Ketosis Gluconeogenesis

Increased fatty acid oxidation is a characteristic of starvation and of diabetes meUims, leading to ketone body production by the Ever (ketosis). Ketone bodies are acidic and when produced in excess over long periods, as in diabetes, cause ketoacidosis, which is ultimately fatal. Because gluconeogenesis is dependent upon fatty acid oxidation, any impairment in fatty acid oxidation leads to hypoglycemia. This occurs in various states of carnitine deficiency or deficiency of essential enzymes in fatty acid oxidation, eg, carnitine palmitoyltransferase, or inhibition of fatty acid oxidation by poisons, eg, hypoglycin. 

Individuals with chronic liver disease may have disorders of fluid and electrolyte balance, including ascites, edema, and effusions. Alterations of whole body potassium induced by vomiting and diarrhea, as well as severe secondary aldosteronism, may contribute to muscle weakness and can be worsened by diuretic therapy. The metabolic derangements caused by metabolism of large amounts of ethanol can result in hypoglycemia, as a result of impaired hepatic gluconeogenesis, and in ketosis, caused by excessive lipolytic factors, especially increased cortisol and growth hormone. 

To minimize ketosis, a slow but steady degradation of nonessential proteins would provide three-, four-, and five-carbon products essential to the formation of glucose by gluconeogene-sis. This would avoid the inhibition of the citric acid cycle that occurs when oxaloacetate is withdrawn from the cycle to be used for gluconeogenesis. The citric acid cycle could continue to degrade acetyl-CoA, rather than shunting it into ketone body formation. 

The activities of biotin-dependent carboxylases fall in deficiency, resulting in impaired gluconeogenesis, with accumulation of lactate, pyruvate, and alanine, and impaired lipogenesis, with accumulation of acetyl CoA, resulting in ketosis. There are also changes in the fatty acid composition of membrane lipids. A variety of abnormal organic acids are excreted by bothbiotin-deficient patients and experimental animals (as shown in Table 11.1). 

However, the role of oxaloacetate in the pathogenesis of ketosis has become clearer with our knowledge of the mechanism regulating gluconeogenesis and the function of ketone bodies as respiratory fuel. 

An important consequence of this distortion of homeostasis is that the more severe the gluconeogenesis, the more severe the ketosis. One substrate— oxaloacetate—is the pivot that regulates the coincidence of the two processes. Oxaloacetate is at the crossroads between glycolysis, gluconeogenesis, and the Krebs cycle. 

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