Nutrition and Integration of

metabolism
 Outline
• Energy requirement
• Major metabolic pathways and key junctions
• Metabolic profile of organs
• Endocrine Pancreatic Hormones
• Food Intake, Fasting and Starvation
• diabetes mellitus
• Health benefits of fasting
 Nutrition
• Diet is the total of all the foods and drinks ingested
by an individual.
• The food or foodstuff is the individual food that is
ingested; and
• nutrients are chemically defined components
required by the body.
 Energy requirement

The amount of energy required by a human is

expressed in kJ/ d (kilojoule per day) or
kilocalorie (kcal; 1 kcal = 4.187 kJ).
actual requirements are based on age, sex, body
weight, and in particular on physical activity.
 It is recommended that about half of the energy
intake should be in the form of carbohydrates, a
the second at most in the form of fat, and The
rest as protein
Energy Requirements Are Estimated by
Measurement of Energy Expenditure
Energy requirement
 BMR and energy expenditure
• Energy expenditure required to maintain body function at
a complete rest is called the basal metabolic rate (BMR).
• Total daily energy expenditure is a sum of basal metabolic
rate(BMR), the thermic effect of food and the energy used
up in physical activity.
• Energy expenditure can be measured by:
direct calorimetry by measuring of heat production or
Indirect calorimetry ; the rate of oxygen consumption
• In health, physical activity is the most important
changeable component of energy expenditure. It is
normally expressed as multiplies of the BMR.
There is an energy expenditure of 20 kJ/L of
oxygen consumed regardless of whether the fuel
being metabolized is carbohydrate, fat, or
protein.
Measurement of the ratio of the volume of
carbon dioxide produced to volume of oxygen
consumed (respiratory quotient; RQ) is an
indication of the mixture of metabolic fuels being
oxidized .
Energy requirement
1. Resting metabolic rate:
 The energy expended by an individual in a
resting but not sleeping , postabsorptive state is
called the resting, formerly, basal metabolic rate
(RMR).
represents the energy required to carry out the
normal body functions
an adult, the RMR is about 1800 kcal for men (70
kg) and 1300 kcal for women (50 kg).
From fifty to seventy percent of the daily energy
expenditure in sedentary individuals is
attributable to the RMR .
 2. Thermic effect of food:
The production of heat by the body increases as
much as thirty percent above the resting level
during the digestion and absorption of food.
This effect is called the thermic effect of food or
diet-induced thermogenesis.

Over a 24-hour period, the thermic response to

food intake may amount to five to ten percent of
the total energy expenditure.
 3. Physical activity

The amount of energy consumed depends on the

duration and intensity of the exercise.
The daily expenditure of energy can be estimated by
carefully recording the type and duration of all activities.

In general, a sedentary person requires about 30 to

50% percent more than the resting caloric requirement
for energy balance

whereas a highly active individual may require 100 %

percent or more calories above the RMR.
 Energy Requirements Increase With Activity

The most useful way of expressing the energy cost

of physical activities is as a multiple of BMR.

Sedentary activities use only about 1.1–1.2 ×

BMR.
 By contrast, vigorous exertion, such as climbing
stairs, cross-country skiing, walking uphill, etc,
may use 6–8 × BMR.
 Energy content of food
 The energy content of food is calculated from the heat
released by the total combustion of food in a calorimeter
is expressed in kilocalories (Kcal or Cal).
 The standard conversion factors for determining the
metabolic caloric value of fat, protein, and carbohydrate
are
 Requirement for protein in humans

Recommended Dietary Allowance (RDA) for protein is

computed for proteins of mixed biologic value at 0.8
g/kg of body weight for adults.
People who exercise strenuously on a regular basis
may benefit from extra protein to maintain muscle
mass;
– A daily intake of about 1 g/kg has been
recommended for athletes.
– To support growth, children should consume 2
g/kg/day.
 Daily protein requirements for selected age groups

Age g/day males g/day females

0-3 months 12.5 12.5
10-12 months 14.9 14.9
4-6 years 19.7 19.7
15-18 years 55.2 45
19-50 years 55.5 45
50+ years 53.3 46.5
 Carbohydrates

