Influence of Glucose, Insulin, and Glucagon on Sodium Balance in Fasting Obese Subjects

INFLUENCE OF GLUCOSE, INSULIN, AND GLUCAGON ON SODIUM BALANCE INFASTING OBESE SUBJECTS JAROSLAW KOLANOWSKl* Since the classical study of Benedict on the metabolic consequences of prolonged fasting [1], it has been established that the excessive weight loss of the first days of fast results mainly from a negative salt and water balance. Further studies, made possible by the introduction of prolonged fast for treatment of intractable obesity [2-4], have indicated that natriuresis attending starvation usually reaches a peak after 2-4 days of starvation and spontaneously declines thereafter [5-9]. It is also well established that carbohydrate refeeding rapidly reverses the negative salt and water balance, hence a rapid decline in the rate ofweight loss [7, 10-13]. The reduction in sodium excretion occurs after both oral or intravenous glucose administration [14], is demonstrable within a few hours after a single glucose load, and persists for at least 2 days despite a continuing fast [13, 15, 16]. Interestingly, the introduction of an isocaloric but carbohydrate-free and protein-rich diet to previously normally fed subjects leads to an enhancement in sodium excretion comparable in magnitude to the natriuresis of total fast [17, 18]. Hence, it has been proposed that fast-induced natriuresis is a consequence of decreased glucose availability rather than ofcaloric withdrawal per se. In keeping with this proposal is the fact that sodium balance is maintained equilibrated despite a drastic reduction in food intake when small amounts of glucose (50 g daily) are given as sole caloric supply [19]. Although the above observations have been confirmed by several studies (for more complete references see [20]), no satisfactory explanation for the underlying mechanisms has been proposed. The progressive decrease in natriuresis observed after 3-4 days of fast probably results from hypovolemia and the resultant rise in aldosterone secretion [8, 1 2, 20-22], but the reasons for the enhancement in renal sodium excretion at the beginning offast and for the antinatriuretic effect ofcarbohydrate refeeding remain unclear. Gamble, Ross, and Tisdall [23] first proposed that the rise in metabolically generated anions was responsible for the ?Endocrine Unit, Department of Physiology, University of Louvain, U.CL. 5530, Avenue Hippocrate 55, B-1200 Brussels, Belgium.© 1979 by The University of Chicago. 003 1-5982/79/2203-0079$01.00 366 I Jaroslaw Kolanowski ¦ Sodium Balance in Fasting fasting natriuresis, sodium matching anionic ketone bodies in urine in order to maintain electroneutrality. This concept was extended to account for the antinatriuretic effect of carbohydrate refeeding after Goldblatt [24] reported that glucose exerts a strong antiketogenic effect in fasting subjects. Recently the relationship between ketonuria and sodium excretion during fasting and following refeeding has been reevaluated [25-27], indicating that the failure of ammonium excretion to match the increasing output of organic acids may partially explain the natriuresis of the early phase of fasting. The concomitant decline in ketonuria and natriuresis upon refeeding or following an isolated glucose load given during a fast [27] further suggests an important role of changes in ketone body excretion in these alterations of renal sodium excretion. However, a negative salt and water balance, though of lesser magnitude, is also observed after institution of a nonketogenic hypocaloric diet [18], and when fasting subjects are refed with protein there is a significant reduction in natriuresis despite persisting elevated ketonemia and ketonuria [11, 27]. Moreover, a considerably reduced but significant transient fasting natriuresis also occurs after ammonium chloride-induced metabolic acidosis prior to fast [28] despite the enhancement of ammoniuria at the onset of fast. All these observations clearly indicate that, in addition to shifts in organic acid and ammonium excretion, other factors may come into play in the fast-induced natriuresis. Changes in plasma insulin levels as well as in glucose utilisation by the kidney may represent these additional factors . It has also been proposed that hyperglucagonemia may be involved. Let us review critically the extent to which insulin, glucagon, or glucose itself could influence renal sodium excretion in fasting subjects. Possible Effect of Insulin on Renal Sodium Reabsorption in Fasting And Carbohydrate-refed Subjects The rapid fall in blood glucose levels occurring within the first 2 days of fast is paralleled by a decrease in plasma insulin...