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24."12Control of Glycogenolysis 755 24.12 Controlof glycogenolysis AIM: Todescribethe hormonol control of glycogenolysis. Glucagon and epinephrine stimulate glycogenolysis. Recallfrom Section23.7that phosphorylase,an important enzyne catalyst of glycogenolysis,is converted from an inactive form (phosphorylaseb) to an active form (phosphorylasea) upon phosphorylation byATP This conversion is subject to hormonal control by glucagon, a peptide hormone. lVhen levels ofblood glucoseare low glucagonproduced bythe pancreas entersthe bloodstreamand is carried to its target cells-the primary target of glucagonis liver cells.Glucagonstimulatesthe production of cAMP (Fig. 24.10),which activatesa protein kinaseby binding to it. The protein kinase catalyzesthe phosphorylation of phosphorylaseb, producing phosphorylase a. Phosphorylasea then begins to catalyzethe breakdor,rrnof glycogen. The end result of the action of glucagonis to raisethe level of glucosein the blood. Another hormone that stimulates the breakdo'ornof glycogen is epinephrine (adrenaline).Epinephrine is often cailed the "flight or flght" hormone becauseit is secretedby the adrenalglandsin responseto a threat of bodily harm. The main effect of epinephrine is on muscle cells,which may need energy to meet the threat. The nervous system is also mobilized Stimulus (low blood glucose) + Glucagon F i g u r e2 4 . 1 0 Clucagonpromotesthe breakdownof glycogen stored in liver cellsto glucose.Someof the glucoseproducedby livercellsis carriedby the blood to other tissues. Liver cell Glucose [enters blood) 756 in LivingOrganisms 24 Carbohydrates CHAPTER simultaneously.Within moments of the releaseof epinephrine, all systems are go.You may have experienced the unique feeling that results-perhaps at a crucial point in an athletic contest, in an automobile accident or nearaccident, or by stepping on a snake on a woodland trail. The path leading from epinephrine production to glycogenolysisin muscle is similar to the path used in the liver. There is, however, one major difference. Becausemuscle cells lack the enzyme necessary to hydrolyze glucose G-phosphateto glucose and glucose 6-phosphate cannot easily pass through cell membranes, all the glucose 6-phosphate produced by glycogenolysisin muscle cells is used for glycolysiswithin the muscle. 24.1t Glucoseobsorption AIMS: To describethe productionond functionof insulin.To nomethe termsfor low and high sugor levelsin the blood, To describethe physiologic effectsof low and high sugar levelsin the blood. To explain the phrose "storvotionin the midstof plenty" os oPPliedto diobetes. Insulin stimulates the absorption of glucose by tissue cells. Although all cells degrade glucose, most carbohydrate mdtabolism occurs in three places in the body: the muscle, the fatty tissue, and the liver. Liver cells present no barrier to the entry of glucose from the blood. The passage of blood glucose through the membranes of muscle and fat cells must be stimulated bythe peptide hormone insulin (Fig.24.11). Proinsulin, an inactive form of insulin, is synthesized as a single peptide chain in the pancreas. Proinsulin is packaged in granules and converted to active insulin within the granulesby the action of peptidases.The activation of proinsulin to insulin is very similar to the activation of zymogens to active en4lmes. Upon releaseinto the bloodstream, insulin initiates a chain of eventsby which blood glucose is permitted to enter muscle and fat cells (Fig. 24.12). Achain Bchain - co2H NHz - 24.1I Figure structure of human Theprimary insulin. 