• Carbohydrates should constitute between 45%

and 65% of daily caloric intake.
• Dietary carbohydrate intake in the form of simple
and refined sugars and starches should be limited.
• Consuming a high-fiber diet provides bulk without
the addition of significant calories.
 Lipids
• Fat should constitute less than 30% total calories—10%
each of polyunsaturated, monounsaturated, and
saturated fatty acids.
• Cholesterol intake should be no more than 300 mg/day.
• Essential fatty acids such as linoleic and a-linolenic
acids cannot be synthesized by humans and are
required in the diet.
• These polyunsaturated fatty acids are required for the
synthesis of prostaglandins and other eicosanoids
 Integration of metabolism
• The functions of cells and tissues in all organisms
require energy that normally is obtained from ingested
food containing proteins, lipids, and carbohydrates.
• Excess chemical substances capable of supplying energy
are stored and released as needed to maintain
homeostasis.
• The metabolisms of those chemical substances takes
place simultaneously and are closely interrelated and
integrated

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 Major Metabolic Pathways
1. Glycolysis
2. Gluconeogenesis
3. Glycogen Metabolism
4. Fatty Acid Metabolism
5. Citric Acid Cycle
6. Oxidative Phosphorylation
7. Amino Acid Metabolism
Only the liver can carry out all of the reaction, the major
pathways.
21
22
23
 How Is Metabolism Integrated in Multicellular
Organism?
• Organ systems in complex multicellular organisms have
arise to carry out specific physiological functions.
• Such specialization depends on coordination of
metabolic responsibilities among organs so that the
organism as a whole can thrive
• Organs differ in the metabolic fuels they prefer as
substrates for energy production (see Figure)

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Figure 1 Metabolic relationships
among the major human organs.
 Cont’d

• The major fuel depots in animals are:

 glycogen in liver and muscle;
 Triacylglycerols in adipose tissue; and
 Protein, mostly in skeletal muscle
• The usual order of preference for use of these is
glycogen → triacylglycerol → protein
• The tissues of the body work together to maintain
energy homeostasis

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 Liver

• The liver is the primary site of glycogen deposition and

blood glucose maintenance.
• It also plays a central role in lipid, protein, and nitrogen
homeostasis.
• Its metabolic energy is derived primarily from fatty acid
oxidation.

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01/21/2023 28
 Adipose Tissue

 Energy for adipocyte function is derived primarily from

fatty acid oxidation and TCA cycle activity.
 Insulin stimulates the transport of glucose into adipose
cells.
 Adipose tissue stores triacylglycerol
 Adipocytes hydrolyze the triacylglycerol and release
fatty acids and glycerol.

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 Muscle

• Muscle uses all available fuels from blood.

• Muscle contains almost four times as much glycogen as does the
liver.
• This glycogen is readily converted into glucose 6-phosphate for
use within muscle cells.
• Muscle lacks glucose 6-phosphatase and so it does not export
glucose.
 Rather, muscle retains glucose, its preferred fuel for bursts
of activity.
 Insulin stimulates the transport of glucose into muscle cells.

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• During starvation, muscle protein provides amino acids.
• In resting muscle: Fatty acids are the major fuel.
• In actively contracting skeletal muscle:
 The major fuels are glycolysis, and much of the pyruvate
formed is reduced to lactate, some of which flows to the
liver, where it is converted into glucose (Cori cycle).
 In addition, a large amount of alanine is formed in active
muscle by the transamination of pyruvate.

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 Brain
 The brain needs a continuous supply of glucose
 Glucose is the primary fuel for the brain
 Fatty acids do not serve as fuel for the brain.
 b/c they are bound to albumin in plasma and so do not traverse
the blood-brain barrier.
 Under prolonged starvation ketone bodies can replace glucose as
a fuel for the brain

01/21/2023 32
 Heart
• The heart can function well on glucose, oxidizing it
anaerobically or aerobically,
 It preferentially uses the fatty acids for its
energy needs.
• Cardiac muscle does not contribute significantly to
fuel homeostasis, but its ability to utilize any
metabolic fuel makes it a "scavenger.

