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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