Chapter 5 Glucose homeostasis

7/22/2019 Chapter 5 Glucose homeostasis

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Chapter 5

Endocrine Regulation of Glucose Metabolism

Overview of Glucose Homeostasis

G lucose meta bolism is critical t o norma l physiologica l functioning. G lucose acts bothas a source of energy and as a source of starting material for nearly all types ofbiosynt hetic rea ctions. The diagr a m sh ow s th e ma jor play ers in th e regula tion an dutilization of plasma glucose.

Figure 1. The organs that control plasma glucose levels. The normal plasma glucose

concentra tion va ries betw een a bout 70 an d 120 mg/dL (3.9-6.7 mM). Note t ha t w hole

blood glucose values are about 10-15%lower than plasma values due to the removal

of cellular components during preparation of plasma.

The bra in uses a bout 120 gra ms of glucose da ily: 60-70% of the t ota l body glucosemetabolism. The brain has lit t le stored glucose, and no other energy stores. Brainfunction begins t o become seriously a ffected w hen g lucose levels fa ll below ~ 40mg/dL; levels of glucose significa nt ly below t his can lea d to perma nent da ma ge an ddeat h. The bra in cann ot use fat ty a cids for energy (fat ty a cids do not cross t he blood-brain barrier); ketone bodies can enter the brain and can be used for energy inemergencies. The brain can only use glucose, or, under conditions of starvation,ketone bodies (acetoacetate and hydroxybutyrate) for energy.

The diet is one source of circula tin g glucose, an d provides carbon a nd energy sources

for liver gluconeogenesis.

The liver is the major metabolic regulatory organ. About 90%of a ll circula tin gglucose not derived directly from the diet comes from the liver. The liver containssignificant amounts of stored glycogen available for rapid release into circulation,and is capable of synthesizing large quantit ies of glucose from substrates such aslactate, amino acids, and glycerol released by other t issues. In addition tocontrolling plasma glucose, the liver is responsible for synthesis and release of thelipoproteins that adipose and other tissues use as the source of cholesterol and free

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Chapter 5. Gl ucose Homeosta sis End ocr i n e -- D r . B r and t

fat ty a cids. During prolonged sta rva tion, the liver is t he source of both glucose an dth e ketone bodies requ ired by th e bra in t o repla ce glucose. The liver uses glycolysisprimarily as a source of biosynthetic intermediates, with amino acid and fatty acidbreakdown providing the majority of its fuel.

Like the liver, the kidney has the ability to release glucose into the blood. Under

normal conditions gluconeogenesis in the kidney provides only a small contributionto the total circulating glucose; however, during prolonged starvation, the kidneycontribution may approach that of the liver. Kidney function is critical for glucosehomeostasis for another reason; plasma glucose continuously passes through thekidney a nd m ust be efficiently r eabsorbed to prevent losses.

The muscle cannot release glucose into circulation; however, its ability torapidly increase its glucose uptake is crit ical for dealing with sudden increases inplasma glucose. Skeletal muscle has an additional role in maintaining plasmaglucose levels: it releases free amino acids into circulation to serve as substrates forliver gluconeogenesis. The m uscle ca n use glucose, fa tt y a cids, a nd ketone bodies forenergy. The muscle normally maintains significant amounts of stored glycogen,sma ll amounts of fat ty a cids, an d cont a ins a large pool of protein th a t can be brokendown in emergencies. The resting muscle uses fatty acids as its primary energysource; however, glucose (from its own glycogen stores and from circulation), ispreferred for rapid energy generation (e.g. in sudden exercise).

The adipose tissue is the major site of fatty acid storage. Fatty acids are stored inthe form of triacylglycerol, which is synthesized in the adipose tissue from glycerol-phosphate and free fatty acids. The glycerol-phosphate used must be derived fromglycolysis in the adipose tissue; free glycerol cannot be phosphorylated becauseadipocytes lack the relevant kinase. In conditions when liver gluconeogenesis isnecessary the adipose tissue supplies free fatty acids and glycerol to the circulation

to be ta ken up by the liver as substra te.Finally, the pancreas is the source of insulin and glucagon, two of the mostimportant metabolic regulatory hormones. The synthesis, release, and actions ofth ese hormones is th e ma jor subject of this cha pter.

