Ketone bodies diabetes mellitus

Higher than normal quantities of ketone bodies present in the blood or urine constitute ketonemia (hyperke-tonemia) or ketonuria, respectively. The overall condition is called ketosis. Acetoacetic and 3-hydroxybutyric acids are both moderately strong acids and are buffered when present in blood or other tissues. However, their continual excretion in quantity progressively depletes the alkah reserve, causing ketoacidosis. This may be fatal in uncontrolled diabetes mellitus. 

The three fat fuels and their metabolism are involved directly or indirectly in diseases such as diabetes mellitus, syndrome X, obesity, atherosclerosis and coronary heart disease, which are discussed in other chapters in this book. This section considers the problems associated with high blood levels of ketone bodies and long-chain fatty acids. 

During anaerobic glycolysis in the muscles and erythrocytes, glucose is converted into lactate, releasing protons in the process (see p. 338). The synthesis of the ketone bodies acetoacetic acid and 3-hydroxybutyric acid in the liver (see p. 312) also releases protons. Normally, the amounts formed are small and of little influence on the proton balance. If acids are formed in large amounts, however (e. g., during starvation or in diabetes mellitus see p. 160), they strain the buffer systems and can lead to a reduction in pH (metabolic acidoses lactacidosis or ketoacidosis). 

If the production of ketone bodies exceeds the demand for them outside the liver, there is an increase in the concentration of ketone bodies in the plasma (ketonemia) and they are also eventually excreted in the urine (ketonu-ria). Both phenomena are observed after prolonged starvation and in inadequately treated diabetes mellitus. Severe ketonuria with ketoacidosis can cause electrolyte shifts and loss of consciousness, and is therefore life-threatening (ketoacidotic coma). 

Shifts in the concentrations of the physiological components of the urine and the appearance of pathological urine components can be used to diagnose diseases. Important examples are glucose and ketone bodies, which are excreted to a greater extent in diabetes mellitus (see p. 160). 

FIGURE 21-19 Regulation of triacylglycerol synthesis by insulin. Insulin stimulates conversion of dietary carbohydrates and proteins to fat. Individuals with diabetes mellitus lack insulin in uncontrolled disease, this results in diminished fatty acid synthesis, and the acetyl-CoA arising from catabolism of carbohydrates and proteins is shunted instead to ketone body production. People in severe ketosis smell of acetone, so the condition is sometimes mistaken for drunkenness (p. 909). 

Taking precautions to prevent proteolysis, Banting and Best (later aided by biochemist J. B. Collip) succeeded in December 1921 in preparing a purified pancreatic extract that cured the symptoms of experimental diabetes in dogs. On January 25,1922 (just one month later ), their insulin preparation was injected into Leonard Thompson, a 14-year-old boy severely ill with diabetes mellitus. Within days, the levels of ketone bodies and glucose in Thompson s urine dropped dramatically the extract saved his life. In 1923, Banting and MacLeod won the Nobel Prize for their isolation of insulin. Banting immediately announced that he would share his prize with Best MacLeod shared his with Collip. 

C. Excessive production of ketone bodies in diabetes mellitus... 

When the rate of formation of ketone bodies is greater than the rate of their use, their levels begin to rise in the blood (ketonemia) and eventually in the urine (ketonuria). These two conditions are seen most often in cases of uncontrolled, type 1 (insulin-dependent) diabetes mellitus. In such individuals, high fatty acid degradation produces excessive amounts of acetyl CoA. It also depletes the NAD+ pool and increases the NADH pool, which slows the TCA cycle (see p. 112). This forces the excess acetyl CoA into the ketone body pathway. In diabetic individuals with severe ketosis, urinary excre-... 

Definition of ketoacidosis and example of a disease where it occurs Ketoacidosis occurs when the rate of formation of ketone bodies is greater than the rate of use, as seen in cases of uncontrolled, insulin-dependent diabetes mellitus... 

The three compounds, acetoacetate, acetone, and 3-hydroxybutyrate, are known as ketone bodies.60b The inability of the animal body to form the glucose precursors, pyruvate or oxaloacetate, from acetyl units sometimes causes severe metabolic problems. The condition known as ketosis, in which excessive amounts of ketone bodies are present in the blood, develops when too much acetyl-CoA is produced and its combustion in the critic acid cycle is slow. Ketosis often develops in patients with Type I diabetes mellitus (Box 17-G), in anyone with high fevers, and during starvation. Ketosis is dangerous, if severe, because formation of ketone bodies produces hydrogen ions (Eq. 17-5) and acidifies the blood. Thousands of young persons with insulin-dependent diabetes die annually from ketoacidosis. 

