Metabolic effects

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I. OVERVIEW

Individual tissues do not function in isolation, but rather form part of acommunity in which one tissue may provide substrates to another, orprocess compounds produced by other organs. Communicationbetween tissues is mediated by the nervous system, by the availabilityof circulating substrates, and by variation in the levels of plasma hor-mones (Figure 24.1). The integration of energy metabolism is con-trolled primarily by the actions of hormones, including insulin,glucagon, catecholamines, epinpehrine and norepinephrine. Changesin the circulating levels of these hormones allow the body to storeenergy when food is available in abundance or to make stored energyavailable, for example, during "survival crises," such as famine, severeinjury, and "fight or flight" situations. This chapter describes the struc-ture, secretion, and metabolic effects of the two hormones that mostprofoundly affect energy metabolism, insulin and glucagon.

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LIVER ADIPOSE

• Hormones• Nervous system• Circulating substrates

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MUSCLE BRAIN

II. INSULIN

Insulin is a polypeptide hormone produced by the ~-cells of the isletsof Langerhans, clusters of cells that comprise about 1% of the massof the pancreas. Insulin is one of the most important hormones coor-dinating the utilization of fuels by tissues. Its metabolic effects areanabolic, favoring, for example, synthesis of glycogen, triacylglycerols,and protein.

Figure 24.1Mechanisms of communicationbetween four major tissues.

Lippincott's 'Illustrated Reviews: Biochemistry, Second Edition,by Pamela C. Champe and Richard A. Harvey.J. B. Lippincott Company, Philadelphia, PA © 1994. 269

278 24. Metabolic Effects of Insulin and Glucagon

lOW BLOOD GLUCOSE

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ACTH Autonomic nervous system

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pancreaS •...../

Glycogenolysis

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Cortisol Epinephrine Norepinephrine Glucagon

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oGluconeogenesis ++ ++

+, ++,+++ Weak, moderate, or strong stimulationo No effect

Figure 24.12Actions of the glucoregulatory hormones in response to low blood glucose.

• cose by peripheral tissues. Epinephrine is not normally essentialin combating hypoglycemia, but it can assume a critical rolewhen glucagon secretion is deficient, for example, in the latestages of insulin-dependent diabetes mellitus (see p. 299). Theprevention or correction of hypoglycemia fails when the secre-tion of both glucagon and epinephrine are deficient.

2. Cortisol and growth hormone: These hormones are less impor-tant in the short-term maintenance of blood glucose concentra-tions; rather, they playa role in the long-term management ofglucose metabolism.

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IV. Hypoglycemia279

c. Types of hypoglycemia

Hypoglycemia may be divided into two groups: postprandial(sometimes called reactive hypoglycemia) and fasting hypo-glycemia.

1. Postprandial hypoglycemia: This is the more common of thetwo syndromes. It is caused by an exaggerated insulin releasefollowing a meal, prompting a transient hypoglycemia with mildadrenergic symptoms. The plasma glucose level returns to nor-mal even if the patient is not fed. The only. treatment usuallyrequired is that the patient eat frequent small meals rather thanthe usual three large meals.

2. Fasting hypoglycemia: Low blood glucose occurring during fast-ing is rare but is more likely to present as a serious medicalproblem. Fasting hypoglycemia tends to produce neuroglycope-nia symptoms and may result from a reduction in the rate of glu-cose production by the liver. Thus, low blood glucose levels areoften seen in patients with hepatocellular damage or adrenalinsufficiency or in fasting individuals who have consumed largequantities of ethanol. Alternately, fa~ting hypoglycemia may bedue to an increased rate of glucose utilization by the peripheraltissues, most commonly due to elevated insulin resulting from apancreatic p-cell tumor. If left untreated, a patient wittt fastinghypoglycemia may lose consciousness and experience convul-sions and coma.

