1741–7.

11. Forouhi NG, Ye Z, Rickard AP, Khaw KT, Luben R, Langenberg C, Wareham NJ.

Circulating 25-hydroxyvitamin D concentration and the risk of type 2 diabetes: results from the European Prospective Investigation into Cancer (EPIC)-Norfolk cohort and updated meta-analysis of prospective studies. Diabetologia.; 2012;55:2173–82.

12. Calvo-Romero JM, Ramiro-Lozano JM. Vitamin D Levels in Patients With Type 2

Diabetes Mellitus. J Investig Med.; 2015;63:921–3.

13. Anderson RL, Ternes SB, Strand KA, Rowling MJ. Vitamin D homeostasis is

compromised due to increased urinary excretion of the 25-hydroxycholecalciferol- vitamin D-binding protein complex in the Zucker diabetic fatty rat. Am J Physiol Endocrinol Metab. 2010;299:E959-67.

14. Nykjaer A, Dragun D, Walther D, Vorum H, Jacobsen C, Herz J, Melsen F, Christensen

EI, Willnow TE. An endocytic pathway essential for renal uptake and activation of the steroid 25-(OH) vitamin D3. Cell. 1999;96:507–15.

15. Hayes A, Duffy S, O’Grady M, Jakobsen J, Galvin K, Teahan-Dillon J, Kerry J, Kelly

A, O’Doherty J, Higgins S, et al. Vitamin D-enhanced eggs are protective of wintertime serum 25-hydroxyvitamin D in a randomized controlled trial of adults. Am J Clin Nutr

[Internet]. 2016;104:629–37. Available from: https://www.ncbi.nlm.nih.gov/pubmed/27488236

16. Mattila PH, Valkonen E, Valaja J. Effect of different vitamin D supplementations in

poultry feed on vitamin D content of eggs and chicken meat. J Agric Food Chem.; 2011;59:8298–303.

17. Browning LC, Cowieson AJ. Vitamin D fortification of eggs for human health. J Sci

Food Agric.; 2014;94:1389–96.

18. Narayan KM V, Boyle JP, Thompson TJ, Gregg EW, Williamson DF. Effect of BMI

on lifetime risk for diabetes in the U.S. Diabetes Care.; 2007;30:1562–6.

19. Hu FB, Manson JE, Stampfer MJ, Colditz G, Liu S, Solomon CG, Willett WC. Diet,

lifestyle, and the risk of type 2 diabetes mellitus in women. N Engl J Med.; 2001;345:790–7.

20. Ford ES, Williamson DF, Liu S. Weight change and diabetes incidence: findings from

a national cohort of US adults. Am J Epidemiol.; 1997;146:214–22.

21. Colditz GA, Willett WC, Rotnitzky A, Manson JE. Weight gain as a risk factor for