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 Kidneys
 The kidneys eliminate noxious material while preserving
important metabolites;
 normally, very little glucose, ketone bodies, or amino acids is wasted.
 Renal tissue is important in amino acid homeostasis
 Rely primarily on fatty acid oxidation for energy.
 About 80% of the total energy produced by the kidneys is:
Utilized in the active transport processes involved in urine
formation.
It readily oxidizes fatty acids, ketone bodies, glucose, and
amino acids.

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01/21/2023 35
 Endocrine Pancreatic Hormones

• The endocrine pancreas is pivotal in metabolic homeostasis and

an integral component of metabolic regulation.
• It is composed of 1-2 million islets of Langerhans scattered
throughout the organ.
• The islets contain at least four cell types α, β, γ, and δ-that
secrete glucagon, insulin, somatostatin, and pancreatic
polypeptide, respectively.

01/21/2023 36
 Insulin
• Insulin is secreted by β-cells of the islets of Langerhans of the
pancreas.
• It is composed of an α chain of 21 amino acids and a β chain
of 30 amino acids.
 the chains being held together by two disulfide bonds.
• The molecular weight of insulin monomer is 5500 Da.
• The precursor of insulin within the β-cells of the islet of
Langerhans is the single chain preproinsulin.

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 Stimulation of insulin secretion by glucose
• Insulin secretion is stimulated by glucose.
• Insulin secretion is also stimulated by gastrointestinal
hormones and some amino acids, such as leucine,
arginine, and lysine.
• The glucose concentration in the β-cell of pancreas is
sensed by the β-cell glucose transporter GLUT-2.
• Glucose is carried into the cell by GLUT-2, where it is
phosphorylated to form glucose 6-phosphate (Glc-6-P)
by glucokinase which is a part of the glucose-sensing
mechanism.
01/21/2023 38
 Cont’d
• Increased availability of Glc-6-P increases the rate of
glucose utilization and ATP production in the β-cell.
 This changes the flux of ions across the cell membrane,
depolarizes the cell and increases the concentration of
cytoplasmic free calcium.
 The final result is insulin exocytosis.
• The principal effect of insulin on blood glucose is its
uptake into muscle and adipose tissue via the recruitment
and translocation of glucose transporter 4 (GLUT4).

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 Degradation of insulin

• Insulin is catabolized (inactivated) primarily in the liver,

kidney and placenta.
• Liver degrades about 50% of insulin during its first
passage through this organ.
• An insulin-specific protease and glutathione- insulin
trans dehydrogenase are involved.
• The glutathione- insulin trans dehydrogenase reduces the
disulfide bonds with separation of α- and β- chains,
which are subjected to rapid proteolysis.

01/21/2023 40
 Biological actions of insulin
 Insulin affects virtually every tissue. Mainly:
 In the Liver:
 It stimulates both glycolysis and glycogen synthesis.

 It suppresses lipolysis and promotes the synthesis of the

long-chain fatty acids (lipogenesis).
 In the adipose tissue:
 It stimulates triglyceride synthesis from glycerol-3-
phosphate and fatty acids.
 In muscle:
 insulin stimulates glucose transport, glucose metabolism,
and glycogen synthesis.
 Insulin also increases cellular uptake of amino acids and
stimulates protein synthesis
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 Glucagon
• Glucagon is a small, single chain, 29-amino-acid peptide,
with a molecular weight of 3485 Da.
• Glucagon focuses energy metabolism on the endogenous
production of glucose.
• Its main effect is the mobilization of the fuel reserves for
the maintenance of the blood glucose level between
meals.
• Glucagon stops the storage of metabolic fuels.

01/21/2023 43
 Glucagon
• The primary targets for glucagon are the liver and adipose
tissue.
• In the liver:
 It stimulates hepatic glycogenolysis, gluconeogenesis, and
ketogenesis.
 Inhibits glycogen synthesis and glycolysis.
• In the adipocyte tissue:
 Stimulate lipolysis to provide fatty acids to tissues for
which glucose is not the obligatory fuel.
 Inhibit lipogenesis

01/21/2023 44
 Glucagon
• Secretion of Glucagon is stimulated by:
 Low blood glucose levels
 Gastrin and cholecystokinin,
 Stress and catecholamines
• Secretion of glucagon is inhibited by:
 High levels of glucose