Glycolysis and Gluconeogenesis

Glycolysis (Figure 2) is a major energy production pathway used at least to somedegree in a ll cells. In a ddition, glycolytic intermediates a nd products a ct a s carbonsources for near ly a ll biosynt hetic rea ctions, an d t he reducing equiva lents required

for most biosynthetic reactions are derived from the flow of glucose through thepentose phosphate pathway. Glucose homeostasis is thus of central importance inmeta bolism and is heavily regula ted.

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Glucose Glucose-6-P G lucose-1-P Glycogen

Fructose-6-P

Fructose-1,6-P 2

G lyceraldehyde-3-P + Dihy droxyacetone-P

P hosphoenolpyruva t e Oxa loa cet a t e

H exokin ase

Glucose-6-

Phospha t a se

Phospho

glucoisomerase

F ruc t o se

B i s Ph osph a ta se

Aldolase

Phosphoeno l p y r u va t e

ca r box y k i nase

Phospho

glucomutase

Glycogen

Syn thase

Phosphory lase

TCA intermedia tes

Glucose

G l u c o k i n a s e

Phospho f r u c t o k i nase

Tr iose phosphate

isomerase

1,3-Bisphosphoglycerate

Glyceraldehyde-3-phosphatedehydrogenase

Phosphoglycerate

kinase

3-Phosphoglycerate

2-Phosphoglycerate

Phosphoglycerate

mutase

Enolase

Pyruva t e

Py r u v a t e

k i n a s e

Glycerol

Pyruvate

carboxylase

Lac ta te

TCA Cycle

Fat ty acid biosynthesis

Amino a cid biosynt hesis

Nucleotide biosynt hesis}{

Amino acids

Pentose phosphat e path wa y

UDP-Glucose

UDP-Glucose

Pyrophosphorylase

Serine

Figure 2. The glycolytic, gluconeogenic, pentose phosphate, and glycogen synthetic

pathways. The primary regulated steps are catalyzed by the underlined enzymes.

Note the convergence of the pathways at glucose-6-phosphate. Note also that

although glucose can be phosphorylated in all tissues, the reversal enzyme glucose-6-

phosphatase is only found in liver and kidney.

Metabolism of free glucose begins with a phosphorylation reaction that yieldsglucose-6-phosphate. This reaction is catalyzed by hexokinase in most tissues.

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Hexokinase ha s a relatively high a ffinity for glucose; in most t issues th e rat e of thehexokinase reaction is limited by the rate of glucose import into the cell, or byglucose-6-phosphate inhibition of the enzyme. In the liver and pancreas, anotherenzyme, glucokinase, also catalyzes this reaction. Unlike hexokinase, glucokinasehas relatively low affinity for glucose and is regulated by glucose regulatoryhormones; glucokinase thus acts as a mechanism for the liver to remove excess

glucose from circulation. In liver, although not in pancreas, glucokinase proteinsynt hesis is regulated by insulin a nd glucagon.

The Km of hexokinase is


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the enzyme; liver pyruvate kinase is also regulated by several allosteric effectors.Muscle uses a different isozyme of pyruvate kinase; muscle pyruvate kinase is notinhibited by phosphorylation.

Liver pyruvate kinase gene expression has been shown to be stimulated by glucose metabolites

directly activating transcription factors. Glucose metabolites are also thought to increase GLUT2and (in -cells) insulin gene expression. These findings suggest that glucose can act to regulate itsown metabolism in a fashion at least partially independent of insulin, and may prove useful in

developing new therapies for diabetes.

Gluconeogenesis (Figure 2) is the reverse of glycolysis. Many of the enzymesinvolved are easily reversible, and are common to both pathways. However, thereactions cat a lyzed by phosphofructokina se an d pyruva te kina se ar e not reversible.The gluconeogenic pathway must use different enzymes to reverse these steps.These enzymes (phosphoenolpyruvate carboxykinase and fructose-bis-phosphatase)a re the ones regula ted by hormonal stimuli.

Under normal circumstances, alanine is the preferred liver gluconeogenic substrate.However, all amino acids except leucine can be used as substrate forgluconeogenesis. Alan ine a nd gluta mine a re th e ma jor (~ 50% of t ota l) a mino acidsreleased by mus cle, a lth ough they comprise only a bout 15% of muscle protein.Alanine is produced in muscle from pyruvate derived from both glycolysis anda mino acid metabolism.

