05.17 Metabolic Effects of Insulin and Glucagon_W2016-2

7/25/2019 05.17 Metabolic Effects of Insulin and Glucagon_W2016-2

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Metabolic effects of insulin and glucag


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Learning objectivesOn completion of the study of this topic the students should be able to;

Explain the structure of insulin in order to recognize the peptide chains, total numacids present and disulfide bridges

Outline the synthesis of pre-proinsulin, proinsulin and insulin in the pancreatic be Evaluate the clinical importance of estimation of C peptide to assess the insulin

ifferentiate the factors that stimulate and inhibit insulin secretion

Outline the se!uence of mechanisms by "hich glucose stimulates insulin secreti

#llustrate the orientation of insulin receptor in the target cell membranes$ %ecognbinding site and site of autophosphorylation in the insulin receptor

Outline the mechanism of action of insulin emphasizing the role of insulin receptoreceptor substrates %'(

%elate the influence of insulin on transport of glucose into the muscle and adipos

Evaluate the regulatory effects of insulin on) *lycolysis, *lycogen metabolism, *+entose phosphate path"ay, atty acid biosynthesis, .* synthesis, /ipolysis &b.* in adipose tissues and amino acid metabolism$ .pply this 0no"ledge to pred

metabolic derangements in insulin deficiency


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Metabolic integration bet"een major tissues

1etabolism in ma2or tissues- does 3O

occur in isolation Exchange of substrates bet"een tissues #nsulin 4 glucagon play 0ey roles


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S S

7 11

6

7

S

S

2

0

1

9

S

S

. Chain

5 C

#tructure of insulin

+olypeptide hormone

'ecreted by 6-cells of islets of /angerhans in the endocrine pa

Consists of t"o polypeptide chains . 4 5 connected by disulf

bridges

. chain- 78 amino acids, 5 chain- 9: amino acids


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Biosy

insuli


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Biosynthesis of insulin

C$peptide Essential for proper insulin folding %eleased along "ith insulin into circulation alf-life in plasma is longer than that of insulin . good indicator of insulin production 4 secretion, can be mea

plasma to assess endogenous insulin secretion


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Regulation of insulin secretion#timulation of insulin secretion

a$ *lucose) glucagon-li0e protein-8 &*/+-8(, gastric

inhibitory polypeptide &*#+(, < sensitivity of -cells to glucose

*# hormones- released from small intestine afteringestion of food

Cause an anticipatory rise in insulin levels


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McGrawHill Education:Integrative Medical Biochemistry Examination and Board Review, Michael King

*lucose in blood? en

cells &*/@-7( ? glyc

increase in.+? inh

.+ dependent AB ch&channel is closed for

? depolarization ? a

voltage gated calcium

Entry of calciuminto

increase in intracellulausion of insulin conta

exocytotic vesicles "it

membrane ? %nsulin

&lucose$stimulated secretion of insulin

'ulfonylureas

GK

GLP-1, GIP

[Ca2+]

'


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%nhibition of insulin secretion

#nsulin synthesis 4 release decreases due to

'carcity of dietary fuels

'tress &eg) vigorous exercise, infections(

1ediated by epinephrine&released from adrenal med

Causes mobilization of glucose from liver &glycogenoly

fatty acids from adipose tissue &lipolysis(

Overrides the normal glucose-stimulated release of ins


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%nsulin receptor mechanism of action 1embrane-bound

receptor

"o subunits

&extracellular(, t"o 6subunits span themembrane; connectedby disulfide bridges

subunits bindinsulin

6 subunits haveintrinsic tyrosine0inase activity, containautophosphorylationsites


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5inding of insulin to subunits activates tyrosine0inase activity phosphorylation of tyrosineresidues of 6 subunits

#nitiates a cascade of cell-signaling responses

+hosphorylation of insulinreceptor substrates %'(

#%' interact "ith othersignaling molecules, bringingabout biological effects ofinsulin

#nsulin actions terminated bydephosphorylation of receptor

%nsulin receptor mechanism of action


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Metabolic effects of insulin

#nsulin has anabolic effects on

8$ Carbohydrate metabolism

7$ /ipid metabolism9$ +rotein metabolism

%nsulin and cellular glucose upta)e

$#nsulin promotes glucose upta0e by cells, its utilization and

$#ncreases transport of glucose into s0eletal 4 cardiac musadipose tissue

$#ncreases the number of glucose transporters on the memthese cells &*/@-D(


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%nsulin$mediated recruitment of glucose transporters (

to the cell membrane


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%nsulin

&lucose upta)e

(adipose- muscle!

