Intermediary /Integration of Metabolism

By>>

Mengistu W B.pharm ,MSc in Biochm

August, 2012/20
jimma university

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 CONTENTS
Major Concepts
• Metabolism
• Three phase of metabolism
• Metabolic pathways are mainly regulated at three levels
• Metabolic branch point /Flow of key metabolic substrates
• Pathway interactions
• Metabolic Effects of different Hormones
• Metabolism of specialized tissues and organ interrelationship with their
role
❖ Metabolism in fed state .in fasting state & prolonged fasting/ starvation state
• Type- 1 and 2 – diabetes difference , Inter-tissue relationships
• Metabolic Alterations in Dm

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 Metabolism
Metabolism
• the entire network of chemical reactions carried out by living cells
• includes coordination, regulation and energy requirement
• it is summation of all chemical reactions in an organism.
• Metabolites - small molecule intermediates in the degradation
and synthesis of polymers
• Most organism use the same general pathway for extraction and
utilization of energy
• Metabolism relies on thousands of sequential enzymatically
controlled reactions

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 Metabolism…
• Metabolic differences are best studied by dividing all living
organisms into two categories
• Autotrophs - organisms that use atmospheric CO2 as their sole
source of carbon.
• Heterotrophs - life forms that obtain energy by ingesting complex
carbon compounds
• Heterotrophs are divided into aerobs and anaerobs.

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 Intermediary metabolism
Intermediary metabolism.
Products from one reaction often become the reactant for the next
- metabolites.
Metabolic Pathway
• A series of reactions with a specific purpose (e.g. degradation of
glucose, synthesis of fatty acids)
❖ Linear – Glycolysis
❖ Cyclic - Citric Acid Cycle
❖ Spiral - Fatty acid biosynthesis
Metabolic paths of two types
Catabolism (Degradation path)
• Complex organic molecules are degraded to simpler species/ATP
Anabolism
• Biosynthesis of more complex organic compounds requires
energy.
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 Metabolic pathways
▪ The various metabolic pathways by which carbohydrates,
fat and proteins are processed as
• metabolic fuels for energy supply or as
• precursors in the biosynthesis of compounds or
• for maintenance growth are interrelated and well coordinated
▪ Interrelation of metabolism could be considered at the
following levels:
A. The flow of key metabolites between different metabolic pathways
B. The interdependence of different organs in maintaining an appropriate
metabolic state for the body

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 Phase of metabolism

fig 1 Three stages of metabolism 7

Fig.2 Three stages and their relationship with various amino acids
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Fig.3 general mechanism of cellular respiration
 The chemistry of metabolism
• Six categories of biochemical reactions have been identified.
• Oxidation-reduction
• Group-transfer
• Hydrolysis
• Non hydrolytic cleavage
• Isomerization and rearrangement
• Bond formation reactions using energy from ATP

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 Metabolic pathways are regulated at three levels
The flow of intermediates through metabolic pathways is
controlled by three mechanisms:
1) Allosteric activation and inhibition of enzymes
2) Covalent Modification of enzyme; Phosphorylation/dephosphorylation
(integrated via hormones)

3 ) induction-repression of enzyme or Control enzyme levels

The first and the most immediately responsive form of
regulation is through the action of allosteric enzymes, which are
capable of altering their catalytic activity, in response to
stimulatory or inhibitory effectors molecules

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 Metabolic pathways regale…
Allosteric activation and inhibition of enzymes
The first level Allosteric enzymes regulation are usually
located at or near;
– the beginning of a multienzyme sequence and
– catalyze rate-limiting step which is an essentially
irreversible reaction

Catabolic pathways: End product ATP generated by

phosphorylation of ADP, often functions as :
o an allosteric inhibitor of an early step in catabolism or
o may be stimulated by the positive modulators ADP or AMP

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 Metabolic pathways are regulated con’t …
• In anabolic pathways, the biosynthetic end product often
functions as an allosteric inhibitor of an early step
• An allosteric enzyme in a given pathway may also be
specifically responsive to intermediates or products of other
metabolic pathways
• Major pathways regulated in this manner are glycolysis,
gluconeogenesis, glycogen metabolism and fatty acid
synthesis.

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 Metabolic pathways are regulated con’t …
A second level Hormonal regulation
• Hormones are chemical messengers,
secreted by different endocrine
glands and carried by blood to other
tissues or organs, then may
stimulate or inhibit some specific
metabolic activity
• The major hormones that regulate
the pathways of fuel metabolism are
insulin & glucagon.. etc.
• In liver, all effects of glucagon are
reversed by insulin, and some of the
pathways that insulin activates are
inhibited by glucagon
Fig. 4 mechanism of glucagon regulate
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the pathways
 Metabolic pathways are regulated con’t …
• Third level of metabolic regulation via enzyme Induction &
repression
• Is exerted through control of the concentration of a given enzyme
in the cell
• The concentration of an enzyme at any given time is the result of:
✓ a balance between the rate of its synthesis and
✓ the rate of its degradation.
Enzyme Induction & repression
• The rate of synthesis of certain enzymes is greatly increased under
certain conditions so that the actual concentration of the enzyme
in the cell is increased substantially
• liver cell can turn the biosynthesis of specific enzymes on or off,
depending on the nature of the incoming nutrients or substrate
availability & visversa 15
 Flow of key metabolic substrates between different pathways

• Certain metabolites may be used as intermediates in different

pathways
• The control of the direction of flux of these intermediates is a
significant factor in the integration of metabolism at the cellular
level
• Fig 5 depict the interrelationship of metabolism and denote the
control point for regulating metabolic flow in these pathways
• The metabolic processes involving various Biomolecules are
interconnected through certain branch compounds which lie at
junctions of the major metabolic pathways
• Some important branch compounds are glucose 6- phosphate ,
pyruvate and acetyl CoA,.