01/21/2023 45
 Glucagon
• Glucagon opposes the actions of insulin.
• The [insulin]/[glucagon] ratio determines the metabolic
fate of fuels due to the induction or repression of
appropriate enzymes.
• Enzymes induced by a high [insulin]/[glucagon] ratio and
repressed by a low ratio are
 Glucokinase
 Acetyl-CoA carboxylase
 β-hydroxy- β-methylglutaryl-CoA (HMG-CoA)
reductase

01/21/2023 46
 Cont’d

 pyruvate kinase,
 6-phosphofructo- 1-kinase,
 fructose-2,6-bisphosphatase.
• Enzymes induced by a low [insulin]/[glucagon] ratio and
repressed by a high ratio are
 Glucose-6-phosphatase,
 Phosphoenolpyruvate carboxykinase, and
 Fructose-l,6-bisphosphatase.

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 Food Intake, Fasting and Starvation

Normal Starved-Fed Cycle:

1. fed state -> after a meal
2. Early fasting state -> during the night
3. Refed state -> after breakfast
late fasting state(starvation) -> more than two
days with out food.
-> Major goal is to maintain blood-glucose level!

48
 1. fed state
Glucose + Amino acids -> transport from intestine to blood
Dietary lipids transported -> lymphatic system -> blood
Glucose stimulates -> secretion of insulin
Insulin( signals fed state):
stimulates storage of fuels and synthesis of proteins
high level -> glucose enters muscle + adipose tissue (TAG synthesis)
stimulates glycogen synthesis in muscle + liver
suppresses gluconeogenesis by the liver
accelerates glycolysis in liver -> increases synthesis of fatty acids
accelerates uptake of blood glucose into liver -> built up of glycogen
stores
49
50
 2. Early Fasting State
Blood-glucose level drops after several hours after the meal -> decrease in
insulin secretion -> rise in glucagon secretion
Low blood-glucose level -> stimulates glucagon secretion of α-cells of the
pancreas
Glucagon:-> signals starved state -> main target organ is liver
- mobilizes glycogen stores (break down)
- inhibits glycogen synthesis
- inhibits fatty acid synthesis
- stimulates gluconeogenesis in liver
large amount of glucose in liver released to blood stream -> maintain
blood-glucose level, Muscle + Liver use fatty acids as fuel when blood-
glucose level drops
51
 Hormonal response in well fed and fasting
state(summary)
WELL-FED STATE FASTING STATE

Hormones  Insulin  Glucagon,

Adrenaline, Cortisol

Hyperglycemia Hypoglycemia
Response of  Glycogenesis  Lipolysis
the body  Lipogenesis  Ketogenesis
 Protein synthesis  Proteolysis
 3. Refed State
• Fat is processed in same way as normal fed state

• First -> Liver does not absorb glucose from blood (diet)
• Liver still synthesizes glucose to refill liver’s glycogen stores

• When liver has refilled glycogen stores + blood-glucose level still

rises -> liver synthesizes fatty acids from excess glucose

54
 Preferred fuels By Human body In the Well-Fed and
Fasting States( summary)
Organs Well-Fed Fasting
Liver Glucose & Fatty acids Fatty acids

Resting skeletal Glucose & Fatty acids & KB

Muscle Fatty acids
Cardiac muscle Fatty acids FA,AA & KB
Adipose tissue Glucose Fatty acids
Brain Glucose Glucose ,Later KB
RBCs Glucose Glucose
 Prolonged Starvation
Well-fed 70 kg human -> fuel reserves about 161,000
kcal
 energy needed for a 24 h period -> 1600 kcal - 6000
kcal
 sufficient reserves for starvation up to 1 – 3
months, depend on Reserve Fat stores in Adiposecytes
 however glucose reserves are exhausted in 1 day
Even under starvation -> blood-glucose level must be
above 40 mg/100 ml
Fuel changes from Glucose to Fatty acids to
Ketone bodies 56
 Prolonged Starvation
First priority -> provide sufficient glucose to brain and other tissues that
are dependent on it
Second priority -> preserve protein -> shift from utilization of glucose to
utilization of fatty acids + ketone bodies
-> mobilization of TAG in adipose tissues + gluconeogenesis by liver ->
muscle shift from glucose to fatty acids as fuel
After 3 days of starvation -> liver forms large amounts of ketone bodies
(shortage of oxaloacetate) -> released into blood -> brain and heart start to
use ketone bodies as fuel
After several weeks of starvation -> ketone bodies major fuel of brain and
fatty acids for muscle, liver and heart
After depletion of TAG stores -> proteins degradation accelerates -> death
due to loss of heart, liver, and kidney function
57
58
 Cont’d

Figure: Fuel Choice During Starvation.

