11. Integration of Metabolism New Version 1

8/21/2019 11. Integration of Metabolism New Version 1

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INTEGRATION OF METABOLISM

Questions:

1. What is normal loo! su"ar le#el$ %es&rie the me&hanisms an! 'a&tors

that re"ulate loo! su"ar le#el. A!! a note on insulin !e(&ien&). * A+ril

,-. What is normal loo! "lu&ose le#el$ Write in !etail aout its re"ulation.*

Mar&h //0. Write in !etail aout "lu&ose haemostasis in the human or"anism an!

a!! a note on its iome!i&al im+ortan&e. * O&t //0. What are the normal 'astin" an! +ost +ran!ial loo! "lu&ose le#els$

E2+lain ho3 normal loo! "lu&ose le#el is maintaine!. A!! a note on the

!isru+tion o' hormonal re"ulation o' Bloo! "lu&ose. * Au" //44. Short notes: Inter+retation o' "lu&ose toleran&e test. *O&t 1,,-

1. The human body functions as one community. Communication between tissues is

mediated by the nervous system, by the availability of circulating substrates and by

variation in the levels of plasma hormones.

2. The integration of energy metabolism is controlled primarily by the action of

hormones, including insulin, glucagon and catecholamines (epinephrine and norepinephrine.

0. The four ma!or organs important in fuel metabolism are liver, adipose tissue mus&le

an! rain.

REG5LATION OF BLOO% GL56OSE

1. Normal #alues:1. "asting plasma glucose levels# 70$110 mg%dl2. &ost prandial# ' 10 mg%dl). &lasma value is slightly higher than whole blood glucose because of *+Cs

with less water. rine contains no glucose up to plasma level of 1-0 mg%dl this is called renal

threshold. Re"ulation o' loo! "lu&ose:

1. "actors maintaining entry of glucose into blood#1. /bsorption from intestines2. lycogenolysis). luconeogenesis. lucagon. teroid

2. "actors causing depletion#1. Tissue utili3ation2. lycogen synthesis

). lucose converted to fat. 4nsulin

). &ost prandial regulation#1. /fter a meal blood glucose level increases which stimulates insulin secretion

by beta cells of pancreas2. 4nsulin facilitates entry of glucose to cells e5cept brain for utili3ation). 4nsulin helps conversion of e5tra glucose to glycogen and fat

. *egulation of fasting state#1. "asting levels are maintained by hepatic glycogenolysis for ) hrs2. luconeogenesis if fasting continues


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). lucagon, epinephrine, glucocorticoids, growth hormone, /CT6, and Thyro5in

act as hyperglycaemic hormones.. 6ormone regulations#

1. 4nsulin# hypoglycaemic1. lowers blood glucose2. favours glycogenesis). promotes lycolysis

. inhibits luconeogenesis2. lucagon# hyperglycaemic

1. 4ncreases blood glucose2. 4ncreases luconeogenesis). &romotes glycogenolysis. decreases glycogenesis. inhibits lycolysis. releases amino acid form muscles

). Cortisol# hyperglycaemic1. 4ncreases blood glucose2. 4ncreases luconeogenesis). releases amino acid form muscles

. 8pinephrine (/drenalin# hyperglycaemic

1. 4ncreases blood glucose2. 4ncreases luconeogenesis). &romotes glycogenolysis. releases upta9e of aminoacids

. rowth hormone# hyperglycaemic1. 4ncreases blood glucose2. inhibits lycolysis). mobili3es fatty acids from adipose tissue

. :isruption of hormone control#6yperglycaemia (:iabetes mellitus

1. ;etabolic disease due to absolute or relative de this is due to defectiveluco9inase and increase in threshold for glucose induced insulin secretion

. 8ndocrine# ome tumours can produce counter$regulatory hormones that

oppose the action of insulin or inhibit insulin secretion. These counter$

regulatory hormones are glucagon, epinephrine, growth hormone and cortisol.