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Figure 5 . The enzyme of the glycolytic pathways link up the metabolism of glucose
with fat and amino acid metabolism. Substrates in boxes are important in
interaction of the glycolytic pathway with other pathways
 Metabolic branch compounds/points
Metabolic branch point of Glucose 6-phosphate
1. Glucose 6-phosphate may be converted to:
(i) Glucose in gluconeogenic tissues
(ii) Glucose 1-phosphate which is used in glycogen synthesis
(iii) Pyruvate through glycolysis.
(iv) Ribose 5-phosphate, a substrate for nucleic acid synthesis,
via the pentose phosphate pathway.

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 Metabolic branch con’t…
2. pyruvate, the degradation
product of glycolysis and
glucogenic amino acids can
be converted to acetyl CoA.
• Pyruvate may also be
converted to:
a. Oxaloacetate and metabolized
via the TCA cycle.
b. Acetyl CoA by pyruvate Figure 6. Metabolic branch point of pyruvate
dehydrogenase.
c. Alanine via transamination.
d. Lactate in muscle tissue

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3. Acetyl Co A may undergo the following actions
❖ Converted to cholesterol which can synthesize steroids.

Figure 7. Branch point of acetyl COA

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 Pathway interactions….

• The citric acid cycle links carbohydrate and fat metabolism and is
involved in the metabolism of amino acids.
• It provides an important control point for regulating metabolite
flow in these pathways
• The enzyme of the glycolytic pathway link up the metabolism of
glucose and other carbohydrates with fat and amino acid
metabolism

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Figure 8. Pathway interactions: Major oxidative pathways may also act as routes linking
other pathways.
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Figure 9: Interrelationship of metabolism at the cellular level 23
 Metabolic Effects of different Hormones
INSULIN STIMULATES UTILIZATION
OF NUTRIENTS
• insulin stimulates glycogen , fat, protein
synthesis and glycolysis while inhibiting
glycogenolysis and gluconeogenesis by
reversing cAMP-induced phosphorylations
This is achieved by two mechanisms
• 1. Insulin stimulates cAMP
phosphodiesterase , which degrades cAMP
to AMP.
• 2. Insulin stimulates phosphatase-1, the
enzyme that dephosphorylates the
important targets of the cAMP- activated
protein kinase A: stimulated glycogen
synthase
The basal metabolic rate (BMR) is the amount
of energy that a resting person consumes in
the postabsorptive” state 8 to 12 hours after
the last meal. Figure 10. insulin stimulates utilization of
nutrients 24
 Table Metabolic Effects of Insulin

Most of the other insulin effects included here are actions on the rate of synthesis or
degradation of the affected enzyme.
* Insulin acts indirectly by promoting the dephosphorylation of phosphofructokinase-2/
fructose-2,6-bisphosphatase, thereby increasing the level of fructose-2,6-bisphosphate.
Insulin acts by promoting the dephosphorylation of the enzyme 25
 INSULIN STIMULATES UTILIZATION OF NUTRIENTS…
❖ Insulin increases
(1) glucose uptake in muscle and adipose via recruitment of GLUT-4
transporters w/c are located in intracellular storage vesicles
& move to the cell surface and fuse with the plasma membrane
(2) glycogenesis in liver and muscle via activation of GS;
(3) amino acid uptake and protein synthesis in most tissues
(4) fat synthesis in liver, lactating mammary glands and, to a lesser
extent, adipose tissue via activation of ACC.
Note: Insulin affects enzymatic activity by covalent dephosphoryla-
tion and transcriptional regulation

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 INSULIN STIMULATES UTILIZATION OF NUTRIENTS…
• The mechanisms by which insulin stimulates glucose metabolism
are different in different tissues
• Insulin decreases the activity of intracellular HSL and
• increases the activity of membrane-associated extracellular LPL
enzymes that degrade TAGs carried in circulating LP particles
– (CMs and VLDLs), respectively.
• Insulin activates a phosphatase that dephosphorylates
(inactivates) HSL.
• In contrast, insulin increases expression of the gene for LPL in
adipocytes

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 Mechanism of Insulin Action
• When insulin binds to its membrane receptor, the series of
events occur.
• The process is regulated through internalization of the insulin–
receptor /tyrosine kinase receptor ,
• then subsequently the insulin is degraded in the lysosomes, and
the receptor is either recycled or degraded
• Insulin receptor binding initiates a signaling cascade that includes
PKB ( Akt) activation, which,
– causes GLUT-4 recruitment from the intracellular vesicular pool to muscle
and adipocyte plasma cell membranes,
• enabling facilitated uptake of glucose for energy or fat formation

