Gluconeogenesis is an anabolic process which synthesizes glucose from non-carbohydrate precursors like lactate, alanine, glycerol and pyruvate. The process occurs in the liver when levels of blood glucose are low. Its purpose is to provide glucose as energy fuel to tissue like the RBC where continuous glucose supply is critical.
Gluconeogenesis is essentially a reversal of the steps of glycolysis, with by-pass enzymatic reactions circumventing three energy barriers that prevent easy reversal.
Gluconeogenesis and glycolysis are reciprocally regulated by allosteric and hormonal factors, Chapter 5 Section 7
REGULATION OF BLOOD GLUCOSE
The maintenance of stable levels of blood glucose is an excellent example of homeostasis in our body. The elucidation of the mechanisms of glucose metabolism that enable this steady state, has been an outstanding achievement in biochemistry. The doggedness and brilliant analytical skills with which scientists have worked to understand the pathways and their regulations, are worthy of respect and admiration. No wonder so many of them (Warburg, Meyerhoff, Krebs, the Coris, Sutherland…the list goes on) have been awarded the Nobel Prize!
Fig 5.7.1. Sources of blood glucose (dietary source of glucose has not been shown) (Source: Vander et al, 2001, p 596 fig 18-2)
The sources of glucose in the blood are dietary intake, and hepatic glycogenolysis and gluconeogenesis. All tissues take in glucose from the blood, though the extent to which they
depend exclusively on glucose as energy fuel are different. As mentioned earlier, the brain and RBC need continuous and adequate supply of glucose.
The concentration of blood glucose varies before and after meals. In a normal adult, blood glucose levels in the post- absorptive state are maintained between 4.5-5.5 mmol/L. However, a carbohydrate meal can increase these levels to 6.5-7.2 mmol/L (hyperglycemia), while starvation can decrease it to 3.3-3.9 mmol/L (hypoglycemia). Hyperglycemia may also be due to metabolic disorders like diabetes mellitus. Hypoglycemia may be caused by vigorous muscle excercise, pregnancy, or drugs. A sudden drop in the concentration of blood glucose causes convulsions and may be fatal, but a more gradual decrease can enable metabolic adaptations to some extent.
The primary organ in maintaining stable levels of glucose in the blood is the liver. At normal levels of blood glucose, the liver is a net producer of glucose. We have already seen that hepatic glycogenolysis and gluconeogenesis release glucose into the blood, while glycogenesis stores excess glucose as glycogen. As levels of blood glucose rise (as in hepatic portal vein after a meal) the liver switches its enzymatic machinery from production to uptake of glucose. It helps that, unlike extrahepatic tissues, the liver has the requisite glucose transporter for rapid uptake of glucose from the blood when the levels are on the rise. When blood glucose is low, the liver shifts its own metabolism from utilization of glucose for energy to the oxidation of fatty acids. Under conditions of hypoglycemia, the increased use of fatty acids and ketone bodies as energy fuels, also has a “sparing” effect on blood glucose essential to the RBC and neural tissues.
The ability of the liver to adjust its glucose metabolism with the levels of blood glucose, is largely due to the hormones insulin and glucagon. Both hormones are produced by the pancreas; the α- cells of the islets of Langerhans secrete glucagon while the β-cells secrete insulin.
Fig 5.7.2. Relation between the levels of plasma glucose and the secretion of glucagon and insulin.
(Source: Vander et al, 2001, p 604 fig 18- 9)
Low blood glucose shifts the ratio of [insulin]/[glucagon] in the blood in favor of glucagon, while high blood glucose favors insulin over glucagon. We have already learnt how glucagon stimulates hepatic glycogenolysis and gluconeogenesis in order to boost blood glucose levels. On the other hand, the rise in [insulin] parallels that of [glucose] in the blood, and stimulates hepatic glycogenesis and glycolysis. Additionally, insulin increases entry of glucose into extrahepatic tissues for glycolysis, into muscle cells for glycogenesis, and into adipose tissue for triglyceride synthesis. All these events tend to lower [blood glucose].
Fig 5.7.3. Blood levels of glucose, glucagon and insulin after moderate exercise (Source: Vander et al, 2001 p 607 fig 18-11)
Fig 5.7.4. The activities of hepatic glycogen phosphorylase and glycogen synthase in the liver after infusion of glucose (Source: Berg et al, 2002, fig21.21)
The adrenal catecholamines and glucocorticoids tend to raise levels of blood glucose when there is increased demand for glucose in muscle and other tissues. Epinephrine is secreted by the adrenal medulla, and also by the sympathetic nerve endings, in response to stressful stimuli like fear, excitement, hemorrhage and hypoglycemia. This causes increased glycogenolysis in both muscle and liver.
Fig 5.7.5. Interaction between the levels of plasma glucose and the secretion of epinephrine (Source: Vander et al, 2001 p 602 fig 18-10)
Cortisol from the adrenal cortex is permissive to gluconeogenesis. Adenohypophyeal hormones like STH and ACTH are also anti-insulinic in action.
Fig 5.1.6. Comparison of the blood levels of glucose in normal and diabetic
individuals at different time intervals in a glucose tolerance test . (Source:
Murray et al, 2003, p,161 fig19-6)
By now it would be apparent to you that insulin is essential for glucose entry into tissues, as well as for its storage as glycogen in the liver. The deficiency of insulin causes diabetes mellitus, a disorder with devastating effects throughout the body if left undetected and untreated. High blood levels of glucose between meals and low readings in a “glucose tolerance” test are indicative of the disorder. Drugs are used to stimulate insulin secretion in Type 2 diabetes (NIDDM i.e. non-insulin dependent diabetes mellitus), while insulin per se has to be administered in Type 1 diabetes (IDDM i.e. insulin dependent diabetes mellitus).