Gluconeogenesis is inhibited by ethanol (ethanol metabolism in the liver uses upNAD, and therefore prevents the conversion of lactate to pyruvate). In normalindividuals, liver glycogen breakdown yields sufficient glucose to maintain plasmalevels until the ethanol has been metabolized. In conditions of malnutrit ion or

poorly managed diabetes mellitus, ethanol inhibition of gluconeogenesis may resultin hypoglycemia.

Pancreatic Anatomy and Function

The pancreas has two major functions: it produces and releases digestive enzymes,and it produces and releases the two major hormones responsible for the endocrinecont rol of glucose meta bolism: insulin a nd g lucagon.

The exocrine pan crea s comprises a bout 98% of the ma ss of the orga n. The a cina rcells syn thesize a nd secrete th e digestive enzymes (try psin, chym otry psin, elast a se,amylase, and others) that break down food into simpler components that can be

a bsorbed by the int estine.

The endocrine pa ncreas is comprised of sma ll groups of cells distr ibuted t hr oughoutthe organ. These groups, the Islets of Langerhans, consist of four cell types (, , ,and F). The islet composition varies in different parts of the pancreas (posteriorprimarily F-cells with some -cells, and anterior primarily -cells with some a ndsmaller amounts of -cells). Each cell type secretes one major hormone: the -cellsare the insulin producing cells, while the -cells produce glucagon, the -cells

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produce soma tosta tin, a nd the F cells produce Pa ncrea tic P olypeptide.

The function of pan crea tic soma tosta tin a ppea rs t o be limited t o inhibit ion of insulinand glucagon release; the function of Pancreatic Polypeptide is unknown. Thecontrol of insulin and glucagon release is discussed in detail in the next fewsections.

Synthesis and Release of Insulin

Insulin is a peptide hormone. It is synthesized in the rough endoplasmic reticulumas part of an 11.5 kDa precursor protein called pre-proinsulin. The endoplasmicreticulum-targeting sequence is cleaved during peptide synthesis to releaseproinsulin. Proinsulin is packaged into secretory vesicles, where it is processed intoth e ma tur e peptide hormone (Figur e 3).

The ha lf-life of circulat ing insu lin is a bout 5 min utes; t he ma jor sit es of degra da tiona re the liver an d kidney. U nder n orma l conditions, some proinsulin secretion occurs,amounting to 3-5%of the insulin secretion; during periods of high rates of insulin

release, the processing tends to be less complete, and therefore proinsulin releaseconstitutes a larger proportion of the total released peptides. The releasedproinsulin has a longer half-life than insulin. It cross-reacts with the insulin RIA,a nd t herefore pla sma insulin levels include a bout 10-20% proinsulin . Pr oinsulinha s some a ctivity, but only ~ 10%of tha t of insulin.

The C-peptide also has a longer half-life than insulin. Measurement of C-peptide isuseful for monitoring pancreatic -cell a ctivity beca use it does n ot cross-rea ct in th einsulin RIA and is not present in th erapeutic insulin prepara tions.

N

C

A cha in

B chain

C-peptide

(31 A.A.)

P roinsulin Ma ture insulin (51 A.A.)

Specific

pr ocessi ng

pr oteases

Figure 3. Clea va ge of proinsulin t o form ins ulin a nd C -peptide.

Mature insulin is composed of two peptide chains (the A and B-chains) linked by disulfide bonds. A

connecting sequence, termed the C-peptide, is removed to produce the mature hormone; the mature

hormone and the C-peptide are released by the -cells in equimolar amounts along with smallamounts of unprocessed proinsulin. Cleavage of proinsulin is catalyzed by a protease that recognizes

dibasic sequences (e.g. Lys-Arg). An exopeptidase then removes the basic residues to yield the

ma tur e insulin a nd C -peptide. (This sy stem is a lso responsible for the processing (in other cell types)

of a va riety of peptide hormone precursors, such a s glucagon a nd ACTH .)

The mature insulin forms hexameric crystals with zinc ions in the secretory vesicles. This process is

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thought to increase the amount of insulin that can be stored in vesicles of a given size. The crystals

dissolve upon relea se into circulat ion.

The C-peptide was long thought to be inactive. Recent studies, however, have suggested that some

complications of diabetes may actually be alleviated or prevented by injection of C-peptide. The

mecha nism by w hich C-peptide may be acting is under investiga tion.

