Ketosis, diabetic

Fery, R, and Balasse, E. O. (1985). Ketone body production and disposal in diabetic ketosis. Diabetes 34,326-332. 

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. 

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 basic form of ketosis occurs in starvation and involves depletion of available carbohydrate coupled with mobihzation of free fatty acids. This general pattern of metabohsm is exaggerated to produce the pathologic states found in diabetes meUitus, twin lamb disease, and ketosis in lactating catde. Nonpathologic forms of ketosis are found under conditions of high-fat... 

Ketosis is mild in starvation but severe in diabetes meUitus and ruminant ketosis. 

Ketosis, a metabohc adaptation to starvation, is exacerbated in pathologic conditions such as diabetes mellitus and ruminant ketosis. 

Diabetic ketoacidosis A reversible but life-threatening short-term complication primarily seen in patients with type 1 diabetes caused by the relative or absolute lack of insulin that results in marked ketosis and acidosis. 

Hyperosmolar hyperglycemic state A potentially fatal short-term complication most commonly seen in older patients with type 2 diabetes caused by an insufficiency of insulin action that leads to alterations of osmolality and hyperglycemia, but without the ketosis and acidosis seen in diabetic ketoacidosis. 

Type 1 Autoimmune disease resulting in an absolute deficiency of insulin. Formerly referred to as juvenile onset diabetes, type I DM or insulin dependent diabetes mellitus (IDDM). Ketosis is common in poorly controlled subjects. 

Type 2 Peripheral tissue resistance to the action of insulin Insulin secretory defects Includes those formerly classified as adult onset diabetes, type II DM or non-insulin dependent diabetes mellitus (NIDDM). Ketosis is rare. 

As part of a study to quantify contributors of stress to hyperglycemia and ketosis in diabetes, normal hepatocytes and adipocytes in tissue culture were treated with cortisol and analyzed by Northern blotting using a gene-specific probe. The results of one experiment are shown below. 

Addition of ethyl acetate to a specimen having a transaminase activity of 47 units was responsible for the following increases in enzyme activity 10 mg/100 ml, 60 units 20 mg/100 ml, 77 units 40 mg/100 ml, 107 units and 80 mg/100 ml, 150 units. Transaminase activity in these specimens determined by another method ranged from 32 to 34 units (C7). Thus, when serum from patients with ketosis is assayed for aspartate aminotransferase activity by the diazo method, false elevations of activity may be recorded due to reaction of acetoacetic acid. In Table 11 are shown some values obtained by the diazo method and by an ultraviolet NADH NAD aspartate aminotransferase technique (B12). Examination of the medical records of these patients indicated that they were either diabetics who were in ketosis or individuals who were eating very poorly and had some degree of starvation ketosis. Similar elevations have been observed in patients receiving p-aminosalicylic acid (G6). 

C7. Chen, J. C., Marster.s, E,., and Wieland, E. G., Diabetic ketosis. Interpretation of elevated serum glutamic-oxaloacetic transaminase (SCOT) by multichannel chemical analysis. Diabetes 19, 730-731 (1970). 

The symptoms of type 2 diabetes include hyperglycemia without the ketosis associated with type 1 disease due to residual effects of insulin on ketone body synthesis. 

Glucocorticoids not only break down protein but also stimulate the catabolism of lipids in adipose tissue and enhance the actions of other lipolytic agents. This occurrence results in an increase in plasma free fatty acids and an enhanced tendency to ketosis. The mechanism of this lipolytic action is unknown. The net effect of the biochemical changes induced by the glucocorticoids is antagonism of the actions of insulin. These biochemical events promote hyperglycemia and glycosuria, which are similar to the diabetic state. 

Contraindications Diabetic complications, such as ketosis, acidosis, and diabetic coma, severe liver or renal impairment, sole therapy fortype 1 diabetes mellitus, or hypersensitivity to sulfonylureas... 

Acetone and several other ketones are produced in the liver as a result of fat metabolism. Ketone blood levels are typically about 0.001%. Lack of carbohydrates in a person s diet results in greater metabolism of fats, which leads to a greater concentration of ketone in the blood. This condition is called ketosis. People on low carbohydrate diets and diabetics have problems with ketosis because of their increase dependence on fats for metabolism. 

In moderate metabolic acidosis which occurs in cases of mild renal insufficiency, infant diarrhoea, diabetic ketosis etc. 

Overproduction of ketone bodies in uncontrolled diabetes or severely reduced calorie intake can lead to acidosis or ketosis. 

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). 

Acetone is volatile and is exhaled, and in uncontrolled diabetes, the breath has a characteristic odor sometimes mistaken for ethanol. A diabetic individual who is experiencing mental confusion due to high blood glucose is occasionally misdiagnosed as intoxicated, an error that can be fatal. The overproduction of ketone bodies, called ketosis, results in greatly increased concentrations of ketone bodies in the blood (ketonentia) and urine (lcetonuria). 

The ketone bodies are carboxylic acids, which ionize, releasing protons. In uncontrolled diabetes this acid production can overwhelm the capacity of the blood s bicarbonate buffering system and produce a lowering of blood pH called acidosis or, in combination with ketosis, ketoacidosis, a potentially life-threatening condition. 

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-... 

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. 

---