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1,3.;.bis-Phosphoglycarate. . .•3. Hypoglycemia and alcohol intoxication: Alcohol is metabolized ·tt

in the liver by two oxidation reactions. Ethanol is first converted 3-Phosphoglycerate.to acetaldehyde by alcohol dehydrogenase (Figure 24.13). . ·tt·Acetaldehyde is subsequently oxidized to acetate by aldehyde 2-Phosptlog1ycerate

dehydrogenase, an enzyme inhibited by disulfiram, a drug that . ,(.f ....has found some use in patients desiring to stop alcohol inges- ..../'T. PhosPhOe~OIPyru~~te.....

tion." In each reaction electrons are transferred to NAD+ result- ,./ Pyruvate" <'Lactateing in a massive increase in the concentration of cytosolic {..'•

NADH. The abundance of NADH favors the reduction of pyru- \, ... :'•

vate to lactate, and oxaloacetate to malate. Recall from p. 99 .....<..that pyruvate and oxaloacetate are both intermediates in the····· ..·,··Ox~lo~c~tatEl<. ...

synthesis of glucose by gluconeogenesis. Thus the ethanol- .....•.•..•............•...Ji'·~~~~.: ..........................•..•mediated increase in NADH causes the intermediates of gIUCO-<H. ..,<.-.~.,/.<

neogenesis to be diverted into alternate reaction pathways, ... .. ., .. Mal~t~~P:::<resulting in decreased synthesis of glucose. This can precipitate.; '<".. ~H."HC<:;:;··HH·.:,,';: .: .; '"... . . : : :, :.. .: : .. :;¥ ~:-,-.,: ',:: . . :;.'.:. .. .

hypoqlycernla, particularly in individuals who have depleted their H>'/X/:,':"':(; .. >;i,~>~>...~ :.: :: .:::-. :.':-;::..::..-:;;.: :..:.:: : ,. ..' '..:... .."" : ,. .• ,.:

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stores of liver glycogen. [Note: Recall from p. 135 that the mobi- "'HH~' -.H.,::·::.,:;~.·;~:i:.}:<:/.r . • !>;~•.•X+};::,~,;:..:.;[,~'<:;;:·:,;:\H~.:,••.·;(iX::'}<s;.:

lization of liver glycogen is the body's first defense against hypo-glycemia. Thus, individuals who are starved or malnourished ...... :... ... .. '.

have depleted glycogen stores and must rely on gluconeo-;EtnanpfH Aceta.(d~JiYQe.··..~.:...·.,.· ::.:~.:~QeJa(.-;genes is to maintai n their blood gIucose Ieve Is.] Hypog Iycemia·:\::· ...A/OO/j()/ .. . , 'AldehYlle'" .'.can produce many of the behaviors associated with alcohol ....i·~~rq(~(lJm~$~i...>u,·d~/:!~~~~~«:.)\i;!;N;0,':intoxication agitation, impaired judgement, and combative-ness. Thus, alcohol consumption in vulnerable individuals-those who are starved or have engaged in prolonged, strenuousexercise can produce hypoglycemia that may contribute to thebehavioral effects of alcohol.

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Figure 24.13Effect of ethanol metabolism onhepatic gluconeogenesis.

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Correct choice = D. cAMP is not directly involvedas a second messenger in the action of insulin.

280 24. Metabolic Effect of Insulin and Glucagon

Study Questions: Choose the ONE best answer. 24.4 Which one of the following inhibits the release ofinsulin from the ~-cells?

A. HyperglycemiaB. Elevated levels of norepinephrineC. Elevated levels of arginineD. Elevated levels of glucagonE. Secretin

24.1 In which one of the following tissues is glucose trans-port into the cell enhanced by insulin?

A. BrainB. LensC. Red blood cellsD. Adipose tissueE. Liver

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Correcf answer = B. In emergency situations, .. release of..,nOrepinephrine by t~e sympat~~tio.~.er..

Y,o:U$;sy~t~mhar9~lyreplace~. p~.~sma. g~u¢,Qseconcentration as the controlling influen,ce..ov~r ~-. ..cen secretion. .'