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 Mechanism of Insulin Action…
• In contrast, hepatocytes contain the insulin-insensitive GLUT-2
but insulin have GLUT-4 on muscle and adipocyte cell
membranes which very sensitive .
• Blood glucose levels rise with the blunt insulin receptor on their
surface of adipocytes and muscle cells : due to a decrease in
function GLUT-4
• Glucose metabolism in brain and erythrocytes is not insulin
dependent
• They must keep consuming glucose, even in the fasting state,
when the insulin level is low.
• Insulin’s most important effect on fat metabolism is a powerful
inhibition of lipolysis in adipose tissue.
• In the liver excess carbohydrate convert to fat through glycolysis,
pyruvate dehydrogenase reaction, and fatty acid biosynthesis

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 GLUCAGON MAINTAINS THE BLOOD GLUCOSE LEVEL
• During starvation, the body covers most of its energy needs from
adipose tissue–derived fatty acids. However,
• neurons and other specialized cell types, such as erythrocytes,
cannot oxidize fatty acids and therefore depend on a steady
supply of glucose
• Glucagon is specialized for the maintenance of a normal blood
glucose level during fasting.
• Its secretion from the pancreatic α-cells increases in response to
hypoglycemia
• Epinephrine and norepinephrine, produced from Tyr in the
adrenal medulla and sympathetic nervous system, stimulate
glucagon secretion from pancreatic cells.
• Amino acids (e.g., Arg) derived from a protein,containing meal
also will induce glucagon release.
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 Metabolic Effects of Glucagon…
• With a high-protein, low-carbohydrate diet,
the free amino acids released from protein
component stimulate pancreatic glucagon
secretion.
• Acting through its second messenger cyclic
AMP (cAMP), glucagon stimulates hepatic
glucose production by glycogenolysis and
gluconeogenesis.
• Its actions on the pathways of glucose
metabolism are opposite those of insulin ,
glucagon acts almost exclusively on the liver
• Glucagon’s primary target is the liver, where Figure 12 . Mechanism of
it acts to maintain blood glucose levels. Glucagon released from α cells
• Like insulin, glucagon has covalent and of pancreas in metabolism
transcriptional effects.
• [ Note: Skeletal muscles do not express the
glucagon receptor.]
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 Metabolic Effects of Glucagon…
• Glucagon bound to its membrane GPCR
on hepatocytes promotes FA oxidation,
ketogenesis, glycogenolysis, and
gluconeogenesis, effects mediated
through protein phosphorylation by
PKA.
• Note: Hepatic FA oxidation supplies ATP
and NADH for gluconeogenesis
and acetyl CoA for ketogenesis.
• Epinephrine inhibits insulin secretion
and, when bound to its GPCR, is the
primary signal in adipocytes for the
PKA-mediated activation of HSL and
subsequent lipolysis that provides FAs
to the liver.
• It also promotes glycogenolysis.

Figure 13 Glucagon bound to its membrane

GPCR on hepatocytes 32
 Table Metabolic Effects of Glucagon on the Liver

*Both the enzyme phosphorylations and the effects on gene expression are mediated by
cyclic AMP (cAMP).
Mediated by the cAMP-dependent phosphorylation of phosphofructokinase2 and a
decreased cellular concentration of fructose-2,6-bisphosphate.

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 CATECHOLAMINES MEDIATE THE FLIGHT-ORFIGHT RESPONSE

Norepinephrine and Epinephrine

• Next to fasting, physical exertion is a recurrent challenge for
human metabolism.
• Energy generation in the muscles needs to be augmented
enormously, and energy has to be supplied to the muscles from
stored liver glycogen and adipose tissue triglycerides.
• These responses are coordinated by the catecholamines
norepinephrine(noradrenaline) and epinephrine (adrenaline).
• The catecholamines are stress hormones & are released
– during physical exertion,
– in response to psychological stress.

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 CATECHOLAMINES MEDIATE …
• Stress usually meant the need to be prepared for physical
effort: the flight-or-fight response
• The catecholamines can raise:
the cellular cAMP level through β-adrenergic receptors and
the calcium level through α1-adrenergic receptors.
• Muscle and adipose tissue have mainly β-adrenergic
receptors, and the liver has both β and α1 adrenergic
receptors

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 Table Metabolic Effects of Norepinephrine &Epinephrine

↑and ↓, Weak or inconsistent effect; ↑↑and ↓↓, moderately strong effect; ↑↑↑and
↓↓↓, strong effect.
*Effects mediated by enzyme phosphorylation.
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 Catecholamines
• The catecholamines are functional antagonists of Insulin that
raise the blood levels of glucose and fatty acids.
• They are not very important for blood glucose regulation under
ordinary conditions, but their release is potently stimulated by
hypoglycemia.
• Therefore hypoglycemic episodes in metabolic diseases are
always accompanied by signs of excessive sympathetic activity
• including pallor, sweating, and tachycardia .

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 Stress hormones
The glucocorticoids prepare the body for the action of epinephrine.
They stimulate the synthesis of the adipose tissue lipases.
They also increase gluconeogenesis from amino acids
o by causing net protein breakdown in peripheral tissues and
o inducing phosphoenolpyruvate (PEP) carboxykinase in the liver.
Excess glucose-6-phosphate produced by gluconeogenesis is
diverted into;
➢ Glycogen synthesis, thus providing more substrate for epinephrine-
induced glycogenolysis
❑ Glucocorticoids and catecholamines
they are stress hormones w/c are troublemakers rather than
lifesavers
Patients suffering from infections, autoimmune diseases,
malignancies, injuries, surgery, or psychological upheaval have
elevated levels of these hormones
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 Stress hormones…
Cortisol/ glucocorticoidis also a stress hormone
• Especially chronic stress stimulates cortisol secretion from the
adrenal cortex through corticotropin-releasing hormone from
the hypothalamus
• the actions of the glucocorticoids are synergistic with epinephrine,
but there is an important difference
• Epinephrine works through the second messengers cAMP and
calcium, whereas
• the glucocorticoids are mainly gene regulators.
• Therefore epinephrine induces its effects in a matter of seconds,
• but most glucocorticoid effects are cumulative over hours to days.

