Chapter 6 Starvation and Diabetes Mellitus Starvation Glucose and glycogen stores are sufficient for about one day in the absence of food intake In conditions of food deprivation lasting longer than one day a variety of metabolic changes take place Insulin levels decrease and glucagon levels increase due to falling plasma glucose The result of these changes is an increase in liver gluconeogenesis and a sharp decrease in glucose uptake by the muscle and adipose tissue In prolonged starvation the kidney begins significant gluconeogenesis eventually achieving levels nearly equivalent to those of the liver Over a period of several days the brain switches from glucose as the primary fuel to a mixture of glucose and ketone bodies eventually ketone bodies may provide 65 of the total fuel requirements of the brain Ketone body production by the liver is dependent on the insulin glucagon ratio when this ratio is reduced for several days ketone body production rises markedly CoA O 2 CH3 C S CoA O O CH3 C CH2 C S CoA Acetoacetyl CoA Acetyl CoA Acetyl CoA CoA OH O HOOC CH2 C CH2 C S CoA CH3 3 Hydroxy 3 methylglutaryl CoA Acetyl CoA OH NAD NADH O CO2 O HOOC CH2 C CH3 HOOC CH2 C CH3 CH3 C CH3 Hydroxybutyrate Acetoacetate Acetone Ketone bodies the compounds hydroxybutyrate and acetoacetate are synthesized from acetyl CoA as shown above Ketone body synthesis is a consequence of the fact that acetyl CoA cannot be used as a substrate for gluconeogenesis During starvation or untreated diabetes mellitus the liver has a limited amount of amino acids and glycerol available to be converted to glucose The brain cannot use free fatty acids or fatty acids obtained from lipoproteins because they do not cross the blood brain barrier However the brain can use ketone bodies Note that the ketone bodies are organic acids the release of large amounts of ketone bodies into circulation reduces plasma pH During starvation the kidney compensates by making the urine more acidic in diabetic ketoacidosis the ketone body production exceeds the ability of the kidney to compensate and kidney function tends to become compromised by the altered blood flow to the kidney and therefore the pH of the blood decreases Acetoacetate can be decarboxylated non enzymatically to acetone acetone is a volatile molecule with a characteristic smell that can often be detected on the breath of an individual in diabetic ketoacidosis 71 Chapter 6 Diabetes Mellitus Endocrine Dr Brandt Some blood cells especially erythrocytes require glucose and are essentially incapable of using other fuel sources After a few days of starvation only the blood cells and the brain use significant amounts of glucose with the other tissues deriving their energy from other sources Insulin remains detectable but at significantly reduced levels during prolonged fasting In addition the pancreas becomes somewhat refractory and upon refeeding an individual may become glucose intolerant for several days until normal insulin secretion responses are restored During starvation growth hormone levels rise although response to growth hormone appears to decrease and IGF I levels decrease in spite of the elevation in growth hormone However some growth hormone effects such as enhanced lipolysis are elevated Glucocorticoid levels change relatively little in starvation however normal levels are required for survival of prolonged fasting In contrast although catecholamine levels rise somewhat in response to the initial hypoglycemia during fasting lack of catecholamine action e g in adrenal medullary insufficiency does not have detectable deleterious effects Finally decreased thyroid hormone production and in particular decreased conversion of T4 to T3 in peripheral tissues result in decreased basal metabolic rate This results in an increased efficiency of fuel utilization and in reduced protein breakdown during caloric restriction and starvation However decreases in thyroid hormone levels require several days to have significant effects Early in starvation the muscle acts as a source of free amino acids for gluconeogenesis Over time muscle protein degradation decreases probably as a result of decreased thyroid hormone and increased growth hormone levels Lipolysis of triacylglycerol stores in adipose tissue provides the majority of the fuel required for survival The lifetime of an individual in the absence of food varies depending on the size of the fat stores Fuel Reserves The body stores three types of fuel carbohydrate protein and fat Table I summarizes the distribution of this fuel among the tissues of the body The carbohydrate stores predominately glycogen with small amounts of circulating glucose contain sufficient energy to support metabolism for about one day In principle the various protein stores could provide fuel for a prolonged fast in practice most of the protein has a functional role in the form of enzymes contractile proteins and structural molecules However some protein degradation is often necessary to support gluconeogenesis since fatty acids cannot be used as substrate for glucose synthesis Note that the brain and blood do not contain degradable protein these tissues obviously contain protein but in general this protein is exempt from degradation for fuel The major energy reservoir is provided by the fat stores of adipose tissue 72 Chapter 6 Diabetes Mellitus Endocrine Dr Brandt Table I Fuel reserves of typical 70 kg individual Available energy kcal Organ Glucose glycogen Triacylglycerols Degradable Protein Brain 8 0 0 Blood 60 45 0 Liver 400 450 400 1200 450 24 000 Muscle Adipose tissue 80 135 000 modified from Stryer 1995 Biochemistry 4th Ed 40 Triacylglycerol has a much higher energy density than protein or carbohydrate There are two reasons for this metabolism of pure fat releases about 9 kcal g while protein and carbohydrate contain about 4 kcal g These figures are slightly misleading in vivo metabolism of protein or carbohydrate yields only about 1 kcal g of stored substrate due to the large amount of water associated with these compounds In contrast triacylglycerol is hydrophobic and therefore little water is associated with fat stores metabolism of the fat stored in adipose tissue yields nearly the full 9 kcal g This is good news for individuals attempting to carry their energy stores with them the weight of glycogen equivalent in energy to the normal fat stores of a 70 kg man would be about 100 kg On the other hand in contemplating weight loss each