•Correct answer .= D. The major tissues, in whichglucose transport requires insulir are m'us~le··~ncf...adipose tissue. The ~e.tabolismdt~he·liver

, respond~ to ins~lintbut hepatic glucoSf>transpot:t . .is rapid and dceenot require insulin..; ,. '

Correct choice = C,_Insulin decreases the activityof hormone-sensitive lipase in adipose tissue.Increasing, glucose transport and glycogen syn-thesis are part of the anabolic actions of insulin.

24.5 Which one of the following is NOT a direct action ofinsulin binding to the cell membrane?A. Activation of tyrosine kinase activity of the ~-subunit

of the insulin receptor.\

B. Phosphorylation of the intracellutardornain of theinsulin receptor.

C. Phosphorylation of intracellular proteins.D. Activation of adenylate cyclase.E. Increased activity of and number of glucose trans-

port molecules in the cell membrane.

24.2 Insulin does all of the following EXCEPT:A. enhance glucose transport into muscle.B. enhance glycogen formation by liver.C. increase lipolysis in adipose tissue.D. inhibit gluconeogenesis in liver.E. enhance amino acid transport into muscle.

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24.3 All of the following statements about glucagon arecorrect EXCEPT:A. High levels of blood glucose decrease the release

of glucagon from the a-cells of the pancreas.B. Glucagon levels increase following ingestion of a

protei n-rich meal.C. Glucagon increases the intracellular levels of cAMP

in liver cells, causing an increase in glycogenbreakdown.

D. Glucagon is the only hormone. important in combat-ing hypoglycemia.

E. Glucagon stimulates the formation of ketone bodiesby the liver.

24.6 Which one of the following statements concerninghypoglycemia is NOT correct?

A. Postprandial hypoglycemia is the less commonform of low blood sugar.

B. Fasting hypoglycemia may be observed in individu-als who have consumed large amounts of ethanol.

C. Fasting hypoglycemia may result from a pancreatic~-cell tumor.

D. The symptoms of hypoglycemia include anxiety,palpitations, tremor, and sweating.

E. Glucagon and epinephrine are the most importantmediators of the acute response to hypoglycemia.

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270,

24. Metabolic Effects of Insulin and Glucagon ~

Figure 24.2Structure of human insulin. [Note: Amino acid residu~s different in bovine insulin are shown in black (.)and in porcine insulin in gray ( ).]

Signalsequence

A. Structure of insulin,

Insulin is composed of 51 amino acids arranged in two polypeptidechains, designated A and B, which are linked together by twodisulfide bridges (Figure 24.2). The insulin molecule also containsan intramolecular disulfide bridge between amino acid residues 6and 11 of the A chain. Beef insulin differs from human insulin atthree amino acid positions, whereas pork insulin varies at only oneposition an alanine instead of threonine at the C-terminal end ofthe 8 chain of the human hormone.

1. Synthesis of human insulin from porcine insulin: Two methodsare available to prepare human insulin commercially. One is asemisynthetic process in which the terminal alanine of the ~chain of porcine insulin is replaced with threonine.

B chain A chain

coo-Insulin

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Signal sequence C-peptidePreproinsulin Proinsulin

Figure 24.3Formation of human insulin from preproinsulin.

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II. Insulin 271

Polypeptide synthesis is initiatedwith formation of an N-terminalsignal peptide, which penetratesthrough the membrane of the RER.

Genes coding for insulin aretranscribed to mRNA in thenucleus.

r:I After moving to the cytoplasm,~ mRNA is translated by the

polysome attached to RER.

The signal peptide is cleavedand prolnsulln is formed inthe cisternal space.

Further elongation directs thepolypeptide chain into the lumen ofthe RER, resulting in the formationof preproinsulin.

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Proinsulin is transportedfrom RER to the Golgicomplex, where it is cleavedforming insulin.

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Secretory granules arereleased by exocytosis.Insulin and C-peptide in

secretory granules.

Figure 24.4Intracellular movements of insulin and its precursors. RER = rough endoplasmic reticulum.