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 Stress hormones…
• During an extended any stress
• cortisol induced the lipases in his adipose tissue and built up the
glycogen stores in his liver, soon epinephrine immediately
stimulated the release of fatty acids from adipose tissue and of
glucose from the liver
• Cortisol-induced protein breakdown leads to negative nitrogen
balance and muscle wasting.
• Because the stress hormones oppose the metabolic effects of
insulin,
• seriously ill patients have insulin resistance and poor glucose
tolerance.

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 Stress hormones…
• The insulin requirement of insulin-dependent diabetic patients
rises substantially during otherwise harmless infections or other
illnesse
• Some cytokines, which are released by white blood cells during
infections and other diseases, have metabolic effects similar to
the stress hormones.
• Interleukin-1 stimulates proteolysis in skeletal muscle, and
• tumor necrosis factor promotes lipolysis in adipose tissue.
• These mediators contribute to the weight loss that is common in
patients with malignancies or chronic infections.

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Table Metabolic Actions of Cortisol & Other Glucocorticoids

The glucocorticoid effects are mediated by altered rates of enzyme synthesis.

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Fig. 14 Plasma levels of hormones and nutrients at different times after the last meal.
mM, mmol/liter.

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 Metabolism of specialized tissues and organ
interrelationship
▪ All the metabolic pathways are not present in all cells and
tissues and their distribution varies among the major tissues.
▪ The types of fuels that are metabolized and stored also vary
depending on the tissue . Moreover,
▪ The metabolic profile of the major tissues vary depending on
the metabolic state of the body
▪ Understanding of Interrelationship of metabolic pathways
among organ would be helpful in developing a rational
approach for the treatment of diseases whenever one
encounters abnormalities

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Figure 15. Inter-relationship of metabolism among major organs/tissues of body

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 I. Metabolism in the Fed State
Liver in the Absorptive State
In the absorptive state(the 2- to 4-hour period
after eating), insulin release from the pancreas
is increased in response to the presence of
digestive products in the portal vein.
• The liver plays a central role in regulating
the metabolism of glucose in blood and
other metabolic fuels.
• In the absorptive condition, all organs share
the nutrients made available by digestion of
food by the intestine.
• PPP, pentose phosphate pathway; FA, fatty Effect of insulin on
acids; TAG, triacylglycerol. glycogen synthesis and
degradation and on VLDL
• Most low molecular weight metabolites synthesis in the liver.
that appear in the blood after digestion are
first carried to the liver from the intestine
through the portal vein
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 Metabolism in the Fed State con’t…
1. Major role of the liver include the following:
• The liver is responsible for the maintenance of blood glucose
levels.
• During the fed state, the liver takes up excess glucose and amino
acids stores it as glycogen / fatty acids.
• Some glucose is metabolized by the pentose phosphate pathway
for use in biosynthetic reactions by the liver /produce NADPH
• The liver manage the plasma lipoproteins
• Amino acid levels are also elevated in the blood after a meal,
and this wealth of raw materials is managed by the liver in one of
several ways.

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 Metabolism in the Fed State con’t…
✓ Amino acids are used directly by the liver for synthesis of new
proteins.
✓ Insulin promotes the uptake of branched-chain amino acids
(valine, leucine, and isoleucine) by muscle and stimulating on
muscle protein synthesis
✓ Some of the excess amino acids are released into bloodstream
for utilization by other tissues or alternatively, metabolized
their carbon skeletons to store for later use to produce energy.

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 Metabolism in the Fed State con’t…
• [ Note: PFK-1is allosterically activated by fructose 2,6-bisP made
by PFK-2.
• The kinase domain of PFK-2 is active when the bifunctional
protein is dephosphorylated.
• The hepatic isoform of PK also is dephosphorylated and active.]
• FA synthesis is favored by acetyl CoA availability ( PDH is active
and the TCA cycle is inhibited) and ACC activation.
• TAG synthesis is favored by the availability of the glycerol
backbone from glycolysis and of FAs.
• In G6PD deficiency, the PPP of glucose utilization is inhibited,
decreasing the for hepatic FA (and cholesterol)
.

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Fig.16. Metabolism in the Fed State
 Nonhepatic Tissues in the Absorptive State
2. Adipose tissue
• where much of the body’s energy reserves are stored as fats,
specifically triacylglycerols, so its role after a
• meal is to convert any excess fuel to fat.
• Insulin action increases glucose uptake by individual fat cells and
this accelerates metabolic activity.
• The rate of glycolysis is increased to provide Acetyl CoA for
energy in TCA ,
• Acetyl CoA for fatty acid synthesis (triacylglycerols) using
glycerol 3-phosphate . Besides pentose phosphate pathway is
stimulated to
• produce NADPH, which may be needed later for fatty acid
synthesis
• There is net synthesis of glycogen for storage

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 Nonhepatic Tissues in the Absorptive State
• FA synthesis is not a major pathway in human adipocytes under
most conditions, Adipocytes obtain FAs primarily from the
degradation of exogenous(dietary) TAGs in CMs exocytosed from
intestine and endogenous TAGs in VLDLs exocytosed from liver.
• LPL attached to the endothelial lining of capillaries in adipose
tissue (and activated by apo C II on LP surfaces) degrades the TAGs
to glycerol and FAs.
• Note: In adipose tissue, insulin upregulates LPL expression.
• It also causes HSL dephosphorylation and inactivation, thereby
inhibiting intracellular lipolysis.