Insulin is r eleased from the -cell in response to eleva ted pla sma glucose, ma nn ose,and some amino acids, especially leucine (Figure 4). Stimulation of insulin releaseby glucose ca n be enha nced by oth er hormones (especia lly th ose released by t he gut ,such as gastrin inhibitory peptide and cholecystokinin; this is why insulin releasedue to oral administration is greater than release due to intravenous infusion ofglucose), by arginine and some other amino acids, and by -adrenergic agonists.Insulin release is inhibited by somatostatin, by cortisol, and by catecholaminesact ing via -adrenergic receptors. Although specific and -adrenergic agonistsha ve opposite effects on insulin release, th e net effect of phys iological cat echolam inea ction is st rongly inhibitory.

(+ )

(+ )

(+ )

pre-pro-insulin proinsulin

HighPlasmaGlucose

GLUT 2

Glucose

Glycolysis

Rough Endoplasmi c Reticul um

Golgi

InsulinRelease

Leucine

Arginine

Glucagon

T r an scr i p t i on

R e l e a s e

Regulat ors ofInsulin relea se

(+ )Somatosta t in

()

-adrenergicagonists

()

Regulat ors ofInsulin relea se

(+ )

Figure 4. Insulin release is affected by a variety of different posit ive and negative

stimuli.

Prolonged high levels of glucose decrease the -cell response to the glucosestimulation, without altering -cell responsiveness to other stimuli. Although notcompletely understood, this appears to be due at least in part to a decrease in thea mount of G LU T2 glucose tra nsporter in the -cell membra ne. P rolonged eleva tionof glucose (such as that caused by hypersecretion of glucocorticoids) may exhaustthe -cell stores of insulin and exceed the ability of the -cell to synthesizeadditional hormone, resulting in hyperglycemia; it is possible that this down-

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regula tion of GL U T2 is one mechan ism for reducing risk of -cell exhaustion.

Transcription of the insulin gene and translation of the insulin mRNA arestimulated by glucose. Acute increases in glucose levels largely affect secretion ofpre-formed insulin from secretory vesicles and mRNA translation and stability,while chronic increases in glucose levels increase transcription of insulin mRNA.

Increases in transcription and translation require some time to become effective.Stimulation with glucose may therefore result in two phases of insulin release(Figure 5); a rapid phase, due to release of pre-formed hormone from maturevesicles, and a slower phase requiring synthesis of new protein. During onset ofType I diabetes the rapid phase disappears first , because basal insulin secretionra tes become such a la rge proport ion of the rema ining -cell ca pacity t ha t st orage ofpre-formed in sulin in vesicles is n o longer possible.

Time

Glucose Sti mul ati on

Rapid

phaseSlow phase

Figure 5. The two phases of insulin secretion observed during prolonged stimulation

with glucose. The rapid phase represents release of previously synthesized hormone;

the slow phase represents the induction of new hormone synthesis (the delay is due

to the t ime required for transcription, protein synthesis and post-translationalprocessing. T ime scal es: rapid phase begins less than one minute after st imulation,

an d ends a bout 10 minutes la ter; slow phase begins about 15-20 minutes a fter init ial

st imula tion, an d ends when stimulation ends.

Mechanism of Insulin Action

Insulin action is mediated by the insulin receptor, a complex multi-subunit cellsurface glycoprotein. Binding of insulin activates the intrinsic tyrosine kinasea ctivity of th e receptor. Tyrosine phosphoryla tion of the insu lin receptor itself a nd ofsome other proteins is thought to be required for insulin action. As a result of thesephosphorylation (and probably other) events, a number of other intracellular

proteins are activated, including several kinases, phosphatases, and transcriptionfactors. One important enzyme activated by the second messenger cascade isphosphodiesterase, which decreases cellular cAMP levels. Insulin action isillustra ted in F igure 6.

Acute increases in insulin levels result in phosphoryla tion or de-phosphoryla tion ofexisting proteins (e.g. the enzymes involved in the glycolytic and gluconeogenicpathways), which have rapid but transient effects on their activity. High levels of

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insulin, or prolonged stimulation by insulin results in alterations in the rate oftra nscription of a va riety of genes, an d t herefore in increased or decreased capa cityfor t he processes mediat ed by t hose gene products.