2. SyntheSiS of human insulin by recombinant DNA technology:Recombinant DNA techniques can also be used to preparehuman insulin. Human insulin has the same potency as piginsulin but is absorbed more quickly and has a shorter durationof action after subcutaneous injection.1

B. Biosynthesis of insulin

The processing and transport of intermediates that occur duringsynthesis of insulin are shown in Figures 24.3 and 24.4. Note thatthe biosynthesis involves two inactive precursors, preproinsulin

1See p. 280 for Infolink references to other books-in this series.•

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Meal

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Figure 24.5Changes in blood levels of glucose,insulin, and glucagon after ingestionof a carbohydrate-rich meal.

Figure 24.6Regulation of insulin release frompancreatic ~-cells.

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and proinsulin, which are sequentially cleaved to form the activehormone. Insulin is stored in the cytosol in granules that, given theproper stimulus (see below), are released by exocytosis (seep. 159 for a discussion of the synthesis of proteins destined forsecretion). Insulin is degraded by the enzyme insulinase present inthe liver and to a lesser extent in the kidneys. Insulin has a plasmahalf-life of approximately 6 minutes. This short duration of actionpermits rapid changes in circulating levels of the hormone.

C. Regulation of insulin secretion

1.'Stimulation of insulin secretion: Insulin secretion by the p-cellsof the islets of Langerhans of the pancreas is closely coordinat-ed with the release of glucagon by the pancreatic a-cells (seep. 275). The relative amounts of insulin and glucagon releasedby the pancreas are regulated so that the rate of hepatic glu-cose production is kept equal to the use of glucose by peripher-al tissues. In view of its coordinating role, it is not surprising thatthe ~-cell responds to a variety of stimuli. ln particular, insulinsecretion is increased by:

a. Glucose: The ~-cells are the most important glucose-sensingcells in the body. Ingestion of glucose or a carbohydrate-richmeal leads to a'rise in blood glucose, which is a signal forincreased insulin secretion (as well as decreased glucagonrelease; Figure 24.5). Glucose is the most important stimulusfor insulin secretion.

b. Amino acids: Ingestion of protein causes a transient rise inplasma amino acid levels, which in turn induces the immedi-ate secretion of insulin. Elevated plasma arginine is a partie-ulary potent stimulus for insulin secretion.

c. Gastrointestinal hormones: The intestinal peptide secretin,as well as other gastrointestinal hormones, stimulates insulinsecretion. These hormones are released after the ingestionof food. They cause an anticipatory rise in insulin levels inthe portal vein before there is an actual rise in blood glucose.This may account for the fact that the same amount of glu-cose given orally induces a much greater secretion of insulinthan if given intravenously.

d. Glucagon: Glucose stimulates the secretion of insulin and •inhibits the release of glucagon. This latter action is impor-tant in type I diabetes (see p. 295) where ~-cell destructionremoves the inhibitory influence of insulin on glucagonrelease. Many of the symptoms of the disease are due tounrestrained activity of glucagon on target tissues.

2. Inhibition of insulin secretion: The synthesis and release ofinsulin are decreased when there is a scarcity of dietary fuelsand also during periods of trauma (see p. 291). These effectsare mediated primarily by epinephrine, which is secreted by theadrenal medulla in response to stress, trauma, or extreme exer-cise. Under these conditions, the release of epinephrine is con-trolled largely by.the nervous system. Epinephrine has a direct

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II. Insulin 273

effect on energy metabolism, causing a rapid mobilization ofenergy-yielding fuels, including glucose from the liver (seep. 143) and fatty acids from adipose tissue (see p. 181). In addi-tion, epinephrine can override the normal glucose-stimulatedrelease of insulin. Thus, in emergency situations, the sympa-thetic nervous system largely replaces plasma glucose concen-tration as the controlling influence over ~-cell secretion. The reg-ulation of insulin secretion is summarized in Figure 24.6.