8.g. Cushing?s disease thyroto5icosis acromegaly. :rug induced# steroids beta bloc9ers. &ancreatic disease#

7. &ancreatic disease# &ancreatectomy leads to the clearest e5ample of

secondary diabetes. Cystic


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6auses:

1. &ost prandial# due to reactive insulin secretion

2. "asting#

). 4nsulin$induced hypoglycaemia

1. 4nsulin in!ected for diabetes

2. "actitious insulin in!ection (;unchausen syndrome). 85cessive eAects of oral diabetes drugs, beta$bloc9ers, or drug

interactions

. 4nsulin$secreting pancreatic tumour

. /lcohol induced hypoglycaemia often lin9ed with 9etoacidosis

. /limentary (rapid !e!unal emptying with e5aggerated insulin

response /fter gastrectomy dumping syndrome or bowel bypass

surgery or resection

. /cBuired adrenal insuciency

7. /cBuired hypopituitarism

-. :etermination glucose#1. lucose o5idase method#

1. 4t converts glucose to gluconic acid and hydrogen pero5ide.&ero5idase converts 62=2 into 62= and nascent = which o5idise the

substrate into coloured substrate. The intensity of colour will give the

concentration of glucose.2. The above reagent mi5ture can also be mounted on a plastic


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(active phosphorylated forms are glycogen phosphorylase, fructose bisphosphate

phosphatase and hormone$sensitive lipase of adipose tissue. Covalent modi


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proteins. The liver has limited capacity to degrade the branched$chain amino

acids (leucine, isoleucine, and valine which are metaboli3ed in the muscle

A%I STORAGE %E


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0. Fat Metaolism: "atty acids are of secondary importance as a fuel for muscle in

the well$ fed state in which glucose is the primary source of energy.

. Amino A&i! Metaolism:

1. In&rease! +rotein s)nthesis# /n increase in amino acid upta9e and protein

synthesis occurs in the absorptive period after ingestion of a meal containing

protein ( stimulated by insulin.

. In&rease! u+ta@e o' ran&he!*&hain amino a&i!s: ;uscle is the principal sitefor degradation of branched$chain amino acids. Geucine, isoleucine, and valine are

ta9en up by muscle, where they are used for protein synthesis and as sources of

energy

BRAIN

/lthough forming only 2I of the adult weight, the brain accounts for 20I of the basal o5ygen

consumption of the body at rest. The brain uses energy at a constant rate. Formally, glucose

its primary fuel to the brain, because in the fed state the concentration of 9etone bodies is too

low to be an energy source. 4f the blood glucose levels fall below appro5imately )0 mg %dl

(normal blood glucose is 70$@0 mg%dl cerebral function is impaired.

/. 6aroh)!rate Metaolism: 4n the well$fed state, the brain uses glucose e5clusively as a

fuel, completely o5idi3ing about 10 g % day glucose to carbon dio5ide and water. The

brain contains no stores of glycogen, and is therefore completely dependent on the

availability of blood glucose.

+. Fat Metaolism: The brain has no signi


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fasting. Thus hepatic glyconeolysis is a transient response to early

fasting. /dultLs liver contains 100 g of glycogen in the well $fed state.

iii. In&reaase! Glu&oneo"ensis: gluconeogensis begins E hours after

the last meal and becomes fully active as liver glycogen stores are

depleted. luconeogenesis plays an essential role in maintaining blood

glucose during both overnight and prolonged fasting. The main sources

for gluconeogenesis are amino acids, glycerol and lactate.. Fat Metaolism:

i. In&rease! 'att) a&i! o2i!ation: The o5idation of fatty acids derived

from adipose tissue is the ma!or source of energy in hepatic tissue in the

post absorptive state.

ii. In&rease! S)nthesis o' ?etone o!ies: The availability of circulating

9etone bodies is important in fasting because they can be used as fuel

by most tissues including brain, once their level in blood is suciently

high. This reduces the need for gluconeogenesis from amino acids, thus

slowing the loss of essential protein. Ketone body synthesi3e is favored

when the concentration of acetyl Co/, produced from fatty acid

o5idation e5ceeds the o5idative capacity of the tricarbo5ylic acid (TC/

cycle. nli9e fatty acids Ketone bodies are water Esoluble, and appear

in the blood and urine by the second day of a fast.