The plasma levels of fatty acids and ketone bodies increase in starvation,
whereas that of glucose decreases.
01/21/2023 59
 Metabolic changes in starvation overview
Early stage (2 days)
• Glycogenolysis and gluconeogenesis are important source of blood
glucose.
Energy from alternate source (β oxd’n of FA and KB).
Intermediate stage (24 days)
• glycogen stores mostly depleted not serve as source blood glucose.
• FA ,KB supplied to heart, kidney ,muscles.
Advanced stage (>24 days)
• KB supplies to heart, kidney ,muscles is decreased , limited to brain
only.
• Heart, kidney ,muscles on FA as main source.
• Gluconeogenesis will enhanced due to increased activity of
enzymes pyruvate carboxylase, fructose 1,6 bisphosphatas,
 Diabetes mellitus
• Diabetes is a group of metabolic disease involving fatty
acids, amino acids and glucose metabolism
characterized by hyperglycaemia and dislipidemia.
• All forms of diabetes mellitus appear to involve
disruption of pancreatic beta-cell function.
• The incidence of diabetes is increasing globally and is
predicted to increase substantially in the future
without appropriate prevention.
 Types of diabetes mellitus
• Idiopathic (primary) diabetes is divided into two main types;
insulin dependent and non-insulin-dependent. Insulin-
dependent diabetes mellitus, IDDM ( type 1 diabetes) is defined
by the development of ketoacidosis in the absence of insulin
therapy
Non-insulin-dependent diabetes mellitus, NIDDM ( type 2
diabetes) is characterized by persistent hyperglycemia but rarely
leads to ketoacidosis.
• There are other types of DM called Maturity onset type diabetes
of the young (MODY) happens due to gene mutation and
characterized by onset prior to age 25.
 Type 1 diabetes
• Autoimmune destruction of pancreatic beta cells leading to
insulin deficiency & characterized by hyperglycaemia.
• Early age diabetes
• Insulin-dependent. All patients need insulin.
• Most patients non-obese (weight loss)
• Partly genetic and partly environmental
• Pancreatic alpha cells (glucagon-producing) are also
affected( increased glucagon secretion)
• 85% of patients have antibodies(outoimmune)
• 80% or more of beta cells need to be destroyed before
hyperglycaemia occurs(beta cell destruction).
• Patients highly prone to diabetic ketoacidosis (DKA)
 Type 2 DM

• Characterised by hyperglycaemia due to insulin resistance

and/or inadequate insulin secretion
• Usually over 40 years of age are affected
• The exact cause is unknown but genetics and sedentary life
style are the two main risk factors.
• Type 2 diabetes pts have detectable levels of circulating
insulin. 
• The major clinical complications of type 2 diabetes are the
result of persistent hyperglycemia which leads to numerous
pathophysiological consequences.
• Patients are highly prone to hyperglycaemic hyperosmolar
non ketotic syndrome(HHNKS)
 Comparison of type 1 and type 2 diabetes mellitus
  Type 1 Type 2
Onset usually under 20 years usually over 40 years of
of age age
Insulin synthesis absent: immune preserved: combination of
destruction of β-cells impaired β-cell function
and insulin action
Plasma insulin low or absent low, normal, or high
concentration
Genetic inheritance not associated with HLA
susceptibility associated with HLA polygenic
antigens
Islet cell antibodies at yes no
diagnosis
Obesity uncommon common
Ketoacidosis yes possible as a result of
major stress
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Maturity Onset(start) Diabetes of the Young
(MODY)
*Also called monogenic diabetes
*Often misdiagnosed as having type1 or type 2 diabetes
*An autosomal dominant form of diabetes that occurs in young people
(under 25)
*Impaired (reduced) glucose-induced secretion of insulin by Islet beta-
cells
*There are multiple mutations that can cause MODY. These include
glucokinase mutations and mutations involved that affect glucose
signalling-to-insulin secretion in beta cells.
Symptoms vary between types
• No insulin resistance or beta cell destruction (no autoantibodies)-
dysfunctional beta cells generally involving poor insulin secretion in
response to blood glucose levels.
 Other types of diabetes
• Gestational diabetes pregnancy induced
• “Neonatal diabetes”
• “Mitochondrial diabetes” e.g. MIDD syndrome
• Drug-induced diabetes (corticosteroids, statins,
antipsychotics)
• Pancreatitis-associated diabetes
 General metabolic features of diabetes