D. Metabolic effects of insulin

1. Effects on carbohydrate metabolism: The 'effects of insulin onglucose metabolism are most prominent in three tissues: liver,muscle, and adipose. In the liver, insulin decreases the produc-tion of glucose by inhibiting gluconeogenesis and the break-down of glycogen. In muscle and liver, insulin increases glyco-gen synthesis. In muscle and adipose tissue, insulin increasesglucose uptake by increasing the number of glucose trans-porters in the cell membrane. The intravenous administration ofinsulin thus causes an immediate decrease in the concentrationof blood glucose.

2. Effects on lipid metabolism: Adipose tissue responds withinminutes to administration of insulin, which causes a markedreduction in the release of fatty acids:

8. Decrease in triacylglycerol degradation: Insulin decreasesthe level of circulating fatty acids by inhibiting the activity ofhormone-sensitive lipase in adipose tissue. Insulin probablyacts by promoting the dephosphorylation and, hence, inacti-vation of the enzyme (see pp. 181, 282).

b. Increased triacylglycerol synthesis: Insulin increases thetransport and metabolism of glucose into adipocytes, provid-ing the substrate glycerol 3-phosphate for triacyglycerol syn-thesis. Insulin also increases lipoprotein lipase acitivity ofadipose tissue, providing fatty acids for esterification.

3. Effects on protein synthesis: Insulin stimulates the entry ofamino acids into cells and protein synthesis, in most tissues.

E. Mechanism of insulin action

Insulin binds to specific, high-affinity receptors in the cell mem-brane of most tissues, including liver, muscle, and adipose. This isthe first step in a cascade of reactions ultimately leading to adiverse array of biologic actions.

1. Insulin receptor: The insulin receptor is synthesized as a singlepolypeptide that is glycosylated and cleaved into (J.- and f)-sub-units, which are then assembled into a tetramer linked by disul-fide bonds (Figure 24.7). A hydrophobic domain in each f)-sub-unit spans the plasma membrane. The extracellular a-subunitcontains the insulin binding site. The cytosolic domain of thep-subunit is a tyrosine kinase, which is activated by insulin.

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Insulin binding activatesreceptor tyrosine kinaseactivity in the intracellulardomain of ~-subunit of the ."'."'.','insulin receptor. ,

r:I Tyrosine residues of~ the ~-subunit are auto ...

phosphorylated.

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a Receptor tyrosine kinaseU phosphorylates other

proteins, for example,insulin receptor substrate(IRS).

n Phosphorylated IRS promotes~ activation of other protein

Ji;YH kinases and phosphatases,......,..,."...,... leading to biologic actions

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of insulin.

Figure 24.7Insulin receptor. IRS = Insulin receptorsubstrate.


a Glucose transportersa increase insulin-mediated uptake ofglucose into cell.

. 1:1 Activated receptor promotes

..g recruitment of glucose trans-porters from intracellular poolto cell membrane.

nWhen insulin levelsIIJIdecrease,glucose

transporters move fromcell membrane to intra-cellular storage pool, I';~<;····;";-;;;'?~.'····

where they can berecycled.

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a Vesicles fuse toW form an organelle

called the endosome.

Insulin binds toits receptor inthe cell membrane.

Figure 24.8Insulin causes cells to recruit transporters from intracellular stores.

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2. Signal transduction: The binding of insulin to the a-subunits ofthe insulin receptor induces conformational changes that aretransduced to the ~-subunits, promoting a rapid autophosphory-lation of a specific tyrosine residue of each ~-subunit (seeFigure 24.7). However, the molecules that link receptor tyrosinekinase to the intracellular effects of insulin are not firmly estab-lished. It is known that at least some of the actions of insulin aremediated by phosphorylation or dephosphorylation of serine orthreonine residues of target proteins. Thus, it has been pro-posed that receptor tyrosine kinase activity leads to phosphory-lation of tyrosines of a peptide, called insulin receptor substrate(IRS). Phosphorylated IRS appears to interact with a number ofintracellular proteins. Insulin binding thus unleashes a complexcascade of phosphorylation and dephosphorylation reactions.These actions are terminated by dephosphorylation of thereceptor.