8. A!i+ose Tissue in Fastin":

a. 6aroh)!rate Metaolism: lucose transport into the adipocyte and its

metabolism are depressed due to low levels of blood insulin .This leads to a

decrease in fatty acid and triacyl$ glycerol synthesis.

. Fat Metaolism:

i. In&rease! !e"ra!ation o' tria&l)"l)&erols# The activation of

hormone E sensitive lipase and subseBuent hydrolysis of stored

triacylglycerol are stimulated by high levels of catecoholamines

(epinephrine and particularly norepinephrine.

ii. In&rease! release o' 'att) a&i!s: "atty acids resulting from thehydrolysis of stored triacylglycerol are released into the blood. +ound to

albumin, they are transported to other tissues for use as fuel. &art of the

fatty acids is o5idi3ed in the adipose tissue to produce energy. The

glycerol produced from triacylglycerol degradation is used by the liver

for gluconeogenesis.

iii. %e&rease! u+ta@e o' 'att) a&i!: 4n fasting, lipoprotein lipase activity

of adipose tissue is low. Thus, circulating triacylglycerol of lipoproteins is

not available for triacylglycerol synthesis in adipose tissue.

". Restin" S@eletal Mus&le in Fastin":

a. *esting muscle uses fatty acids as its ma!or fuel source. +y contrast, e5ercising

muscle initially uses its glycogen stores as a source of energy. :uring intense

e5ercise, glucose $$phosphate derived from glycogen is converted to lactate

by anaerobic glycolysis. /s these glycogen reserves are depleted, free fatty

acids provided by the mobili3ation of triacylglycerol from adipose tissue

become the ma!or sources.

b. Carbohydrate ;etabolism# lucose transport and subseBuent glucose

metabolism are depressed because of low blood insulin.

c. Fat Metaolism: :uring the


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only fatty acids. This leads to a further increase in the already elevated levesl

of blood 9etone bodies.

d.


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b. 4mpaired glucose tolerancec. 4mpaired fasting glycaemia

. econdary to other causes#a. 8ndocrine# Cushing?s disease thyroto5icosis acromegalyb. :rug induced# steroids beta bloc9ersc. &ancreatic disease# chronic pancreatitis calculus pancreas hemochromatosis

cystic


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iii. /therosclerosis and microangiopathyiv. Cataract and retinopathyv. &eripheral neuropathy

@. Gab tests#1. +lood and urinary glucose monitoring2. Gipid pro


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a. tarvation, e5ercise, liver disease, hyperthyroidism and hypothyroidism

the results will be abnormal

b. Crticosteroid stressed test# this could unmas9 the prediabetic state

Re!u&in" sustan&e in urine: - drops of urine in ml of +enedict?reagent boiled for 2

minutes

4nterpretation# 0.I green 1 I yellow 1.I orange 2 I red

&ositive +enedict?s test#1. ugars#

1. lucose2. "ructose). Gactose. alactose. &entose

. Fon sugar reductants#1. lucuronides2. alicylates). /scorbic acid. 6omogentesic acid

Gl)&ate! 7: ;"l)&os)late! 7B=:1. 4n hyperglycaemia glucose is added to proteins in body called glycation2. lycated haemoglobin in *+C is called 6+/1). 6b/1c forms -0I of the total 6b/1 molecules. 6b/1c estimation gives information about long term glycemic control (10$12

wee9s. Formal Halue of 6b/1c is $7I in diabetes it goes up to -$1I

lycated albumin# this is called fructosamino albumin estimation will give information of

glycemic control for the past 2$) wee9s

Mana"ement:

a. :ietb. 85ercisec. =ral hypoglycaemic agents# sulphonyl urea and biguanidesd. 4nsulin

6ypoglycaemia# &roves fatal

a. '0 mg%dl is hypoglycaemiab. Cause#

i. insulin or other drug overdoseii. post prandial hypoglycaemiaiii. 4nsulin secreting tumoursiv. Hon ier9e?s disease

INS5LIN

Questions:1. What is the normal loo! su"ar le#el$ %es&rie the me&hanisms an!