• Essentially all forms of diabetes have, in common,

impaired pancreatic beta cell function.
• Diabetes is a disease involving impaired metabolism of
glucose, lipids and amino acids/proteins
• Reduced glucose uptake by cells/ hyperglycemia
• Increased catabolism of proteins
• Increased lipolysis with increased fatty acid oxidation
• Ketogenesis
• Diabetic dyslipidemia (high TG, low HDL, smaller dense
LDL particles)
 Metabolic basis of DM symptoms
• The combination of increased hepatic glucose production and reduced
peripheral tissues metabolism leads to elevated plasma glucose levels;
• When the capacity of the kidneys to absorb glucose is
surpassed, glucosuria ensues.
• Glucose is an osmotic diuretic and an increase in renal loss of glucose
is accompanied by loss of water and electrolytes, leading polyuria.
• The result of the loss of water (polyuria) leads to the activation of the
thirst mechanism (polydipsia).
• The negative caloric balance which results from the glucosuria and
tissue catabolism leads to an increase in appetite and food intake
(polyphagia).
• Weight loss occurs due to increased catabolism
 Biochemical mechanisms of DM complication
• DKA occurs due to increased lipolysis is a very fatal
condition that can lead to acidemia causing coma and
death.
• As the glucose level rises in the blood the blood
becomes more viscous which makes circulation of the
blood in the small capillaries difficult.
• The reduced circulation results in progressive vascular
complications leading to diabetic retinopathy,
peripheral neuropathy, Nephropathy, stroke, heart
attack poor wound healing, and erectile dysfunction.
 Advanced Glycation End-products (AGEs) and DM complications

• Exposure of cells and biomolecules to high levels of glucose

for long periods of time leads to GLYCATION, which is a non-
enzymatic reaction of glucose with amino groups of proteins
and other molecules.
• Glycosylation of proteins and other macromolecules in cells
and blood leads to chronic changes in the structure and
function of these molecules and cellular components.
• accumulating of AGEs are responsible for many of the
complications, particularly the microvascular complications,
of diabetes..
• AGEs can also elicit abnormal immune responses, leading to
cellular damage.
 SUPPLEMENT

Health benefits of
fasting
Health benefits of fasting

• Facilitate fat metabolism

• Promote greater satiety by increasing leptin response
• Increase overall body metabolism by boosting the level of
thyroid hormone.
• Encourages insulin sensitivity
Health benefits of fasting

• Improves cardiovascular function, blood composition and

blood pressure by reducing cholesterol level, Blood
triglycerides and salt.
• Decreases blood sugar and stabilized it
• Intermittent fasting improves, heart muscle performance,
reduce free radical damage and increase the growth of
blood vessels in side the heart.
• Slow aging and enhance longevity
Health benefits of fasting

• Decreases inflammation
• Increase resistance to oxidative stress( free radical
damage)
• Increase cell recycling and outophagy by which old
cells can be replaced by new and healthier cells
• Increase growth regulation and protect from the
formation and growth of cancer cells(can also used
for cancer treatment with chemotherapy)
Health benefits of fasting

• Boost brain health, cognition & memory by

protecting it from free radicals and by enhancing
healthy stress response
• Increase skin integrity
• It promotes your immune response by replacing
old macrophages by new and active macrophages
through a mechanism known as outophagy