Fuel Metabolism in Starvation
Annual Review of Nutrition
Vol. 26: 1-22 (Volume publication date August 2006)
First published online as a Review in Advance on May 9, 2006
- studying carbohydrate metabolism using C14 in liver slices from normal and alloxan diabetic rats. Fructose uptake was similar; however, labeled glucose conversion into glycogen, fat, and CO2 were all diminished in the diabetic. Insulin therapy corrected the deficiency.
- In contrast to muscle, glucose permeated the liver cell wall equally in normal and diabetic patients
- Many small points were clarified regarding adipose tissue, such as the release of free glycerol with the fatty acids mobilized during fasting or epinephrine stimulation
- But all of these studies suggested that the role of insulin in fasting is very important, perhaps as important as its role in the fed state.
- We also fasted two type 2 diabetics, who differed from the normals by better nitrogen conservation. They were slightly more efficient, in keeping with the concept of James Neel (at Michigan) that type 2 diabetes may have been an evolutionary selective advantage in a starving population.
- Three very intelligent obese subjects were selected for a five- to six-week starvation study (Figures 1 and 2). Urinary nitrogen excretion fell to 4–5 grams/day, and catheterization of the jugular, as we expected, showed some two thirds of brain fuel consumption to be D-ß-hydroxybutyrate and acetoacetate, markedly diminishing the need for muscle proteolysis to provide gluconeogenic precursors
- About two fifths of fatty acid metabolism in the whole body is via hepatic ketogenesis, some 100 to 150 grams/day. Yet there is still significant brain metabolism of glucose
- Total splanchnic glucose production in several weeks' starvation amounts to approximately 80 grams daily. About 10–11 grams/day come from glucose synthesis from ketone bodies, 35–40 grams from recycled lactate and pyruvate, 20 grams from fat-derived glycerol, and the remaining 15–20 grams from protein-derived amino acids, mainly alanine
- The kidneys in starvation produce about two fifths of new glucose.
- Next, I turn to the question of what controls hepatic glucose production. It appears simply to be the rate of release of alanine from muscle as reflected by its blood concentration
- Elevated levels of ß-hydroxybutyrate inhibit adipose release of free fatty acids (73, 81), but insulin is necessary for this effect.
- However, caloric homeostasis in a 70-kg man on protein alone is incompatible with life since the maximum rate of urea synthesis is insufficient to provide even basal calories, about 1000–1300 Kcal/day, or 250–325 grams of protein
- Veech and colleagues discovered that administering ß-hydroxybutyrate to the perfused rat heart in place of glucose increased work output but decreased oxygen consumption
- Essentially, any cell challenged by low oxygen availability or by a toxin interfering with mitochondrial function should benefit by utilizing ß-hydroxybutyrate in preference to any other substrate, including glucose, lactate, pyruvate, or fatty acids. In a very simple experiment, mice given ß-hydroxybutyrate exposed to 4% oxygen survived longer.