Prolonged high levels of insulin result in desensitization (de-coupling of thereceptor from t he cellular responses) an d down-regulation (decreased amounts of

the receptor on the cell-surface). These phenomena protect the cell from over-stimulation (similar effects are seen with a number of other hormones).Desensitizat ion a nd down-regulation of the insulin receptor a re importa nt in TypeII diabetes, since these phenomena occur upon prolonged high levels of insulin andcontribute to the insulin resistance that characterizes the disorder. It is thereforepreferable, although not always possible, to avoid use of exogenous insulin for TypeII diabetics, since this tends to further down-regulate the receptor and worsen thedesensitiza tion tha t ha s alread y occurred.

Insulin

Insulinreceptor

Insulin

othersecond

messengers

P lasma

membrane

-S-S-

IRS

GLUT4

GLUT4

Proteinphosphorylation

a nd dephosphorylat ion

Genetranscript ional

effects ReducedcAMP levels

Translocationt o

plasma membrane(+ )Auto-

phosphorylation

Figure 6. Intracellular effects of insulin binding to the insulin receptor. Insulin

binding activates the insulin receptor tyrosine kinase. The phosphorylation of various

intracellular proteins results in changes in activity of the proteins, in altered gene

transcription rates for specific genes, and (in muscle and adipose tissue) in

translocation of the GLUT4 glucose transporter to the plasma membrane, and

therefore increased glucose uptake into these tissues.

Insulin receptor phosphorylates at least four insulin receptor substrate proteins (IRS-1 through

IRS-4) on tyrosine residues. The tyrosinephosphorylatedforms of the IRS proteins ar e thought to a ct

as second messengers for a variety of intracellular responses. Serine phosphorylation of the IRS

proteins or of the insulin receptor, in contrast, attenuates or abolishes the effect of insulin. Thus,

insulin acting a lone ha s insulin a ction; other hormones ma y decrease or prevent th ese actions by

increasing activity of some serine kinases.

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One important short term effect of insulin action is a translocation of the GLUT4glucose transporter to the cell surface in muscle and adipose tissue. Stimulation ofthe cell for longer periods results in altered rates of transcription of a variety ofproteins, including decreased rate of GLUT4 transcription.

At least five different glucose transport proteins are known. These proteins mediate the passive ( i .e.non-energy dependent) transport of glucose across the plasma membrane of various cell types. They

were na med in order of discovery.

GLUT1 and GLUT3 are found in most t issues and are especially important in transport of glucose

into the bra in. G LU T1 and G LU T3 have a high a ffinity for glucose, and therefore tra nsport glucose

efficiently throughout the normal range of plasma glucose concentration.

GLUT2 is found primarily in pancreas and liver. It has a low affinity for glucose and therefore

mediates glucose tra nsport only during h igh plasma glucose levels. GL UT2 is the tra nsporter t ha t is

responsible for allowing the -cells to sense hyperglycemia, and for transporting high glucose levelsinto the liver for storage.

G LU T4 is t he primar y h ormonally-responsive tra nsporter. G LU T4 is found primarily in muscle an d

adipose t issue, wh ere it is normally sequestered in intra cellular vesicles; it is tra nslocated t o plasma

membrane in response to insulin, resulting in enhanced glucose uptake. In contrast, cortisol

decreases the amount of GLUT4 in the plasma membrane. Prolonged high levels of the hormones

that affect GLUT4 localization result in effects on GLUT4 gene transcription in the opposite

direction of the effects on activity; thus GLUT4 gene transcription is increased by high levels of

glucocorticoids and inhibited by high levels of insulin. However, GLUT4 expression is also reduced

by low insulin sta tes, such as in m uscle during fast ing, and in insulin-resistant adipose t issue.

The remaining GLUT gene products are much less important for glucose transport. GLUT5 is found

in gut, liver a nd spermat ozoa, and is thought to function primarily a s a fructose tra nsporter. G LU T6

is thought to be a non-functional pseudogene. GLUT7 is an intracellular liver protein responsible for

glucose-6-phosphat e tra nsport in to th e endopla smic reticulum.

In contrast to the passive transport mediated by GLUT gene products, the kidney and intestine

contain active (energy dependent) glucose pumps that catalyze the transport of glucose against a

concentration gradient. These pump proteins are responsible for the absorption of glucose from the

diet and the reabsorption of glucose in the kidney.

The kidney is very efficient under normal conditions; however, at plasma glucose concentrations

a bove about 180 mg/dL, t he kidney pump becomes sa tur a ted. G lucose from concentra tions a bove 180

mg/dL th erefore ends up in t he urin e.

