Ketone Bodies Are Overproduced in Diabetes and during Starvation

Starvation and untreated diabetes mellitus lead to overproduction of ketone bodies, with several associated medical problems. During starvation, gluconeogenesis depletes citric acid cycle intermediates, diverting acetyl-CoA to ketone body production (Fig.17–20). In untreated diabetes, when the insulin level is insufficient, extrahepatic tissues cannot take up glucose efficiently from the blood, either for fuel or for conversion to fat. Under these conditions, levels of malonyl-CoA (the starting material for fatty acid synthesis) fall, inhibition of carnitine acyltransferase I is relieved, and
fatty acids enter mitochondria to be degraded to acetyl-CoA—which cannot pass through the citric acid cycle because cycle intermediates have been drawn off for use as substrates in gluconeogenesis. The resulting accumulation of acetyl-CoA accelerates the formation of ketone bodies beyond the capacity of extrahepatic tissues to oxidize them. The increased blood levels of acetoacetate and D- -hydroxybutyrate lower the blood pH, causing the condition known as acidosis. Extreme acidosis can lead to coma and in some cases death. Ketone bodies in the blood and urine of untreated
diabetics can reach extraordinary levels—a blood concentration of 90 mg/100 mL (compared with a normal level of 3 mg/100 mL) and urinary excretion of 5,000
mg/24 hr (compared with a normal rate of 125 mg/
24 hr). This condition is called ketosis. Individuals on very low-calorie diets, using the fats stored in adipose tissue as their major energy source, also have increased levels of ketone bodies in their blood
and urine. These levels must be monitored to avoid the dangers of acidosis and ketosis (ketoacidosis).