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Title: Precursors of hexoneogenesis within the human mammary gland

Author
item MOHAMMAD, MAHMOUD - Children'S Nutrition Research Center (CNRC)
item MANINGAT, PATRICIA - Rockefeller University
item SUNEHAG, AGNETA - Children'S Nutrition Research Center (CNRC)
item HAYMOND, MOREY - Children'S Nutrition Research Center (CNRC)

Submitted to: American Journal of Physiology - Endocrinology and Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/1/2015
Publication Date: 4/1/2015
Citation: Mohammad, M.A., Maningat, P., Sunehag, A., Haymond, M.W. 2015. Precursors of hexoneogenesis within the human mammary gland. American Journal of Physiology - Endocrinology and Metabolism. 308(8):E680-E687.

Interpretive Summary: Milk sugar (lactose) is composed of two simple sugars, glucose and galactose, linked together. Milk sugar is the most abundant nutrient in breastmilk and provides nearly half of the total energy needs of the infant. Lactose synthesis may indirectly control milk volume and production as a result of its high concentration. Accordingly, it is important to understand the source and how lactose is synthesized in the breast. We know from our previous studies that after an overnight fast, some glucose (30%) and galactose (50%) are produced within breast, itself (hexoneogenesis). However, we do not know from what sources these two sugars are synthesized in the breast. In our present study, we investigated the role of possible sources including acetate, glutamine, lactate and glycerol in healthy breastfeeding women fasted for 24 hours. The results of our study showed that glycerol, alone, provides most of the source for this process. We proposed that the release of glycerol into the breast, as a result of the transport and breakdown of plasma triglycerides (fats), is the source of the glycerol. This study increases our understanding of the source and how lactose is synthesized in the breast which, in turn, helps us to provide treatment for women who desire to breastfeed, but are having difficulties with breastfeeding.

Technical Abstract: The human mammary gland is capable of de novo synthesis of glucose and galactose (hexoneogenesis); however, the carbon source is incompletely understood. In this study, we investigated the role of acetate, glutamine, lactate and glycerol as potential carbon sources for hexoneogenesis. Healthy breastfeeding women were studied following a 24-h fast on two occasions separated by 1-3 wk. Five women were infused with [U-13C]lactate or [1,2-13C2]glutamine and five women with [U-13C]glycerol or [1,2-13C2]acetate. Enrichments of 13C in plasma and milk substrates were analyzed using GC-MS. Infusion of labeled lactate, glycerol, glutamine, and acetate resulted in plasma glucose being 22.0+/-3.7, 11.2+/-1.0, 2.5+/-0.5, and 1.3+/-0.2% labeled, respectively. Lactate, glutamine, or acetate did not contribute to milk glucose or galactose (0-2%). In milk, 13C-free glycerol enrichment was one-fourth that in plasma but free glycerol concentration in milk was fourfold higher than in plasma. Using [U-13C]glycerol and by accounting for tracer dilution, glycerol alone contributed to 10+/-2 and 69+/-11% of the hexoneogenesis of milk glucose and galactose, respectively. During [U-13C]glycerol infusion, the ratio of M3 enrichment on 4-6 carbons/M3 on 1-3 carbons of galactose was higher (P<0.05, 1.22+/-0.05) than those of glucose in plasma (1.05+/-0.03) and milk (1.07+/-0.02). Reanalysis of samples from a previous study involving [U-13C]glucose infusion alone suggested labeling a portion of galactose consistent with pentose phosphate pathway (PPP) activity. We conclude that, although lactate contributed significantly to gluconeogenesis, glycerol alone provides the vast majority of substrate for hexoneogenesis. The relative contribution of the PPP vs. the reversal Embden-Meyerhof pathway to hexoneogenesis within the human mammary gland remains to be determined.