Chapter 6Starvation and Diabetes MellitusStarvationGlucose and glycogen stores are sufficient for about one day in the absence of foodintake. In conditions of food deprivation lasting longer than one day a variety ofmetabolic changes take place. Insulin levels decrease and glucagon levels increasedue to falling plasma glucose. The result of these changes is an increase in livergluconeogenesis and a sharp decrease in glucose uptake by the muscle and adiposetissue. 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 toa 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 isdependent on the insulin:glucagon ratio; when this ratio is reduced for several days,ketone body production rises markedly.CH2COHCH2COS CoACH3HOOCCH3COS CoAAcetyl CoA2CH3COCH2COS CoAAcetoacetyl CoACoAAcetyl CoACoA3-Hydroxy-3-methylglutaryl-CoACH2COCH3HOOCAcetoacetateNADHNAD+CH2CCH3HOOCOHHydroxybutyrateAcetyl CoAAcetoneCH3COCH3CO2Ketone bodies (the compounds hydroxybutyrate and acetoacetate) are synthesized from acetyl CoA asshown above. Ketone body synthesis is a consequence of the fact that acetyl CoA cannot be used as asubstrate for gluconeogenesis. During starvation (or untreated diabetes mellitus) the liver has alimited amount of amino acids and glycerol available to be converted to glucose. The brain cannot usefree fatty acids or fatty acids obtained from lipoproteins because they do not cross the blood brainbarrier. However, the brain can use ketone bodies. Note that the ketone bodies are organic acids; therelease of large amounts of ketone bodies into circulation reduces plasma pH. During starvation thekidney compensates by making the urine more acidic; in diabetic ketoacidosis, the ketone bodyproduction exceeds the ability of the kidney to compensate (and kidney function tends to becomecompromised 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 witha characteristic smell that can often be detected on the breath of an individual in diabeticketoacidosis.71Chapter 6. Diabetes Mellitus Endocrine -- Dr. BrandtSome blood cells (especially erythrocytes) require glucose, and are essentiallyincapable of using other fuel sources. After a few days of starvation, only the bloodcells and the brain use significant amounts of glucose, with the other tissuesderiving their energy from other sources.Insulin remains detectable but at significantly reduced levels during prolongedfasting. In addition, the pancreas becomes somewhat refractory, and upon refeedingan individual may become glucose intolerant for several days until normal insulinsecretion responses are restored.During starvation, growth hormone levels rise, although response to growthhormone appears to decrease, and IGF-I levels decrease in spite of the elevation ingrowth hormone. However, some growth hormone effects, such as enhanced lipolysisare elevated.Glucocorticoid levels change relatively little in starvation; however, normal levelsare required for survival of prolonged fasting. In contrast, although catecholaminelevels rise somewhat in response to the initial hypoglycemia during fasting, lack ofcatecholamine action (e.g., in adrenal medullary insufficiency) does not havedetectable deleterious effects.Finally, decreased thyroid hormone production, and in particular, decreasedconversion 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 proteinbreakdown during caloric restriction and starvation. However, decreases in thyroidhormone levels require several days to have significant effects.Early in starvation the muscle acts as a source of free amino acids forgluconeogenesis. Over time muscle protein degradation decreases, probably as aresult of decreased thyroid hormone and increased growth hormone levels. Lipolysisof triacylglycerol stores in adipose tissue provides the majority of the fuel requiredfor survival. The lifetime of an individual in the absence of food varies, dependingon the size of the fat stores.Fuel ReservesThe body stores three types of fuel: carbohydrate, protein, and fat. Table Isummarizes the distribution of this fuel among the tissues of the body.The carbohydrate stores, predominately glycogen with small amounts of circulatingglucose, contain sufficient energy to support metabolism for about one day. Inprinciple, the various protein stores could provide fuel for a prolonged fast; inpractice, most of the protein has a functional role (in the form of enzymes,contractile proteins, and structural molecules). However, some protein degradationis often necessary to support gluconeogenesis, since fatty acids cannot be used assubstrate for glucose synthesis. (Note that the brain and blood do not contain“degradable protein”; these tissues obviously contain protein, but in general thisprotein is exempt from degradation for fuel.) The major energy reservoir is providedby the fat stores of adipose tissue.72Chapter 6. Diabetes Mellitus Endocrine -- Dr. BrandtTable I.Fuel reserves of “typical” 70 kg individualAvailable energy (kcal)OrganGlucose/glycogen Triacylglycerols Degradable ProteinBrain 8 0 0Blood 60 45 0Liver 400 450 400Muscle 1200 450 24,000Adipose tissue 80 135,000 40(modified from Stryer (1995) Biochemistry, 4th Ed.)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, whileprotein and carbohydrate contain about 4 kcal/g. These figures are slightlymisleading; in vivo, metabolism of protein or carbohydrate yields only about 1 kcal/gof stored substrate due to the large amount of water associated with thesecompounds. In contrast, triacylglycerol is hydrophobic, and therefore little water isassociated with fat stores; metabolism of the fat stored in adipose tissue yieldsnearly the full 9 kcal/g. This is good news for individuals attempting to carry theirenergy stores with them -- the weight of glycogen equivalent in energy to the normalfat stores of a 70 kg man would be about 100 kg! On the other hand, incontemplating weight loss, each