Insulin Action in Target Tissues

The liver is the main site of action of the pancreatic hormones. Because blood flowfrom the pancreas proceeds directly to the liver, and because the liver is the majorsite of ina ctiva tion of most peptide hormones, th e liver is exposed t o higher levels ofpancreat ic hormones tha n a ny other t issue.

In liver, insulin stimulates glycogen synthesis and inhibits glycogen breakdown. Italso stimulates glycolysis and inhibits gluconeogenesis. In addition to its effects on

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glucose metabolism, insulin has a variety of anabolic actions in the liver,stimulating lipid synthesis and release and protein synthesis, and inhibiting thebrea kdown of th ese compound s.

The liver has some ability to respond directly to high levels of plasma glucose byincreasing glucose uptake and glycogen synthesis in an insulin-independent

manner; however, the majority of liver glucose regulatory functions require insulina ction. The liver h a s a bout 300,000 insulin receptors per cell (a very la rge n umber),but experiences maximal response to insulin when a small fraction of the receptorsare occupied; this allows the organ to respond to insulin even when the plasmainsulin concentr a tion is less th a n t he Kdfor the receptor.

In muscle, insulin stimula tes a mino acid upta ke and protein synt hesis, and glucoseuptake and incorporation into glycogen. The muscle plays an important role ina bsorbin g th e ma jorit y (80-95%) of sudden in crea ses in pla sm a glucose levels, suchas those observed during a rich carbohydrate meal. The muscle expressessignificant amounts of the GLUT4 glucose transporter, which, upon insulinstimulation, is translocated to the plasma membrane (see Figure 6), allowing amassive increase in glucose uptake. During exercise the muscle becomes moresensitive to insulin action and therefore retains the ability to import glucose fromcirculat ion in s pite of th e exercise-induced reduction in insulin levels.

Insulin stimulates glucose uptake into adipose tissue, and has three major actionswhich result in net fat deposition: 1) insulin increases the amount of lipoproteinlipase, an enzyme that mediates release of free fatty acids from circulatinglipoproteins; 2) insulin stimulates synthesis of glycerol-phosphate (required fortriacylglycerol synthesis) from glucose; and 3) insulin inhibits hormone-sensitivelipase, the enzym e responsible for t he first st ep in tr ia cylglycerol breakdow n.

The brain does not depend on insulin for glucose uptake, and insulin probably doesnot ha ve a direct meta bolic role in th e CNS . However, some evidence suggests th a tinsulin may act as a behavioral modulator, with high levels of insulin promotingdecreased food intake, and low levels acting as a caloric deprivation signal. Sincethese behaviors are extremely complex and therefore difficult to measureaccurately, and since insulin is only one of many hormones and other stimuli thata ffect feeding beha vior, the role of insulin in th e CNS is poorly underst ood.

The insulin resistance resulting from glucocorticoid action is also observed in theCNS. Individuals with low glucocorticoid levels generally have difficulty gainingweight; this may in part be due to the increased sensitivity to insulin (andconseq uent decrea sed feeding impulse) resulting fr om th e low glucocort icoid a ction.

Diabetics (in particular Type II diabetics) often exhibit significant weight gain inspite of restoration of insulin action; however, this is probably largely due tonorma lizat ion of meta bolism a nd prevention of glucose loss in th e urine.

Glucagon

The other major regulatory hormone of the pancreas is glucagon, a 29 amino acidpeptide synthesized as part of a 160 amino acid precursor. This precursor alsocontains several other peptide hormones: glucagon-like peptide-1 (GLP-1), glucagon-

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like peptide-2 (GLP-2), and glicentin-related peptide. In the intestine, glucagon isnot separated from glicentin-related peptide, resulting in a peptide called glicentin.G LP -1 ma y be furt her processed to a s horter form G LP -1[7-37], w hich (unlike G LP -1 its elf) is a pow erful stimu la tor of insulin release.

In serum samples, the glucagon RIA actually measures a mixture of proglucagon,

glicentin, G LP -1, and G LP -2 as w ell a s glucagon; glucagon normally comprises only30-40%of th e imm unorea ctive ma teria l meas ured.