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 Nonhepatic Tissues in the Absorptive
• GLUT-4, found in muscle and adipose
tissue, is sequestered in intracellular
vesicles.
• In response to insulin, the transporters
move to the plasma membrane and
allow blood glucose uptake.
• Mutations that decrease GLUT-4 traffi
cking would prevent glucose uptake and
cause hyperglycemia.
• [ Note: In T1D, the lack of insulin results
in intracellular retention of GLUT-4 and,
consequently, hyperglycemia.] Fig.17 adipose tissue have insulin
receptor GLUT-4

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FIG : 18 metabolic pathways in l iver during fasting 54
 Metabolism in the Fed State con’t…
3. Skeletal muscle
is the major consumer of metabolic fuel and oxygen, owing to its
great mass compared with other tissues.
✓ stores glucose in the fed state, but cannot release glucose
into circulation
Its major role include the following:
a. As it does in adipose tissue, insulin promotes increased
glucose uptake by skeletal muscle.
a. The glycogen stores of muscle are not extensive and can be
depleted within a few minutes of intensive exercise, but the
high level of glucose 6 phosphate availability after a meal
allows glycogen synthesis to replenish the stores.
b. Insulin action and the availability of adequate energy and
amino acids stimulate ;
✓ net synthesis of muscle protein, with suppression of protein
degradation 55
 Nonhepatic Tissues in the Absorptive
• A key metabolic differences exist between muscle and liver is
that insulin greatly stimulates the transport of glucose into
muscle cells but only slightly stimulates its transport into liver
cells.
• BCAAs are catabolized primarily by muscles, the primary
location of BCAA transaminase that initiates their degradation.
• [ Note :Metabolism of straight-chain amino acids occurs
primarily in the liver, which has low levels of BCAA
transaminase.]
4. Brain tissue
• The brain is dependent on blood glucose (requiring 140 g/day)
because it has limited supplies of glycogen and TAGs.
• Additionally, FFAs do not efficiently pass through the BBB, thus
making little contribution to ATP production in brain
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 ll. Metabolism in the Fasting State
During the fasting state (4–24 hours after the last meal), blood glucose
levels begin to fall, precipitating major changes in metabolism with a
switch over from an anabolic state to a catabolic condition in order to
maintain blood glucose levels
Glucagon/ Insulin levels increase in the blood.
The glucagon target the liver cell
It is secreted by the α cells of the pancreas in response to a
low blood-sugar level in the fasting state .
A. Metabolism in the Fasting State in liver
it has critical role as central organ for synthesis and distribution of fuel,the
liver export of glucose to peripheral tissues during a short-term fast.

The decreased insulin/glucagon ratio leads to inhibition of glycogen

synthesis and increased glycogenolysis to supply some of the body’s
glucose needs
 Metabolism in the Fasting in liver
1. Stimulation of degradation of glycogen
• Glucagon binds to cell surface receptors and activates
adenylate cyclase, causing cAMP levels in liver cells to rise
• cAMP activates protein kinase A, which phosphorylates and
inactivates glycogen synthase
• At the same time, protein kinase A stimulates glycogen
degradation by a two step mechanism.
• Protein kinase A phosphorylates & activate phosphorylase
kinase.
• This enzyme, in turn, phosphorylates and activates glycogen
phosphorylase
• PKA also phosphorylates HSL.

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 Metabolism in the Fasting in liver…
Glycogenolysisis an immediate, short-lived response to fasting,
whereas gluconeogenesisis slower, sustainable, and dependent on
proteolysis and lipolysis
The two metabolic priorities in fasting are to
• (a) maintain adequate blood glucose levels for glucose-
dependent tissues (e.g., RBCs) and
• (b) provide KBs to supply energy to tissues that can use KBs (e.g.,
muscle and brain), thereby decreasing glucose use
• [Note:KB availability results in decreased muscle proteolysis.]

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 Metabolism in the Fasting in liver….
2. STIMULATION OF GLUCONEOGENESIS
• Hormonal changes cause peripheral tissues to release
precursors that provide carbon for gluconeogenesis,
specifically lactate, amino acids, and glycerol.
• Regulatory mechanisms promote the conversion of
gluconeogenic precursors to glucose
• These mechanisms prevent the occurrence of potential
futile cycles, which would continuously convert substrates
to products while consuming energy but producing no
useful result

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 Metabolism in the Fasting in liver….
• Gluconeogenesis is stimulated in the liver and blocks glycolysis by
lowering the level of F-2,6-BP
• Additional effects include an increase in TAG and protein
catabolism resulting in increased availability of FAs for oxidation
and glycerol and glucogenic amino acids for gluconeogenesis.
• The rise in gluconeogenesis causes hyperglycemia
• By 24 hours of fasting, gluconeogenesis provides all the blood
glucose
• [ Note: Glucose is generated from the glucose 6-P product of both
processes by hepaticand (renal) glucose 6-phosphatase.]

