Adaptation, constraint, and the function of the gluconeogenic pathway

Abstract

Gluconeogenesis is responsible for the de novo synthesis of glucose (and glycogen) from precursors including lactate, amino acids, glycerol, and fructose. This metabolic sequence is highly constrained by design features including enzyme composition and tissue localization, but demonstrates a variety of adaptive patterns which are critical to the maintenance of blood glucose levels optimal for animal function. This review identifies the adaptive responses of gluconeogenesis when glucose levels are challenged by changes in diet (both quality and quantity) and in activity level, and by environmental disturbances. Five adaptive patterns are identified: (i) quantitative changes in gluconeogenic enzyme activities and their subcellular distribution; (ii) alterations in tissue demand for glucose; (iii) existence of in situ skeletal muscle lactate cycling; (iv) quantity and type of gluconeogenic precursors; and (v) regulation of gluconeogenesis. The validity of the omnivorous mammalian model in our understanding of gluconeogenesis is discussed.