Physical therapists and occupational therapists may help reinforce the importance of patient compliance during pharmacologic management of diabetes mellitus. Therapists can question whether patients have been taking their medications on a routine basis. Regular administration of insulin is essential in preventing a metabolic shift toward ketone body production and subsequent ketoacidosis, especially in patients with type 1 diabetes. In addition, therapists can help explain that adequate control of blood glucose not only prevents acute metabolic problems but also seems to decrease the incidence of the neurovascular complications. 

Because insulin normally inhibits lipolysis, a diabetic has an extensive lipolytic activity in the adipose tissue. As is seen in Table 21.4, plasma fatty acid concentrations become remarkably high. /3-Oxidation activity in the liver increases because of a low insulin/glucagon ratio, acetyl-CoA carboxylase is relatively inactive and acyl-CoA-camitine acyltransferase is derepressed. /3-Oxidation produces acetyl-CoA which in turn generates ketone bodies. Ketosis is perhaps the most prominent feature of diabetes mellitus. Table 21.5 compares ketone body production and utilization in fasting and in diabetic individuals. It may be seen that, whereas in the fasting state ketone body production is roughly equal to excretion plus utilization, in diabetes this is not so. Ketone bodies therefore accumulate in diabetic blood. 

Source Data from Fenselau, A. Ketone body metabolism in normal and diabetic man. In Brownlee M, ed. Diabetes mellitus, Vol. III. New York Garland STPM Press, 1981, p. 145. 

Table 21.5 Ketone Body Production and Utilization in Fasting and Diabetes Mellitus (g/24 h) ...

Certain pathological conditions can lead to a life-threatening rise in the blood levels of the ketone bodies. Most common of these conditions is diabetic ketosis in patients with insulin-dependent diabetes mellitus. The absence of insulin has two major biochemical consequences. First, the liver cannot absorb glucose and consequently cannot provide oxaloacetate to process fatty acid-derived acetyl CoA (Section 17.3.1). Second, insulin normally curtails fatty acid mobilization by adipose tissue. The liver thus produces large amounts of ketone bodies, which are moderately strong acids. The result is severe acidosis. The decrease in pH impairs tissue function, most importantly in the central nervous system. 

Diabetes mellitus, the most common serious metabolic disease, is due to metabolic derangements resulting in an insufficiency of insulin and an excess of glucagon relative to the needs of the individual. The result is an elevated blood-glucose level, the mobilization of triacylglycerols, and excessive ketone-body formation. Accelerated ketone-body formation can lead to acidosis, coma, and death in untreated insulin-dependent diabetics. 

The answer is e. (Murray, pp 190—198. Scriver, pp 1521—1552. Sack, pp 121-138. Wilson, pp 287-317.) The major fate of acetoacetyl CoA formed from condensation of acetyl CoA in the liver is the formation of 3-hydroxy-3-methylglutaryl CoA (HMG CoA). Under normal postabsorp-tive conditions, HMG CoA production occurs in the cytoplasm of hepatocytes as part of the overall process of cholesterol biosynthesis. However, in fasting or starving persons, as well as in patients with uncontrolled diabetes mellitus, HMG CoA production occurs in liver mitochondria as part of ketone body synthesis. In this process, HMG CoA is cleaved by HMG CoA lyase to yield acetoacetate and acetyl CoA. The NADH-dependent enzyme P-hydroxybutyrate dehydrogenase converts most of the acetoacetate to P-hydroxybutyrate, These two ketone bodies, acetoacetate and P-hydroxybutyrate, diffuse into the blood and are transported to peripheral tissues. 

Mobilization of fats with the production of ketone bodies occurs during fasting and starvation, but ketone production is well controlled. During uncontrolled diabetes mellitus, ketogenesis proceeds at a rate that exceeds the buffering capacity of the blood to produce ketoacidosis. 

See A Clinical Perspective Diabetes Mellitus and Ketone Bodies in Chapter 23. 

Ketosis, abnormally high levels of blood ketone bodies, is a situation that arises under some pathological conditions, such as starvation, a diet that is extremely low in carbohydrates (as with the high-protein liquid diets), or uncontrolled diabetes mellitus. The carbohydrate intake of a diabetic is normal, but the carbohydrates cannot get into the cell to be used as fuel. Thus diabetes amounts to starvation in the midst of plenty. In diabetes the very high concentration of ketone acids in the blood leads to ketoacidosis. The ketone acids are relatively strong acids and therefore readily dissociate to release H+. Under these conditions the blood pH becomes acidic, which can lead to death. 

Starvation, a diet low in carbohydrates, and diabetes mellitus are conditions that lead to the production of ketone bodies. 

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