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 Metabolism in the Fasting in liver….
3. STIMULATION OF LIPOLYSIS
• The hormonal changes that occur during fasting Catecholamine-
mediated HSL activation causes degradation of adipose TAGs to
FAs and glycerol
• Glycerol are sent into blood and taken up by the liver for
gluconeogenesis
• Fatty acids become the major fuel of the body and are oxidized to
CO2 and H2O by various tissues, which enables these tissues to
decrease their utilization of glucose
• The FAs are oxidized to acetyl CoA, which is used for ketogenesis
(rather than being oxidized), because the rise in NADH from FA β-
oxidation inhibits the TCA cycle in a prolonged fast .
• ketone bodies made , enter the blood and serve as an additional
fuel source for the muscle and the brain.
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 Metabolism in the Fasting in liver….
• The liver is unable to use KBs (it lacks thiophorase), and they
are sent out for use by nonhepatic tissues (e.g., brain and
muscle)
• Both muscle and liver use fatty acids as fuel when the blood-
glucose level drops. Thus,
• the blood-glucose level is kept at or above 80 mg/dl by three
major factors:
(1) the mobilization of glycogen by the liver and the release
of glucose, by hyperglycemic hormone
(2) the release of fatty acids by adipose tissue, and
(3) the shift in the fuel from glucose to fatty acids by muscle
and the liver the release of amino acids from muscle protein
63
Fig 19. Metabolic and fuel movements during early stages of fasting. Glycogenolysis and
glyconeogenesis are speeded up to maintain normal blood glucose level, and ketone
body synthesis is increased for use as fuel molecules (FA fatty acids, KB ketone bodies).
64
 Fasting State metabolism con’t…
B Skeletal muscle
in its resting state can satisfy most of its energy needs by oxidation
of fatty acids taken up from blood, and during the early stages of
fasting, protein degradation in the muscle is increased.
• Some of the carbons skeletons derived by removal of the
amino groups from the amino acids can be used for
synthesis of glucose via gluconeogenesis.
• Some a/acid carbon skeletons yield acetyl CoA and are used
for synthesis fuel, ketone bodies, which become more
important as the fast extends past 24 hours

• .

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 Fasting State metabolism con’t…
C. In adipose tissue
It reduced glucose availability via the blood and
the low insulin/ glucagon ratio lead to net degradation of TAG to
their component fatty acids and glycerol to meet the energy needs
of most tissues (exception of the CNS).
1. The fatty acids are oxidized to provide the energy needs of the
adipocytes themselves.
2. As the fast progresses, more of the adipose-derived fatty acids are
transported in the blood stream as complexes with albumin and
taken up by the liver.
3. The glycerol backbones from triacylglycerol breakdown are sent to
the liver for use in gluconeogenesis.

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D. Brain tissue
• The energy needs of the
brain and other glucose-
requiring organs are
satisfied during the post-
absorptive period through
provision of glucose by the
liver

Fig 20 Energy level during different time fed state

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 llI. Metabolism During Starvation
If fasting extends past 2 days, which is considered to be a
long-term fast further changes in fuel synthesis and use by
several organs can occur, principally a conversion from a
glucose economy to one dominated by ketone bodies as fuel
In addition to the effects of a low insulin/glucagon ratio, long-term
changes in metabolism during starvation are induced by the
corticosteroid & cortisol.

68
 lll. Metabolism During Starvation in hepatic tissue
A. Metabolism During Starvation in hepatic tissue
The liver is again the major organ that synthesizes the principal
long-term fuel, ketone bodies
eg acetoacetate, and B-hydroxybutyrate, which are made from both
amino acids and fatty acids.
• In prolonged fasting, triacylglycerol degradation in adipose tissue
becomes maximal and sustained.
• Protein breakdown in skeletal muscle can only be sustained for
10–14 days,
• further degradation of protein would severely compromise contractile
capability.
• Within a few days of fasting, the brain adapts to be able to utilize
ketone bodies as fuel and becomes less dependent on glucose.

69
 Starvation in hepatic tissue con’t…
• Ketogenesis can result in metabolic acidosis if production
outpaces use because the KBs acetoacetate and β -
hydroxybutyrateare organic acids
• Their dissociation in aqueous solutions produces H , thereby
decreasing blood pH.
• [ Note: KBs spare glucose for glucose-dependent tissues (e.g.,
RBCs), reducing gluconeogenesis and preserving muscle.]

B Skeletal muscle
Cortisol promotes net protein breakdown in skeletal muscle to
provide amino acids as precursors for gluconeogenesis and
ketone body synthesis (ketogenesis).

70
 Starvation in hepatic tissue con’t…
• In long-term fasting ( starvation), KBs are the brain’s primary fuel
source.
• β-Hydroxybutyrate is oxidized to acetoacetate, which is
converted by thiophorase to acetoacetyl CoA that is cleaved to
two acetyl CoA for oxidation in the TCA cycle.
• Gucose metabolism decreased in both adipose and muscle tissue
in the fasting state b/c :
• Glucose metabolism in adipose and muscle tissue is decreased in
the fasting state because these tissues contain insulin-dependent
GLUT-4.
• Consequently, they are not able to take up glucose from the
blood when insulin is low.