.

&lycolysis

.

&lycogenesis

(liver- muscle!.

&luconeogenesi'

&lycogenolys'

/M0 shunt

(liver!.

Lipogenesis(liver- adipose!

.

Lipolysis (adip'

*pta)e of amino acids

protein synthesis (most

tissues!

.

0rotein degradation (m

'

Metabolic effects of

insulin (hypoglycemic!


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#nsulin plasma half-life F minutes

#nsulin bound to receptor is internalized, insulin degradeinsulin-degrading enzyme &liver, 0idney(

%eceptors may be degraded or recycled to the cell surfa+ime course of insulin actions

glucose upta0e &"ithin seconds(

dephosphorylation of 0ey enzymes &minutes to hrs(

increase in amount of 0ey enzymes &induction; hrs to da

&l


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&lucagon 7G a$a polypeptide secreted by

pancreas

'ynthesized as preproglucagon,

glucagon by proteolysisRegulation of glucagon secretio

'timulated by

/o" plasma glucose &primary sti

.mino acids &eg) arginine( from a

Epinephrine &from adrenal medu

norepinephrine &sympathetic ner

&lucagon secretion inhibited by Elevated blood glucose and insulin &follo"ing a carbohydrate-

meal(


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Mechanism of action of

glucagon (through &$protein

coupled receptor!


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&lucagon

&lycolysis.

&lycogenesis

(liver!

.

&luconeogenesi

&lycogenolys

'

1atty acid synthesis(liver! .

Lipolysis (adip

effect

'

*pta)e of amino acids by liver for

gluconeogenesis

.

Metabolic effects of glucagon (hyperglycem

'

.

Beta oidation of 1

)etogenesis (liver!

% li d l t h i bl d l


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%nsulin and glucagon response to changes in blood glu


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/ormones involved in blood glucose regulatio

ypoglycemic hormone)decreases blood glucose level

%nsulin

3ormal fasting blood glucose level) F:-8:: mgHdl

yperglycemic horincrease blood gluc &lucagon 4pinephrine Cortisol &ro"th hormon

3C+/


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%nfluence of other hyperglycemic hormones on blood

level

Epinephrine decreases glycogenesis 4 increases glycogenoly

Cortisol increases gluconeogenesis 4 decreases glucose utilizextrahepatic tissues

*ro"th hormone decreases glucose upta0e and utilization by

.C increases cortisol synthesis 4 secretion

5et effect: raising of blood glucose level

*lucagon, catecholamines, cortisol 4 * called counterregulat

hormones


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/ypoglycemia

/o"er than normal blood glucose level

Iery critical if blood glucose falls belo" D: mgHd/

#s a medical emergency &brain re!uires glucose supply frfor its energy metabolism(

#f transient, can cause cerebral dysfunction

#f severe 4 prolonged, can cause brain death

1ultiple mechanisms exist for prevention of or correction

hypoglycemia


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#ymptoms of hypoglycemia

.drenergic symptoms &mediated

by release of catecholamines(

3euroglycopenia symp

by impaired delivery ofthe brainanxietypalpitationtremors"eating

headacheconfusionslurred speech

seizurescoma 4 death

.drenergic symptoms occur "hen blood glucose drops abrup 3euroglycopenic symptoms result from a gradual decline in b

glucose &belo" D: mgHd/(

&lucoregulatory systems activated by hypoglyce


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&lucoregulatory systems activated by hypoglyce

#n response ypothal

glucorec

release o&by .3'(

by anteri +ancreat

release g hese ho

the hypo

+ypes of hypoglycemia


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+ypes of hypoglycemia

8$ #nsulin-induced hypoglycemia

#n diabetic patients on insulin treatment

7$ +ost-prandial hypoglycemiaCaused by an exaggerated insulin release after a meal

9$ asting hypoglycemia) symptoms appear at night or ear

$ /iver damage

$ .drenal insufficiency$ .lcohol-induced &refer gluconeogenesis(

$ #nsulinoma &insulin secreting tumors(

$ #nborn errors of metabolism


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/ypoglycemia in infants

Convulsions, tremors, attac0s of apnea

#nfants born to diabetic mothers

#ntrauterine malnutrition, prematurity

*lycogen storage disorders &Eg) Ion *ier0e>s(

ereditary fructose intolerance

.drenal insufficiency, hypopituitarismisorders of 6-oxidation &Carnitine deficiency, C+

deficiency, 1C. deficiency(

Concept map for


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Concept map for

metabolic effects

of insulin

glucagon

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05.17 Metabolic Effects of Insulin and Glucagon_W2016-2