6.4: Gluconeogenesis

In a well-fed animal, most cells can store a small amount of glucose as glycogen. All cells break glycogen down as needed to retrieve nutrient energy as G-6-P. Glycogen hydrolysis, or glycogenolysis, produces G-1-P that is converted to G-6-P, as we saw at the top of Stage 1 of glycolysis. But, glycogen in most cells is quickly used up between meals. Therefore, most cells depend on a different, external source of glucose other than diet. Those sources are liver and to a lesser extent, kidney cells, that can store large amounts of glycogen after meals. In continual feeders (for examples cows and other ruminants), glycogenolysis is ongoing. In intermittent feeders (like us), liver glycogenolysis can supply glucose to the blood for 6-8 hours between meals, to be distributed as needed to all cells of the body. Thus, you can expect to use up liver and kidney glycogen reserves after a good night’s sleep, a period of intense exercise, or any prolonged period of low carbohydrate intake (fasting or starvation). Under these circumstances, animals use gluconeogenesis (literally, new glucose synthesis) in liver and kidney cells to provide systemic glucose to nourish other cells. As always in otherwise healthy individuals, the hormones insulin and glucagon regulate blood glucose homeostasis, protecting against hypoglycemia (low blood sugar) and hyperglycemia (high blood sugar) respectively. The gluconeogenic pathway produces glucose from carbohydrate and non-carbohydrate precursor substrates. These precursors include pyruvate, lactate, glycerol and gluconeogenic amino acids. The latter are amino acids that can be converted to alanine. Look at the side-by-side reactions of glycolysis and gluconeogenesis on the next page. Look for the two bypass reactions, catalyzed by two carboxylases and two phosphatases (brown in the illustration) and the glycolytic reactions that function in reverse during gluconeogenesis.

If glycolysis is an exergonic pathway, then gluconeogenesis must be an endergonic one. In fact, while glycolysis through two pyruvates generates a net of two ATPs, gluconeogenesis from two pyruvate to glucose costs 4 ATPs and two GTPs! Likewise, gluconeogenesis is only possible if the bypass enzymes are present. These are necessary to get around the three biologically irreversible reactions of glycolysis. Except for the bypass reactions, gluconeogenesis is essentially a reversal of glycolysis.

As drawn in the pathways above, glycolysis and gluconeogenesis would seem to be cyclic. In fact this apparent cycle was recognized by Carl and Gerti Cori, who shared the 1947 Nobel Prize for Medicine or Physiology with Bernardo Houssay for discovering how glycogen is broken down to pyruvate in muscle (in fact most) cells, which can then be used to resynthesize glucose in liver cells. Named after the Coris, The Cori Cycle, shown below, recognizes the interdependence of liver and muscle in glucose breakdown and resynthesis.

In spite of this free energy requirement, gluconeogenesis is energetically favorable in liver and kidney cells! This is because the cells are open systems. The accumulation of pyruvate in liver cells and a rapid release of new glucose into the blood drives the energetically favorable reactions of gluconeogenesis forward. Thus, under gluconeogenic conditions, glucose synthesis occurs with a negative DG’, a decline in actual free energy. Of course, glycolysis and gluconeogenesis are not simultaneous! Which pathways operate in which cells is tightly controlled.

Glycolysis is the norm in all cell types, even in liver and kidney. However, the cessation of glycolysis in favor of gluconeogenesis in the latter cells is under hormonal control, as illustrated below.

Key in turning on liver gluconeogenesis is the role of glucocorticoid hormones. What causes the secretion of glucocorticoids? A long night’s sleep, fasting and more extremely, starvation are forms of stress. Stress responses starts in the hypothalamic- pituitary axis. Different stressors cause the hypothalamus to secrete a neurohormone that in turn, stimulates the release of ACTH (adrenocorticotropic hormone) from the pituitary gland. ACTH then stimulates the release of cortisone and other glucocorticoids from the cortex (outer layer) of the adrenal glands. As the name glucocorticoid suggests, these hormones participate in the regulation of glucose metabolism. Here is what happens at times of low blood sugar (e.g., when carbohydrate intake is low):

1. Glucocorticoids stimulate the synthesis of gluconeogenic bypass enzymes in liver cells.

2. Glucocorticoids stimulate protease synthesis in skeletal muscle, causing hydrolysis of the peptide bonds between amino acids. Gluconeogenic amino acids circulate to the liver where they are converted to pyruvate, a major precursor of gluconeogenesis. Some amino acids are ketogenic; they are converted to Acetyl-S-CoA, a precursor to ketone bodies.

(1). Glucocorticoids stimulate increased levels of enzymes including lipases that catalyze hydrolysis of the ester linkages in triglycerides (fat) in adipose and other cells. This generates fatty acids and glycerol.

(2). Glycerol circulates to liver cells that take it up convert it to G-3-P, augmenting gluconeogenesis. Fatty acids circulate to liver cells where they are oxidized to Acetyl-S-CoA that is then converted to ketone bodies. and released to the cisculation.

(3). Most cells use fatty acids as an alternate energy nutrient when glucose is limiting. , and while heart and brain cells depend on glucose for energy, brain cells can use ket9one bodies as an alternate energy course.

essential roles of glucocorticoids

1. It’s a pity that we humans cannot use fatty acids as gluconeogenic substrates! Plants and some lower animals have a glyoxalate cycle pathway that can convert the products of fatty acid oxidation (acetate) directly into carbohydrates that can enter the gluconeogenic pathway. Lacking this pathway, we (and higher animals in general) cannot convert fats to carbohydrates, in spite of the fact that we can all too easily convert the latter to the former!

   The dark side of bad eating habits is prolonged starvation that can overwhelm the gluconeogenic response. You see this in reports from third world regions suffering starvation due to drought or other natural disaster, or war. The spindly arms and legs of starving children result from muscle wasting as the body tries to provide the glucose necessary for survival. When the gluconeogenic response is inadequate to the task, the body can resort to ketogenic fat metabolism. Think of this as a last resort, leading to the production of ketone bodies and the “acetone breath” in starving people.