71
 Non-hepatic Tissues during Starvation …
C .Adipocytes tissue
• Cortisol also increases the rate of triglyceride
breakdown (lipolysis) in adipose tissue & It
caue releasing the FFAs from intracellular
lipolysis into the blood, and to make KBs in
liver ,Glycerol for formation of glucose
D. brain tissue :
Beside glucose , brain adapt to use of the
alternative fuel, ketone bodies, which is derived
mainly from degradation of fatty acids

Fig 21 brain adapt to use of the

alternative fuel, ketone bodies,
72
Figure 22 . Metabolic activities of major organs during long-term fasting. With glycogen
stores in the liver and muscle depleted, gluconeogenesis is the sole means of providing
for the glucose needs of some organs, while many organs, even the brain, adapt to use of
the alternative fuel, ketone bodies, which is derived mainly from degradation of fatty
acids. FA, fatty acids; PPP, pentose phosphate pathway; TAG, triacylglycerol. 73
 Absorptive State Summary
In the absorptive state:
1. Blood glucose levels and the insulin/ glucagon ratio are increased.
2.Circulating TAG-rich LPs (CMs primarily but also VLDLs) are increased.
3.Amino acids from digestion are available in the blood.
4. KBs are virtually absent.
5.Synthesis of glycogen, TAGs, and proteins is increased.
• A useful “ rule of thumb” for the absorptive state is that covalently regulated
enzymes involved in nutrient storage processes (e.g., hepatic PK, the kinase
domain of hepatic PFK-2, GS, and ACC) are active when they are
dephosphorylated.
• PDH also is active when dephosphorylated, thereby allowing the conversion of
glucose to acetyl CoA for FA (and cholesterol) biosynthesis.
• Enzyme induction (e.g., of ACC) in response to hormonal signals also plays a
role

74
 An autoimmune
disease beta cell
s are destroyed
by immune
system

Figure : Comparison of type 1 and type 2 diabetes.

75
 TYPE 1 DIABETES
▪ The disease is characterized by an absolute deficiency of insulin
caused by :
o an auto - immune attack on the β cells of the pancreas However,
o symptoms appear abruptly when 80–90% of the β cells have been destroyed
▪ it is not possible to diagnose the disease prior to appearance of
symptoms
▪ At this point, the pancreas fails to respond adequately to
ingested glucose & result in chronic hyperglycemia ,with
elevated risk for ketoacidosis and a variety of long-term
complications,
✓ including retinopathy, neuropathy, nephropathy, and cardiovascular
complications.
▪ Insulin therapy is required to restore metabolic control
✓ promotes glucose uptake by tissues
✓ inhibits gluconeogenesis, lipolysis, and proteolysis
 Metabolic Changes in Type 1 Diabetes
• Insulin dependent diabetes mellitus (IDDM) was once called
juvenile onset diabetes because:-
– it usually appears in childhood or in the teens, but it is not
limited to these patients.
• Untreated, IDDM is characterized by hyperglycemia, hyper-
lipoproteinemia (chylomicrons and VLDLs) and severe ketoacidosis
• IDDM besides being a disease of defects in carbohydrate
metabolism alone, diabetes causes abnormalities in fat and protein
metabolism in such patients as well.
• The hyperglycemia results in part from the inability of the insulin
dependent tissues to take up plasma glucose from diet
• The decrease insulin /glucagon ratio can promote more
• gluconeogenesis process from muscle protein as precursor

77
 Metabolic Changes in Type1D con’t…
• The ketoacidosis results from increased lipolysis in the adipose
tissue and accelerated fatty acid oxidation in liver.
• the products of which are NADH, acetyl CoA, and ATP.
• The buildup of ATP and NADH inhibits TCA cycle enzymes, pushing
acetyl CoA to ketogenesis
• Excessive KB production can result in DKA
• Hyper chylomicronemia (hypertriglyceridemia ) is the result of low
lipoprotein lipase activity in adipose tissue capillaries
– an enzyme dependent on insulin for its synthesis.
• [ Note:FAs in excess of the liver’s capacity to oxidize them are
converted to TAGs and secreted as VLDLs, contributing to
hypertriglyceridemia.]
• Although insulin therapy does not cure the diabetes, its use
markedly alters the clinical course of the disease. 78
 Metabolic Changes in Type1D con’t…

Figure 23 Inter tissue relationships in type 1 diabetes

79
 Metabolic Changes in Type1D con’t…
• The metabolic disruption in type 1 diabetes is due to
decrease insulin /glucagon action in liver, muscle, and adipose
tissues.
Elevated levels of blood Glucose and ketones are the hallmarks
of untreated type 1 diabetes mellitus.
Ketosis results from increased mobilization of fatty acids from
adipose tissue, combined with accelerated hepatic fatty acid β-
oxidation
Failure of insulin to suppress, gluconeogenesis in liver
leads to ;
over production of new glucose, which cause the elevation
of blood glucose
b/c no uptake of dietary glucose by muscle and adipose.
80
 Metabolic Changes in Type1D con’t…
• In the absence of insulin and in response to glucagon stimulation,
triacylglycerol degradation in adipose tissue and the flood of
fatty acids reaching the liver leads to;
– ketone body synthesis .
• Tight control of blood sugar, by injections of insulin per day
has now been proved to reduce the microvascular
complications of diabetes (renal and retinal diseases).