Release of glucagon from the -cells is stimulated by low plasma glucose and bycatecholamines and glucocorticoids. Release of glucagon is inhibited by insulin andsomatostatin. Release of glucagon is also inhibited by glucose; it is not knownwhether this is a direct effect of glucose on the -cell, or an indirect consequence ofeleva ted insu lin levels.

Glucagon has actions opposite to those of insulin, and therefore functions tomaintain plasma glucose levels between meals. However, unlike insulin, glucagona ction is proba bly limited to the liver, with limited effects in oth er tissues. G lucagon

stimulates liver amino acid uptake, gluconeogenesis, and glucose release, andinhibits glycolysis and fa tt y a cid synth esis.

The glucagon receptor is coupled to adenylyl cyclase, and glucagon actions aremediated by elevation in cAMP levels. In general, actions of glucagon are mediatedby increased phosphorylation of existing enzymes. Prolonged stimulation byglucagon may have some effects on gene transcription, usually in the oppositedirection from that of insulin. If the insulin:glucagon ratio is low for a prolongedperiod (i .e. several days), an alteration in liver enzyme levels occurs, which causesincreased production of ketone bodies.

Somatostatin

Somatostatin is released from the -cells under control of the same stimuli thatresult in insulin release. Somatostatin is thought to act primarily as a paracrineregulator of insulin release, preventing insulin levels from rising too rapidly. It mayalso have an endocrine role as an inhibitor of nutrient absorption in the gut,although this is not completely established. The somatostatin in circulation isthought to be derived from the pancreas, and not from the hypothalamus (whichproduces this peptide in order t o inhibit gr owt h hormone relea se from t he pituita ry).

Somatostatin is produced as part of a larger precursor. Pre-prosomatostatin (116a mino acids) is cleaved t o release t he 28 amino a cid prosoma tosta tin upon tra nsportinto th e endoplasmic reticulum. The 14 amino a cid ma ture soma tosta tin is relea sedfrom prosoma tosta tin by t he dibasic processing protease system.

The Islet of Langerhans

One important regulator of pancreatic hormone release is the paracrine signalingthat occurs within the islets. Insulin inhibits its own release, and also inhibits therelease of glucagon. Glucagon inhibits its own release, and stimulates insulinrelease. Somatostatin inhibits the release of both insulin and glucagon. The local

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changes in hormone levels act as a primary negative feedback mechanism toprevent excessive changes in pancreatic hormone levels. This is illustrated by theeffects of untreated Type I diabetes mellitus, in which the loss of insulin inhibitionof glucagon secretion results in overproduction of glucagon; the high levels ofglucagon in the absence of insulin action throughout the body result in the severemeta bolic cha nges of dia betic ketoa cidosis (see Cha pter 6).

Counter-regulatory Hormones

Glucagon (discussed above), the catecholamines epinephrine and norepinephrine,glucocorticoids, and growth hormone all act to raise plasma glucose levels. Theiractions generally oppose those of insulin, and as a group, they are called counter-regulatory hormones. Due to the dependence of the brain on plasma glucose forenergy, hypoglycemia can rapidly result in unconsciousness, brain damage, anddeat h; t he counter-regulatory hormones a ct to prevent hypoglycemia. I t is th oughtthat the variety of systems that oppose insulin action are in part a safetymechanism to prevent hypoglycemia; the influence of a variety of systems onglucose homeosta sis a lso reflects t he cent ra l import a nce of glucose in meta bolism.

Epinephrine is released by the adrenal medulla in response to hypoglycemia (aswell as other stress stimuli), and as part of the preparation for exercise.Norepinephrine is released from sympathetic neurons. Both catecholamines havesignificant roles in maintaining glucose levels in exercise (especially in supportingth e ma ssive increa se in glucose use by the mus cle), a nd in s tr ess-relat ed conditions.Catecholamines stimulate glucagon release and inhibit insulin release, causing adecrease in insulin:glucagon ratio and therefore having indirect effects on liverglucose metabolism. Epinephrine also has direct effects in stimulating livergluconeogenesis, muscle glycolysis, and glycogen breakdown in both tissues. (Note

that glycolysis regulation by epinephrine is different in liver (inhibited) and muscle(stimulated); this is due in part to the presence of different isozymes of pyruvatekinase in the two tissues.) Catecholamine action is covered in more detail inCha pter 4.

