Gluconeogenesis, process

Protein degradation and amino acid metabolism are highly elevated in the diabetic, because the stimulatory effect of insulin on protein synthesis is nonexistent and the relative excess of glucagon and glucocorticoids causes protein breakdown to continue. Indeed, muscle wasting is a cardinal symptom of the untreated diabetic. Insulin also inhibits amino add release into the bloodstream, and this may be a reason a moderate rise in plasma amino add levels is observed in the diabetic. Such increased amino adds are largely of the branched-chain type, and alanine levels are in fact lower than normal. Nevertheless, alanine uptake by the liver is twice that of the normal individual, and it continues to be a major actor in the gluconeogenesis process. 

Central control of glucose homeostasis critically depends on the brain s ability to sense extracellular [glucose]. Within hypothalamus at least two types of neurons were identified which are presumably involved in this process. They are either glucose excited or glucose inhibited. Both types of neurons appear to be involved in the control of feeding, hepatic gluconeogenesis,... 

The citric acid cycle is the final common pathway for the aerobic oxidation of carbohydrate, lipid, and protein because glucose, fatty acids, and most amino acids are metabolized to acetyl-CoA or intermediates of the cycle. It also has a central role in gluconeogenesis, lipogenesis, and interconversion of amino acids. Many of these processes occur in most tissues, but the hver is the only tissue in which all occur to a significant extent. The repercussions are therefore profound when, for example, large numbers of hepatic cells are damaged as in acute hepatitis or replaced by connective tissue (as in cirrhosis). Very few, if any, genetic abnormalities of citric acid cycle enzymes have been reported such ab-normahties would be incompatible with life or normal development. 

The citric acid cycle is not only a pathway for oxidation of two-carbon units—it is also a major pathway for interconversion of metabolites arising from transamination and deamination of amino acids. It also provides the substtates for amino acid synthesis by transamination, as well as for gluconeogenesis and fatty acid synthesis. Because it fimctions in both oxidative and synthetic processes, it is amphibolic (Figure 16—4). 

Gluconeogenesis is the process of converting noncarbohydrates to glucose or glycogen. It is of particular importance when carbohydrate is not available from the diet. Significant substrates are amino acids, lactate, glycerol, and propionate. 

The synthesis of glucose from noncarbohydrate sources is referred to as the gluconeogenesis. It is feasible only in certain organism tissues. The major site for gluconeogenesis is the liver. To a lesser extent, the kidneys and intestinal mucosa are involved in this process. 

Removal by the liver Lactate and protons are transported into the cells and then converted to glucose via gluconeogenesis. The overall process is... 

In fact, these two processes are metabolically linked. The oxidation generates ATP whereas gluconeogenesis utilises this ATP. Consequently, in the well-fed human, gluconeogenesis is essential for oxidation of amino acids, otherwise oxidation is limited by the need to utilise the ATP (Chapter 8). The reactions in which amino acids are converted to compounds that can enter the gluconeogenic pathway are described in Chapter 8. The position in the gluconeogenic pathway where amino acids, via their metabolism (Chapter 8), enter the pathway is indicated in Figure 6.23. 

The situation is, however, different in starvation. In this condition, it is the degradation of muscle protein that provides the amino acids for gluconeo-genesis, so that all the oxo-acids generated (except those for lysine and lencine) are nsed to synthesise the glucose required for oxidation by the brain. Hence, a process other than amino acid oxidation mnst generate the ATP required by gluconeogenesis. This process is fatty acid oxidation. 

Figure 8.13 The central role of transdeamination in metabolism of amino adds and further metabolism of the oxoacids in the liver. The box contains the reactions for conversion of the amino acids to their respective oxoacids. Processes are as follows (1) digestion of protein in the intestine and absorption of resultant amino acids, (2) degradation of endogenous protein to amino acids (primarily but not exclusively muscle protein), (3) protein synthesis, (4) conversion of amino acid to other nitrogen-containing compounds (see Table 8.4), (5) oxidation to CO2, (6) conversion to glucose via gluconeogenesis, (7) conversion to fat.

If starvation lasts for more than 24 hours, the rate of degradation of body protein (process 2) exceeds the rate of protein synthesis (process 3). The resultant amino acids are converted to oxoacids, most of which are converted to glucose (process 6) which is released and used predominantly by the brain (see Chapter 6). In this condition, the ATP required for gluconeogenesis is obtained from the oxidation of fatty acids (Figure 8.14(b)). 

Figure 8.30 Different roles of periportal and perivenous cells in the liver in respect of glutamine metabolism. Glutamine is converted to glucose in periportal cells via gluconeogenesis in perivenous cells, ammonia is taken up, to form glutamine, which is released into the blood. This emphasises the importance of the liver in removing ammonia from the blood, i.e. if possesses two process to ensure that all the ammonia is removed.

This compartmentation of processes in the liver cells occurs with other pathways glycolysis occurs mainly in the perivenous cells whereas gluconeogenesis occurs mainly in the periportal cells (Chapter 6). 

Alcohol impairs some metabolic processes, including gluconeogenesis which, in some conditions, is an essential process for wellbeing and normal behaviour (Chapters 6 and 14). 

Glucose must be synthesised if trauma or infection results in anorexia the process is gluconeogenesis. 

Initially the level of insulin decreases, favouring increased rates of lipolysis, fatty acid oxidation, muscle protein degradation, glycogenolysis and gluconeogenesis. It soon increases, however, as a result of insulin resistance, when the stimulation of the above processes will depend on the cytokine levels. For details of endocrine hormone effects, see Chapter 12. For details of cytokines see Chapter 17. 

Figure 21.20 Diagram of a tori q/de in a patient with a tumour. Lactate produced from glucose by tumour cells is converted back to glucose in the liver (gluconeogenesis) and released into the blood for re-uptake by tumour cell, an ATP-reguiring process. Note that muscle, immune cells and red blood cells will also contribute to the cycle (see. Chapter 6 Figure 6.10).

The intermediates of the tricarboxylic acid cycle are present in the mitochondria only in very small quantities. After the oxidation of acetyl-CoA to CO2, they are constantly regenerated, and their concentrations therefore remain constant, averaged over time. Anabolic pathways, which remove intermediates of the cycle (e.g., gluconeogenesis) would quickly use up the small quantities present in the mitochondria if metabolites did not reenter the cycle at other sites to replace the compounds consumed. Processes that replenish the cycle in this way are called anaplerotic reactions. 

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