81
 TYPE 1 DIABETES con’t …
• In some ways, the metabolic profile of a patient with
uncontrolled type 1 diabetes resembles that of the starved
patient, except the absence of insulin
• But the ketoacidosis of diabetes is much more severe than in
starvation & associated with hyperglycemia.
• Peripheral tissues (such as kidneys , skeletal muscle, and
adipose) recepters retain normal responsiveness to insulin,
so management of the disease involves subcutaneous insulin
injection with monitoring of blood glucose several times per
day.

82
Ketone Bodies are an Alternate Energy Source During Fasting
/prolong

Figure 24 Ketone Bodies are energy Source During Fasting /prolong

Short-term fast: Fatty acids are source of ketone bodies

Long-term fast: Amino acids are source of ketone bodies

83
 TYPE 2 DIABETES MELLITUS
• Non insulin dependent diabetes mellitus (NIDDM) accounts for
80–90% of the diagnosed cases of diabetes and is also called
maturity onset diabetes
• It usually occurs in middle aged obese people
• Non insulin dependent diabetes is characterized by hyperglycemia
often with hypertriglyceridemia.
• The ketoacidosis characteristic is not commonly observed
• Increased levels of VLDL are probably the result of increased
hepatic triacylglycerol synthesis stimulated by hyperglycemia and
hyperinsulinemia.

84
 TYPE 2 DIABETES
• The greater the adipose tissue mass , the greater the
production of TNFα , which acts to impair insulin receptor
function.
• An inverse relationship between insulin levels and the
number of insulin receptors present on the plasma
membranes.
• In addition, there are defects within insulin responsive cells
at sites beyond the receptor.
Dysfunctional B-cells results from inadequate glucose sensing to stimulate inulin
secretion ,elevated glucose levels in the b/d
Factor that can damage or destroys B- cells can be hyperglycimia, glucotoxicity ,
lipotoxicity , hy poxia & ROS
Glucotoxicity : it is decrease in insulin secretion & increase in inulin resistance due
to chronic hyperglycemic is know accepted in Glucose toxicity& it worsening dm
by affecting the secretion of B-cells
85
 TYPE 2 DIABETES
• Insulin is present at normal to elevated levels in this form of the
disease.
• Obesity often precedes the development of insulin independent
diabetes and appears to be the major contributing factor
• Obese patients are usually hyper insulinemic.
• Very recent data implicate increased levels of expression of tumor
necrosis factor-α (TNFα) in adipocytes of obese individuals as a
cause of the resistance.
▪ insulin resistance when our body cells resists the normal effect of
insulin & fall to up take glucose
▪ It is universal present in almost obese individual with typ-2 DM
Cause
• Genetics , aging , excess body weight , lack of exercise & smoking
• Avoid saturated fats & trans fats which boosts insulin resistance
86
 TYPE 2 DIABETES con’t…
• Although there is an insulin, it is not as high as in a person who
is obese
• In other words, there is a relative deficiency in the insulin
supply from the β- cells.
• Therefore, this disease is caused not only by insulin resistance
but also by impaired β -cell function resulting in relative insulin
deficiency.
• Diet can often control the disease in the obese diabetic
• If the patient can be motivated to lose weight, insulin receptors
will increase in number, and the post-receptor abnormalities
will improve, which will increase both tissue sensitivity to insulin
and glucose tolerance

87
Figure 25 Non-insulin dependent diabetes mellitus.

88
 Type 2 Diabetes…
• The non insulin dependent diabetic tends not to develop
ketoacidosis but nevertheless develops many of the same
complications as the insulin dependent diabetic, that is, nerve, eye,
kidney, and coronary artery disease
• Hypertriacylglycerolemia with secretion of increased VLDL can lead
to long-term elevated risk of atherosclerosis, although this is a
complicated, multifactorial process.
– Other long-term complications are similar to those caused by
type 1 diabetes, likely due to the chronic hyperglycemia
• An acute complication of T2D is a hyperosmotic Hyperglycemic
state (most common in the elderly) that presents with very high
blood glucose levels,
• severe dehydration, and altered mental status, Coma and death
can result.
89
 Type 2 Diabetes…
• Most obese individuals with insulin
resistance do not develop T2D, the most
common form of diabetes, because still-
functional pancreatic cells produce
suffi-cient insulin to maintain normal
blood glucose levels.
• [ Note:Patients who do develop T2D
have a combination of insulin resistance
and dysfunctional cells but do not
require insulin to sustain life.]

Figure 25. Obesity fosters

insulin resistance via changes
in adipose secretions

90
 TYPE 2 DIABETES con’t…
• In insulin resistance, normal (or elevated) insulin levels fail to
elicit the expected biologic response. Obesity fosters insulin
resistance (shown) via changes in adipose secretions.
• The major secretory changes include increased inflammatory
cytokine(e.g., IL-6) and leptin production and decreased anti-
inflammatory adiponectin production.
• Inflammation contributes to insulin resistance (and to CHD).

91
 Metabolic Alterations in Dm con’t…

Fig.: Metabolic changes in diabetes mellitus

92
 2 Diabetes con’t…
When lifestyle changes alone are insufficient to manage
blood glucose levels, a variety of hypoglycemic agents can be
used.
• Sulfonylureas, stimulate insulin secretion by the beta cells.
• Biguanides such as metformin suppress liver gluconeogenesis
and enhance insulin action in muscle..

93
THANKS !!

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