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III. Glucagon 275

3. Membrane effects of insulin: Glucose transport in many tissues,such as skeletal muscle and adipocytes, increases in the pres-ence of insulin (Figure 24.8). Insulin promotes the recruitment ofglucose transporters from a pool located in intracellular vesi-cles. [Note: Some tissues have insulin-independent systems forglucose transport (Figure 24.9). For example, hepatocytes, ery-throcytes, and cells of the nervous system, intestinal mucosa,renal tubules, and cornea do not require insulin for glucoseuptake (see p. 88 for a discussion of GLUT-4, an insulin-sensi-tive glucose transport protein).]

•4. Receptor regulation: Binding of insulin is followed by internaliza-

tion of the hormone-receptor complex. Once inside the cell,insulin is degraded in the Iysosomes. The receptors may bedegraded but most are recycled to the cell surface. Elevated lev-els of insulin promote the degradation of receptors, thusdecreasing the number of surface receptors. This is one type of"down-regulation ."

5. Time course of insulin actions: The binding of insulin provokesa wide range of actions. The most immediate response is anincrease in glucose transport into cells, which occurs within-sec-onds of insulin binding to its membrane receptor. Insulin-induced changes in enzymic activity occur over minutes tohours and reflect changes in the phosphorylation states of exist-ing proteins. Insulin also initiates an increase in the amount ofmany enzymes, such as glucokinase, phosphofructokinase, andpyruvate kinase, which requires hours to days (see p. 97).These changes reflect an increase in gene transcription, mRNA,and enzyme synthesis.

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Figure 24.9Characteristics of glucose transportin various tissues.

III. GLUCAGON

Glucagon is a polypeptide hormone secreted by the a-cells of thepancreatic islets. Glucagon, along with epinephrine, cortisol, andgrowth hormone (the "counterregulatory hormones"), opposes manyof the actions of insulin (see Figure 24.12). Most importantly,glucagon acts to maintain blood glucose levels by activation of hepaticglycogenolysis and gluconeogenesis. Glucagon is composed of 29amino acids arranged in a single polypeptide chain. Unlike insulin, theamino acid sequence of glucagon is the same in all mammalianspecies examined to date. Glucagon is synthesized as a large precur-sor molecule that is converted to glucagon through a series of selec-tive proteolytic cleavages, similar to those described for insulinbiosynthesis (see Figure 24.3).

A. Stimulation of glucagon secretion

The a-cell is responsive to a variety of stimuli that signal actual orpotential hypoglycemia (Figure 24.10). Specifically, glucagonsecretion is increased by:

Figure 24.10Regulation of glucagon release frompancreatic a...cells.

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1. Low blood glucose: A decrease in plasma glucose concentra-tion is the primary stimulus for glucagon release. During anovernight or prolonged fast, elevated glucagon levels preventhypoglycemia (see p. 277 for a discussion of hypoglycemia).

2. Amino acids: Amino acids derived from a meal containing pro-tein stimulate the release of both glucagon and insulin. Theglucagon effectively prevents hypoglycemia that would other-wise occur as a result of increased insulin secretion that occursafter a protein meal.

3~Epinephrine: Elevated levels of circulating epinephrine pro-duced by the adrenal medulla, norepinephrine produced bysympathetic innervation of the pancreas, or both stimulate therelease of glucagon. Thus, during periods of stress, trauma, orsevere exercise, the elevated epinephrine levels can overridethe effect on the a-cell of circulating substrates. In these situa-tions regardless of the concentration of blood glucose-glucagon levels are elevated in anticipation of-Increased glucoseuse. In contrast, insulin levels are depressed.

.• B. Inhibition of glucagon secretion•Glucagon secretion is markedly decreased by elevated blood sugarand by insulin. Both of these substances are increased followingingestion of glucose or a carbohydrate-rich meal (see Figure 24.5).The regulation of glucagon secretion is summarized in Figure 24.10.

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c. Metabolic effects of glucagon

1. Effects on carbohydrate metabolism: The intravenous adminis-tration of glucagon leads to an immediate rise in blood sugar.This results from an increase in the breakdown of liver (not mus-cle) glycogen (see p. 143) and an increase in gluconeogenesis(see p. 102).