'a&tors that re"ulate loo! su"ar le#el. A!! a note on insulin !e(&ien&).

A+ril 1,,-. Short notes: stru&ture an! 'un&tion o' human insulin. Se+ // Fe

//Fe //0. %es&rie the io&hemi&al a&tions o' insulin in &aroh)!rateD li+i! an!

+rotein metaolism. Name the !isor!er asso&iate! 3ith insulin

!e(&ien&). 7o3 !o )ou &on(rm the !ia"nosis$ A+ril //1


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4nsulin is a polypeptide hormone produced by the +$cells of the islets of Gangerhans of

the pancreas. 4nsulin is one of the most important hormones coordinating the

utili3ation of fuels by tissues. 4ts metabolic eAects are anabolic stimulating the

synthesis of glycogen (glycogensis, triacylglycerols (lipogenesis and protein.

Stru&ture:

1. 4t is a protein hormone with 2 polypeptide chains / chain with 21 aminoacidsand + chain with )0 aminoacids

2. Two chains lin9ed by disulphide bonds between /7 to +7 and /20 to + 1@). There is an intrachain disulphide lin9 in / chain between and 11 aminoacids. pecies variation is restricted to aminoacids @,@ and 10 of / chain and C terminal

of + chainBios)nthesis o' Insulin:

1. 4nsulin is a polypeptide hormone of 1 amino acids that is composed of two

polypeptide chains. 4t is synthesi3ed as a single polypeptide chain but is cleaved

in three places before secretion to form the C$peptide and the active insulin

molecule containing the / and + chains.

2. 4nsulin is


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2. Glu&ose: ingestion of glucose or a carbohydrate rich meal leads to a rise in blood

glucose which stimulates insulin secretion. lucose is the most important

stimulus for insulin secretion. /s blood glucose level increases, the insulin

secretion also correspondingly increases. lucose induces a biphasic response to

insulin secretion. / discharge of insulin from the beta cell storage pool occurs

during the initial rapid phase of insulin release within


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a. 8levated levels of insulin increase the degradation of receptors, thus

decreasing the number of surface receptors. This is one type of down

regulation.

b. Time &ourse o' insulin a&tions: /fter insulin binding to the receptors

the responses will be#

i. 4ncrease glucose transport (seconds.

ii. Change in en3yme activity (change in phosphorylation statesminutes to hours

iii. 4ncrease in the amount of en3ymes e.g gluco9inase,

phosphofructo9inase, and pyruvate 9inase (hours to days this

means increase protein synthesis

. 4nsulin activates en3ymes li9e lycogen synthase, pyruvate 9inase, etc by

covalent modi


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c-peptide

1. 4nsulin is a polypeptide hormone of 1 amino acids that is composed of two

polypeptide chains. 4t is synthesi3ed as a single polypeptide chain but is

cleaved in three places before secretion to form the C$peptide and the active

insulin molecule containing the / and + chains. The / chain has 21 amino

acids and + chain has )0 amino acids. These two chains are !oined together

by two disulphide bonds.2. 4nsulin is


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i. Lo3 loo! "lu&ose: hypoglycemia is the primary stimulus for

glucagon secretion.

ii. Amino a&i!s: stimulate the secretion of both glucagon and insulin.

iii. E+ine+hrine an! nore+ine+hrine: stimulate glucagon secretion

(during stress, trauma or severe e5ercise

0. Inhiition o' "lu&a"on se&retion: lucagon secretion is mar9edly decreased by

elevated blood sugar and by insulin (carbohydrate$rich meal.. Metaoli& E9e&ts o' Glu&a"on:

1. 8Aects on carbohydrate metabolism# The most important action of glucagon

is to maintain blood glucose levels by stimulation of hepatic glycogenolysis

and gluconeogenesis

. 8Aects on lipid metabolism# lucagon stimulates hepatic o5idation of fatty

acids and formation of 9etone bodies. The lipolytic eAect of glucagon in

adipose tissue is minimal in humans

0. 8Aects on protein metabolism# lucagon increases the upta9e of amino acids

by the liver for gluconeogenesis

4. Me&hanism o' a&tion o' "lu&a"on :

1. lucagon binds to high$anity receptors on the cell membrane of the

hepatocyte S activation of adenylate cyclase in the plasma membraneS

increase c/;& (second messenger.

. c/;& activates protein 9inase and increases the phosphorylation of speci6EMIA

1. 6ypoglycemia is characteri3ed by#

a. Central nervous system symptoms, including confusion, aberrant behavior, or

coma

b. / simultaneous blood glucose level eBual to or less than 0 mg%dl and

c. ymptoms being corrected within minutes following the administration ofglucose. 6ypoglycemia is a medical emergency

2. The central nervous system has an absolute need for a continuous supply of blood

glucose as a fuel for energy metabolism. Transient hypoglycemia can causes

cerebral dysfunction, but severe, prolonged hypoglycemia causes brain death. The

most important hormonal changes to correct hypoglycemia are elevated glucagon

and epinephrine combined with decrease insulin secretion.

). S)m+toms o' h)+o"l)&emia: The symptoms of hypoglycemia can be divided to

two groups,

a. A!rener"i& s)m+toms: /n5iety, palpitation, tremor, and sweat. These

symptoms are due to increased epinephrine secretion regulated by the

hypothalamus due to hypoglycemia. These symptoms occur when the blood

glucose levels fall rapidly.

b. Feuroglypenic ymptoms# The decrease glucose supply to the brain leads to

brain dysfunction causing headache, confusion, slurred speech, sei3ures,

coma and death. These symptoms result from a gradual decrease in blood

glucose.

. Glu&ore"ulator) S)stems: 6umans have two overlapping glucose$regulating

systems that are activated by hypoglycemia#

a. The islets of Gangerhans, which secrete glucagon


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b. The glucoreceptors in the hypothalamus stimulate the secretion of both

epinephrine (through the autonomic nervous system and /CT6 and growth

hormone (6 by the anterior pituitary gland. lucagon, epinephrine, cortisol

and 6 are called the counterregulatory hormones because they antagoni3e

the action of insulin on glucose utili3ation.

c. Glu&a"on an! E+ine+hrine: 6ypoglycemia is corrected by decreased

secretion of insulin and increased secretion of glucagon, epinephrine, cortisol,and growth hormone. lucagon and epinephrine are most important in the

acute, short$ term regulation of blood glucose levels. lucagon stimulates

hepatic glycogenolysis and gluconeogenesis. 8pinephrine stimulates

glycogenolysis and lipolysis, inhibits insulin secretion, and inhibits insulin

dependent upta9e of glucose by tissues.

d. 6ortisol an! Gro3th hormone: These hormones are less important in the

short term regulation of blood glucose levels, but they are important in the

long term regulation of glucose metabolism. They stimulate gluconeogenesis.

. T)+es o' h)+o"l)&emia: 6ypoglycemia may be divided into three groups

a. Insulin in!u&e! h)+o"l)&emia: 6ypoglycemia occurs freBuently in patients

with diabetes receiving insulin treatment. ;ild hypoglycemia in fully

conscious patients is treated by oral administration of carbohydrate. ;ore

commonly, patients with hypoglycemia are unconscious or have lost the

ability to coordinate swallowing. 4n these cases, glucagon, administered

subcutaneously or intramuscularly, is the treatment of choice

b.

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11. Integration of Metabolism New Version 1