Over the last two decades, renewed interest and expertise in and about breastfeeding has occurred in the U.S. and Western Europe. Human milk is universally accepted as the ideal food for infants and breastfeeding has real and potential benefits for the mother, the infant and to their relationship. In the United States only 50 percent of women choose to breastfeed their infants despite all of the real and potential advantages to both the infant and mother. A number of these women have been unsuccessful in their attempts to breastfeed (insufficient milk syndrome) and others are known to be at high risk of breastfeeding failure (women with premature infants and teenage mothers). The primary determinant of milk volume is lactose production. If we could understand the factors which regulate lactose production, we might be better able to design interventional strategies for individuals struggling to breastfeed successfully. The present proposal is designed to determine the metabolic consequences of breastfeeding in women and to determine the metabolic precursors of lactose and the hormone substrate factors regulating lactose synthesis, a major determinant of milk volume in humans. The two overriding hypotheses to be tested are: 1. The carbohydrate demands of lactose production result in an increase in maternal glucose production and/or a sparing of maternal glucose by increased lipolysis and ketogenesis, 2. The glucose and galactose in human lactose are partially derived from gluconeogenesis within the breast, and this process is regulated by both hormones and substrate availability. To test the first hypothesis eight lactating and eight control women will be studied to determine whether: a) the rates of maternal glucose production and gluconeogenesis are increased in both the fed and fasted state when compared to non-lactating women; and b) the rates of lipolysis and ketogenesis are increased (an accelerated state of fasting) in the nursing mothers when compared to non-lactating women. The second hypothesis will be tested employing a nearly identical study design in three separate protocols. In the first of these, we will determine whether a significant portion of the glucose and galactose in breast milk lactose is derived from sources of carbon other than plasma glucose. In the second one, we will determine whether rhGH treatment for 7 days increases: a. Hepatic gluconeogenesis in both lactating and non-lactating women and b. lactose (milk) production, in part, by increasing gluconeogenesis in the breast. In the final protocol, we will determine if an infusion of amino acids or of glucose for a period of 12 hrs will increase or decrease, respectively, the fraction of galactose carbon derived from gluconeogenesis in breast of lactating women. Understanding the metabolic consequences of lactation on maternal metabolism and the regulation of lactose synthesis will give new insights into the regulation of human milk production, thus, providing new strategies to improve the number of successfully breastfeeding women and to help those women who in the past have struggled and/or failed breastfeeding their infants. This, in turn, will have significant health and economic impact.
| Chung, Stephanie T; Chacko, Shaji K; Sunehag, Agneta L et al. (2015) Measurements of Gluconeogenesis and Glycogenolysis: A Methodological Review. Diabetes 64:3996-4010 |
| Mohammad, Mahmoud A; Maningat, Patricia; Sunehag, Agneta L et al. (2015) Precursors of hexoneogenesis within the human mammary gland. Am J Physiol Endocrinol Metab 308:E680-7 |
| Hsia, Daniel S; Tarai, Sarah G; Alimi, Amir et al. (2015) Fluid management in pediatric patients with DKA and rates of suspected clinical cerebral edema. Pediatr Diabetes 16:338-44 |
| Chung, Stephanie T; Hsia, Daniel S; Chacko, Shaji K et al. (2015) Increased gluconeogenesis in youth with newly diagnosed type 2 diabetes. Diabetologia 58:596-603 |
| Mohammad, Mahmoud A; Sunehag, Agneta L; Haymond, Morey W (2014) De novo synthesis of milk triglycerides in humans. Am J Physiol Endocrinol Metab 306:E838-47 |
| Mohammad, Mahmoud A; Haymond, Morey W (2013) Regulation of lipid synthesis genes and milk fat production in human mammary epithelial cells during secretory activation. Am J Physiol Endocrinol Metab 305:E700-16 |
| Mohammad, Mahmoud A; Hadsell, Darryl L; Haymond, Morey W (2012) Gene regulation of UDP-galactose synthesis and transport: potential rate-limiting processes in initiation of milk production in humans. Am J Physiol Endocrinol Metab 303:E365-76 |
| Mohammad, Mahmoud A; Sunehag, Agneta L; Rodriguez, Luisa A et al. (2011) Galactose promotes fat mobilization in obese lactating and nonlactating women. Am J Clin Nutr 93:374-81 |
| Maningat, Patricia D; Sen, Partha; Rijnkels, Monique et al. (2009) Gene expression in the human mammary epithelium during lactation: the milk fat globule transcriptome. Physiol Genomics 37:12-22 |
| Coss-Bu, Jorge A; Sunehag, Agneta L; Haymond, Morey W (2009) Contribution of galactose and fructose to glucose homeostasis. Metabolism 58:1050-8 |
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