13 ta co2H 24.13Glucose Absorption 757 Stimulus (high glucose concentration in blood) n Insulin Tissue cell .....i ::= l : ::-:-:. .:::. Figure 24.12 lnsulinstimulates the uptakeof glucosebytissuecellsby starting a process that eventually renders thecellmembranes permeable to glucose. Thesecondmessenger for the process is probablycGMP ratherthancAMP. Dseenlers scientists believe that the second messengerfor insulin is cyclic guanosine monophosphate lcGMl), a compound similar in structure to cAMp \fhen glucoseenterstissuecells,the blood glucoseconcentration decreases.The drop in blood sugar is th.ehypoglycemiceffectofinsulin. A flaw in any rink of the chain-from the production of insulin to the uptake of glucose by tissues-is a serioushealth problem. Hypoglycemia Hlpoglycemia hypo(Greek): below glyc: glucose haima (Greek): blood Hyperglycemia hyper(Greek): above glyc: glucose haima (Greek): blood Glycosuria glyco (Greek): sweet uria (Greek): urine and hyperglycemia A blood glucoselevel between 70 and 90 mg/100 mL of blood is normal. And it is important that the blood sugar concentration be kept in this range. People who experience mild hypoglycemia-low blood sugar-may become pale, weak, and nervous. Severehypoglycemia, a blood sugar level of lessthan 20 mg of glucoseper 100 mL of blood, leads to shock, conr,,ulsions, coma, and finally death. There also can be too much of a good thing. Hyperglycemia-high blood sugar-for a short time is not usually harmful, but prolonged hyperglycemia is a syrnptom of diabetes mellitus. Diabetes mellitus Diabetes mellitus is afamily of diseasesin which the uptake of btood gtucoseby tissuesis impaired. Blood glucose levels may become so high that glycosuria-the appearanceof glucosein the urine-begins to occur. Loss of body water that is needed to eliminate excessglucose can severely 758 in LivingOrganisms 24 Carbohydrates CHAPTER Glycosuriaoccasionallyoccurs during pregnancybecauseofhormonal changes.As long as blood glucoselevelsare normal, this is usually not a seriouscondition. dehydrate a patient with untreated diabetes.The name diabetesmellitusliterally means "sweet siphon." Although there is plenty of glucose in the blood, glucose cannot reach tissueswhere it is urgently needed' Thus these untreated patients experienceweight loss and constant hunger. This is nothing more or lessthan starvation in the midst of plenty. There are many causesof diabetes,not all of which arewell understood' In type I (insulin-dependent or juvenile-onset) diabetes,which usually appears in children before age 10, practically no insulin is produced by the victim's pancreas.Type I diabetes is usually treated by daily injections of insulin. The insulin dose must be carefully regulated,though; too much insulin produces insulin shock. Caused by seuerehypoglycemla, insulin shock bears the potential for corna and death. Diabetics often carry candy bars to eat if they feel the onset of insulin shock. Type II (non-insulindependent or maturity-onset) diabetics, those in whom q,Tnptoms appear during young adulthood or middle age, appear to produce insulin but the releaseis delayed. About 20Toof type II diabetics require insulin. In many others, releaseof their o'orninsulin can be stimulated by drugs such as tolbutamide. H cH3-cH2-cH2-cHz HO llll -N-C-N-S lttl oo CHs Tolbutamide Diabetes has many more effects on metabolism and health than the few mentioned here.More of theseeffectsare consideredin the next chapter. The insulin used to treat human diabetics formerly came from rabbits and cattle. The amino acid sequencesof the insulin of these speciesand humans are similar enough that no severe allergic response usually occurred.Today,human insulin is being produced on a commercial scale by bacteria. A functional gene for the sgrthesis of human insulin was insertedinto the bacteriaby the gene-splicingmethod describedin Section 20.13.The genetically engineered bacteria are a convenient source of human insulin for treatment of diabetes. 24.8 EXERCISE PRACIICE Insulin is a peptide of 51 amino acid residues.Explain why this hormone cannot be administeredorally to patientswith diabetesbut must be given intravenously. sq$tu€3w&ffiY Glucoseis a major source of energy for living creatures, and some of the reactions by which it is oxidized to carbon dioxide provide a common pathway for the oxidation of fats and amino acids. Glucoseis oxidized in three stages:(1) oxidation to pyruvate in glycolysis, (2) formation of acetyl CoA from pyruvate,and (3) oxidation ofthe acetyl group of acetyl CoA to carbon dioxide in the citric acid cycle. For eachmolecule of glucoseoxidized,the citric acid cyclealsoproducessixmoleculesof NADH, two of FADH2,and two of AIP'vVhen oxygen is available,