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2. Effects on lipid metabolism: Glucagon favors hepatic oxidationof fatty acids and the subsequent formation of ketone bodiesfrom acetyl CoA. The lipolytic effect of glucagon in adipose tis-sue is minimal in humans.

Biologiceffect

3. Effects on protein metabolism: Glucagon increases uptake ofamino acids by the liver, resulting in increased availability of car-bon skeletons for gluconeogenesis. As a consequence, plasmalevels of amino acids are decreased.

Figure 24.11Mechanism of action of glucagon.[Note: For clarity, G-protein activationof adenylate cyclase has beenomitted; see Figure 6.8 for a moredetailed representation.]

D. Mechanism of action of glucagon

Glucagon binds to high-affinity receptors on the cell membrane ofthe hepatocyte. The receptors for glucagon are distinct from thosethat bind insulin or epinephrine. Glucagon binding results in activa-tion of adenylate cyclase in the plasma membrane (Figure 24.11).This causes a rise in cAMP (the "second messenger"), which inturn activates cAMP-dependent protein kinase and increases thephosphorylation of specific enzymes or other proteins. This cas-cade of increasing enzymic activities results in the phosphoryla-

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IV. Hypoglycemia 277

tion-mediated activation or inhibition of key regulatory enzymesinvolved in carbohydrate and lipid metabolism. An example ofsuch a cascade is presented for the case of glycogen degradationon p. 143 and Figure 13.10.

IV. HYPOGLYCEMIA

The central nervous system has an absolute requirement for a contin-uous supply of blood-borne glucose to serve as a fuel for energymetabolism. Transient hypoglycemia can cause carebral dysfunction,whereas severe, prolonged hypoglycemia causes brain death. It istherefore not surprising that the body has multiple overlapping mech-anisms to prevent or correct hypoglycemia. The most important hor-mone changes in combating hypoglycemia are elevated glucagon andepinephrine, combined with the diminished release of insulin.

A. Symptoms of hypoglycemia

The symptoms of hypoglycemia, usually considered a blood glu-cose concentration of 45 mg/dL or less, can be divided into two c~-egories. Adrenergic symptoms anxiety, palpitation, tremor, andsweating are mediated by epinephrine release regulated by thehypothalamus in response to hypoglycemia. Usually adrenergicsymptoms (that is, symptoms mediated by elevated epinephrine)occur when blood glucose levels fall abruptly, The second categoryof hypoglycemic symptoms is neuroglycopenic. Neuroglycopenia-the impaired delivery of glucose to the brain results in impair-ment of brain function causing headache, confusion, slurredspeech, seizures, coma, and death. Neuroglycopenic symptomsoften result from a gradual decline in blood glucose, often to levelsbelow 40 mg/dL. The slow decline in glucose deprives the eNS offuel but fails to trigger an epinephrine response.

B. Glucoregulatory systems

Humans have two overlapping glucose-regulating systems thatare activated by hypoglycemia: (1) the islets of Langerhans, whichrelease glucagon, and (2) receptors in the hypothalamus, whichrespond to abnormally low concentrations of blood glucose. Thehypothalamic glucoreceptors can trigger both the secretion ofepinephrine (mediated by the autonomic nervous system) andrelease of ACTH and growth hormone (GH) by the anterior pitu-itary (Figure 24.12). Glucagon, epinephrine, cortisol, and growthhormones are sometimes called the "counterregulatory" hormonesbecause each opposes the action of insulin on glucose utilization.

1. Glucagon and eplnephrlne: Hypoglycemia is combatted bydecreased release of insulin and increased secretion ofglucagon, epinephrine, cortisol, and growth hormone (seeFigure 24.12). Glucagon and epinephrine are most important inthe acute, short-term regulation of blood glucose levels.Glucagon stimulates hepatic glycogenolysis and gluconeogene-sis. Epinephrine promotes glycogenolysis and lipolysis, inhibitsinsulin secretion, and inhibits the insulin-mediated uptake of glu-

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Metabolic effects

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