Glucocorticoids (primarily cortisol in humans) are released from the adrenal cortexin response to stress; one such stress is a decrease in plasma glucose.Glucocorticoids stimulate gluconeogenesis and glycogen synthesis in the liver, andreduce muscle and adipose tissue glucose uptake. They also acutely inhibit insulinrelease, and over longer term, insulin action; prolonged cortisol hypersecretion canresult in diabetes. Glucocorticoid synthesis, release, and action are covered in moredeta il in Ch a pters 2 a nd 3.

Growth hormone is released in response to falling plasma glucose levels. Theactions of growth hormone related to increases in plasma glucose are poorlyunderstood. The only established actions of growth hormone in this regard are astimulation of lipolysis and an inhibition of insulin action. In acromegaly, theoverproduction of grow th hormone ca n lead t o dia betes.

The effect of the meta bolic regula tory h ormones is summa rized in Ta ble I.

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Table I.Hormonal Regulation of Metabolism

Insulin Glucagon Epinephrine Cortisol GrowthHormone

LiverG lycogen breakdown G lycogen syn thesis

Gluconeogenesis Glycolysis

G lucose relea se G lucose upta ke

G lucagon receptor

Skeletal MuscleG lycogen breakdown G lycogen syn thesis

Glycolysis

G lucose upta ke

P rotein cata bolism

Amino acid uptake Amino a cid releas e

Adipose TissueLipolysis

G lucose upta ke

PancreasInsulin relea se

G luca gon release

Systemic EffectsInsulin a ction *

*Note: Insulin obviously has insulin actions, hence the ; however, prolonged high levels of insu lindecrease th e insulin response in t arget t issues.

Note: epinephrine effects on muscle glycolysis are relatively small except during exercise. Glucoseuptake in muscle is stimulated by exercise, but is probably not directly affected by epinephrine.

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Effect of Food Ingestion on Pancreatic Hormone Release

The pancreas alters its release of insulin and glucagon in response to changes inpla sma glucose an d other circulat ing nut rients. One ma jor cause of these changes iseating. The response to a meal varies significantly depending on the composition ofthe food.

Intravenous infusion of glucose elicits a smaller rise in insulin release than doesoral administration of an equivalent amount of glucose. The greater increase ininsulin levels caused by actually eating is thought to be due to gastrointestinalpeptide hormones. These peptides are released in response to food absorption andpotent ia te t he glucose effect on insulin r elea se.

When eat ing a meal r ich in ca rbohydra te, insulin levels rise a nd glucagon levels fall .The decrease of glucagon is due to inhibition of its release by insulin, and to theelevation in plasma glucose.

When eating a meal rich in protein, insulin levels rise, because insulin secretion is

stimulated by amino acids. Glucagon levels also rise; glucagon release is alsostimulated by amino acids. In this case, unopposed insulin action would result inhypoglycemia, since little glucose is being absorbed; glucagon must increase tomaintain plasma glucose.

When eating a mixed meal, insulin levels rise, and glucagon levels rise, fall, orremain unchanged as appropriate to maintain plasma glucose. The pancreas usesits a bility t o monitor th e influx of nutrients, supplemented by signals in the form ofintestinal peptide hormones, to regulate the disposal of the nutrients withoutallowing an undue change in plasma glucose (glucose levels usually rise to theupper limit of th e norma l ra nge, ~ 120 mg/dL, but litt le further). Mimicking th istailored change in pancreatic hormone release is difficult to achieve by injections ofinsulin, an d explains part of th e problem fa ced by individuals w ith Type I dia betes.

References

Bliss (1982) The Di scover y of I nsul in. Un iversity of Chicago Pr ess, Chicago.

P hillipe (1991) St ructur e and pan creat ic expression of the insulin a nd gluca gon genes. En docr. Rev.

12: 252-271.

Schwar t z et a l. (1992) Insulin in the brain: a hormonal regulator of energy balance. En docr. Rev.

13: 387-414.

Stryer (1995) Chapter 30: Integration of Metabolism. Biochemistry, 4th ed. W.H. Freeman &Company, New York.

Chea tha m & Ka hn (1995) Insulin a ction a nd t he insulin signaling netw ork. En docr. Rev. 16: 117-142.

St ephens & P ilch (1995) The meta bolic regulat ion an d vesicular t ra nsport of G LU T4, the ma jor

insulin-responsive glucose tr a nsporter. En docr . Rev. 16: 529-546.

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Chapter 5 Glucose homeostasis